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  • CLASSES

    Other Antineoplastic Agents

    BOXED WARNING

    Adrenal insufficiency, infection, shock, surgery, trauma

    In patients taking mitotane, severe adrenal insufficiency and adrenal crisis occurs in the setting of shock or severe trauma and the response to shock is impaired. Mitotane should be immediately discontinued following shock or severe trauma and not restarted until recovery. Administer hydrocortisone and monitor for escalating signs of shock. Patients should be warned to contact their clinician immediately if serious injury, serious illness, or infection occurs. Mitotane causes varying levels of adrenal insufficiency in treated patients as a result of its mechanism of action. During routine mitotane therapy, measure free cortisol and corticotropin (ACTH) levels every 2 to 3 weeks for the first 3 months, and every 4 to 6 weeks thereafter once a plateau is reached. Mitotane alters the adrenal and extra-adrenal metabolism of steroids, and glucocorticoid replacement therapy is necessary in most patients. Monitor for and institute corticosteroid replacement. Because of increased glucocorticoid clearance, a higher dose of hydrocortisone (50 mg/day or more) may be needed; some patients require additional fludrocortisone. Patients receiving mitotane or patients in whom mitotane therapy has been recently discontinued should be observed for conditions that may increase the risk for severe adrenal insufficiency. Because surgery may increase physiologic stress and increase the risk for insufficiency, patients should inform their prescribers of any planned surgery or related procedures. Early symptoms of adrenal insufficiency include unusual fatigue and muscle weakness, dizziness or orthostasis, nausea, vomiting or diarrhea, loss of appetite, and stomachache.

    DEA CLASS

    Rx

    DESCRIPTION

    Adrenocortical cytotoxic antineoplastic agent; structurally related to chlorophenothane (DDT)
    Used to treat adrenocortical cancer
    Boxed warning for severe adrenal insufficiency and adrenal crisis in the setting of shock or severe trauma

    COMMON BRAND NAMES

    Lysodren

    HOW SUPPLIED

    Lysodren Oral Tab: 500mg

    DOSAGE & INDICATIONS

    For the treatment of inoperable adrenocortical cancer, both functional and non-functional types.
    Oral dosage
    Adults

    2 to 6 g/day orally (total daily dose) given in 3 or 4 divided doses; increase doses incrementally, or as tolerated, to achieve a blood concentration of 14 to 20 mg/L. Temporarily withhold treatment in the case of shock or severe trauma due to adrenal crisis; temporary discontinuation may also be necessary for CNS toxicity. In a retrospective, single-center study, mitotane was initially dosed at 10 g/day (range, 4 to 16 g), and maintained at 7 g/day (range, 3 to 20 g); blood levels were not monitored. Hormonal secretion was controlled in 75% of patients (n = 59), and 8 patients had partial tumor regression. Survival was not affected by mitotane therapy (regression coefficient, -0.928 +/- 0.790; p = 0.24). In a retrospective case series of 96 patients from 1959 to 1992, 62 patients with adrenocortical carcinoma were treated with mitotane at some point during the course of their disease. In patients with primary tumors (n = 29), a response to therapy was seen in 42.9% of patients with mitotane trough concentrations 14 mg/L or more (n = 14) compared to 0% in patients with trough levels less than 14 mg/L (n = 15) (p = 0.004); 3 of 6 patients who responded had a complete response, with durations of 5, 69, and 190 months. In patients with recurrent tumors (n = 23), 69.2% of patients with trough concentrations 14 mg/L or more (n = 13) had a responses to therapy compared to 0% of those with trough levels less than 14 mg/L (n = 10) (p < 0.0008); 5 of 9 patients who responded had a complete response lasting for 2 to 120 months. Overall, mitotane trough levels 14 mg/L or more were independently associated with improved survival (univariate analysis, p < 0.01; multivariate analysis, p = 0.01); however, after total resection, adjuvant mitotane (n = 11) did not influence survival.

    For the treatment of Cushing's syndrome†.
    Oral dosage
    Adults

    Usual dose range: 0.5 to 5 grams/day PO, given in 3 divided doses. Retrospective studies show approximately 80% urinary free cortisol normalization. Mitotane is rarely used to treat Cushing's syndrome; experts recommend that use be limited to patients with adrenocortical cancer who have endogenous Cushing's disease.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    Maximum dosage is dependent on mitotane serum concentrations.

    Geriatric

    Maximum dosage is dependent on mitotane serum concentrations.

    Adolescents

    Safe and effective use has not been established.

    Children

    Safe and effective use has not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Hepatic impairment may interfere with the metabolism of mitotane and drug accumulation can occur. Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no baseline dosage adjustments are needed.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Hazardous Drugs Classification
    NIOSH 2016 List: Group 1
    NIOSH (Draft) 2020 List: Table 1
    Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
    Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure.

    Oral Administration

    Mitotane is administered orally, with or without food.

    STORAGE

    Lysodren:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Mitotane therapy should not be given to individuals who have demonstrated a previous hypersensitivity to mitotane.

    Adrenal insufficiency, infection, shock, surgery, trauma

    In patients taking mitotane, severe adrenal insufficiency and adrenal crisis occurs in the setting of shock or severe trauma and the response to shock is impaired. Mitotane should be immediately discontinued following shock or severe trauma and not restarted until recovery. Administer hydrocortisone and monitor for escalating signs of shock. Patients should be warned to contact their clinician immediately if serious injury, serious illness, or infection occurs. Mitotane causes varying levels of adrenal insufficiency in treated patients as a result of its mechanism of action. During routine mitotane therapy, measure free cortisol and corticotropin (ACTH) levels every 2 to 3 weeks for the first 3 months, and every 4 to 6 weeks thereafter once a plateau is reached. Mitotane alters the adrenal and extra-adrenal metabolism of steroids, and glucocorticoid replacement therapy is necessary in most patients. Monitor for and institute corticosteroid replacement. Because of increased glucocorticoid clearance, a higher dose of hydrocortisone (50 mg/day or more) may be needed; some patients require additional fludrocortisone. Patients receiving mitotane or patients in whom mitotane therapy has been recently discontinued should be observed for conditions that may increase the risk for severe adrenal insufficiency. Because surgery may increase physiologic stress and increase the risk for insufficiency, patients should inform their prescribers of any planned surgery or related procedures. Early symptoms of adrenal insufficiency include unusual fatigue and muscle weakness, dizziness or orthostasis, nausea, vomiting or diarrhea, loss of appetite, and stomachache.

    Driving or operating machinery, neurotoxicity

    Central nervous system (CNS) toxicity, including sedation, lethargy, and vertigo, have been reported in patients treated with mitotane; these occurrences are more common in patients with plasma concentrations greater than 20 mcg/mL. Discontinue mitotane in patients with CNS toxicity; 7 to 10 days after resolution of symptoms, mitotane therapy may be restarted at a lower dose (decreased by 500 to 1,000 mg). Ambulatory patients should be cautioned about driving or operating machinery, or performing other hazardous pursuits requiring mental and physical alertness. Behavioral and neurological assessments should be made at regular intervals, since neurotoxicity may be reversible after discontinuation of the drug.

    Pregnancy

    Mitotane can cause fetal harm when administered to a pregnant woman. Abnormal pregnancy outcomes such as preterm births and early pregnancy loss have been reported in limited post-marketing reports of human patients exposed to mitotane during pregnancy. Animal reproduction studies have not been conducted. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Women of childbearing potential are advised to use effective contraception during treatment and after discontinuation of treatment for as long as mitotane plasma levels are detectable.

    Ovarian cyst, vaginal bleeding

    Ovarian macrocysts (ovarian cyst), often bilateral and multiple, have been reported in premenopausal patients treated with mitotane; complications have included adnexal torsion and hemorrhagic cyst rupture. Female patients should seek medical care if vaginal bleeding or pelvic pain occur. In some patients, symptoms improved after mitotane therapy was discontinued.

    Contraception requirements, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during mitotane treatment. Mitotane can cause fetal harm or loss if taken by the mother during pregnancy. Females should avoid pregnancy and use effective contraception during and after discontinuation of therapy for as long as mitotane plasma levels are detectable. Females of reproductive potential should undergo pregnancy testing prior to initiation of mitotane. Women who become pregnant while receiving mitotane should be apprised of the potential hazard to the fetus. Surgical intervention is the only treatment option that has the potential to radically alter the outcome for patients with adrenocortical carcinoma; however, there is a risk of inducing premature labor, especially in the third trimester. Adjuvant mitotane therapy may be considered, but since it crosses the placenta and is teratogenic, postpone treatment until as soon as possible after delivery.

    Breast-feeding

    Mitotane has been detected in breast milk. Because of the potential for serious adverse reactions in a nursing infant from mitotane, advise women to discontinue breast-feeding during mitotane therapy and after treatment discontinuation for as long as mitotane plasma levels are detectable.

    ADVERSE REACTIONS

    Severe

    hemorrhagic cystitis / Delayed / Incidence not known
    retinopathy / Delayed / Incidence not known

    Moderate

    depression / Delayed / 15.0-40.0
    ataxia / Delayed / Incidence not known
    confusion / Early / Incidence not known
    dysarthria / Delayed / Incidence not known
    adrenocortical insufficiency / Delayed / Incidence not known
    proteinuria / Delayed / Incidence not known
    hematuria / Delayed / Incidence not known
    blurred vision / Early / Incidence not known
    hypertension / Early / Incidence not known
    orthostatic hypotension / Delayed / Incidence not known
    neutropenia / Delayed / Incidence not known
    hypothyroidism / Delayed / Incidence not known
    growth inhibition / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    hypercholesterolemia / Delayed / Incidence not known
    hypertriglyceridemia / Delayed / Incidence not known
    vaginal bleeding / Delayed / Incidence not known

    Mild

    nausea / Early / 0-80.0
    anorexia / Delayed / 0-80.0
    vomiting / Early / 0-80.0
    diarrhea / Early / 0-80.0
    vertigo / Early / 15.0-40.0
    dizziness / Early / 15.0-40.0
    rash / Early / 0-15.0
    lethargy / Early / Incidence not known
    headache / Early / Incidence not known
    drowsiness / Early / Incidence not known
    weakness / Early / Incidence not known
    diplopia / Early / Incidence not known
    fever / Early / Incidence not known
    flushing / Rapid / Incidence not known
    gynecomastia / Delayed / Incidence not known
    arthralgia / Delayed / Incidence not known
    myalgia / Early / Incidence not known
    pelvic pain / Delayed / Incidence not known

    DRUG INTERACTIONS

    Abacavir; Dolutegravir; Lamivudine: (Moderate) Dolutegravir plasma concentrations may be reduced when administered concurrently with mitotane; thereby increasing the risk for HIV treatment failures or the development of viral-resistance. Data are insufficient to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Mitotane is a strong CYP3A inducer and dolutegravir is partially metabolized by this isoenzyme.
    Abemaciclib: (Major) Avoid coadministration of mitotane with abemaciclib due to decreased exposure to abemaciclib and its active metabolites, which may lead to reduced efficacy. Consider alternative treatments. Abemaciclib is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by approximately 70% in healthy subjects.
    Abiraterone: (Major) Avoid the concomitant use of mitotane with abiraterone due to potential for decreased exposure to abiraterone. If coadministration cannot be avoided, increase the frequency of abiraterone administration to twice daily; resume previous abiraterone dosing after mitotane is discontinued. Mitotane is a strong CYP3A4 inducer and abiraterone is a CYP3A4 substrate. In a pharmacokinetic study involving healthy subjects, another strong CYP3A inducer decreased the mean AUC of abiraterone by 55%.
    Acalabrutinib: (Major) Avoid the concomitant use of acalabrutinib and mitotane. If coadministration cannot be avoided, increase the acalabrutinib dose to 200 mg PO twice daily. Decreased acalabrutinib exposure may occur. Acalabrutinib is a CYP3A4 substrate; mitotane is a strong CYP3A4 inducer. In healthy subjects, the Cmax and AUC values of acalabrutinib were decreased by 68% and 77%, respectively, when acalabrutinib was coadministered with another strong CYP3A4 inducer for 9 days.
    Acetaminophen: (Minor) Use caution if mitotane and acetaminophen are used concomitantly, and monitor for decreased efficacy of acetaminophen. Mitotane is a strong CYP3A4 inducer and acetaminophen is a minor (10% to 15%) CYP3A4 substrate; coadministration may result in decreased plasma concentrations of acetaminophen.
    Acetaminophen; Aspirin, ASA; Caffeine: (Minor) Use caution if mitotane and acetaminophen are used concomitantly, and monitor for decreased efficacy of acetaminophen. Mitotane is a strong CYP3A4 inducer and acetaminophen is a minor (10% to 15%) CYP3A4 substrate; coadministration may result in decreased plasma concentrations of acetaminophen.
    Acetaminophen; Aspirin: (Minor) Use caution if mitotane and acetaminophen are used concomitantly, and monitor for decreased efficacy of acetaminophen. Mitotane is a strong CYP3A4 inducer and acetaminophen is a minor (10% to 15%) CYP3A4 substrate; coadministration may result in decreased plasma concentrations of acetaminophen.
    Acetaminophen; Aspirin; Diphenhydramine: (Moderate) Mitotane can cause sedation, lethargy, vertigo, and other CNS side effects. Concomitant administration of mitotane and CNS depressants, including sedating h1-blockers, may cause additive CNS effects. (Minor) Use caution if mitotane and acetaminophen are used concomitantly, and monitor for decreased efficacy of acetaminophen. Mitotane is a strong CYP3A4 inducer and acetaminophen is a minor (10% to 15%) CYP3A4 substrate; coadministration may result in decreased plasma concentrations of acetaminophen.
    Acetaminophen; Caffeine: (Minor) Use caution if mitotane and acetaminophen are used concomitantly, and monitor for decreased efficacy of acetaminophen. Mitotane is a strong CYP3A4 inducer and acetaminophen is a minor (10% to 15%) CYP3A4 substrate; coadministration may result in decreased plasma concentrations of acetaminophen.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with mitotane can decrease dihydrocodeine levels, resulting in less metabolism by CYP2D6 and decreased dihydromorphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. If coadministration is necessary, monitor for reduced efficacy of dihydrocodeine and signs of opioid withdrawal; consider increasing the dose of dihydrocodeine as needed. If mitotane is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs or respiratory depression and sedation. Mitotane is a strong inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine. (Minor) Use caution if mitotane and acetaminophen are used concomitantly, and monitor for decreased efficacy of acetaminophen. Mitotane is a strong CYP3A4 inducer and acetaminophen is a minor (10% to 15%) CYP3A4 substrate; coadministration may result in decreased plasma concentrations of acetaminophen.
    Acetaminophen; Caffeine; Pyrilamine: (Moderate) Mitotane can cause sedation, lethargy, vertigo, and other CNS side effects. Concomitant administration of mitotane and CNS depressants, including sedating h1-blockers, may cause additive CNS effects. (Minor) Use caution if mitotane and acetaminophen are used concomitantly, and monitor for decreased efficacy of acetaminophen. Mitotane is a strong CYP3A4 inducer and acetaminophen is a minor (10% to 15%) CYP3A4 substrate; coadministration may result in decreased plasma concentrations of acetaminophen.
    Acetaminophen; Chlorpheniramine: (Moderate) Mitotane can cause sedation, lethargy, vertigo, and other CNS side effects. Concomitant administration of mitotane and CNS depressants, including sedating h1-blockers, may cause additive CNS effects. (Minor) Use caution if mitotane and acetaminophen are used concomitantly, and monitor for decreased efficacy of acetaminophen. Mitotane is a strong CYP3A4 inducer and acetaminophen is a minor (10% to 15%) CYP3A4 substrate; coadministration may result in decreased plasma concentrations of acetaminophen.
    Acetaminophen; Chlorpheniramine; Dextromethorphan: (Moderate) Mitotane can cause sedation, lethargy, vertigo, and other CNS side effects. Concomitant administration of mitotane and CNS depressants, including sedating h1-blockers, may cause additive CNS effects. (Minor) Use caution if mitotane and acetaminophen are used concomitantly, and monitor for decreased efficacy of acetaminophen. Mitotane is a strong CYP3A4 inducer and acetaminophen is a minor (10% to 15%) CYP3A4 substrate; coadministration may result in decreased plasma concentrations of acetaminophen.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Mitotane can cause sedation, lethargy, vertigo, and other CNS side effects. Concomitant administration of mitotane and CNS depressants, including sedating h1-blockers, may cause additive CNS effects. (Minor) Use caution if mitotane and acetaminophen are used concomitantly, and monitor for decreased efficacy of acetaminophen. Mitotane is a strong CYP3A4 inducer and acetaminophen is a minor (10% to 15%) CYP3A4 substrate; coadministration may result in decreased plasma concentrations of acetaminophen.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Mitotane can cause sedation, lethargy, vertigo, and other CNS side effects. Concomitant administration of mitotane and CNS depressants, including sedating h1-blockers, may cause additive CNS effects. (Minor) Use caution if mitotane and acetaminophen are used concomitantly, and monitor for decreased efficacy of acetaminophen. Mitotane is a strong CYP3A4 inducer and acetaminophen is a minor (10% to 15%) CYP3A4 substrate; coadministration may result in decreased plasma concentrations of acetaminophen.
    Acetaminophen; Chlorpheniramine; Phenylephrine : (Moderate) Mitotane can cause sedation, lethargy, vertigo, and other CNS side effects. Concomitant administration of mitotane and CNS depressants, including sedating h1-blockers, may cause additive CNS effects. (Minor) Use caution if mitotane and acetaminophen are used concomitantly, and monitor for decreased efficacy of acetaminophen. Mitotane is a strong CYP3A4 inducer and acetaminophen is a minor (10% to 15%) CYP3A4 substrate; coadministration may result in decreased plasma concentrations of acetaminophen.
    Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with mitotane can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If mitotane is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Mitotane is a strong CYP3A4 inducer. (Minor) Use caution if mitotane and acetaminophen are used concomitantly, and monitor for decreased efficacy of acetaminophen. Mitotane is a strong CYP3A4 inducer and acetaminophen is a minor (10% to 15%) CYP3A4 substrate; coadministration may result in decreased plasma concentrations of acetaminophen.
    Acetaminophen; Dextromethorphan: (Minor) Use caution if mitotane and acetaminophen are used concomitantly, and monitor for decreased efficacy of acetaminophen. Mitotane is a strong CYP3A4 inducer and acetaminophen is a minor (10% to 15%) CYP3A4 substrate; coadministration may result in decreased plasma concentrations of acetaminophen.
    Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Mitotane can cause sedation, lethargy, vertigo, and other CNS side effects. Concomitant administration of mitotane and CNS depressants, including sedating h1-blockers, may cause additive CNS effects. (Minor) Use caution if mitotane and acetaminophen are used concomitantly, and monitor for decreased efficacy of acetaminophen. Mitotane is a strong CYP3A4 inducer and acetaminophen is a minor (10% to 15%) CYP3A4 substrate; coadministration may result in decreased plasma concentrations of acetaminophen.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Minor) Use caution if mitotane and acetaminophen are used concomitantly, and monitor for decreased efficacy of acetaminophen. Mitotane is a strong CYP3A4 inducer and acetaminophen is a minor (10% to 15%) CYP3A4 substrate; coadministration may result in decreased plasma concentrations of acetaminophen.
    Acetaminophen; Dextromethorphan; Guaifenesin; Pseudoephedrine: (Minor) Use caution if mitotane and acetaminophen are used concomitantly, and monitor for decreased efficacy of acetaminophen. Mitotane is a strong CYP3A4 inducer and acetaminophen is a minor (10% to 15%) CYP3A4 substrate; coadministration may result in decreased plasma concentrations of acetaminophen.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Minor) Use caution if mitotane and acetaminophen are used concomitantly, and monitor for decreased efficacy of acetaminophen. Mitotane is a strong CYP3A4 inducer and acetaminophen is a minor (10% to 15%) CYP3A4 substrate; coadministration may result in decreased plasma concentrations of acetaminophen.
    Acetaminophen; Dextromethorphan; Pseudoephedrine: (Minor) Use caution if mitotane and acetaminophen are used concomitantly, and monitor for decreased efficacy of acetaminophen. Mitotane is a strong CYP3A4 inducer and acetaminophen is a minor (10% to 15%) CYP3A4 substrate; coadministration may result in decreased plasma concentrations of acetaminophen.
    Acetaminophen; Dichloralphenazone; Isometheptene: (Minor) Use caution if mitotane and acetaminophen are used concomitantly, and monitor for decreased efficacy of acetaminophen. Mitotane is a strong CYP3A4 inducer and acetaminophen is a minor (10% to 15%) CYP3A4 substrate; coadministration may result in decreased plasma concentrations of acetaminophen.
    Acetaminophen; Diphenhydramine: (Moderate) Mitotane can cause sedation, lethargy, vertigo, and other CNS side effects. Concomitant administration of mitotane and CNS depressants, including sedating h1-blockers, may cause additive CNS effects. (Minor) Use caution if mitotane and acetaminophen are used concomitantly, and monitor for decreased efficacy of acetaminophen. Mitotane is a strong CYP3A4 inducer and acetaminophen is a minor (10% to 15%) CYP3A4 substrate; coadministration may result in decreased plasma concentrations of acetaminophen.
    Acetaminophen; Guaifenesin; Phenylephrine: (Minor) Use caution if mitotane and acetaminophen are used concomitantly, and monitor for decreased efficacy of acetaminophen. Mitotane is a strong CYP3A4 inducer and acetaminophen is a minor (10% to 15%) CYP3A4 substrate; coadministration may result in decreased plasma concentrations of acetaminophen.
    Acetaminophen; Hydrocodone: (Major) Concomitant use of hydrocodone with mitotane can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Additionally, mitotane can cause sedation, lethargy, vertigo, and other CNS adverse reactions; additive CNS effects may occur initially when mitotane is given concurrently with hydrocodone. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal and/or additive CNS depression; consider adjusting the dose of hydrocodone as needed. If mitotane is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. (Minor) Use caution if mitotane and acetaminophen are used concomitantly, and monitor for decreased efficacy of acetaminophen. Mitotane is a strong CYP3A4 inducer and acetaminophen is a minor (10% to 15%) CYP3A4 substrate; coadministration may result in decreased plasma concentrations of acetaminophen.
    Acetaminophen; Ibuprofen: (Minor) Use caution if mitotane and acetaminophen are used concomitantly, and monitor for decreased efficacy of acetaminophen. Mitotane is a strong CYP3A4 inducer and acetaminophen is a minor (10% to 15%) CYP3A4 substrate; coadministration may result in decreased plasma concentrations of acetaminophen.
    Acetaminophen; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with mitotane is necessary; consider increasing the dose of oxycodone as needed. If mitotane is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. (Minor) Use caution if mitotane and acetaminophen are used concomitantly, and monitor for decreased efficacy of acetaminophen. Mitotane is a strong CYP3A4 inducer and acetaminophen is a minor (10% to 15%) CYP3A4 substrate; coadministration may result in decreased plasma concentrations of acetaminophen.
    Acetaminophen; Pamabrom; Pyrilamine: (Moderate) Mitotane can cause sedation, lethargy, vertigo, and other CNS side effects. Concomitant administration of mitotane and CNS depressants, including sedating h1-blockers, may cause additive CNS effects. (Minor) Use caution if mitotane and acetaminophen are used concomitantly, and monitor for decreased efficacy of acetaminophen. Mitotane is a strong CYP3A4 inducer and acetaminophen is a minor (10% to 15%) CYP3A4 substrate; coadministration may result in decreased plasma concentrations of acetaminophen.
    Acetaminophen; Pentazocine: (Minor) Use caution if mitotane and acetaminophen are used concomitantly, and monitor for decreased efficacy of acetaminophen. Mitotane is a strong CYP3A4 inducer and acetaminophen is a minor (10% to 15%) CYP3A4 substrate; coadministration may result in decreased plasma concentrations of acetaminophen.
    Acetaminophen; Pseudoephedrine: (Minor) Use caution if mitotane and acetaminophen are used concomitantly, and monitor for decreased efficacy of acetaminophen. Mitotane is a strong CYP3A4 inducer and acetaminophen is a minor (10% to 15%) CYP3A4 substrate; coadministration may result in decreased plasma concentrations of acetaminophen.
    Acrivastine; Pseudoephedrine: (Moderate) Mitotane can cause sedation, lethargy, vertigo, and other CNS side effects. Concomitant administration of mitotane and CNS depressants, including sedating h1-blockers, may cause additive CNS effects.
    Adagrasib: (Major) Avoid concurrent use of adagrasib and mitotane due to the risk of decreased adagrasib exposure which may reduce its efficacy. Adagrasib is a CYP3A substrate and mitotane is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced adagrasib exposure by more than 66%.
    Alfentanil: (Moderate) Consider an increased dose of alfentanil and monitor for evidence of opioid withdrawal if coadministration with mitotane is necessary. If mitotane is discontinued, consider reducing the alfentanil dosage and monitor for evidence of respiratory depression. Coadministration of a CYP3A4 inducer like mitotane with alfentanil, a CYP3A4 substrate, may decrease exposure to alfentanil resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to alfentanil. Alfentanil plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
    Alfuzosin: (Moderate) Use caution if mitotane and alfuzosin are used concomitantly, and monitor for decreased efficacy of alfuzosin and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and alfuzosin is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of alfuzosin.
    Aliskiren: (Moderate) Use caution if mitotane and aliskiren are used concomitantly, and monitor for decreased efficacy of aliskiren and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and aliskiren is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of aliskiren.
    Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) Use caution if mitotane and aliskiren are used concomitantly, and monitor for decreased efficacy of aliskiren and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and aliskiren is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of aliskiren.
    Almotriptan: (Moderate) Use caution if mitotane and almotriptan are used concomitantly, and monitor for decreased efficacy of almotriptan and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and almotriptan is a CYP3A4 substrate (approximately 12%); coadministration may result in decreased plasma concentrations of almotriptan.
    Alosetron: (Moderate) Use caution if mitotane and alosetron are used concomitantly, and monitor for decreased efficacy of alosetron and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and alosetron is a minor (18%) CYP3A4 substrate; coadministration may result in decreased plasma concentrations of alosetron.
    Alpelisib: (Major) Avoid coadministration of alpelisib with mitotane due to decreased exposure to alpelisib which could decrease efficacy. Alpelisib is a CYP3A4 substrate; mitotane is a strong CYP3A4 inducer.
    Alprazolam: (Moderate) Monitor for reduced efficacy of alprazolam and signs of benzodiazepine withdrawal if coadministration with mitotane is necessary. Alprazolam is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease alprazolam concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Additionally, monitor for excessive sedation and somnolence during coadministration of alprazolam and mitotane. Concurrent use may result in additive CNS depression.
    Amiodarone: (Major) Use caution if mitotane and amiodarone are used concomitantly, and monitor for decreased efficacy of amiodarone and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and amiodarone is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of amiodarone.
    Amitriptyline: (Major) Use caution if mitotane and amitriptyline are used concomitantly, and monitor for decreased efficacy of amitriptyline and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and amitriptyline is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of amitriptyline. Additionally, mitotane can cause sedation, lethargy, vertigo, and other CNS adverse reactions; additive CNS effects may occur initially when mitotane is given concurrently with amitriptyline.
    Amlodipine: (Moderate) Use caution if mitotane and amlodipine are used concomitantly, and monitor for decreased efficacy of amlodipine and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and amlodipine is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of amlodipine.
    Amlodipine; Atorvastatin: (Major) Use caution if mitotane and atorvastatin are used concomitantly, and monitor for decreased efficacy of atorvastatin and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and atorvastatin is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of atorvastatin. (Moderate) Use caution if mitotane and amlodipine are used concomitantly, and monitor for decreased efficacy of amlodipine and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and amlodipine is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of amlodipine.
    Amlodipine; Benazepril: (Moderate) Use caution if mitotane and amlodipine are used concomitantly, and monitor for decreased efficacy of amlodipine and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and amlodipine is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of amlodipine.
    Amlodipine; Celecoxib: (Moderate) Use caution if mitotane and amlodipine are used concomitantly, and monitor for decreased efficacy of amlodipine and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and amlodipine is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of amlodipine.
    Amlodipine; Olmesartan: (Moderate) Use caution if mitotane and amlodipine are used concomitantly, and monitor for decreased efficacy of amlodipine and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and amlodipine is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of amlodipine.
    Amlodipine; Valsartan: (Moderate) Use caution if mitotane and amlodipine are used concomitantly, and monitor for decreased efficacy of amlodipine and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and amlodipine is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of amlodipine.
    Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Use caution if mitotane and amlodipine are used concomitantly, and monitor for decreased efficacy of amlodipine and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and amlodipine is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of amlodipine.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Coadministration of mitotane and clarithromycin may decrease clarithromycin serum concentrations due to CYP3A4 enzyme induction. While the 14-OH-clarithromycin active metabolite concentrations are increased, this metabolite has different antimicrobial activity compared to clarithromycin. The intended therapeutic effect of clarithromycin could be decreased. It is not clear if clarithromycin activity against other organisms would be reduced, but reduced efficacy is possible. Alternatives to clarithromycin should be considered in patients who are taking potent CYP3A4 inducers. (Moderate) Use caution if mitotane and omeprazole are used concomitantly, and monitor for decreased efficacy of omeprazole and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and omeprazole is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of omeprazole.
    Apremilast: (Major) Avoid coadministration of apremilast with mitotane due to decreased plasma concentrations of apremilast. Apremilast is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the single-dose apremilast AUC and Cmax by 72% and 43%, respectively.
    Aprepitant, Fosaprepitant: (Major) Avoid the concurrent use of mitotane with aprepitant, fosaprepitant due to substantially decreased exposure of aprepitant. If these drugs must be coadministered, monitor for a decrease in the efficacy of aprepitant. After administration, fosaprepitant is rapidly converted to aprepitant and shares the same drug interactions. Mitotane is a strong CYP3A4 inducer and aprepitant is a CYP3A4 substrate. When a single dose of aprepitant (375 mg, or 3 times the maximum recommended dose) was administered on day 9 of a 14-day rifampin (strong CYP3A inducer) regimen, the AUC of aprepitant decreased approximately 11-fold and the mean terminal half-life decreased by 3-fold.
    Aripiprazole: (Major) Because aripiprazole is partially metabolized by CYP3A4, the manufacturer recommends that the oral aripiprazole dose be doubled over 1 to 2 weeks when a strong CYP3A4 inducer, such as mitotane, is added to aripiprazole therapy with subsequent adjustments based upon clinical response. If these agents are used in combination, the patient should be carefully monitored for a decrease in aripiprazole efficacy. When mitotane is withdrawn from the combination therapy, the aripiprazole dose in adults should be reduced to the original level over 1 to 2 weeks. Avoid concurrent use of Abilify Maintena with a CYP3A4 inducer when the combined treatment period exceeds 14 days because aripiprazole blood concentrations decline and may become suboptimal. In adults receiving 662 mg, 882 mg, or 1,064 mg of Aristada and receiving a strong CYP3A4 inducer, no dosage adjustment is necessary; however, the 441 mg dose should be increased to 662 mg if the CYP inducer is added for more than 2 weeks. Avoid concurrent use of Aristada Initio and strong CYP3A4 inducers.
    Artemether; Lumefantrine: (Contraindicated) Concomitant use of mitotane and artemether is contraindicated. Mitotane is a strong inducer of CYP3A4 and artemether is a substrate of this isoenzyme; therefore, coadministration may lead to decreased artemether concentrations and possible reduction in antimalarial activity. Coadministration of another strong CYP3A4 inducer, rifampin, in 6 HIV and tuberculosis co-infected adults caused reductions in the AUC of artemether, dihydroartemisinin (metabolite of artemether), and lumefantrine by 89%, 85%, and 68%, respectively. (Contraindicated) Concomitant use of mitotane and artemether; lumefantrine is contraindicated. Mitotane is a strong inducer of CYP3A4 and both components of artemether; lumefantrine are substrates of this isoenzyme; therefore, coadministration may lead to decreased artemether; lumefantrine concentrations and possible reduction in antimalarial activity. Coadministration of another strong CYP3A4 inducer, rifampin, in 6 HIV and tuberculosis co-infected adults caused reductions in the AUC of artemether, dihydroartemisinin (metabolite of artemether), and lumefantrine by 89%, 85%, and 68%, respectively.
    Asenapine: (Minor) Use caution if mitotane and asenapine are used concomitantly. Mitotane is a strong CYP3A4 inducer and asenapine is a CYP3A4 substrate in vitro. Coadministration may result in decreased plasma concentrations of asenapine; however, no dosage adjustment of asenapine is necessary.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Concomitant use of codeine with mitotane can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If mitotane is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Mitotane is a strong CYP3A4 inducer.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with mitotane can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If mitotane is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Mitotane is a strong CYP3A4 inducer.
    Aspirin, ASA; Omeprazole: (Moderate) Use caution if mitotane and omeprazole are used concomitantly, and monitor for decreased efficacy of omeprazole and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and omeprazole is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of omeprazole.
    Aspirin, ASA; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with mitotane is necessary; consider increasing the dose of oxycodone as needed. If mitotane is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Atazanavir: (Contraindicated) Atazanavir is contraindicated for use with mitotane. Mitotane is a strong CYP3A4 inducer and atazanavir is a CYP3A4 substrate; coadministration significantly reduces plasma concentrations of atazanavir, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. When coadministered with another strong CYP3A4 inducer (rifampin 600 mg daily; n = 16), the ratio of atazanavir pharmacokinetic parameters was significantly affected as follows (where 1 = no change): Cmax, 0.47 (90% CI, 0.41 to 0.53), AUC, 0.28 (90% CI, 0.25 to 0.32), and Cmin, 0.02 (90% CI, 0.02 to 0.03).
    Atazanavir; Cobicistat: (Contraindicated) Atazanavir is contraindicated for use with mitotane. Mitotane is a strong CYP3A4 inducer and atazanavir is a CYP3A4 substrate; coadministration significantly reduces plasma concentrations of atazanavir, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. When coadministered with another strong CYP3A4 inducer (rifampin 600 mg daily; n = 16), the ratio of atazanavir pharmacokinetic parameters was significantly affected as follows (where 1 = no change): Cmax, 0.47 (90% CI, 0.41 to 0.53), AUC, 0.28 (90% CI, 0.25 to 0.32), and Cmin, 0.02 (90% CI, 0.02 to 0.03). (Contraindicated) Coadministration of mitotane with cobicistat is contraindicated. Mitotane is a strong inducer of CYP3A4; cobicistat is a substrate of this enzyme. Concurrent use may result in significant decreases in the plasma concentrations of cobicistat, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance.
    Atogepant: (Major) Avoid use of atogepant and mitotane when atogepant is used for chronic migraine. Use an atogepant dose of 30 or 60 mg PO once daily for episodic migraine if coadministered with mitotane. Concurrent use may decrease atogepant exposure and reduce efficacy. Atogepant is a CYP3A substrate and mitotane is a strong CYP3A inducer. Coadministration with a strong CYP3A inducer resulted in a 60% reduction in atogepant overall exposure and a 30% reduction in atogepant peak concentration.
    Atorvastatin: (Major) Use caution if mitotane and atorvastatin are used concomitantly, and monitor for decreased efficacy of atorvastatin and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and atorvastatin is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of atorvastatin.
    Atorvastatin; Ezetimibe: (Major) Use caution if mitotane and atorvastatin are used concomitantly, and monitor for decreased efficacy of atorvastatin and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and atorvastatin is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of atorvastatin.
    Atropine; Difenoxin: (Moderate) Concurrent administration of diphenoxylate/difenoxin with mitotane can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration.
    Avacopan: (Major) Avoid concomitant use of avacopan and mitotane due to the risk of decreased avacopan exposure which may reduce its efficacy. Avacopan is a CYP3A substrate and mitotane is a strong CYP3A inducer. Concomitant use of another strong CYP3A inducer decreased avacopan overall exposure by 93%.
    Avanafil: (Major) The concomitant use of mitotane with avanafil is not recommended; if coadministration cannot be avoided, monitor for decreased efficacy of avanafil. Mitotane is a strong CYP3A4 inducer and avanafil is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of avanafil. The potential effect of CYP inducers on avanafil has not been evaluated.
    Avapritinib: (Major) Avoid coadministration of avapritinib with mitotane due to the risk of decreased avapritinib efficacy. Avapritinib is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of avapritinib by 92% and 74%, respectively.
    Axitinib: (Major) Avoid coadministration of axitinib with mitotane due to the risk of decreased efficacy of axitinib. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Axitinib is a CYP3A4/5 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4/5 inducer significantly decreased the plasma exposure of axitinib in healthy volunteers.
    Azelastine; Fluticasone: (Moderate) Use caution if mitotane and fluticasone are used concomitantly, and monitor for decreased efficacy of fluticasone and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and fluticasone is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of fluticasone.
    Barbiturates: (Moderate) Mitotane can cause sedation, lethargy, vertigo, and other CNS side effects. Concomitant administration of mitotane and CNS depressants may cause additive CNS effects. Mitotane should be used cautiously with other drugs that may cause CNS depression including barbiturates.
    Bedaquiline: (Major) Avoid concurrent use of bedaquiline with mitotane due to the potential for decreased efficacy of bedaquiline. Mitotane is a strong CYP3A4 inducer and bedaquiline is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of bedaquiline. When administered concurrently with another strong CYP3A4 inducer (rifampin 600 mg PO daily for 21 days, the bedaquiline AUC decreased by 52% in one study.
    Belumosudil: (Major) Increase the dosage of belumosudil to 200 mg PO twice daily when coadministered with mitotane. Belumosudil is a CYP3A4 substrate and mitotane is a strong CYP3A inducer; concomitant use may result in decreased belumosudil exposure and reduced belumosudil efficacy. Coadministration with another strong CYP3A inducer decreased belumosudil exposure by 72% in healthy subjects.
    Benzhydrocodone; Acetaminophen: (Moderate) Concurrent use of benzhydrocodone with mitotane may decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. If concomitant use is necessary, consider increasing the benzhydrocodone dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Discontinuation of mitotane may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. If mitotane is discontinued, consider a benzhydrocodone dosage reduction and monitor patients for respiratory depression and sedation at frequent intervals. Benzhydrocodone is a prodrug of hydrocodone. Mitotane is a strong inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of hydrocodone. (Minor) Use caution if mitotane and acetaminophen are used concomitantly, and monitor for decreased efficacy of acetaminophen. Mitotane is a strong CYP3A4 inducer and acetaminophen is a minor (10% to 15%) CYP3A4 substrate; coadministration may result in decreased plasma concentrations of acetaminophen.
    Bortezomib: (Major) Avoid the concomitant use of mitotane with bortezomib; if coadministration cannot be avoided, monitor for decreased efficacy of bortezomib. Mitotane is a strong CYP3A4 inducer and bortezomib is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of bortezomib.
    Bosutinib: (Major) Avoid the concomitant use of mitotane with bosutinib; if coadministration cannot be avoided, monitor for decreased efficacy of bosutinib. Mitotane is a strong CYP3A4 inducer and bosutinib is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of bosutinib. After 6 days of administration of rifampin (600 mg/day), another strong CYP3A4 inducer, to healthy volunteers in a cross-over trial (n = 24), the Cmax and AUC values of bosutinib (single dose) were decreased by 86% and 94%, respectively.
    Brentuximab vedotin: (Major) Concomitant use of mitotane with brentuximab vedotin should be undertaken with caution as it could result in decreased plasma concentrations of brentuximab, leading to reduced efficacy. Mitotane is a strong CYP3A4 inducer and monomethyl auristatin E (MMAE), one of the 3 components released from brentuximab vedotin, is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of MMAE. Concomitant administration of brentuximab vedotin and rifampin, another strong CYP3A4 substrate, decreased the exposure of MMAE by approximately 46%.
    Brexpiprazole: (Major) If coadministration of mitotane and brexpiprazole is necessary, the brexpiprazole dose should be doubled over 1 to 2 weeks and the patient should be carefully monitored for a decrease in brexpiprazole efficacy. If mitotane is discontinued, the brexpiprazole dose should be reduced to the original level over 1 to 2 weeks. Mitotane is a strong CYP3A4 inducer and brexpiprazole is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of brexpiprazole.
    Brigatinib: (Major) Avoid coadministration of brigatinib with mitotane due to decreased plasma exposure to brigatinib which may result in decreased efficacy. Brigatinib is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased the AUC and Cmax of brigatinib by 80% and 60%, respectively.
    Bromocriptine: (Moderate) Caution and close monitoring are advised if bromocriptine and mitotane are used together. Concurrent use may decrease the plasma concentrations of bromocriptine resulting in loss of efficacy. Bromocriptine is extensively metabolized by the liver via CYP3A4; mitotane is a strong inducer of CYP3A4.
    Brompheniramine: (Moderate) Mitotane can cause sedation, lethargy, vertigo, and other CNS side effects. Concomitant administration of mitotane and CNS depressants, including sedating h1-blockers, may cause additive CNS effects.
    Brompheniramine; Dextromethorphan; Guaifenesin: (Moderate) Mitotane can cause sedation, lethargy, vertigo, and other CNS side effects. Concomitant administration of mitotane and CNS depressants, including sedating h1-blockers, may cause additive CNS effects.
    Brompheniramine; Dextromethorphan; Phenylephrine: (Moderate) Mitotane can cause sedation, lethargy, vertigo, and other CNS side effects. Concomitant administration of mitotane and CNS depressants, including sedating h1-blockers, may cause additive CNS effects.
    Brompheniramine; Phenylephrine: (Moderate) Mitotane can cause sedation, lethargy, vertigo, and other CNS side effects. Concomitant administration of mitotane and CNS depressants, including sedating h1-blockers, may cause additive CNS effects.
    Brompheniramine; Pseudoephedrine: (Moderate) Mitotane can cause sedation, lethargy, vertigo, and other CNS side effects. Concomitant administration of mitotane and CNS depressants, including sedating h1-blockers, may cause additive CNS effects.
    Brompheniramine; Pseudoephedrine; Dextromethorphan: (Moderate) Mitotane can cause sedation, lethargy, vertigo, and other CNS side effects. Concomitant administration of mitotane and CNS depressants, including sedating h1-blockers, may cause additive CNS effects.
    Budesonide: (Moderate) Use caution if mitotane and budesonide are used concomitantly, and monitor for decreased efficacy of budesonide and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and budesonide is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of budesonide. Theoretically, inhibition of CYP3A may also be clinically significant for inhaled forms of budesonide, including budesonide nasal spray.
    Budesonide; Formoterol: (Moderate) Use caution if mitotane and budesonide are used concomitantly, and monitor for decreased efficacy of budesonide and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and budesonide is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of budesonide. Theoretically, inhibition of CYP3A may also be clinically significant for inhaled forms of budesonide, including budesonide nasal spray.
    Budesonide; Glycopyrrolate; Formoterol: (Moderate) Use caution if mitotane and budesonide are used concomitantly, and monitor for decreased efficacy of budesonide and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and budesonide is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of budesonide. Theoretically, inhibition of CYP3A may also be clinically significant for inhaled forms of budesonide, including budesonide nasal spray.
    Bupivacaine Liposomal: (Moderate) Use caution if mitotane and bupivacaine are used concomitantly, and monitor for decreased efficacy of bupivacaine and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and bupivacaine is a CYP3A4 substrate in vitro; coadministration may result in decreased plasma concentrations of bupivacaine.
    Bupivacaine: (Moderate) Use caution if mitotane and bupivacaine are used concomitantly, and monitor for decreased efficacy of bupivacaine and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and bupivacaine is a CYP3A4 substrate in vitro; coadministration may result in decreased plasma concentrations of bupivacaine.
    Bupivacaine; Epinephrine: (Moderate) Use caution if mitotane and bupivacaine are used concomitantly, and monitor for decreased efficacy of bupivacaine and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and bupivacaine is a CYP3A4 substrate in vitro; coadministration may result in decreased plasma concentrations of bupivacaine.
    Bupivacaine; Lidocaine: (Major) Use caution if mitotane and lidocaine are used concomitantly, and monitor for decreased efficacy of lidocaine and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and lidocaine is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of lidocaine. (Moderate) Use caution if mitotane and bupivacaine are used concomitantly, and monitor for decreased efficacy of bupivacaine and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and bupivacaine is a CYP3A4 substrate in vitro; coadministration may result in decreased plasma concentrations of bupivacaine.
    Bupivacaine; Meloxicam: (Moderate) Use caution if mitotane and bupivacaine are used concomitantly, and monitor for decreased efficacy of bupivacaine and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and bupivacaine is a CYP3A4 substrate in vitro; coadministration may result in decreased plasma concentrations of bupivacaine. (Minor) Use caution if mitotane and meloxicam are used concomitantly, and monitor for decreased efficacy of meloxicam and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and meloxicam is a minor CYP3A4 substrate; coadministration may result in decreased plasma concentrations of meloxicam.
    Buprenorphine: (Moderate) Use caution if mitotane and buprenorphine are used concomitantly, and monitor for decreased efficacy of buprenorphine and possible onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine. Mitotane is a strong CYP3A4 inducer and buprenorphine is a CYP3A4 substrate in vitro; coadministration may result in decreased plasma concentrations of buprenorphine. This interaction is most significant if the enzyme-inducing agent is added after buprenorphine therapy has begun; buprenorphine doses may need to be increased. Conversely, buprenorphine doses may need to be decreased if mitotane is discontinued, as buprenorphine plasma concentrations may increase and serious respiratory depression could occur.
    Buprenorphine; Naloxone: (Moderate) Use caution if mitotane and buprenorphine are used concomitantly, and monitor for decreased efficacy of buprenorphine and possible onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine. Mitotane is a strong CYP3A4 inducer and buprenorphine is a CYP3A4 substrate in vitro; coadministration may result in decreased plasma concentrations of buprenorphine. This interaction is most significant if the enzyme-inducing agent is added after buprenorphine therapy has begun; buprenorphine doses may need to be increased. Conversely, buprenorphine doses may need to be decreased if mitotane is discontinued, as buprenorphine plasma concentrations may increase and serious respiratory depression could occur.
    Buspirone: (Major) Use caution if mitotane and buspirone are used concomitantly, and monitor for decreased efficacy of buspirone and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and buspirone is a CYP3A4 substrate in vitro; coadministration may result in decreased plasma concentrations of buspirone. Coadministration with another strong CYP3A inducer, rifampin, decreased the buspirone Cmax by 83.7% and AUC by 89.6%.
    Butalbital; Acetaminophen: (Minor) Use caution if mitotane and acetaminophen are used concomitantly, and monitor for decreased efficacy of acetaminophen. Mitotane is a strong CYP3A4 inducer and acetaminophen is a minor (10% to 15%) CYP3A4 substrate; coadministration may result in decreased plasma concentrations of acetaminophen.
    Butalbital; Acetaminophen; Caffeine: (Minor) Use caution if mitotane and acetaminophen are used concomitantly, and monitor for decreased efficacy of acetaminophen. Mitotane is a strong CYP3A4 inducer and acetaminophen is a minor (10% to 15%) CYP3A4 substrate; coadministration may result in decreased plasma concentrations of acetaminophen.
    Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Concomitant use of codeine with mitotane can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If mitotane is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Mitotane is a strong CYP3A4 inducer. (Minor) Use caution if mitotane and acetaminophen are used concomitantly, and monitor for decreased efficacy of acetaminophen. Mitotane is a strong CYP3A4 inducer and acetaminophen is a minor (10% to 15%) CYP3A4 substrate; coadministration may result in decreased plasma concentrations of acetaminophen.
    Cabotegravir; Rilpivirine: (Major) Concomitant use of mitotane with rilpivirine should be undertaken with caution due to potential decreased rilpivirine concentrations, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. The use of rilpivirine is contraindicated with other specific strong CYP3A inducers, including carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifampin, rifapentine, and St John's wort. Mitotane is a strong CYP3A4 inducer and rilpivirine is a CYP3A4 substrate. Coadministration may result in decreased rilpivirine serum concentrations, which could cause impaired virologic response to rilpivirine.
    Cabozantinib: (Major) Avoid coadministration of cabozantinib with mitotane due to the risk of decreased cabozantinib exposure which could affect efficacy. If concomitant use is unavoidable, increase the dose of cabozantinib. For patients taking cabozantinib tablets, increase the dose of cabozantinib by 20 mg (e.g., 60 mg/day to 80 mg/day; 40 mg/day to 60 mg/day); the daily dose should not exceed 80 mg. For patients taking cabozantinib capsules, increase the dose of cabozantinib by 40 mg (e.g., 140 mg/day to 180 mg/day or 100 mg/day to 140 mg/day); the daily dose should not exceed 180 mg. Resume the cabozantinib dose that was used prior to initiating treatment with mitotane 2 to 3 days after discontinuation of mitotane. Cabozantinib is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased single-dose cabozantinib exposure by 77%.
    Capmatinib: (Major) Avoid coadministration of capmatinib and mitotane due to the risk of decreased capmatinib exposure, which may reduce its efficacy. Capmatinib is a CYP3A substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased capmatinib exposure by 67%.
    Carbamazepine: (Major) Use caution if mitotane and carbamazepine are used concomitantly, and monitor for decreased efficacy of carbamazepine and a possible change in dosage requirements. Carbamazepine dosages may need to be adjusted while the patient is receiving mitotane. Mitotane is a strong CYP3A4 inducer and carbamazepine is a CYP3A4 substrate in vitro; coadministration may result in decreased plasma concentrations of carbamazepine.
    Carbinoxamine: (Moderate) Mitotane can cause sedation, lethargy, vertigo, and other CNS side effects. Concomitant administration of mitotane and CNS depressants, including sedating h1-blockers, may cause additive CNS effects.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Moderate) Mitotane can cause sedation, lethargy, vertigo, and other CNS side effects. Concomitant administration of mitotane and CNS depressants, including sedating h1-blockers, may cause additive CNS effects.
    Carbinoxamine; Phenylephrine: (Moderate) Mitotane can cause sedation, lethargy, vertigo, and other CNS side effects. Concomitant administration of mitotane and CNS depressants, including sedating h1-blockers, may cause additive CNS effects.
    Carbinoxamine; Pseudoephedrine: (Moderate) Mitotane can cause sedation, lethargy, vertigo, and other CNS side effects. Concomitant administration of mitotane and CNS depressants, including sedating h1-blockers, may cause additive CNS effects.
    Cariprazine: (Major) The concomitant use of mitotane with cariprazine is not recommended, as concurrent use of cariprazine with CYP3A4 inducers has not been evaluated and the net effect on active drug and metabolites is unclear. If coadministration cannot be avoided, monitor for decreased efficacy of cariprazine. Mitotane is a strong CYP3A4 inducer and cariprazine is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of cariprazine and its major active metabolites.
    Celecoxib; Tramadol: (Major) Use caution if mitotane and tramadol are used concomitantly, and monitor for decreased efficacy of tramadol and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer. The metabolism of tramadol is stereoselective; the (+) enantiomer preferentially undergoes N-demethylation, mediated by CYP3A4 and CYP2B6, and the (-) enantiomer undergoes O-demethylation via CYP2D6. O-demethylation leads to the production of the active metabolite M1, which is critical to tramadol activity. Because of the role of CYP3A4 in tramadol metabolism, coadministration with mitotane may affect patient response to tramadol.
    Ceritinib: (Major) Avoid concomitant use of ceritinib with mitotane as ceritinib exposure may be decreased, which may reduce its efficacy. Ceritinib is a CYP3A substrate and mitotane is a strong CYP3A inducer. Coadministration with a strong CYP3A inducer decreased ceritinib exposure by 70%.
    Chlophedianol; Dexbrompheniramine: (Moderate) Mitotane can cause sedation, lethargy, vertigo, and other CNS side effects. Concomitant administration of mitotane and CNS depressants, including sedating h1-blockers, may cause additive CNS effects.
    Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) Mitotane can cause sedation, lethargy, vertigo, and other CNS side effects. Concomitant administration of mitotane and CNS depressants, including sedating h1-blockers, may cause additive CNS effects.
    Chlorcyclizine: (Moderate) Mitotane can cause sedation, lethargy, vertigo, and other CNS side effects. Concomitant administration of mitotane and CNS depressants, including sedating h1-blockers, may cause additive CNS effects.
    Chlordiazepoxide: (Major) Use caution if mitotane and chlordiazepoxide are used concomitantly, and monitor for decreased efficacy of chlordiazepoxide and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and chlordiazepoxide is a CYP3A4 substrate in vitro; coadministration may result in decreased plasma concentrations of chlordiazepoxide. Additionally, mitotane can cause sedation, lethargy, vertigo, and other CNS adverse reactions; additive CNS effects may occur initially when mitotane is given concurrently with chlordiazepoxide.
    Chlordiazepoxide; Amitriptyline: (Major) Use caution if mitotane and amitriptyline are used concomitantly, and monitor for decreased efficacy of amitriptyline and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and amitriptyline is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of amitriptyline. Additionally, mitotane can cause sedation, lethargy, vertigo, and other CNS adverse reactions; additive CNS effects may occur initially when mitotane is given concurrently with amitriptyline. (Major) Use caution if mitotane and chlordiazepoxide are used concomitantly, and monitor for decreased efficacy of chlordiazepoxide and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and chlordiazepoxide is a CYP3A4 substrate in vitro; coadministration may result in decreased plasma concentrations of chlordiazepoxide. Additionally, mitotane can cause sedation, lethargy, vertigo, and other CNS adverse reactions; additive CNS effects may occur initially when mitotane is given concurrently with chlordiazepoxide.
    Chlordiazepoxide; Clidinium: (Major) Use caution if mitotane and chlordiazepoxide are used concomitantly, and monitor for decreased efficacy of chlordiazepoxide and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and chlordiazepoxide is a CYP3A4 substrate in vitro; coadministration may result in decreased plasma concentrations of chlordiazepoxide. Additionally, mitotane can cause sedation, lethargy, vertigo, and other CNS adverse reactions; additive CNS effects may occur initially when mitotane is given concurrently with chlordiazepoxide.
    Chlorpheniramine: (Moderate) Mitotane can cause sedation, lethargy, vertigo, and other CNS side effects. Concomitant administration of mitotane and CNS depressants, including sedating h1-blockers, may cause additive CNS effects.
    Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with mitotane can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If mitotane is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Mitotane is a strong CYP3A4 inducer. (Moderate) Mitotane can cause sedation, lethargy, vertigo, and other CNS side effects. Concomitant administration of mitotane and CNS depressants, including sedating h1-blockers, may cause additive CNS effects.
    Chlorpheniramine; Dextromethorphan: (Moderate) Mitotane can cause sedation, lethargy, vertigo, and other CNS side effects. Concomitant administration of mitotane and CNS depressants, including sedating h1-blockers, may cause additive CNS effects.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Mitotane can cause sedation, lethargy, vertigo, and other CNS side effects. Concomitant administration of mitotane and CNS depressants, including sedating h1-blockers, may cause additive CNS effects.
    Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Mitotane can cause sedation, lethargy, vertigo, and other CNS side effects. Concomitant administration of mitotane and CNS depressants, including sedating h1-blockers, may cause additive CNS effects.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Concomitant use of dihydrocodeine with mitotane can decrease dihydrocodeine levels, resulting in less metabolism by CYP2D6 and decreased dihydromorphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. If coadministration is necessary, monitor for reduced efficacy of dihydrocodeine and signs of opioid withdrawal; consider increasing the dose of dihydrocodeine as needed. If mitotane is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs or respiratory depression and sedation. Mitotane is a strong inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine. (Moderate) Mitotane can cause sedation, lethargy, vertigo, and other CNS side effects. Concomitant administration of mitotane and CNS depressants, including sedating h1-blockers, may cause additive CNS effects.
    Chlorpheniramine; Hydrocodone: (Major) Concomitant use of hydrocodone with mitotane can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Additionally, mitotane can cause sedation, lethargy, vertigo, and other CNS adverse reactions; additive CNS effects may occur initially when mitotane is given concurrently with hydrocodone. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal and/or additive CNS depression; consider adjusting the dose of hydrocodone as needed. If mitotane is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. (Moderate) Mitotane can cause sedation, lethargy, vertigo, and other CNS side effects. Concomitant administration of mitotane and CNS depressants, including sedating h1-blockers, may cause additive CNS effects.
    Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Moderate) Mitotane can cause sedation, lethargy, vertigo, and other CNS side effects. Concomitant administration of mitotane and CNS depressants, including sedating h1-blockers, may cause additive CNS effects.
    Chlorpheniramine; Phenylephrine: (Moderate) Mitotane can cause sedation, lethargy, vertigo, and other CNS side effects. Concomitant administration of mitotane and CNS depressants, including sedating h1-blockers, may cause additive CNS effects.
    Chlorpheniramine; Pseudoephedrine: (Moderate) Mitotane can cause sedation, lethargy, vertigo, and other CNS side effects. Concomitant administration of mitotane and CNS depressants, including sedating h1-blockers, may cause additive CNS effects.
    Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
    Cilostazol: (Moderate) Use caution if mitotane and cilostazol are used concomitantly, and monitor for decreased efficacy of cilostazol and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and cilostazol is a CYP3A4 substrate in vitro; coadministration may result in decreased plasma concentrations of cilostazol.
    Cisapride: (Moderate) Use caution if mitotane and cisapride are used concomitantly, and monitor for decreased efficacy of cisapride and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and cisapride is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of cisapride.
    Citalopram: (Moderate) Monitor for decreased efficacy of citalopram if coadministration with mitotane is necessary. Citalopram is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer did not affect citalopram plasma concentrations, but increased clearance of citalopram with strong CYP3A4 inducers is possible.
    Clarithromycin: (Major) Coadministration of mitotane and clarithromycin may decrease clarithromycin serum concentrations due to CYP3A4 enzyme induction. While the 14-OH-clarithromycin active metabolite concentrations are increased, this metabolite has different antimicrobial activity compared to clarithromycin. The intended therapeutic effect of clarithromycin could be decreased. It is not clear if clarithromycin activity against other organisms would be reduced, but reduced efficacy is possible. Alternatives to clarithromycin should be considered in patients who are taking potent CYP3A4 inducers.
    Clemastine: (Moderate) Mitotane can cause sedation, lethargy, vertigo, and other CNS side effects. Concomitant administration of mitotane and CNS depressants, including sedating h1-blockers, may cause additive CNS effects.
    Clindamycin: (Moderate) Monitor for loss of clindamycin efficacy with coadministration of mitotane as concurrent use may decrease clindamycin exposure. Clindamycin is a CYP3A4 substrate; mitotane is a strong inducer of CYP3A4.
    Clomipramine: (Major) Use caution if mitotane and clomipramine are used concomitantly, and monitor for decreased efficacy of clomipramine and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and clomipramine is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of clomipramine. Additionally, mitotane can cause sedation, lethargy, vertigo, and other CNS adverse reactions; additive CNS effects may occur initially when mitotane is given concurrently with clomipramine.
    Clonazepam: (Moderate) Monitor patients for a change in clonazepam dosage requirements when giving concurrently with mitotane. Clonazepam concentration decreases of approximately 38% have been reported when clonazepam is used with strong CYP3A4 inducers. Clonazepam is a CYP3A4 substrate. Mitotane is a strong CYP3A4 inducer.
    Clorazepate: (Major) Use caution if mitotane and clorazepate are used concomitantly, and monitor for decreased efficacy of clorazepate and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer. Clorazepate is a pro-drug converted to N-desmethyldiazepam in the GI tract; N-desmethyldiazepam is metabolized by 2C19 and 3A4. Coadministration may result in decreased plasma concentrations of N-desmethyldiazepam. Additionally, mitotane can cause sedation, lethargy, vertigo, and other CNS adverse reactions; additive CNS effects may occur initially when mitotane is given concurrently with clorazepate.
    Clozapine: (Moderate) The concomitant use of mitotane with clozapine is not recommended; if coadministration cannot be avoided, monitor for decreased efficacy of clozapine and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and clozapine is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of clozapine. Additionally, mitotane can cause sedation, lethargy, vertigo, and other CNS adverse reactions; additive CNS effects may occur initially when mitotane is given concurrently with clozapine.
    Cobicistat: (Contraindicated) Coadministration of mitotane with cobicistat is contraindicated. Mitotane is a strong inducer of CYP3A4; cobicistat is a substrate of this enzyme. Concurrent use may result in significant decreases in the plasma concentrations of cobicistat, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance.
    Cobimetinib: (Major) Avoid the concomitant use of mitotane with cobimetinib due to decreased cobimetinib exposure leading to decreased efficacy. Mitotane is a strong CYP3A4 inducer and cobimetinib is a CYP3A4 substrate in vitro; coadministration may result in decreased plasma concentrations of cobimetinib. Based on simulations, cobimetinib exposure would decrease by 83% when coadministered with a strong CYP3A inducer.
    Codeine: (Moderate) Concomitant use of codeine with mitotane can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If mitotane is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Mitotane is a strong CYP3A4 inducer.
    Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with mitotane can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If mitotane is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Mitotane is a strong CYP3A4 inducer.
    Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of codeine with mitotane can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If mitotane is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Mitotane is a strong CYP3A4 inducer.
    Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of codeine with mitotane can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If mitotane is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Mitotane is a strong CYP3A4 inducer.
    Codeine; Promethazine: (Moderate) Concomitant use of codeine with mitotane can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If mitotane is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Mitotane is a strong CYP3A4 inducer.
    Colchicine: (Major) Use caution if mitotane and colchicine are used concomitantly, and monitor for decreased efficacy of colchicine and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and colchicine is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of colchicine.
    Conjugated Estrogens; Medroxyprogesterone: (Major) Use caution if mitotane and medroxyprogesterone are used concomitantly, and monitor for decreased medroxyprogesterone efficacy. Since the dosage of medroxyprogesterone injections for contraception cannot be modified, an alternate or additional form of contraception should be considered in patients requiring therapy with mitotane. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of mitotane. Mitotane is a strong CYP3A4 inducer and medroxyprogesterone is a CYP3A4 substrate in vitro; coadministration may result in decreased plasma concentrations of medroxyprogesterone. Pregnancies have been reported during therapy with progestin contraceptives in patients receiving other strong CYP3A inducers.
    Copanlisib: (Major) Avoid the concomitant use of copanlisib and mitotane; decreased copanlisib exposure and loss of efficacy may occur. Copanlisib is a CYP3A substrate; mitotane is a strong CYP3A inducer.
    Crizotinib: (Major) Avoid coadministration of crizotinib with mitotane due to decreased plasma concentrations of crizotinib, which may result in decreased efficacy. Crizotinib is primarily metabolized by CYP3A and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the crizotinib AUC and Cmax at steady state by 84% and 79%, respectively.
    Cyclizine: (Moderate) Mitotane can cause sedation, lethargy, vertigo, and other CNS side effects. Concomitant administration of mitotane and CNS depressants, including sedating h1-blockers, may cause additive CNS effects.
    Cyclosporine: (Moderate) Closely monitor cyclosporine concentrations and adjust the dose of cyclosporine as appropriate if coadministration with mitotane is necessary. Concurrent use may decrease cyclosporine exposure resulting in decreased efficacy. Cyclosporine is extensively metabolized by CYP3A and has a narrow therapeutic index; mitotane is a strong CYP3A inducer.
    Cyproheptadine: (Moderate) Mitotane can cause sedation, lethargy, vertigo, and other CNS side effects. Concomitant administration of mitotane and CNS depressants, including sedating h1-blockers, may cause additive CNS effects.
    Daclatasvir: (Contraindicated) Concomitant use of daclatasvir with mitotane is contraindicated due to the potential for hepatitis C treatment failure. Mitotane is a strong CYP3A4 inducer and daclatasvir is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of daclatasvir.
    Dapsone: (Moderate) Monitor for an increase in hemolysis if coadministration of dapsone with mitotane is necessary; dapsone efficacy may also be compromised. Dapsone is a CYP3A4 metabolite and mitotane is a strong CYP3A4 inducer. Strong CYP3A4 inducers may increase the formation of dapsone hydroxylamine, a metabolite associated with hemolysis. Coadministration with another strong CYP3A4 inducer decreased dapsone levels by 7-fold to 10-fold; in leprosy, this reduction has not required a change in dosage.
    Daridorexant: (Major) Avoid concomitant use of daridorexant and mitotane. Coadministration may decrease daridorexant exposure which may reduce its efficacy. Daridorexant is a CYP3A substrate and mitotane is a strong CYP3A inducer. Concomitant use of another strong CYP3A inducer decreased daridorexant overall exposure by over 50%.
    Darifenacin: (Moderate) Use caution if mitotane and darifenacin are used concomitantly, and monitor for decreased efficacy of darifenacin and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and darifenacin is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of darifenacin.
    Darunavir: (Contraindicated) Darunavir is contraindicated for use with mitotane due to potential decreased darunavir concentrations, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Mitotane is a strong CYP3A4 inducer and darunavir is a CYP3A4 substrate. When coadministered with another strong CYP3A4 inducer (rifampin 600 mg daily; n = 16), the ratio of darunavir pharmacokinetic parameters was significantly affected as follows (where 1 = no change): Cmax, 0.44 (90% CI, 0.4 to 0.48) and AUC, 0.21 (90% CI, 0.19 to 0.23).
    Darunavir; Cobicistat: (Contraindicated) Coadministration of mitotane with cobicistat is contraindicated. Mitotane is a strong inducer of CYP3A4; cobicistat is a substrate of this enzyme. Concurrent use may result in significant decreases in the plasma concentrations of cobicistat, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. (Contraindicated) Darunavir is contraindicated for use with mitotane due to potential decreased darunavir concentrations, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Mitotane is a strong CYP3A4 inducer and darunavir is a CYP3A4 substrate. When coadministered with another strong CYP3A4 inducer (rifampin 600 mg daily; n = 16), the ratio of darunavir pharmacokinetic parameters was significantly affected as follows (where 1 = no change): Cmax, 0.44 (90% CI, 0.4 to 0.48) and AUC, 0.21 (90% CI, 0.19 to 0.23).
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Contraindicated) Coadministration of mitotane with cobicistat is contraindicated. Mitotane is a strong inducer of CYP3A4; cobicistat is a substrate of this enzyme. Concurrent use may result in significant decreases in the plasma concentrations of cobicistat, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. (Contraindicated) Darunavir is contraindicated for use with mitotane due to potential decreased darunavir concentrations, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Mitotane is a strong CYP3A4 inducer and darunavir is a CYP3A4 substrate. When coadministered with another strong CYP3A4 inducer (rifampin 600 mg daily; n = 16), the ratio of darunavir pharmacokinetic parameters was significantly affected as follows (where 1 = no change): Cmax, 0.44 (90% CI, 0.4 to 0.48) and AUC, 0.21 (90% CI, 0.19 to 0.23).
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Contraindicated) Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir with mitotane is contraindicated due to the potential for hepatitis C treatment failure. Coadministration may result in reduced systemic exposure to dasabuvir, ombitasvir, paritaprevir and ritonavir. Mitotane is a strong inducer of CYP3A4; dasabuvir (minor), paritaprevir, and ritonavir are substrates of this isoenzyme. (Contraindicated) Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir with mitotane is contraindicated due to the potential for hepatitis C treatment failure. Coadministration may result in reduced systemic exposure to dasabuvir, ombitasvir, paritaprevir and ritonavir. Mitotane is a strong inducer of CYP3A4; dasabuvir (minor), paritaprevir, and ritonavir are substrates of this isoenzyme. (Major) Avoid the concomitant use of mitotane with ritonavir due to the potential for reduced antiretroviral efficacy and the potential development of viral resistance. If coadministration cannot be avoided, monitor for decreased efficacy of ritonavir. Mitotane is a strong CYP3A4 inducer and ritonavir is a CYP3A4 substrates; coadministration may result in decreased plasma concentrations of ritonavir. Another strong CYP3A inducer, rifampin (300 or 600 mg daily for 10 days), decreased the AUC and Cmax of ritonavir (500 mg every 12 hours for 20 days) by 35% and 25%, respectively.
    Dasatinib: (Major) Avoid coadministration of dasatinib and mitotane due to the potential for decreased dasatinib exposure and reduced efficacy. Consider an alternative to mitotane with less potential for enzyme induction. If coadministration cannot be avoided, consider an increased dose of dasatinib and monitor for toxicity. Dasatinib is a CYP3A4 substrate; mitotane is a strong CYP3A4 inducer. Concurrent use of another strong CYP3A4 inducer decreased the mean Cmax and AUC of dasatinib by 81% and 82%, respectively.
    Deflazacort: (Major) Avoid concomitant use of deflazacort and mitotane. Concurrent use may significantly decrease concentrations of 21-desDFZ, the active metabolite of deflazacort, resulting in loss of efficacy. Deflazacort is a CYP3A4 substrate; mitotane is a strong inducer of CYP3A4. Administration of deflazacort with multiple doses of rifampin (a strong CYP3A4 inducer) resulted in geometric mean exposures that were approximately 95% lower compared to administration alone.
    Delavirdine: (Major) Concomitant use of mitotane with delavirdine should be undertaken with caution due to potential decreased delavirdine concentrations, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Mitotane is a strong CYP3A4 inducer and delavirdine is a CYP3A4 substrate. When coadministered with another strong CYP3A4 inducer (rifampin 600 mg daily; n = 16), the delavirdine Cmax decreased by 90% (90% CI, 83% to 94%), the AUC by 97% (90% CI, 95% to 98%), and the Cmin by 100%.
    Desogestrel; Ethinyl Estradiol: (Major) Desogestrel is not recommended for women who require chronic use of drugs that are potent inducers of hepatic enzymes, including mitotane, because contraception efficacy is likely to be reduced. Consider additional or alternative forms of contraception. Mitotane is a strong CYP3A4 inducer and progestins like desogestrel are CYP3A4 substrates. Coadministration may result in decreased plasma concentrations of oral and other hormonal combination contraceptives.
    Dexamethasone: (Major) Use caution if mitotane and dexamethasone are used concomitantly, and monitor for decreased efficacy of dexamethasone and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and dexamethasone is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of dexamethasone.
    Dexbrompheniramine: (Moderate) Mitotane can cause sedation, lethargy, vertigo, and other CNS side effects. Concomitant administration of mitotane and CNS depressants, including sedating h1-blockers, may cause additive CNS effects.
    Dexbrompheniramine; Pseudoephedrine: (Moderate) Mitotane can cause sedation, lethargy, vertigo, and other CNS side effects. Concomitant administration of mitotane and CNS depressants, including sedating h1-blockers, may cause additive CNS effects.
    Dexchlorpheniramine: (Moderate) Mitotane can cause sedation, lethargy, vertigo, and other CNS side effects. Concomitant administration of mitotane and CNS depressants, including sedating h1-blockers, may cause additive CNS effects.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Mitotane can cause sedation, lethargy, vertigo, and other CNS side effects. Concomitant administration of mitotane and CNS depressants, including sedating h1-blockers, may cause additive CNS effects.
    Dexlansoprazole: (Moderate) Use caution if mitotane and dexlansoprazole are used concomitantly, and monitor for decreased efficacy of dexlansoprazole and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and dexlansoprazole is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of dexlansoprazole.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Mitotane can cause sedation, lethargy, vertigo, and other CNS side effects. Concomitant administration of mitotane and CNS depressants, including sedating h1-blockers, may cause additive CNS effects.
    Dextromethorphan; Quinidine: (Major) Use caution if mitotane and quinidine are used concomitantly, and monitor for decreased efficacy of quinidine and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and quinidine is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of quinidine. Quinidine concentrations should be monitored closely after mitotane is added to the treatment regimen.
    Diazepam: (Major) Use caution if mitotane and diazepam are used concomitantly, and monitor for decreased efficacy of diazepam and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer; diazepam is predominantly metabolized by CYP2C19, but at high concentrations, CYP3A4 is also involved. Coadministration may result in decreased plasma concentrations of diazepam. Additionally, mitotane can cause sedation, lethargy, vertigo, and other CNS adverse reactions; additive CNS effects may occur initially when mitotane is given concurrently with diazepam.
    Diclofenac: (Major) Use caution if mitotane and diclofenac are used concomitantly, and monitor for decreased efficacy of diclofenac and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and diclofenac is a CYP3A4 substrate in vitro; coadministration may result in decreased plasma concentrations of diclofenac.
    Diclofenac; Misoprostol: (Major) Use caution if mitotane and diclofenac are used concomitantly, and monitor for decreased efficacy of diclofenac and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and diclofenac is a CYP3A4 substrate in vitro; coadministration may result in decreased plasma concentrations of diclofenac.
    Dienogest; Estradiol valerate: (Major) Dienogest is not recommended for women who require chronic use of drugs that are potent inducers of hepatic enzymes, including mitotane, because contraception efficacy is likely to be reduced. Consider additional or alternative forms of contraception. Mitotane is a strong CYP3A4 inducer and progestins like dienogest are CYP3A4 substrates. Coadministration may result in decreased plasma concentrations of oral and other hormonal combination contraceptives.
    Diltiazem: (Major) Avoid coadministration of diltiazem and mitotane due to decreased plasma concentrations of diltiazem. Diltiazem is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer lowered diltiazem plasma concentrations to undetectable.
    Dimenhydrinate: (Moderate) Mitotane can cause sedation, lethargy, vertigo, and other CNS side effects. Concomitant administration of mitotane and CNS depressants, including sedating h1-blockers, may cause additive CNS effects.
    Diphenhydramine: (Moderate) Mitotane can cause sedation, lethargy, vertigo, and other CNS side effects. Concomitant administration of mitotane and CNS depressants, including sedating h1-blockers, may cause additive CNS effects.
    Diphenhydramine; Ibuprofen: (Moderate) Mitotane can cause sedation, lethargy, vertigo, and other CNS side effects. Concomitant administration of mitotane and CNS depressants, including sedating h1-blockers, may cause additive CNS effects.
    Diphenhydramine; Naproxen: (Moderate) Mitotane can cause sedation, lethargy, vertigo, and other CNS side effects. Concomitant administration of mitotane and CNS depressants, including sedating h1-blockers, may cause additive CNS effects.
    Diphenhydramine; Phenylephrine: (Moderate) Mitotane can cause sedation, lethargy, vertigo, and other CNS side effects. Concomitant administration of mitotane and CNS depressants, including sedating h1-blockers, may cause additive CNS effects.
    Diphenoxylate; Atropine: (Moderate) Concurrent administration of diphenoxylate/difenoxin with mitotane can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration.
    Disopyramide: (Major) Use caution if mitotane and disopyramide are used concomitantly, and monitor serum disopyramide concentrations and adjust the dose of disopyramide if necessary. In addition, disopyramide doses may need to be reduced if mitotane is stopped and disopyramide therapy is continued. Mitotane is a strong CYP3A4 inducer and disopyramide is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of disopyramide.
    Disulfiram: (Moderate) Use caution if mitotane and disulfiram are used concomitantly, and monitor for decreased efficacy of disulfiram and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and disulfiram is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of disulfiram.
    Docetaxel: (Major) Avoid coadministration of docetaxel with mitotane due to decreased plasma concentrations of docetaxel. Docetaxel is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Concomitant use with other strong CYP3A4 inducers increased docetaxel metabolism by 2.6-fold to 32-fold.
    Dolasetron: (Moderate) Use caution if mitotane and dolasetron are used concomitantly, and monitor for decreased efficacy of dolasetron and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and dolasetron is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of dolasetron. When oral dolasetron was administered with rifampin, another strong CYP3A inducer, for 7 days, the AUC and Cmax of hydrodolasetron decreased by 28% and 17%, respectively.
    Dolutegravir: (Moderate) Dolutegravir plasma concentrations may be reduced when administered concurrently with mitotane; thereby increasing the risk for HIV treatment failures or the development of viral-resistance. Data are insufficient to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Mitotane is a strong CYP3A inducer and dolutegravir is partially metabolized by this isoenzyme.
    Dolutegravir; Lamivudine: (Moderate) Dolutegravir plasma concentrations may be reduced when administered concurrently with mitotane; thereby increasing the risk for HIV treatment failures or the development of viral-resistance. Data are insufficient to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Mitotane is a strong CYP3A inducer and dolutegravir is partially metabolized by this isoenzyme.
    Dolutegravir; Rilpivirine: (Major) Concomitant use of mitotane with rilpivirine should be undertaken with caution due to potential decreased rilpivirine concentrations, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. The use of rilpivirine is contraindicated with other specific strong CYP3A inducers, including carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifampin, rifapentine, and St John's wort. Mitotane is a strong CYP3A4 inducer and rilpivirine is a CYP3A4 substrate. Coadministration may result in decreased rilpivirine serum concentrations, which could cause impaired virologic response to rilpivirine. (Moderate) Dolutegravir plasma concentrations may be reduced when administered concurrently with mitotane; thereby increasing the risk for HIV treatment failures or the development of viral-resistance. Data are insufficient to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Mitotane is a strong CYP3A inducer and dolutegravir is partially metabolized by this isoenzyme.
    Donepezil: (Moderate) Use caution if mitotane and donepezil are used concomitantly, and monitor for decreased efficacy of donepezil and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and donepezil is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of donepezil.
    Donepezil; Memantine: (Moderate) Use caution if mitotane and donepezil are used concomitantly, and monitor for decreased efficacy of donepezil and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and donepezil is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of donepezil.
    Doravirine: (Contraindicated) Concurrent administration of doravirine and mitotane is contraindicated due to decreased doravirine exposure, resulting in potential loss of virologic control. At least a 4-week cessation period is recommended before initiating treatment with doravirine. Doravirine is a CYP3A4 substrate; mitotane is a strong CYP3A4 inducer.
    Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Contraindicated) Concurrent administration of doravirine and mitotane is contraindicated due to decreased doravirine exposure, resulting in potential loss of virologic control. At least a 4-week cessation period is recommended before initiating treatment with doravirine. Doravirine is a CYP3A4 substrate; mitotane is a strong CYP3A4 inducer.
    Doxorubicin Liposomal: (Major) Concomitant use of mitotane with doxorubicin should be undertaken with caution as it could result in decreased plasma concentrations of doxorubicin, leading to reduced efficacy. Mitotane is a strong CYP3A4 inducer and doxorubicin is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of doxorubicin.
    Doxorubicin: (Major) Concomitant use of mitotane with doxorubicin should be undertaken with caution as it could result in decreased plasma concentrations of doxorubicin, leading to reduced efficacy. Mitotane is a strong CYP3A4 inducer and doxorubicin is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of doxorubicin.
    Doxylamine: (Moderate) Mitotane can cause sedation, lethargy, vertigo, and other CNS side effects. Concomitant administration of mitotane and CNS depressants, including sedating h1-blockers, may cause additive CNS effects.
    Doxylamine; Pyridoxine: (Moderate) Mitotane can cause sedation, lethargy, vertigo, and other CNS side effects. Concomitant administration of mitotane and CNS depressants, including sedating h1-blockers, may cause additive CNS effects.
    Dronabinol: (Moderate) Use caution if coadministration of dronabinol with mitotane is necessary, and monitor for a decrease in the efficacy of dronabinol. Dronabinol is a CYP2C9 and 3A4 substrate; mitotane is a strong inducer of CYP3A4. Concomitant use may result in decreased plasma concentrations of dronabinol.
    Dronedarone: (Major) Avoid the concomitant use of mitotane with dronedarone; if coadministration cannot be avoided, monitor for decreased efficacy of dronedarone. Mitotane is a strong CYP3A4 inducer and dronedarone is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of dronedarone. The AUC and Cmax of dronedarone were significantly reduced when given with rifampin, another strong CYP3A4 inducer.
    Drospirenone: (Major) Use caution if mitotane and drospirenone are used concomitantly, including combination products such as drospirenone; estradiol, drospirenone; ethinyl estradiol, and drospirenone; ethinyl estradiol; levomefolate. If coadministration is necessary, monitor for decreased efficacy of products containing drospirenone and consider an alternate or additional form of contraception. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of mitotane. Mitotane is a strong CYP3A4 inducer. Although CYP3A4 is a minor elimination pathway for drospirenone, drospirenone is only available in combination with ethinyl estradiol, which is primarily metabolized by CYP3A4. Coadministration may result in decreased plasma concentrations of oral contraceptives.
    Drospirenone; Estetrol: (Major) Use caution if mitotane and drospirenone are used concomitantly, including combination products such as drospirenone; estradiol, drospirenone; ethinyl estradiol, and drospirenone; ethinyl estradiol; levomefolate. If coadministration is necessary, monitor for decreased efficacy of products containing drospirenone and consider an alternate or additional form of contraception. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of mitotane. Mitotane is a strong CYP3A4 inducer. Although CYP3A4 is a minor elimination pathway for drospirenone, drospirenone is only available in combination with ethinyl estradiol, which is primarily metabolized by CYP3A4. Coadministration may result in decreased plasma concentrations of oral contraceptives.
    Drospirenone; Estradiol: (Major) Use caution if mitotane and drospirenone are used concomitantly, including combination products such as drospirenone; estradiol, drospirenone; ethinyl estradiol, and drospirenone; ethinyl estradiol; levomefolate. If coadministration is necessary, monitor for decreased efficacy of products containing drospirenone and consider an alternate or additional form of contraception. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of mitotane. Mitotane is a strong CYP3A4 inducer. Although CYP3A4 is a minor elimination pathway for drospirenone, drospirenone is only available in combination with ethinyl estradiol, which is primarily metabolized by CYP3A4. Coadministration may result in decreased plasma concentrations of oral contraceptives.
    Drospirenone; Ethinyl Estradiol: (Major) Use caution if mitotane and drospirenone are used concomitantly, including combination products such as drospirenone; estradiol, drospirenone; ethinyl estradiol, and drospirenone; ethinyl estradiol; levomefolate. If coadministration is necessary, monitor for decreased efficacy of products containing drospirenone and consider an alternate or additional form of contraception. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of mitotane. Mitotane is a strong CYP3A4 inducer. Although CYP3A4 is a minor elimination pathway for drospirenone, drospirenone is only available in combination with ethinyl estradiol, which is primarily metabolized by CYP3A4. Coadministration may result in decreased plasma concentrations of oral contraceptives.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Major) Use caution if mitotane and drospirenone are used concomitantly, including combination products such as drospirenone; estradiol, drospirenone; ethinyl estradiol, and drospirenone; ethinyl estradiol; levomefolate. If coadministration is necessary, monitor for decreased efficacy of products containing drospirenone and consider an alternate or additional form of contraception. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of mitotane. Mitotane is a strong CYP3A4 inducer. Although CYP3A4 is a minor elimination pathway for drospirenone, drospirenone is only available in combination with ethinyl estradiol, which is primarily metabolized by CYP3A4. Coadministration may result in decreased plasma concentrations of oral contraceptives.
    Dutasteride; Tamsulosin: (Moderate) Use caution if mitotane and tamsulosin are used concomitantly, and monitor for decreased efficacy of tamsulosin and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and tamsulosin is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of tamsulosin.
    Duvelisib: (Major) Avoid coadministration of duvelisib with mitotane. Coadministration may decrease the exposure of duvelisib, which may reduce the efficacy of duvelisib. Duvelisib is a CYP3A substrate; mitotane is a strong CYP3A inducer. In drug interaction studies, coadministration of duvelisib with another strong CYP3A inducer for 7 days decreased duvelisib Cmax and AUC by 66% and 82%, respectively.
    Efavirenz: (Major) Use caution if mitotane and efavirenz are used concomitantly, as coadministration may significantly reduce plasma concentrations of efavirenz, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. When efavirenz is coadministered with rifampin, another strong CYP3A4 inducer, it is recommended to increase efavirenz from 600 mg/day to 800 mg/day (patients >= 50 kg). Mitotane is a strong CYP3A4 inducer and efavirenz is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of efavirenz.
    Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Use caution if mitotane and efavirenz are used concomitantly, as coadministration may significantly reduce plasma concentrations of efavirenz, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. When efavirenz is coadministered with rifampin, another strong CYP3A4 inducer, it is recommended to increase efavirenz from 600 mg/day to 800 mg/day (patients >= 50 kg). Mitotane is a strong CYP3A4 inducer and efavirenz is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of efavirenz.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Use caution if mitotane and efavirenz are used concomitantly, as coadministration may significantly reduce plasma concentrations of efavirenz, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. When efavirenz is coadministered with rifampin, another strong CYP3A4 inducer, it is recommended to increase efavirenz from 600 mg/day to 800 mg/day (patients >= 50 kg). Mitotane is a strong CYP3A4 inducer and efavirenz is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of efavirenz.
    Elacestrant: (Major) Avoid concurrent use of elacestrant and mitotane due to the risk of decreased elacestrant exposure which may reduce its efficacy. Elacestrant is a CYP3A substrate and mitotane is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced elacestrant overall exposure by 86%.
    Elagolix: (Moderate) Concomitant use of elagolix and mitotane may result in decreased concentrations of elagolix; monitor for decreased efficacy with coadministration. Elagolix is a CYP3A substrate; mitotane is a strong inducer of CYP3A.
    Elagolix; Estradiol; Norethindrone acetate: (Major) Avoid coadministration of mitotane with norethindrone if used for contraception; consider an alternate or additional form of contraception. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of mitotane. Patients taking hormonal replacement therapy may need to be monitored for reduced clinical effect while on mitotane, with dose adjustments made based on clinical efficacy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. Women taking hormonal replacement and mitotane should report breakthrough bleeding, hot flashes, or other symptoms to their prescribers. Norethindrone is a substrate of CYP3A4 and mitotane is a strong CYP3A4 inducer. Concurrent administration of mitotane with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin). (Moderate) Concomitant use of elagolix and mitotane may result in decreased concentrations of elagolix; monitor for decreased efficacy with coadministration. Elagolix is a CYP3A substrate; mitotane is a strong inducer of CYP3A.
    Elbasvir; Grazoprevir: (Contraindicated) Concurrent administration of elbasvir; grazoprevir with mitotane is contraindicated due to potential decreased concentrations of both elbasvir and grazoprevir, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Mitotane is a strong CYP3A4 inducer, while both elbasvir and grazoprevir are substrates of CYP3A.
    Eletriptan: (Major) Use caution if mitotane and eletriptan are used concomitantly, and monitor for decreased efficacy of eletriptan and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and eletriptan is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of eletriptan.
    Elexacaftor; tezacaftor; ivacaftor: (Major) Coadministration of elexacaftor; tezacaftor; ivacaftor with mitotane is not recommended as concurrent use may decrease exposure of elexacaftor; tezacaftor; ivacaftor. Elexacaftor, tezacaftor, and ivacaftor are CYP3A4 substrates (ivacaftor is a sensitive CYP3A4 substrate). Mitotane is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer significantly decreased ivacaftor exposure by 89%; elexacaftor and tezacaftor exposures are expected to also decrease during coadministration of strong CYP3A4 inducers. (Major) Coadministration of ivacaftor with mitotane is not recommended due to decreased plasma concentrations of ivacaftor. Ivacaftor is a sensitive CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer significantly decreased ivacaftor exposure by approximately 9-fold. (Major) Do not administer tezacaftor; ivacaftor and mitotane together; coadministration may reduce the efficacy of tezacaftor; ivacaftor. Exposure to ivacaftor is significantly decreased and exposure to tezacaftor may be reduced by the concomitant use of mitotane, a strong CYP3A inducer; both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate). Coadministration of ivacaftor with a strong CYP3A inducer decreased ivacaftor exposure 89%.
    Eliglustat: (Major) The concomitant use of mitotane with eliglustat is not recommended in extensive, intermediate, or poor metabolizers of CYP2D6 (EMs, IMs, PMs). Mitotane is a strong CYP3A4 inducer, and eliglustat is a CYP3A substrate. During clinical trials, systemic exposures (Cmax and AUC) of eliglustat decreased by approximately 90% in EMs and IMs after coadministration of eliglustat 127 mg PO twice daily with another strong CYP3A inducer, rifampin (600 mg PO daily). Of note, the only FDA-approved dose of eliglustat is 84 mg. Additionally, systemic exposures decreased by approximately 95% after coadministration of eliglustat 84 mg PO twice daily with rifampin 600 mg PO once daily in PMs.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Contraindicated) Coadministration of mitotane with cobicistat is contraindicated. Mitotane is a strong inducer of CYP3A4; cobicistat is a substrate of this enzyme. Concurrent use may result in significant decreases in the plasma concentrations of cobicistat, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. (Major) Use caution if mitotane and elvitegravir are used concomitantly, due to potential decreased concentrations of elvitegravir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Mitotane is a strong CYP3A4 inducer and elvitegravir is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of elvitegravir.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Contraindicated) Coadministration of mitotane with cobicistat is contraindicated. Mitotane is a strong inducer of CYP3A4; cobicistat is a substrate of this enzyme. Concurrent use may result in significant decreases in the plasma concentrations of cobicistat, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. (Major) Use caution if mitotane and elvitegravir are used concomitantly, due to potential decreased concentrations of elvitegravir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Mitotane is a strong CYP3A4 inducer and elvitegravir is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of elvitegravir.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) Concomitant use of mitotane with rilpivirine should be undertaken with caution due to potential decreased rilpivirine concentrations, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. The use of rilpivirine is contraindicated with other specific strong CYP3A inducers, including carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifampin, rifapentine, and St John's wort. Mitotane is a strong CYP3A4 inducer and rilpivirine is a CYP3A4 substrate. Coadministration may result in decreased rilpivirine serum concentrations, which could cause impaired virologic response to rilpivirine.
    Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Major) Concomitant use of mitotane with rilpivirine should be undertaken with caution due to potential decreased rilpivirine concentrations, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. The use of rilpivirine is contraindicated with other specific strong CYP3A inducers, including carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifampin, rifapentine, and St John's wort. Mitotane is a strong CYP3A4 inducer and rilpivirine is a CYP3A4 substrate. Coadministration may result in decreased rilpivirine serum concentrations, which could cause impaired virologic response to rilpivirine.
    Encorafenib: (Major) Avoid coadministration of encorafenib and mitotane due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; mitotane is a strong CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
    Entrectinib: (Major) Avoid coadministration of entrectinib with mitotane due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; mitotane is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the entrectinib AUC by 77% in a drug interaction study.
    Enzalutamide: (Major) Avoid coadministration of mitotane with enzalutamide if possible due to decreased enzalutamide exposure which may compromise efficacy. If concomitant use is unavoidable, increase the dose of enzalutamide from 160 mg to 240 mg once daily; the original dose of enzalutamide may be resumed when mitotane is discontinued. Enzalutamide is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 37%.
    Eplerenone: (Moderate) Use caution if mitotane and eplerenone are used concomitantly, and monitor for decreased efficacy of eplerenone and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and eplerenone is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of eplerenone. Coadministration with another strong CYP3A inducer, St. John's Wort, resulted in a small (30%) decrease in the AUC of eplerenone.
    Eravacycline: (Major) Increase the dose of eravacycline to 1.5 mg/kg IV every 12 hours when coadministered with a strong CYP3A4 inducer, such as mitotane. Concomitant use of strong CYP3A4 inducers decreases the exposure of eravacycline, which may reduce its efficacy. When eravacycline was administered with a strong CYP3A4/3A5 inducer, the eravacycline AUC was decreased by 35% and its clearance was increased by 54%.
    Erdafitinib: (Major) Avoid coadministration of erdafitinib and mitotane due to the risk of decreased plasma concentrations of erdafitinib resulting in decreased efficacy. Erdafitinib is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer.
    Erlotinib: (Major) Avoid coadministration of erlotinib with mitotane if possible due to the risk of decreased erlotinib efficacy. If concomitant use is unavoidable, increase the dose of erlotinib in 50 mg increments at 2-week intervals as tolerated (maximum dose, 450 mg). Erlotinib is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased erlotinib exposure by 58% to 80%.
    Escitalopram: (Moderate) Use caution if mitotane and escitalopram are used concomitantly, and monitor for decreased efficacy of escitalopram and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and escitalopram is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of escitalopram.
    Esomeprazole: (Moderate) Use caution if mitotane and esomeprazole are used concomitantly, and monitor for decreased efficacy of esomeprazole and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and esomeprazole is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of esomeprazole.
    Estazolam: (Moderate) Use caution if mitotane and estazolam are used concomitantly, and monitor for decreased efficacy of estazolam and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and estazolam is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of estazolam. Additionally, mitotane can cause sedation, lethargy, vertigo, and other CNS adverse reactions; additive CNS effects may occur initially when mitotane is given concurrently with estazolam.
    Estradiol Cypionate; Medroxyprogesterone: (Major) Use caution if mitotane and medroxyprogesterone are used concomitantly, and monitor for decreased medroxyprogesterone efficacy. Since the dosage of medroxyprogesterone injections for contraception cannot be modified, an alternate or additional form of contraception should be considered in patients requiring therapy with mitotane. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of mitotane. Mitotane is a strong CYP3A4 inducer and medroxyprogesterone is a CYP3A4 substrate in vitro; coadministration may result in decreased plasma concentrations of medroxyprogesterone. Pregnancies have been reported during therapy with progestin contraceptives in patients receiving other strong CYP3A inducers.
    Estradiol; Levonorgestrel: (Major) Levonorgestrel is not recommended for women who require chronic use of drugs that are potent inducers of hepatic enzymes, including mitotane, because contraception efficacy is likely to be reduced. Consider additional or alternative forms of contraception. Mitotane is a strong CYP3A4 inducer and progestins like levonorgestrel are CYP3A4 substrates. Coadministration may result in decreased plasma concentrations of oral and other hormonal combination contraceptives.
    Estradiol; Norethindrone: (Major) Avoid coadministration of mitotane with norethindrone if used for contraception; consider an alternate or additional form of contraception. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of mitotane. Patients taking hormonal replacement therapy may need to be monitored for reduced clinical effect while on mitotane, with dose adjustments made based on clinical efficacy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. Women taking hormonal replacement and mitotane should report breakthrough bleeding, hot flashes, or other symptoms to their prescribers. Norethindrone is a substrate of CYP3A4 and mitotane is a strong CYP3A4 inducer. Concurrent administration of mitotane with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
    Estradiol; Norgestimate: (Major) Norgestimate is not recommended for women who require chronic use of drugs that are potent inducers of hepatic enzymes, including mitotane, because contraception efficacy is likely to be reduced. Consider additional or alternative forms of contraception. Mitotane is a strong CYP3A4 inducer and progestins like norgestimate are CYP3A4 substrates. Coadministration may result in decreased plasma concentrations of oral and other hormonal combination contraceptives.
    Estradiol; Progesterone: (Moderate) Use caution if coadministration of mitotane with progesterone is necessary, as the systemic exposure of progesterone may be decreased resulting in reduced efficacy. Mitotane is a strong CYP3A4 inducer. Progesterone is metabolized primarily by hydroxylation via a CYP3A4. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
    Estrogens affected by CYP3A inducers: (Major) Women taking both estrogens and mitotane should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed mitotane. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of mitotane. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on mitotane, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and mitotane is a strong CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
    Eszopiclone: (Major) Use caution if mitotane and eszopiclone are used concomitantly, and monitor for decreased efficacy of eszopiclone and a possible change in dosage requirements.Mitotane is a strong CYP3A4 inducer and eszopiclone is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of eszopiclone. In a study of healthy subjects, racemic zopiclone coadministered with rifampin produced an 80% reduction in plasma concentrations of zopiclone. This effect would also be expected with eszopiclone.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Major) Levonorgestrel is not recommended for women who require chronic use of drugs that are potent inducers of hepatic enzymes, including mitotane, because contraception efficacy is likely to be reduced. Consider additional or alternative forms of contraception. Mitotane is a strong CYP3A4 inducer and progestins like levonorgestrel are CYP3A4 substrates. Coadministration may result in decreased plasma concentrations of oral and other hormonal combination contraceptives.
    Ethinyl Estradiol; Norelgestromin: (Major) Norelgestromin is not recommended for women who require chronic use of drugs that are potent inducers of hepatic enzymes, including mitotane, because contraception efficacy is likely to be reduced. Consider additional or alternative forms of contraception. Mitotane is a strong CYP3A4 inducer and progestins like norelgestromin are CYP3A4 substrates. Coadministration may result in decreased plasma concentrations of oral and other hormonal combination contraceptives.
    Ethinyl Estradiol; Norethindrone Acetate: (Major) Avoid coadministration of mitotane with norethindrone if used for contraception; consider an alternate or additional form of contraception. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of mitotane. Patients taking hormonal replacement therapy may need to be monitored for reduced clinical effect while on mitotane, with dose adjustments made based on clinical efficacy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. Women taking hormonal replacement and mitotane should report breakthrough bleeding, hot flashes, or other symptoms to their prescribers. Norethindrone is a substrate of CYP3A4 and mitotane is a strong CYP3A4 inducer. Concurrent administration of mitotane with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
    Ethinyl Estradiol; Norgestrel: (Major) Norgestrel is not recommended for women who require chronic use of drugs that are potent inducers of hepatic enzymes, including mitotane, because contraception efficacy is likely to be reduced. Consider additional or alternative forms of contraception. Mitotane is a strong CYP3A4 inducer and progestins like norgestrel are CYP3A4 substrates. Coadministration may result in decreased plasma concentrations of oral and other hormonal combination contraceptives.
    Ethosuximide: (Major) Use caution if mitotane and ethosuximide are used concomitantly, and monitor for decreased efficacy of ethosuximide and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and ethosuximide is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of ethosuximide.
    Etravirine: (Major) The concomitant use of mitotane with etravirine is not recommended due to significant decreases in etravirine plasma concentrations and, thus, possible loss of therapeutic effect. Mitotane is a strong CYP3A4 inducer and etravirine is a CYP3A4 substrate.
    Everolimus: (Major) Avoid coadministration of everolimus with mitotane due to the risk of decreased efficacy of everolimus. If concomitant use is unavoidable, coadministration requires a dose increase for some indications and close monitoring for others. For oncology indications and tuberous sclerosis complex (TSC)-associated renal angiomyolipoma, double the daily dose using increments of 5 mg or less; multiple increments may be required. For patients with TSC-associated subependymal giant cell astrocytoma (SEGA) and TSC-associated partial-onset seizures, assess the everolimus whole blood trough concentration 2 weeks after initiation of mitotane and adjust the dose as necessary to remain in the recommended therapeutic range. Also closely monitor everolimus whole blood trough concentrations in patients receiving everolimus for either kidney or liver transplant and adjust the dose as necessary to remain in the recommended therapeutic range. Everolimus is a sensitive CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC of everolimus by 63%. For indications where everolimus trough concentrations are monitored, the addition of a second strong CYP3A4 inducer in a patient already receiving treatment with a strong CYP3A4 inducer may not require additional dose modification.
    Exemestane: (Major) If coadministration of exemestane with mitotane is necessary, increase the dose of exemestane to 50 mg once daily after a meal. Exemestane is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased exemestane exposure by 54%.
    Ezetimibe; Simvastatin: (Moderate) Use caution if mitotane and simvastatin are used concomitantly, and monitor for decreased efficacy of simvastatin and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and simvastatin is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of simvastatin.
    Fedratinib: (Major) Avoid coadministration of fedratinib with mitotane as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; mitotane is a strong CYP3A4 inducer. Coadministration of fedratinib with another strong CYP3A4 inducer decreased the overall exposure of fedratinib by 81%.
    Felodipine: (Moderate) Use caution if mitotane and felodipine are used concomitantly, and monitor for decreased efficacy of felodipine and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and felodipine is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of felodipine.
    Fenfluramine: (Major) Avoid concurrent use of fenfluramine and mitotane due to the risk of decreased fenfluramine plasma concentrations, which may reduce its efficacy. If concomitant use is necessary, monitor for decreased efficacy and consider increasing fenfluramine dose as needed. If mitotane is discontinued during fenfluramine maintenance treatment, consider gradual reduction in the fenfluramine dosage to the dose administered prior to mitotane initiation. Fenfluramine is a CYP3A substrate and mitotane is a strong CYP3A inducer.
    Fentanyl: (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if concurrent use of mitotane is necessary. If mitotane is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a CYP3A4 inducer like mitotane with fentanyl, a CYP3A4 substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
    Finasteride; Tadalafil: (Major) Avoid coadministration of tadalafil with mitotane in patients with pulmonary hypertension due to decreased plasma concentrations of tadalafil. In patients with erectile dysfunction and/or benign prostatic hyperplasia, consider the potential for loss of efficacy of tadalafil during concurrent administration of mitotane due to reduced tadalafil exposure. Tadalafil is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased tadalafil exposure by 88%.
    Finerenone: (Major) Avoid concurrent use of finerenone and mitotane due to the risk for decreased finerenone exposure which may reduce its efficacy. Finerenone is a CYP3A substrate and mitotane is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased overall exposure to finerenone by 90%.
    Flibanserin: (Major) The concomitant use of mitotane with flibanserin is not recommended due to the potential for decreased efficacy of flibanserin. Mitotane is a strong CYP3A4 inducer and flibanserin is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of flibanserin. In a study of 24 healthy female subjects, another strong CYP3A inducer, rifampin (600 mg daily for 7 days), given prior to flibanserin significantly decreased flibanserin exposure by 95%.
    Flurazepam: (Moderate) Use caution if mitotane and flurazepam are used concomitantly, and monitor for decreased efficacy of flurazepam and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and flurazepam is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of flurazepam. Additionally, mitotane can cause sedation, lethargy, vertigo, and other CNS adverse reactions; additive CNS effects may occur initially when mitotane is given concurrently with flurazepam.
    Flutamide: (Major) Use caution if mitotane and flutamide are used concomitantly, and monitor for decreased efficacy of flutamide and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and flutamide is a CYP3A4 substrate in vitro; coadministration may result in decreased plasma concentrations of flutamide.
    Fluticasone: (Moderate) Use caution if mitotane and fluticasone are used concomitantly, and monitor for decreased efficacy of fluticasone and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and fluticasone is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of fluticasone.
    Fluticasone; Salmeterol: (Moderate) Use caution if mitotane and fluticasone are used concomitantly, and monitor for decreased efficacy of fluticasone and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and fluticasone is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of fluticasone.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) Use caution if mitotane and fluticasone are used concomitantly, and monitor for decreased efficacy of fluticasone and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and fluticasone is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of fluticasone. (Moderate) Use caution if mitotane and vilanterol are used concomitantly (including combination products fluticasone; vilanterol and umeclidinium; vilanterol), and monitor for decreased efficacy of vilanterol and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and vilanterol is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of vilanterol.
    Fluticasone; Vilanterol: (Moderate) Use caution if mitotane and fluticasone are used concomitantly, and monitor for decreased efficacy of fluticasone and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and fluticasone is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of fluticasone. (Moderate) Use caution if mitotane and vilanterol are used concomitantly (including combination products fluticasone; vilanterol and umeclidinium; vilanterol), and monitor for decreased efficacy of vilanterol and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and vilanterol is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of vilanterol.
    Food: (Major) Advise patients to avoid cannabis use during mitotane treatment. Concomitant use may decrease the concentration of some cannabinoids and alter their effects. The cannabinoids delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are CYP3A substrates and mitotane is a strong CYP3A inducer. Concomitant use of a cannabinoid product containing THC and CBD at an approximate 1:1 ratio with another strong CYP3A inducer decreased THC, 11-OH-THC, and CBD peak exposures by 36%, 87%, and 52% respectively.
    Fosamprenavir: (Moderate) Monitor for decreased fosamprenavir efficacy if coadministered with mitotane. Concurrent use may decrease the plasma concentrations of fosamprenavir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Fosamprenavir is a CYP3A substrate and mitotane is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased the fosamprenavir overall exposure by 82%.
    Fostamatinib: (Major) Avoid the concomitant use of fostamatinib with mitotane. Concomitant use of fostamatinib with a strong CYP3A4 inducer decreases exposure to the major active metabolite, R406. R406 is extensively metabolized by CYP3A4; mitotane is a strong CYP3A4 inducer. Concomitant use of fostamatinib with another strong CYP3A4 inducer decreased R406 AUC by 75% and Cmax by 59%.
    Fostemsavir: (Contraindicated) Concomitant use of fostemsavir and mitotane is contraindicated. Use of these drugs together may significantly decrease the plasma concentrations of temsavir, the active moiety of fostemsavir, thereby increasing the risk for HIV treatment failure or development of viral resistance. Temsavir is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer.
    Ganaxolone: (Major) Avoid concurrent use of ganaxolone and mitotane due to the risk of decreased ganaxolone efficacy. If concomitant use is unavoidable, consider increasing ganaxolone dose without exceeding the maximum daily dose. Ganaxolone is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ganaxolone overall exposure by 68%.
    Gefitinib: (Major) Increase the dose of gefitinib to 500 mg PO once daily if coadministration with mitotane is necessary. If mitotane is discontinued, gefitinib at a dose of 250 mg once daily may be resumed 7 days later. Gefitinib is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer reduced gefitinib exposure by 83%.
    Glasdegib: (Major) Avoid coadministration of glasdegib and mitotane due to the potential for decreased glasdegib exposure and risk of decreased efficacy. Glasdegib is a CYP3A4 substrate; mitotane is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the glasdegib AUC by 70% in a drug interaction study.
    Glecaprevir; Pibrentasvir: (Major) Coadministration of glecaprevir with mitotane is not recommended as mitotane may significantly decrease plasma concentrations of glecaprevir resulting in loss of efficacy. Glecaprevir is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer.
    Granisetron: (Major) Use caution if mitotane and granisetron are used concomitantly, and monitor for decreased efficacy of granisetron and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and granisetron is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of granisetron. In a human pharmacokinetic study, hepatic enzyme induction with phenobarbital resulted in a 25% increase in total plasma clearance of IV granisetron; the clinical significance of this change is not known.
    Guaifenesin; Hydrocodone: (Major) Concomitant use of hydrocodone with mitotane can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Additionally, mitotane can cause sedation, lethargy, vertigo, and other CNS adverse reactions; additive CNS effects may occur initially when mitotane is given concurrently with hydrocodone. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal and/or additive CNS depression; consider adjusting the dose of hydrocodone as needed. If mitotane is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of hydrocodone with mitotane can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Additionally, mitotane can cause sedation, lethargy, vertigo, and other CNS adverse reactions; additive CNS effects may occur initially when mitotane is given concurrently with hydrocodone. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal and/or additive CNS depression; consider adjusting the dose of hydrocodone as needed. If mitotane is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer.
    Guanfacine: (Major) Mitotane may significantly decrease guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, doubling the recommended dose of guanfacine should be considered; if mitotane is added in a patient already receiving guanfacine, this escalation should occur over 1 to 2 weeks. If mitotane is discontinued, decrease the guanfacine ER dosage back to the recommended dose over 1 to 2 weeks. Specific recommendations for immediate-release (IR) guanfacine are not available. Guanfacine is primarily metabolized by CYP3A4, and mitotane is a strong CYP3A4 inducer.
    Haloperidol: (Major) Use caution if mitotane and haloperidol are used concomitantly, and monitor for decreased efficacy of haloperidol and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and haloperidol is a CYP3A4 substrate in vitro; coadministration may result in decreased plasma concentrations of haloperidol. Limited data suggest that rifampin, another potent CYP inducer, can increase the metabolism and/or reduce the bioavailability of haloperidol. In one small study (n=12), plasma levels of haloperidol were decreased by a mean of 70% and mean scores on the Brief Psychiatric Rating Scale (BPRS) were increased from baseline during concurrent use of rifampin; discontinuation of rifampin resulted in a mean 3.3-fold increase in haloperidol concentrations in some instances. In another study (n = 11), patients who received increasing doses of carbamazepine had decreasing haloperidol plasma concentrations in linear proportion to the increasing carbamazepine concentrations. Careful monitoring of clinical status is warranted when CYP3A enzyme inducing drugs are administered or discontinued in haloperidol-treated patients. Additionally, mitotane can cause sedation, lethargy, vertigo, and other CNS adverse reactions; additive CNS effects may occur initially when mitotane is given concurrently with haloperidol.
    Homatropine; Hydrocodone: (Major) Concomitant use of hydrocodone with mitotane can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Additionally, mitotane can cause sedation, lethargy, vertigo, and other CNS adverse reactions; additive CNS effects may occur initially when mitotane is given concurrently with hydrocodone. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal and/or additive CNS depression; consider adjusting the dose of hydrocodone as needed. If mitotane is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer.
    Hydrocodone: (Major) Concomitant use of hydrocodone with mitotane can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Additionally, mitotane can cause sedation, lethargy, vertigo, and other CNS adverse reactions; additive CNS effects may occur initially when mitotane is given concurrently with hydrocodone. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal and/or additive CNS depression; consider adjusting the dose of hydrocodone as needed. If mitotane is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer.
    Hydrocodone; Ibuprofen: (Major) Concomitant use of hydrocodone with mitotane can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Additionally, mitotane can cause sedation, lethargy, vertigo, and other CNS adverse reactions; additive CNS effects may occur initially when mitotane is given concurrently with hydrocodone. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal and/or additive CNS depression; consider adjusting the dose of hydrocodone as needed. If mitotane is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer.
    Hydrocodone; Pseudoephedrine: (Major) Concomitant use of hydrocodone with mitotane can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Additionally, mitotane can cause sedation, lethargy, vertigo, and other CNS adverse reactions; additive CNS effects may occur initially when mitotane is given concurrently with hydrocodone. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal and/or additive CNS depression; consider adjusting the dose of hydrocodone as needed. If mitotane is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer.
    Hydrocortisone: (Major) Because of increased glucocorticoid clearance, a higher dose of hydrocortisone (50 mg/day or more) may be needed for the treatment of adrenal insufficiency in patients treated with mitotane; some may require additional fludrocortisone.
    Hydroxyzine: (Moderate) Mitotane can cause sedation, lethargy, vertigo, and other CNS side effects. Concomitant administration of mitotane and CNS depressants, including sedating h1-blockers, may cause additive CNS effects.
    Ibrexafungerp: (Major) Avoid concurrent administration of ibrexafungerp with mitotane. Use of these drugs together is expected to significantly decrease ibrexafungerp exposure, which may reduce its efficacy. Ibrexafungerp is a CYP3A substrate and mitotane is a strong CYP3A inducer.
    Ibrutinib: (Major) Avoid the concomitant use of ibrutinib and mitotane; ibrutinib plasma concentrations may decrease. Ibrutinib is a CYP3A4 substrate; mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ibrutinib exposure by more than 10-fold.
    Ibuprofen; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with mitotane is necessary; consider increasing the dose of oxycodone as needed. If mitotane is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Idelalisib: (Major) Avoid the concomitant use of mitotane with idelalisib; consider alternative agents with less CYP3A4 induction. Mitotane is a strong CYP3A4 inducer and idelalisib is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of idelalisib. In healthy subjects, coadministration of another strong CYP3A inducer, rifampin (600 mg daily for 8 days) with idelalisib (single dose) resulted in a decrease of the geometric mean idelalisib AUC by 75% and geometric mean Cmax by 58% compared with idelalisib alone.
    Ifosfamide: (Moderate) Closely monitor for increased ifosfamide-related toxicities (e.g., neurotoxicity, nephrotoxicity) if coadministration with mitotane is necessary; consider adjusting the dose of ifosfamide as clinically appropriate. Ifosfamide is metabolized to its active alkylating metabolites by CYP3A4; mitotane is a strong CYP3A4 inducer. Concomitant use may increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde.
    Iloperidone: (Major) Use caution if mitotane and iloperidone are used concomitantly, and monitor for decreased efficacy of iloperidone and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and iloperidone is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of iloperidone.
    Imatinib: (Major) Avoid coadministration of imatinib and mitotane if possible due to decreased plasma concentrations of imatinib. If concomitant use is unavoidable, increase the dose of imatinib by at least 50%, carefully monitoring clinical response; imatinib doses up to 1,200 mg per day (600 mg twice daily) have been given to patients receiving concomitant strong CYP3A4 inducers. Imatinib is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer increased imatinib clearance by 3.8-fold, which significantly decreased the mean Cmax and AUC of imatinib.
    Imipramine: (Major) Use caution if mitotane and imipramine are used concomitantly, and monitor for decreased efficacy of imipramine and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and imipramine is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of imipramine. Additionally, mitotane can cause sedation, lethargy, vertigo, and other CNS adverse reactions; additive CNS effects may occur initially when mitotane is given concurrently with imipramine.
    Indacaterol: (Major) Use caution if mitotane and indacaterol are used concomitantly, and monitor for decreased efficacy of indacaterol and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and indacaterol is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of indacaterol.
    Indacaterol; Glycopyrrolate: (Major) Use caution if mitotane and indacaterol are used concomitantly, and monitor for decreased efficacy of indacaterol and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and indacaterol is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of indacaterol.
    Indinavir: (Major) Concomitant use of mitotane with indinavir should be undertaken with caution due to potential decreased indinavir concentrations, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Mitotane is a strong CYP3A4 inducer and indinavir is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of indinavir. Administration of indinavir and another strong CYP3A inducer, rifampin, for one week resulted in a 89% decrease in the indinavir AUC. Concomitant administration of yet another strong CYP3A inducer, St. John's wort, with indinavir to healthy volunteers decreased mean indinavir plasma concentrations by 57% and trough concentrations by 81%.
    Infigratinib: (Major) Avoid concurrent use of infigratinib and mitotane. Coadministration may decrease infigratinib exposure resulting in decreased efficacy. Infigratinib is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC of infigratinib by 56%.
    Irinotecan Liposomal: (Major) Avoid administration of mitotane during treatment with irinotecan and for at least 2 weeks prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates. Mitotane is a strong CYP3A4 inducer. Coadministration with other strong CYP3A4 inducers substantially reduced exposure to irinotecan or SN-38 in both adult and pediatric patients. An appropriate starting dose for patients taking irinotecan with strong CYP3A4 inducers has not been defined.
    Irinotecan: (Major) Avoid administration of mitotane during treatment with irinotecan and for at least 2 weeks prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates. Mitotane is a strong CYP3A4 inducer. Coadministration with other strong CYP3A4 inducers substantially reduced exposure to irinotecan or SN-38 in both adult and pediatric patients. An appropriate starting dose for patients taking irinotecan with strong CYP3A4 inducers has not been defined.
    Isavuconazonium: (Contraindicated) Concomitant use of isavuconazonium with mitotane is contraindicated due to the potential for decreased isavuconazole serum concentrations and treatment failure. Isavuconazole, the active moiety of isavuconazonium, is a sensitive substrate of hepatic isoenzyme CYP3A4; mitotane is a strong inducer of this enzyme. According to the manufacturer, coadministration of isavuconazole with strong CYP3A4 inducers is contraindicated. There was a 97% decrease in isavuconazole serum concentrations when coadministered with rifampin, another strong CYP3A4 inducer.
    Isradipine: (Moderate) Use caution if mitotane and isradipine are used concomitantly, and monitor for decreased efficacy of isradipine and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and isradipine is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of isradipine.
    Istradefylline: (Major) Avoid coadministration of istradefylline with mitotane as istradefylline exposure and efficacy may be reduced. Mitotane is a strong inducer. Istradefylline exposure was decreased by 81% when administered with a strong inducer in a drug interaction study.
    Itraconazole: (Major) The use of mitotane within 2 weeks of itraconazole therapy is not recommended; if coadministration cannot be avoided, monitor for decreased efficacy of itraconazole. Mitotane is a strong CYP3A4 inducer and itraconazole is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of itraconazole.
    Ivabradine: (Major) Avoid the concomitant use of mitotane with ivabradine; if coadministration cannot be avoided, monitor for decreased efficacy of ivabradine. Mitotane is a strong CYP3A4 inducer and ivabradine is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of ivabradine.
    Ivacaftor: (Major) Coadministration of ivacaftor with mitotane is not recommended due to decreased plasma concentrations of ivacaftor. Ivacaftor is a sensitive CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer significantly decreased ivacaftor exposure by approximately 9-fold.
    Ivermectin: (Moderate) Use caution if mitotane and ivermectin are used concomitantly, and monitor for decreased efficacy of ivermectin and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and ivermectin is a CYP3A4 substrate. Coadministration may result in decreased plasma concentrations of ivermectin; however, ivermectin is administered as a single dose, and significant clinical interactions are not expected.
    Ivosidenib: (Major) Avoid coadministration of ivosidenib with mitotane due to decreased plasma concentrations of ivosidenib. Ivosidenib is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer is predicted to decrease ivosidenib exposure at steady-state by 33%.
    Ixabepilone: (Major) Avoid concurrent use of ixabepilone and mitotane due to decreased plasma concentrations of ixabepilone, which may reduce its efficacy. If concomitant use is unavoidable, gradually increase the dose of ixabepilone as tolerated from 40 mg/m2 to 60 mg/m2 and infuse over 4 hours; monitor carefully for ixabepilone-related toxicities. Ixabepilone is a CYP3A substrate and mitotane is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased ixabepilone exposure by 43%.
    Ketoconazole: (Major) Avoid mitotane for 2 weeks prior to and during treatment with ketoconazole. Concomitant use may decrease exposure of ketoconazole and reduce its efficacy. If coadministration cannot be avoided, monitor for decreased efficacy of ketoconazole; a ketoconazole dose increase may be necessary. Ketoconazole is a CYP3A substrate and mitotane is a strong CYP3A inducer.
    Lansoprazole: (Moderate) Use caution if mitotane and lansoprazole are used concomitantly, and monitor for decreased efficacy of lansoprazole and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and lansoprazole is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of lansoprazole.
    Lansoprazole; Amoxicillin; Clarithromycin: (Major) Coadministration of mitotane and clarithromycin may decrease clarithromycin serum concentrations due to CYP3A4 enzyme induction. While the 14-OH-clarithromycin active metabolite concentrations are increased, this metabolite has different antimicrobial activity compared to clarithromycin. The intended therapeutic effect of clarithromycin could be decreased. It is not clear if clarithromycin activity against other organisms would be reduced, but reduced efficacy is possible. Alternatives to clarithromycin should be considered in patients who are taking potent CYP3A4 inducers. (Moderate) Use caution if mitotane and lansoprazole are used concomitantly, and monitor for decreased efficacy of lansoprazole and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and lansoprazole is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of lansoprazole.
    Lansoprazole; Naproxen: (Moderate) Use caution if mitotane and lansoprazole are used concomitantly, and monitor for decreased efficacy of lansoprazole and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and lansoprazole is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of lansoprazole.
    Lapatinib: (Major) Avoid coadministration of lapatinib with mitotane due to decreased plasma concentrations of lapatinib. If concomitant use is unavoidable, gradually titrate the dose of lapatinib from 1,250 mg per day to 4,500 mg per day in patients receiving concomitant capecitabine (HER2-positive metastatic breast cancer), and from 1,500 mg per day to 5,500 mg per day in patients receiving concomitant aromatase inhibitor therapy (HR-positive, HER2-positive breast cancer) based on tolerability. If mitotane is discontinued, reduce lapatinib to the indicated dose. Lapatinib is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Concomitant use with another strong CYP3A4 inducer decreased lapatinib exposure by 72%.
    Larotrectinib: (Major) Avoid coadministration of larotrectinib with mitotane due to decreased larotrectinib exposure and risk of decreased efficacy. If coadministration cannot be avoided, double the larotrectinib dose. If mitotane is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of mitotane. Larotrectinib is a CYP3A4 substrate; mitotane is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the larotrectinib AUC by 81% in a drug interaction study.
    Lefamulin: (Major) Avoid coadministration of lefamulin with mitotane unless the benefits outweigh the risks as concurrent use may decrease lefamulin exposure and efficacy. Lefamulin is a CYP3A4 substrate; mitotane is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the mean AUC of oral and intravenous lefamulin by 72% and 28%, respectively.
    Lemborexant: (Major) Avoid coadministration of lemborexant and mitotane as concurrent use may decrease lemborexant exposure which may reduce efficacy. Lemborexant is a CYP3A4 substrate; mitotane is a strong CYP3A4 inducer.
    Lenacapavir: (Contraindicated) Concurrent use of lenacapavir and mitotane is contraindicated due to the risk of decreased lenacapavir exposure which may result in loss of therapeutic effect and development of resistance. Lenacapavir is a CYP3A substrate and mitotane is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced lenacapavir overall exposure by 84%.
    Leniolisib: (Major) Avoid concomitant use of leniolisib and mitotane. Concomitant use may decrease leniolisib exposure which may reduce its efficacy. Leniolisib is a CYP3A substrate and mitotane is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced leniolisib overall exposure by 78%.
    Leuprolide; Norethindrone: (Major) Avoid coadministration of mitotane with norethindrone if used for contraception; consider an alternate or additional form of contraception. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of mitotane. Patients taking hormonal replacement therapy may need to be monitored for reduced clinical effect while on mitotane, with dose adjustments made based on clinical efficacy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. Women taking hormonal replacement and mitotane should report breakthrough bleeding, hot flashes, or other symptoms to their prescribers. Norethindrone is a substrate of CYP3A4 and mitotane is a strong CYP3A4 inducer. Concurrent administration of mitotane with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
    Levamlodipine: (Moderate) Use caution if mitotane and amlodipine are used concomitantly, and monitor for decreased efficacy of amlodipine and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and amlodipine is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of amlodipine.
    Levoketoconazole: (Major) Avoid mitotane for 2 weeks prior to and during treatment with ketoconazole. Concomitant use may decrease exposure of ketoconazole and reduce its efficacy. If coadministration cannot be avoided, monitor for decreased efficacy of ketoconazole; a ketoconazole dose increase may be necessary. Ketoconazole is a CYP3A substrate and mitotane is a strong CYP3A inducer.
    Levonorgestrel: (Major) Levonorgestrel is not recommended for women who require chronic use of drugs that are potent inducers of hepatic enzymes, including mitotane, because contraception efficacy is likely to be reduced. Consider additional or alternative forms of contraception. Mitotane is a strong CYP3A4 inducer and progestins like levonorgestrel are CYP3A4 substrates. Coadministration may result in decreased plasma concentrations of oral and other hormonal combination contraceptives.
    Levonorgestrel; Ethinyl Estradiol: (Major) Levonorgestrel is not recommended for women who require chronic use of drugs that are potent inducers of hepatic enzymes, including mitotane, because contraception efficacy is likely to be reduced. Consider additional or alternative forms of contraception. Mitotane is a strong CYP3A4 inducer and progestins like levonorgestrel are CYP3A4 substrates. Coadministration may result in decreased plasma concentrations of oral and other hormonal combination contraceptives.
    Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Major) Levonorgestrel is not recommended for women who require chronic use of drugs that are potent inducers of hepatic enzymes, including mitotane, because contraception efficacy is likely to be reduced. Consider additional or alternative forms of contraception. Mitotane is a strong CYP3A4 inducer and progestins like levonorgestrel are CYP3A4 substrates. Coadministration may result in decreased plasma concentrations of oral and other hormonal combination contraceptives.
    Lidocaine: (Major) Use caution if mitotane and lidocaine are used concomitantly, and monitor for decreased efficacy of lidocaine and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and lidocaine is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of lidocaine.
    Lidocaine; Epinephrine: (Major) Use caution if mitotane and lidocaine are used concomitantly, and monitor for decreased efficacy of lidocaine and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and lidocaine is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of lidocaine.
    Lidocaine; Prilocaine: (Major) Use caution if mitotane and lidocaine are used concomitantly, and monitor for decreased efficacy of lidocaine and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and lidocaine is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of lidocaine.
    Lonafarnib: (Contraindicated) Coadministration of lonafarnib and mitotane is contraindicated; concurrent use may decrease lonafarnib exposure, which may reduce its efficacy. Lonafarnib is a sensitive CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the exposure of lonafarnib by 98%.
    Lopinavir; Ritonavir: (Contraindicated) Coadministration of lopinavir and mitotane is contraindicated due to the potential for reduced antiretroviral efficacy and the potential development of viral resistance. If coadministration cannot be avoided, monitor for decreased efficacy of lopinavir. Mitotane is a strong CYP3A4 inducer and lopinavir is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of lopinavir. (Major) Avoid the concomitant use of mitotane with ritonavir due to the potential for reduced antiretroviral efficacy and the potential development of viral resistance. If coadministration cannot be avoided, monitor for decreased efficacy of ritonavir. Mitotane is a strong CYP3A4 inducer and ritonavir is a CYP3A4 substrates; coadministration may result in decreased plasma concentrations of ritonavir. Another strong CYP3A inducer, rifampin (300 or 600 mg daily for 10 days), decreased the AUC and Cmax of ritonavir (500 mg every 12 hours for 20 days) by 35% and 25%, respectively.
    Lorlatinib: (Contraindicated) Coadministration of lorlatinib with mitotane is contraindicated due to the risk of severe hepatotoxicity as well as decreased lorlatinib exposure which may reduce its efficacy. Discontinue mitotane for 3 plasma half-lives prior to initiating therapy with lorlatinib. Lorlatinib is a CYP3A substrate and mitotane is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased lorlatinib exposure by 85% and caused severe (grade 3 or 4) hepatotoxicity in 83% of patients.
    Losartan: (Major) Use caution if mitotane and losartan are used concomitantly, and monitor for decreased efficacy of losartan and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and losartan is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of losartan. Another strong CYP3A inducer, rifampin, decreased the AUC and half-life of losartan by 35% and 50%, respectively. In addition, rifampin decreased the AUC and half-life for the active metabolite of losartan, E-3174, by 40% and 50%, respectively.
    Losartan; Hydrochlorothiazide, HCTZ: (Major) Use caution if mitotane and losartan are used concomitantly, and monitor for decreased efficacy of losartan and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and losartan is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of losartan. Another strong CYP3A inducer, rifampin, decreased the AUC and half-life of losartan by 35% and 50%, respectively. In addition, rifampin decreased the AUC and half-life for the active metabolite of losartan, E-3174, by 40% and 50%, respectively.
    Lovastatin: (Major) Use caution if mitotane and lovastatin are used concomitantly, and monitor for decreased efficacy of lovastatin and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and lovastatin is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of lovastatin.
    Lovastatin; Niacin: (Major) Use caution if mitotane and lovastatin are used concomitantly, and monitor for decreased efficacy of lovastatin and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and lovastatin is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of lovastatin.
    Lumacaftor; Ivacaftor: (Major) Coadministration of ivacaftor with mitotane is not recommended due to decreased plasma concentrations of ivacaftor. Ivacaftor is a sensitive CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer significantly decreased ivacaftor exposure by approximately 9-fold.
    Lumateperone: (Major) Avoid coadministration of lumateperone and mitotane as concurrent use may decrease lumateperone exposure which may reduce efficacy. Lumateperone is a CYP3A4 substrate; mitotane is a strong CYP3A4 inducer. Coadministration of lumateperone with a strong CYP3A4 inducer decreased lumateperone overall exposure by greater than 30-fold.
    Lurasidone: (Contraindicated) Concurrent use of lurasidone with strong CYP3A4 inducers, such as mitotane, is contraindicated. Lurasidone is primarily metabolized by CYP3A4. Decreased blood concentrations of lurasidone are expected when the drug is co-administered with inducers of CYP3A4. When a single dose of lurasidone 40 mg was co-administered with another strong CYP3A inducer, rifampin (1200 mg/day for 8 days), the lurasidone Cmax and AUC values were reduced to one-seventh and one-fifth, respectively, of those seen after administration of lurasidone alone.
    Lurbinectedin: (Major) Avoid coadministration of lurbinectedin and mitotane due to the risk of decreased lurbinectedin exposure which may reduce its efficacy. Lurbinectedin is a CYP3A substrate and mitotane is a strong CYP3A inducer.
    Macimorelin: (Major) Discontinue mitotane and allow a sufficient washout period to pass before administering macimorelin. Use of these drugs together can significantly decrease macimorelin plasma concentrations, and may result in a false positive test for growth hormone deficiency. No drug-drug interaction studies have been conducted; however, macimorelin is primarily metabolized by CYP3A4 and mitotane is a strong CYP3A4 inducer.
    Maprotiline: (Moderate) Use caution if mitotane and maprotiline are used concomitantly, and monitor for decreased efficacy of maprotiline and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and maprotiline is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of maprotiline.
    Maraviroc: (Major) Coadministration of maraviroc, a CYP3A substrate, and mitotane, a strong CYP3A inducer, without a concomitant strong CYP3A inhibitor may decrease maraviroc concentrations, therefore, the adult maraviroc dose should be increased to 600 mg PO twice daily when coadministered with mitotane without a concomitant strong CYP3A inhibitor. Coadministration of maraviroc and mitotane is contraindicated in patients with CrCl less than 30 mL/min. For pediatric patients, concomitant use of maraviroc with a strong CYP3A inducer, without a strong CYP3A inhibitor, is not recommended. If the patient's medication regimen also contains a strong CYP3A inhibitor, the CYP3A inhibitor's actions are expected to exceed that of the inducer; overall, increased maraviroc concentrations are expected.
    Maribavir: (Major) Avoid concomitant use of maribavir and mitotane. Coadministration may decrease maribavir exposure resulting in reduced virologic response. Maribavir is a CYP3A substrate and mitotane is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased the exposure of maribavir by 60%.
    Mavacamten: (Contraindicated) Mavacamten is contraindicated for use with mitotane due to risk for reduced mavacamten efficacy. Concomitant use decreases mavacamten exposure. Mavacamten is a CYP3A substrate and mitotane is a strong CYP3A inducer. The impact that a CYP3A inducer may have on mavacamten overall exposure varies based on the patient's CYP2C19 metabolizer status. Concomitant use of a strong CYP3A inducer is predicted to decrease mavacamten overall exposure by 69% and 87% in poor and normal CYP2C19 metabolizers, respectively.
    Meclizine: (Moderate) Mitotane can cause sedation, lethargy, vertigo, and other CNS side effects. Concomitant administration of mitotane and CNS depressants, including sedating h1-blockers, may cause additive CNS effects.
    Medroxyprogesterone: (Major) Use caution if mitotane and medroxyprogesterone are used concomitantly, and monitor for decreased medroxyprogesterone efficacy. Since the dosage of medroxyprogesterone injections for contraception cannot be modified, an alternate or additional form of contraception should be considered in patients requiring therapy with mitotane. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of mitotane. Mitotane is a strong CYP3A4 inducer and medroxyprogesterone is a CYP3A4 substrate in vitro; coadministration may result in decreased plasma concentrations of medroxyprogesterone. Pregnancies have been reported during therapy with progestin contraceptives in patients receiving other strong CYP3A inducers.
    Mefloquine: (Major) Use caution if mitotane and mefloquine are used concomitantly, and monitor for decreased efficacy of mefloquine and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and mefloquine is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of mefloquine. Another strong CYP3A inducer, rifampin, has been reported to increase the metabolism of mefloquine and reduce mefloquine plasma concentrations in healthy volunteers (decreased mean Cmax by 19% and mean AUC by 68%).
    Meloxicam: (Minor) Use caution if mitotane and meloxicam are used concomitantly, and monitor for decreased efficacy of meloxicam and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and meloxicam is a minor CYP3A4 substrate; coadministration may result in decreased plasma concentrations of meloxicam.
    Mestranol; Norethindrone: (Major) Avoid coadministration of mitotane with norethindrone if used for contraception; consider an alternate or additional form of contraception. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of mitotane. Patients taking hormonal replacement therapy may need to be monitored for reduced clinical effect while on mitotane, with dose adjustments made based on clinical efficacy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. Women taking hormonal replacement and mitotane should report breakthrough bleeding, hot flashes, or other symptoms to their prescribers. Norethindrone is a substrate of CYP3A4 and mitotane is a strong CYP3A4 inducer. Concurrent administration of mitotane with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
    Metformin; Repaglinide: (Major) Use caution if mitotane and repaglinide are used concomitantly, and monitor for decreased efficacy of repaglinide and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and repaglinide is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of repaglinide. When administered with another strong CYP3A inducer, rifampin, repaglinide AUC decreased by 31% and Cmax by 26%.
    Methadone: (Major) Use caution if mitotane and methadone are used concomitantly, and monitor for decreased efficacy of methadone and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and methadone is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of methadone. Concurrent administration of another strong CYP3A inducer, rifampin, and methadone is associated with a 33 to 68% decrease in methadone levels due to induction of methadone metabolism by rifampin.
    Methylprednisolone: (Moderate) Use caution if mitotane and methylprednisolone are used concomitantly, and monitor for decreased efficacy of methylprednisolone and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and methylprednisolone is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of methylprednisolone.
    Metyrapone: (Major) Mitotane suppresses the activity of the adrenal cortex, and may reduce the adrenal response to metyrapone. The manufacturer of metyrapone recommends that any drug that affects adrenal function be discontinued prior to and during metyrapone testing.
    Midazolam: (Moderate) Use caution if mitotane and midazolam are used concomitantly, and monitor for decreased efficacy of midazolam and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and midazolam is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of midazolam. Additionally, mitotane can cause sedation, lethargy, vertigo, and other CNS adverse reactions; additive CNS effects may occur initially when mitotane is given concurrently with midazolam.
    Midostaurin: (Major) Avoid the concomitant use of midostaurin and mitotane as midostaurin exposure may be decreased, which may reduce its efficacy. Midostaurin is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased the exposure of midostaurin and its metabolites CGP62221 and CGP52421 by 96%, 92%, and 59%, respectively.
    Mifepristone: (Major) Avoid the concomitant use of mitotane with mifepristone due to duplication of pharmacodynamic effects and the potential for serious adrenalcortical insufficiency. The safe and effective use of these drugs together has not been established. Additionally, mitotane is a strong CYP3A4 inducer, and coadministration would be expected to decrease plasma concentrations of mifepristone. Avoid co-administration of mifepristone and CYP3A inducers such as mitotane. Use of mifepristone with CYP3A inducers has not been studied.
    Mirtazapine: (Major) Use caution if mitotane and mirtazapine are used concomitantly, and monitor for decreased efficacy of mirtazapine and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and mirtazapine is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of mirtazapine.
    Mitapivat: (Major) Avoid coadministration of mitapivat with mitotane due to decreased mitapivat efficacy. Coadministration decreases mitapivat concentrations. Mitapivat is a CYP3A substrate and mitotane is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased mitapivat overall exposure by 91% to 95%.
    Mobocertinib: (Major) Avoid concomitant use of mobocertinib and mitotane. Coadministration may decrease mobocertinib exposure resulting in decreased efficacy. Mobocertinib is a CYP3A substrate and mitotane is a strong CYP3A inducer. Use of a strong CYP3A inducer is predicted to decrease the overall exposure of mobocertinib and its active metabolites by 92%.
    Modafinil: (Minor) Avoid the concomitant use of mitotane with modafinil; if coadministration cannot be avoided, monitor for decreased efficacy of modafinil. Mitotane is a strong CYP3A4 inducer. A non-CYP related pathway is the most rapid in metabolizing modafinil, suggesting that there is a low probability of substantive effects on the overall pharmacokinetic profile of modafinil due to CYP inhibition by concomitant medications; however, due to the partial involvement of CYP3A in modafinil metabolism, there is a potential for decreased plasma concentrations with strong CYP3A inducers such as mitotane.
    Montelukast: (Minor) Mitotane may reduce the systemic exposure of montelukast. However, dosage adjustment is not likely to be needed. If used together, the manufacturer recommends monitoring for proper montelukast effectiveness as a precaution. Mitotane is a strong CYP3A inducer. Montelukast is metabolized by CYP2C8 (primary), and also CYP2C9 and CYP3A4.
    Naldemedine: (Major) Avoid coadministration of naldemedine with strong CYP3A4 inducers. Naldemedine is metabolized primarily by the CYP3A enzyme system. Strong CYP3A4 inducers, such as mitotane, significantly decrease plasma naldemedine concentrations and may decrease the efficacy of naldemedine treatment.
    Naloxegol: (Major) Coadministration of naloxegol with mitotane is not recommended due to the potential for decreased naloxegol efficacy. Naloxegol is a CYP3A4 substrate; mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased naloxegol exposure by 89%.
    Nanoparticle Albumin-Bound Paclitaxel: (Moderate) Monitor for decreased efficacy of nab-paclitaxel if coadministration with mitotane is necessary due to the risk of decreased plasma concentrations of paclitaxel. Nab-paclitaxel is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer.
    Nanoparticle Albumin-Bound Sirolimus: (Major) Concomitant use of sirolimus and mitotane should be avoided. Mitotane may decrease the systemic exposure of sirolimus. Consider alternative agents with less potential for interaction. If concurrent use cannot be avoided, monitor sirolimus plasma concentrations closely and adjust the dose as necessary. Sirolimus is a substrate of CYP3A4, and mitotane is a potent CYP3A4 inducer.
    Naproxen; Esomeprazole: (Moderate) Use caution if mitotane and esomeprazole are used concomitantly, and monitor for decreased efficacy of esomeprazole and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and esomeprazole is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of esomeprazole.
    Nefazodone: (Moderate) Monitor for decreased efficacy of nefazodone if coadministration with mitotane is necessary. Concomitant use may decrease nefazodone exposure. Nefazodone is a primary CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased nefazodone and hydroxynefazodone exposure by almost 95%.
    Nelfinavir: (Contraindicated) Coadministration of nelfinavir and mitotane is contraindicated due to the potential for subtherapeutic antiretroviral activity and the subsequent possibility for the development of resistant HIV mutations. Mitotane is a strong CYP3A4 inducer and nelfinavir is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of nelfinavir. When administered with another strong CYP3A inducer, rifampin, the plasma AUC, Cmax, and Cmin of nelfinavir decreased by 83%, 76%, and 92%, respectively.
    Neratinib: (Major) Avoid concomitant use of mitotane with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased neratinib exposure by 87%, while exposure to active metabolites M6 and M7 were reduced by 37% to 49%. Concomitant use with other strong inducers of CYP3A4 may also decrease neratinib concentrations.
    Netupitant, Fosnetupitant; Palonosetron: (Major) Avoid the concomitant use of mitotane with netupitant; palonosetron; if coadministration cannot be avoided, monitor for decreased efficacy of netupitant; palonosetron. Mitotane is a strong CYP3A4 inducer. Palonosetron is metabolized via multiple CYP isoenzymes, including CYP3A4, however, netupitant is primarily metabolized via CYP3A4; coadministration may result in decreased plasma concentrations of netupitant. (Minor) Use caution if mitotane and palonosetron are used concomitantly, and monitor for decreased efficacy of palonosetron and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer. Palonosetron is metabolized via multiple CYP isoenzymes, including CYP3A4; coadministration may theoretically result in decreased plasma concentrations of palonosetron, however, the potential for clinically significant drug interactions appears to be low.
    Nevirapine: (Moderate) Use caution and monitor for decreased efficacy of nevirapine if coadministered with mitotane. Concurrent use may decrease the plasma concentrations of nevirapine leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Nevirapine is a CYP3A substrate and mitotane is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased nevirapine exposure by greater than 50%.
    Niacin; Simvastatin: (Moderate) Use caution if mitotane and simvastatin are used concomitantly, and monitor for decreased efficacy of simvastatin and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and simvastatin is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of simvastatin.
    Nifedipine: (Major) Avoid coadministration of nifedipine and mitotane and consider alternative therapy if possible. If coadministration is necessary, monitor the patient closely for desired cardiovascular effects on heart rate, blood pressure, or chest pain. The FDA-approved labeling for some nifedipine products contraindicates coadministration with strong CYP3A4 inducers, while other manufacturers classify the recommendation as a warning. Nifedipine is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration of nifedipine with another strong CYP3A4 inducer reduced the AUC and Cmax of nifedipine by approximately 70%.
    Nilotinib: (Major) Avoid the concomitant use of nilotinib and mitotane; significantly decreased nilotinib exposure and reduced nilotinib efficacy may occur. Nilotinib is a CYPA4 substrate and mitotane is a strong CYP3A4 inducer. In a drug interaction study, coadministration with another strong CYP3A4 inducer decreased nilotinib exposure by approximately 80%
    Nimodipine: (Major) Avoid the concomitant use of mitotane with nimodipine; if coadministration cannot be avoided, monitor for decreased efficacy of nimodipine. Mitotane is a strong CYP3A4 inducer and nimodipine is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of nimodipine.
    Nirmatrelvir; Ritonavir: (Major) Avoid the concomitant use of mitotane with ritonavir due to the potential for reduced antiretroviral efficacy and the potential development of viral resistance. If coadministration cannot be avoided, monitor for decreased efficacy of ritonavir. Mitotane is a strong CYP3A4 inducer and ritonavir is a CYP3A4 substrates; coadministration may result in decreased plasma concentrations of ritonavir. Another strong CYP3A inducer, rifampin (300 or 600 mg daily for 10 days), decreased the AUC and Cmax of ritonavir (500 mg every 12 hours for 20 days) by 35% and 25%, respectively. (Moderate) Monitor for a diminished response to nirmatrelvir if concomitant use of mitotane is necessary. Concomitant use of nirmatrelvir and mitotane may reduce the therapeutic effect of nirmatrelvir. Nirmatrelvir is a CYP3A substrate and mitotane is a strong CYP3A inducer.
    Nisoldipine: (Major) Avoid coadministration of nisoldipine with mitotane due to decreased plasma concentrations of nisoldipine. Alternative antihypertensive therapy should be considered. Nisoldipine is a CYP3A4 substrate and mititane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer lowered nisoldipine plasma concentrations to undetectable levels.
    Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Major) Avoid coadministration of mitotane with norethindrone if used for contraception; consider an alternate or additional form of contraception. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of mitotane. Patients taking hormonal replacement therapy may need to be monitored for reduced clinical effect while on mitotane, with dose adjustments made based on clinical efficacy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. Women taking hormonal replacement and mitotane should report breakthrough bleeding, hot flashes, or other symptoms to their prescribers. Norethindrone is a substrate of CYP3A4 and mitotane is a strong CYP3A4 inducer. Concurrent administration of mitotane with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
    Norethindrone: (Major) Avoid coadministration of mitotane with norethindrone if used for contraception; consider an alternate or additional form of contraception. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of mitotane. Patients taking hormonal replacement therapy may need to be monitored for reduced clinical effect while on mitotane, with dose adjustments made based on clinical efficacy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. Women taking hormonal replacement and mitotane should report breakthrough bleeding, hot flashes, or other symptoms to their prescribers. Norethindrone is a substrate of CYP3A4 and mitotane is a strong CYP3A4 inducer. Concurrent administration of mitotane with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
    Norethindrone; Ethinyl Estradiol: (Major) Avoid coadministration of mitotane with norethindrone if used for contraception; consider an alternate or additional form of contraception. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of mitotane. Patients taking hormonal replacement therapy may need to be monitored for reduced clinical effect while on mitotane, with dose adjustments made based on clinical efficacy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. Women taking hormonal replacement and mitotane should report breakthrough bleeding, hot flashes, or other symptoms to their prescribers. Norethindrone is a substrate of CYP3A4 and mitotane is a strong CYP3A4 inducer. Concurrent administration of mitotane with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
    Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Major) Avoid coadministration of mitotane with norethindrone if used for contraception; consider an alternate or additional form of contraception. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of mitotane. Patients taking hormonal replacement therapy may need to be monitored for reduced clinical effect while on mitotane, with dose adjustments made based on clinical efficacy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. Women taking hormonal replacement and mitotane should report breakthrough bleeding, hot flashes, or other symptoms to their prescribers. Norethindrone is a substrate of CYP3A4 and mitotane is a strong CYP3A4 inducer. Concurrent administration of mitotane with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
    Norgestimate; Ethinyl Estradiol: (Major) Norgestimate is not recommended for women who require chronic use of drugs that are potent inducers of hepatic enzymes, including mitotane, because contraception efficacy is likely to be reduced. Consider additional or alternative forms of contraception. Mitotane is a strong CYP3A4 inducer and progestins like norgestimate are CYP3A4 substrates. Coadministration may result in decreased plasma concentrations of oral and other hormonal combination contraceptives.
    Norgestrel: (Major) Norgestrel is not recommended for women who require chronic use of drugs that are potent inducers of hepatic enzymes, including mitotane, because contraception efficacy is likely to be reduced. Consider additional or alternative forms of contraception. Mitotane is a strong CYP3A4 inducer and progestins like norgestrel are CYP3A4 substrates. Coadministration may result in decreased plasma concentrations of oral and other hormonal combination contraceptives.
    Nortriptyline: (Major) Use caution if mitotane and nortriptyline are used concomitantly, and monitor for decreased efficacy of nortriptyline and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and nortriptyline is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of nortriptyline. Additionally, mitotane can cause sedation, lethargy, vertigo, and other CNS adverse reactions; additive CNS effects may occur initially when mitotane is given concurrently with nortriptyline.
    Olanzapine; Samidorphan: (Major) Avoid the concurrent use of samidorphan and mitotane; decreased samidorphan exposure and loss of efficacy may occur. Samidorphan is a CYP3A substrate and mitotane is a strong CYP3A inducer. Concomitant use of another strong CYP3A inducer reduced samidorphan exposure by 73%.
    Olaparib: (Major) Avoid coadministration of olaparib with mitotane due to the risk of decreasing the efficacy of olaparib. Olaparib is a CYP3A substrate and mitotane is a strong CYP3A4 inducer; concomitant use may decrease olaparib exposure. Coadministration with another strong CYP3A inducer decreased the olaparib Cmax by 71% and the AUC by 87%.
    Oliceridine: (Moderate) Monitor for reduced efficacy of oliceridine and signs of opioid withdrawal if coadministration with mitotane is necessary; consider increasing the dose of oliceridine as needed. If mitotane is discontinued, consider a dose reduction of oliceridine and frequently monitor for signs of respiratory depression and sedation. Oliceridine is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease the plasma concentrations of oliceridine; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Use caution if mitotane and amlodipine are used concomitantly, and monitor for decreased efficacy of amlodipine and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and amlodipine is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of amlodipine.
    Olutasidenib: (Major) Avoid concurrent use of olutasidenib and mitotane due to the risk of decreased olutasidenib exposure which may reduce its efficacy. Olutasidenib is a CYP3A substrate and mitotane is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced olutasidenib exposure by approximately 80%.
    Omaveloxolone: (Major) Avoid concurrent use of omaveloxolone and mitotane. Concurrent use may decrease omaveloxolone exposure which may reduce its efficacy. Omaveloxolone is a CYP3A substrate and mitotane is a strong CYP3A inducer.
    Ombitasvir; Paritaprevir; Ritonavir: (Contraindicated) Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir with mitotane is contraindicated due to the potential for hepatitis C treatment failure. Coadministration may result in reduced systemic exposure to dasabuvir, ombitasvir, paritaprevir and ritonavir. Mitotane is a strong inducer of CYP3A4; dasabuvir (minor), paritaprevir, and ritonavir are substrates of this isoenzyme. (Major) Avoid the concomitant use of mitotane with ritonavir due to the potential for reduced antiretroviral efficacy and the potential development of viral resistance. If coadministration cannot be avoided, monitor for decreased efficacy of ritonavir. Mitotane is a strong CYP3A4 inducer and ritonavir is a CYP3A4 substrates; coadministration may result in decreased plasma concentrations of ritonavir. Another strong CYP3A inducer, rifampin (300 or 600 mg daily for 10 days), decreased the AUC and Cmax of ritonavir (500 mg every 12 hours for 20 days) by 35% and 25%, respectively.
    Omeprazole: (Moderate) Use caution if mitotane and omeprazole are used concomitantly, and monitor for decreased efficacy of omeprazole and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and omeprazole is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of omeprazole.
    Omeprazole; Amoxicillin; Rifabutin: (Major) Use caution if mitotane and rifabutin are used concomitantly, and monitor for decreased efficacy of rifabutin and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and rifabutin is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of rifabutin. (Moderate) Use caution if mitotane and omeprazole are used concomitantly, and monitor for decreased efficacy of omeprazole and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and omeprazole is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of omeprazole.
    Omeprazole; Sodium Bicarbonate: (Moderate) Use caution if mitotane and omeprazole are used concomitantly, and monitor for decreased efficacy of omeprazole and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and omeprazole is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of omeprazole.
    Ondansetron: (Minor) Use caution if mitotane and ondansetron are used concomitantly, and monitor for decreased efficacy of ondansetron and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and ondansetron is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of ondansetron. During pharmacokinetic studies, patients treated with strong CYP3A inducers (i.e., phenytoin, carbamazepine, rifampin) and ondansetron had significantly increased ondansetron clearance, resulting in significant reductions in AUC, Cmax, and half-life. However, these changes in ondansetron exposure are not thought to be clinically relevant.
    Osilodrostat: (Major) Monitor cortisol concentrations and the patient's signs and symptoms closely. Use of mitotane may decrease osilodrostat exposure via CYP induction. Similar pharmacodynamic actions may increase the risk for adrenal insufficiency. Dosage adjustments may be needed. Osilodrostat is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. In addition, mitotane suppresses adrenal activity and may have additive effects with olisodrostat on cortisol levels, but via a different mechanism. Patients should be aware of the symptoms of hypocortisolism and adrenal insufficiency and immediately report if they occur. After discontinuation of mitotane, monitor cortisol concentration and patient's signs and symptoms; a reduction in osilodrostat dose may be needed.
    Osimertinib: (Major) Avoid coadministration of mitotane with osimertinib due to decreased plasma concentrations of osimertinib which may lead to reduced efficacy. If concomitant use is unavoidable, increase the dose of osimertinib to 160 mg once daily. If mitotane is discontinued, reduce the dose of osimertinib to 80 mg once daily after a washout period of 3 weeks. Osimertinib is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased osimertinib exposure by 78%.
    Ospemifene: (Moderate) Use caution if mitotane and ospemifene are used concomitantly, and monitor for decreased efficacy of ospemifene. Mitotane is a strong CYP3A4 inducer and ospemifene is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of ospemifene and a resultant decrease in clinical effect.
    Oxcarbazepine: (Moderate) Monitor MHD, the active metabolite of oxcarbazepine, concentrations during oxcarbazepine dosage titration if mitotane and oxcarbazepine are used concurrently. A dose adjustment of oxcarbazepine may be required after initiation, dosage modification, or discontinuation of mitotane. Mitotane is a strong CYP3A4 inducer. Coadministration with other strong CYP3A4 inducers decreased concentrations of MHD by 25% to 40%.
    Oxybutynin: (Moderate) Mitotane is a strong CYP3A4 inducer and oxybutynin is a CYP3A4 substrate. Coadministration may result in decreased plasma concentrations of oxybutynin. If these drugs are used together, monitor patients for decreased oxybutynin efficacy; oxybutynin dosage adjustments may be needed.
    Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with mitotane is necessary; consider increasing the dose of oxycodone as needed. If mitotane is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Paclitaxel: (Major) Concomitant use of mitotane with paclitaxel should be undertaken with caution as it could result in decreased plasma concentrations of paclitaxel, leading to reduced efficacy. Mitotane is a strong CYP3A4 inducer and paclitaxel is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of paclitaxel.
    Pacritinib: (Contraindicated) Concurrent use of pacritinib with mitotane is contraindicated due to decreased pacritinib exposure which may impair efficacy. Pacritinib is a CYP3A substrate and mitotane is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased pacritinib exposure by 87%.
    Palbociclib: (Major) Avoid coadministration of mitotane with palbociclib due to decreased plasma concentrations of palbociclib, which may result in decreased efficacy. Palbociclib is primarily metabolized by CYP3A4 and mitotane is a strong CYP3A4 inducer. In a drug interaction trial, coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of palbociclib by 85% and 70%, respectively.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Paliperidone: (Major) Avoid using a strong inducer of CYP3A4 if possible during the 1-month injectable dosing interval of Invega Sustenna or the 3-month injectable dosing interval of Invega Trinza. If use of a strong CYP3A4 inducer such as mitotane is required in patients receiving injectable paliperidone, consider management with oral paliperidone. Paliperidone is a P-gp substrate, with minor contributions in metabolism by CYP3A4 and CYP2D6. A dosage increase of oral paliperidone may be required during coadministration of a strong inducer of both CYP3A4 and P-gp. However, concurrent use of oral paliperidone with a strong CYP3A4 inducer alone may not be clinically relevant since in vivo studies show this isoenzyme contributes to only a small fraction of total body clearance.
    Palonosetron: (Minor) Use caution if mitotane and palonosetron are used concomitantly, and monitor for decreased efficacy of palonosetron and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer. Palonosetron is metabolized via multiple CYP isoenzymes, including CYP3A4; coadministration may theoretically result in decreased plasma concentrations of palonosetron, however, the potential for clinically significant drug interactions appears to be low.
    Panobinostat: (Major) Avoid the concomitant use of mitotane with panobinostat due to decreased exposure and possible decreased efficacy. Mitotane is a strong CYP3A4 inducer and panobinostat is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of panobinostat. An approximately 70% decrease in the systemic exposure of panobinostat in the presence of strong inducers of CYP3A was observed in simulations using mechanistic models.
    Paricalcitol: (Moderate) Use caution if mitotane and paricalcitol are used concomitantly, and monitor for decreased efficacy of paricalcitol and a possible change in dosage requirements. Clinicians should monitor plasma iPTH and serum calcium and phosphorous concentrations when mitotane is initiated or discontinued. Mitotane is a strong CYP3A4 inducer and paricalcitol is partially metabolized by CYP3A4; coadministration may result in decreased plasma concentrations of paricalcitol.
    Pazopanib: (Major) Avoid the concomitant use of mitotane with pazopanib due to decreased exposure and possible decreased efficacy. Mitotane is a strong CYP3A4 inducer and pazopanib is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of pazopanib.
    Pemigatinib: (Major) Avoid coadministration of pemigatinib and mitotane due to the risk of decreased pemigatinib exposure which may reduce its efficacy. Pemigatinib is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased pemigatinib exposure by 85%.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Perampanel: (Major) Start perampanel at a higher initial dose of 4 mg once daily at bedtime when using concurrently with mitotane due to a potential reduction in perampanel plasma concentration. If introduction or withdrawal of mitotane occurs during perampanel therapy, closely monitor patient response; a dosage adjustment may be necessary. Mitotane is a strong CYP3A4 inducer, and perampanel is a CYP3A4 substrate.
    Perindopril; Amlodipine: (Moderate) Use caution if mitotane and amlodipine are used concomitantly, and monitor for decreased efficacy of amlodipine and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and amlodipine is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of amlodipine.
    Perphenazine; Amitriptyline: (Major) Use caution if mitotane and amitriptyline are used concomitantly, and monitor for decreased efficacy of amitriptyline and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and amitriptyline is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of amitriptyline. Additionally, mitotane can cause sedation, lethargy, vertigo, and other CNS adverse reactions; additive CNS effects may occur initially when mitotane is given concurrently with amitriptyline.
    Pexidartinib: (Major) Avoid coadministration of pexidartinib with mitotane as concurrent use may decrease pexidartinib exposure which may result in decreased therapeutic response. Pexidartinib is a CYP3A4 substrate; mitotane is a strong CYP3A4 inducer. Coadministration of another strong CYP3A4 inducer decreased pexidartinib exposure by 65%.
    Phenothiazines: (Moderate) Mitotane can cause sedation, lethargy, vertigo, and other CNS side effects. Concomitant administration of mitotane and CNS depressants, including opiate agonists, may cause additive CNS effects.
    Pimavanserin: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends avoiding concomitant use of pimavanserin with strong CYP3A4 inducers, such as mitotane. Strong inducers of CYP3A4 can reduce pimavanserin exposure, potentially decreasing the effectiveness of pimavanserin.
    Pirtobrutinib: (Major) Avoid concurrent use of pirtobrutinib and mitotane due to the risk of decreased pirtobrutinib exposure which may reduce its efficacy. Pirtobrutinib is a CYP3A substrate and mitotane is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced pirtobrutinib overall exposure by 71%.
    Pitolisant: (Major) Monitor for loss of pitolisant efficacy after initiation of mitotane. Increase to double the original daily dose of pitolisant over 7 days in patients stable on 8.9 mg or 17.8 mg once daily (i.e., 17.8 mg or 35.6 mg, respectively). Decrease the pitolisant dose by half if mitotane is discontinued. Pitolisant is a CYP3A4 substrate; mitotane is a strong CYP3A4 inducer. Coadministration of strong CYP3A4 inducers decreases pitolisant exposure by 50%.
    Polatuzumab Vedotin: (Moderate) Monitor for decreased polatuzumab vedotin efficacy during coadministration of mitotane due to the risk of decreased exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; mitotane is a strong CYP3A4 inducer. Strong CYP3A4 inducers are predicted to decrease the exposure of MMAE by 63%.
    Ponatinib: (Major) Avoid coadministration of ponatinib with mitotane due to decreased plasma concentrations of ponatinib. If concomitant use is unavoidable, monitor for reduced efficacy of ponatinib. Ponatinib is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ponatinib exposure by 62%.
    Ponesimod: (Major) Avoid concurrent use of ponesimod and mitotane and monitor for decreased ponesimod efficacy if use is necessary. Ponesimod is a CYP3A substrate and mitotane is a strong CYP3A inducer that may decrease ponesimod exposure.
    Pralsetinib: (Major) Avoid coadministration of mitotane with pralsetinib due to the risk of decreased pralsetinib exposure which may reduce its efficacy. If concomitant use is unavoidable, double the current dose of pralsetinib starting on day 7 of coadministration. After mitotane has been discontinued for at least 14 days, resume the pralsetinib dose taken prior to initiating mitotane. Pralsetinib is a CYP3A substrate and mitotane is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased the pralsetinib AUC by 68%.
    Praziquantel: (Contraindicated) The concomitant use of mitotane with praziquantel is contraindicated due to decreased exposure and efficacy of praziquantel. If treatment with praziquantel is necessary, treatment with mitotane should be discontinued 4 weeks before administration of praziquantel. Treatment with mitotane can then be restarted 1 day after completion of praziquantel treatment. Mitotane is a strong CYP3A4 inducer and praziquantel is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of praziquantel. In a crossover study with a 2-week washout period, administration of praziquantel followed by another strong CYP3A inducer resulted in undetectable plasma concentrations of praziquantel in 7 out of 10 subjects. When praziquantel was administered two weeks after discontinuation of the strong inducer, the mean praziquantel AUC and Cmax were 23% and 35% lower, respectively, than when praziquantel was given alone.
    Prednisolone: (Moderate) Use caution if mitotane and prednisolone are used concomitantly, and monitor for decreased efficacy of prednisolone and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and prednisolone is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of prednisolone.
    Prednisone: (Moderate) Use caution if mitotane and prednisone are used concomitantly, and monitor for decreased efficacy of prednisone and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and prednisone is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of prednisone.
    Pretomanid: (Major) Avoid coadministration of pretomanid with mitotane as concurrent use may decrease pretomanid exposure which may lead to decreased efficacy. Pretomanid is a CYP3A4 substrate; mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased pretomanid exposure by 66%.
    Probenecid; Colchicine: (Major) Use caution if mitotane and colchicine are used concomitantly, and monitor for decreased efficacy of colchicine and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and colchicine is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of colchicine.
    Progesterone: (Moderate) Use caution if coadministration of mitotane with progesterone is necessary, as the systemic exposure of progesterone may be decreased resulting in reduced efficacy. Mitotane is a strong CYP3A4 inducer. Progesterone is metabolized primarily by hydroxylation via a CYP3A4. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
    Pseudoephedrine; Triprolidine: (Moderate) Mitotane can cause sedation, lethargy, vertigo, and other CNS side effects. Concomitant administration of mitotane and CNS depressants, including sedating h1-blockers, may cause additive CNS effects.
    Pyrilamine: (Moderate) Mitotane can cause sedation, lethargy, vertigo, and other CNS side effects. Concomitant administration of mitotane and CNS depressants, including sedating h1-blockers, may cause additive CNS effects.
    Quazepam: (Moderate) Use caution if mitotane and quazepam are used concomitantly, and monitor for decreased efficacy of quazepam and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and quazepam is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of quazepam. Additionally, mitotane can cause sedation, lethargy, vertigo, and other CNS adverse reactions; additive CNS effects may occur initially when mitotane is given concurrently with quazepam.
    Quetiapine: (Major) Use caution if mitotane and quetiapine are used concomitantly. If quetiapine is used with chronic (> 7 to 10 days) mitotane treatment, increase the dose of quetiapine by up to 5-fold, based on clinical response and tolerability. When mitotane is discontinued, reduce the dose of quetiapine to the original level within 7 to 14 days. Mitotane is a strong CYP3A4 inducer and quetiapine is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of quetiapine. Additionally, mitotane can cause sedation, lethargy, vertigo, and other CNS adverse reactions; additive CNS effects may occur initially when mitotane is given concurrently with quetiapine.
    Quinidine: (Major) Use caution if mitotane and quinidine are used concomitantly, and monitor for decreased efficacy of quinidine and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and quinidine is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of quinidine. Quinidine concentrations should be monitored closely after mitotane is added to the treatment regimen.
    Quinine: (Major) Use caution if mitotane and quinine are used concomitantly, and monitor for decreased efficacy of quinine and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and quinine is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of quinine. Another strong CYP3A inducer, rifampin, has been shown to significantly decreases the AUC (75% to 85%) and Cmax (55%) of quinine, resulting in treatment failures; concomitant use should be avoided.
    Rabeprazole: (Moderate) Use caution if mitotane and rabeprazole are used concomitantly, and monitor for decreased efficacy of rabeprazole and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and rabeprazole is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of rabeprazole.
    Ramelteon: (Major) Use caution if mitotane and ramelteon are used concomitantly, and monitor for decreased efficacy of ramelteon and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and ramelteon is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of ramelteon. Administration of another strong CYP inducer, rifampin, for 11 days resulted in a mean decrease of approximately 80% (40% to 90%) in total exposure to ramelteon and metabolite M-II, (both AUC and Cmax) after a single 32 mg dose of ramelteon.
    Ranolazine: (Contraindicated) The concomitant use of mitotane with ranolazine is contraindicated due to decreased ranolazine exposure and efficacy. Mitotane is a strong CYP3A4 inducer and ranolazine is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of ranolazine.
    Regorafenib: (Major) Avoid coadministration of regorafenib with mitotane due to decreased plasma concentrations of regorafenib and increased plasma concentrations of the M-5 active metabolite, which may lead to decreased efficacy. Regorafenib is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the mean AUC of regorafenib by 50% and increased the mean AUC of M-5 by 264%; no change in the mean AUC of M-2 was observed.
    Relugolix; Estradiol; Norethindrone acetate: (Major) Avoid coadministration of mitotane with norethindrone if used for contraception; consider an alternate or additional form of contraception. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of mitotane. Patients taking hormonal replacement therapy may need to be monitored for reduced clinical effect while on mitotane, with dose adjustments made based on clinical efficacy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. Women taking hormonal replacement and mitotane should report breakthrough bleeding, hot flashes, or other symptoms to their prescribers. Norethindrone is a substrate of CYP3A4 and mitotane is a strong CYP3A4 inducer. Concurrent administration of mitotane with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
    Repaglinide: (Major) Use caution if mitotane and repaglinide are used concomitantly, and monitor for decreased efficacy of repaglinide and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and repaglinide is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of repaglinide. When administered with another strong CYP3A inducer, rifampin, repaglinide AUC decreased by 31% and Cmax by 26%.
    Ribociclib: (Major) Avoid coadministration of mitotane with ribociclib due to decreased ribociclib exposure resulting decreased efficacy. Ribociclib is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ribociclib exposure in healthy subjects by 89%.
    Ribociclib; Letrozole: (Major) Avoid coadministration of mitotane with ribociclib due to decreased ribociclib exposure resulting decreased efficacy. Ribociclib is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ribociclib exposure in healthy subjects by 89%.
    Rifabutin: (Major) Use caution if mitotane and rifabutin are used concomitantly, and monitor for decreased efficacy of rifabutin and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and rifabutin is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of rifabutin.
    Rilpivirine: (Major) Concomitant use of mitotane with rilpivirine should be undertaken with caution due to potential decreased rilpivirine concentrations, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. The use of rilpivirine is contraindicated with other specific strong CYP3A inducers, including carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifampin, rifapentine, and St John's wort. Mitotane is a strong CYP3A4 inducer and rilpivirine is a CYP3A4 substrate. Coadministration may result in decreased rilpivirine serum concentrations, which could cause impaired virologic response to rilpivirine.
    Rimegepant: (Major) Avoid coadministration of rimegepant with mitotane; concurrent use may significantly decrease rimegepant exposure which may result in loss of efficacy. Rimegepant is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration of rimegepant with another strong CYP3A4 inducer decreased rimegepant exposure by 80%.
    Riociguat: (Major) Use caution if mitotane and riociguat are used concomitantly, and monitor for decreased efficacy of riociguat and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and riociguat is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of riociguat.
    Ripretinib: (Major) Avoid coadministration of ripretinib with mitotane. Coadministration may decrease the exposure of ripretinib and its active metabolite (DP-5439), which may decrease ripretinib anti-tumor activity. Ripretinib and DP-5439 are metabolized by CYP3A4 and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased ripretinib exposure by 61% and decreased DP-5439 exposure by 57%.
    Risperidone: (Major) The manufacturer of oral risperidone recommends a slow upward titration of the risperidone dose as needed up to double the patient's usual dose during use of a strong 3A4 inducer like mitotane. When using Risperdal Consta, the patient will require close monitoring for 4 to 8 weeks when starting mitotane. A lower dose of Risperdal Consta may be prescribed between 2 to 4 weeks before the planned discontinuation of mitotane to adjust for the expected increase in plasma concentrations of risperidone and its active metabolite. For patients treated with the recommended dose of Risperdal Consta 25 mg and discontinuing mitotane, it is recommended to continue the 25 mg dose unless a reduction to 12.5 mg or discontinuation of treatment is indicated. The efficacy of the 12.5 mg dose has not been studied in clinical trials. When initiating mitotane in patients receiving the long-acting subcutaneous risperidone injection (Perseris), close monitoring for 4 to 8 weeks is recommended. In patients receiving 90 mg of Perseris, consider increasing the dose to 120 mg. In patients receiving 120 mg of Perseris, additional oral risperidone may need to be considered. Upon discontinuation of mitotane in patients receiving 120 mg of Perseris, the dose of Perseris and additional use of oral risperidone should be re-evaluated and adjusted if necessary. For patients receiving 90 mg of Perseris, the current dose of Perseris may be maintained unless clinical circumstances require interruption of Perseris treatment.
    Ritonavir: (Major) Avoid the concomitant use of mitotane with ritonavir due to the potential for reduced antiretroviral efficacy and the potential development of viral resistance. If coadministration cannot be avoided, monitor for decreased efficacy of ritonavir. Mitotane is a strong CYP3A4 inducer and ritonavir is a CYP3A4 substrates; coadministration may result in decreased plasma concentrations of ritonavir. Another strong CYP3A inducer, rifampin (300 or 600 mg daily for 10 days), decreased the AUC and Cmax of ritonavir (500 mg every 12 hours for 20 days) by 35% and 25%, respectively.
    Rivaroxaban: (Major) Use caution if mitotane and rivaroxaban are used concomitantly, and monitor for decreased efficacy of rivaroxaban and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and rivaroxaban is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of rivaroxaban.
    Roflumilast: (Major) Concomitant use of mitotane with roflumilast is not recommended; if coadministration cannot be avoided, monitor for decreased efficacy of roflumilast. Mitotane is a strong CYP3A4 inducer and roflumilast is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of roflumilast. In an open-label, three-period, fixed-sequence study in 15 healthy volunteers, coadministration of another strong CYP3A inducer, rifampin (600 mg once daily for 11 days), with a single oral dose of roflumilast 500 mcg resulted in reduction of roflumilast Cmax and AUC by 68% and 79%, respectively. The pharmacokinetics of the active metabolite roflumilast N-oxide were also affected; roflumilast N-oxide Cmax was increased by 30% and AUC was decreased by 56%.
    Rolapitant: (Major) Avoid the concomitant use of mitotane with rolapitant; if coadministration cannot be avoided, monitor for decreased efficacy of rolapitant. Mitotane is a strong CYP3A4 inducer and rolapitant is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of rolapitant. When another strong CYP3A4 inducer, rifampin (600 mg once daily), was administered for 7 days before and 7 days after a single dose of rolapitant (180 mg), the mean Cmax and AUC of rolapitant were decreased by 30% and 85%, respectively; additionally, the mean half-life decreased from 176 hours to 41 hours.
    Romidepsin: (Major) Avoid the concomitant use of mitotane with romidepsin due to possible decreases in exposure and efficacy. Mitotane is a strong CYP3A4 inducer and romidepsin is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of romidepsin. Formal drug interaction studies have not been completed for romidepsin.
    Ropivacaine: (Moderate) Use caution if mitotane and ropivacaine are used concomitantly, and monitor for decreased efficacy of ropivacaine and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer. Ropivacaine is a CYP3A4 substrate, although inhibition of this enzyme does not lead to clinically relevant changes in ropivacaine clearance; coadministration may theoretically result in decreased plasma concentrations of ropivacaine.
    Ruxolitinib: (Moderate) Monitor patients frequently and adjust the ruxolitinib dose based on safety and efficacy if coadministered with mitotane; decreased ruxolitinib exposure is possible. Ruxolitinib is a CYP3A4 substrate; mitotane is a strong CYP3A4 inducer. Coadministration of another strong CYP3A4 inducer decreased ruxolitinib Cmax and AUC by 32% and 61%, respectively. The relative exposure to ruxolitinib's active metabolites increased approximately 100%.
    Saquinavir: (Major) Concomitant use of mitotane with saquinavir should be undertaken with caution due to potential decreased saquinavir concentrations, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Mitotane is a strong CYP3A4 inducer and saquinavir is a CYP3A4 substrate.
    SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
    Sedating H1-blockers: (Moderate) Mitotane can cause sedation, lethargy, vertigo, and other CNS side effects. Concomitant administration of mitotane and CNS depressants, including sedating h1-blockers, may cause additive CNS effects.
    Segesterone Acetate; Ethinyl Estradiol: (Major) Segesterone is not recommended for women who require chronic use of drugs that are potent inducers of hepatic enzymes, including mitotane, because contraception efficacy is likely to be reduced. Consider additional or alternative forms of contraception. Mitotane is a strong CYP3A4 inducer and progestins like segesterone are CYP3A4 substrates. Coadministration may result in decreased plasma concentrations of oral and other hormonal combination contraceptives.
    Selegiline: (Moderate) Use caution if selegiline and mitotane are used concomitantly. Although mitotane is a strong CYP3A4 inducer and selegiline is a CYP3A4 substrate, adequate studies have not been conducted to evaluate its effect, if any, on the effectiveness of selegiline.
    Selpercatinib: (Major) Avoid coadministration of selpercatinib and mitotane due to the risk of decreased selpercatinib exposure which may reduce its efficacy. Selpercatinib is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased selpercatinib exposure by 87%.
    Selumetinib: (Major) Avoid coadministration of selumetinib and mitotane due to the risk of decreased selumetinib exposure which may reduce its efficacy. Selumetinib is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased selumetinib exposure by 51%.
    Sibutramine: (Moderate) Use caution if mitotane and sibutramine are used concomitantly, and monitor for decreased efficacy of sibutramine and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and sibutramine is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of sibutramine.
    Sildenafil: (Major) Use caution if mitotane and sildenafil are used concomitantly, and monitor for decreased efficacy of sildenafil and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and sildenafil is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of sildenafil. Population pharmacokinetic analysis of data from patients in clinical trials indicated approximately 3-fold the sildenafil clearance when it was co-administered with mild CYP3A inducers.
    Silodosin: (Major) Use caution if mitotane and silodosin are used concomitantly, and monitor for decreased efficacy of silodosin and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and silodosin is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of silodosin.
    Simeprevir: (Major) Concomitant use of mitotane with simeprevir is not recommended as it could result in decreased plasma concentrations of simeprevir, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Mitotane is a strong CYP3A4 inducer and simeprevir is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of simeprevir. When coadministered with another strong CYP3A4 inducer (rifampin 600 mg daily; n = 18), the ratio of simeprevir pharmacokinetic parameters was significantly affected as follows (where 1 = no change): Cmax, 1.31 (90% CI, 1.03 to 1.66), AUC, 0.52 (90% CI, 0.41 to 0.67), and Cmin, 0.08 (90% CI, 0.06 to 0.11).
    Simvastatin: (Moderate) Use caution if mitotane and simvastatin are used concomitantly, and monitor for decreased efficacy of simvastatin and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and simvastatin is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of simvastatin.
    Simvastatin; Sitagliptin: (Moderate) Use caution if mitotane and simvastatin are used concomitantly, and monitor for decreased efficacy of simvastatin and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and simvastatin is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of simvastatin.
    Siponimod: (Moderate) Concomitant use of siponimod and mitotane is not recommended for patients with CYP2C9*1/*3 and *2/*3 genotypes due to a significant decrease in siponimod exposure. Use of siponimod with mitotane is not recommended in any patient if they are also receiving a moderate CYP2C9 inducer. Siponimod is a CYP2C9 and CYP3A4 substrate; mitotane is a strong CYP3A4 inducer. Coadministration with a moderate CYP2C9/strong CYP3A4 dual inducer decreased siponimod exposure by 57%.
    Sirolimus: (Major) Concomitant use of sirolimus and mitotane should be avoided. Mitotane may decrease the systemic exposure of sirolimus. Consider alternative agents with less potential for interaction. If concurrent use cannot be avoided, monitor sirolimus plasma concentrations closely and adjust the dose as necessary. Sirolimus is a substrate of CYP3A4, and mitotane is a potent CYP3A4 inducer.
    Sofosbuvir; Velpatasvir: (Major) Avoid coadministration of velpatasvir with mitotane. Taking these drugs together may significantly decrease velpatasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. Velpatasvir is a CYP3A4 substrate; mitotane is a potent inducer of CYP3A4.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Avoid coadministration of velpatasvir with mitotane. Taking these drugs together may significantly decrease velpatasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. Velpatasvir is a CYP3A4 substrate; mitotane is a potent inducer of CYP3A4. (Major) Avoid coadministration of voxilaprevir (a CYP3A4 substrate) with moderate to strong inducers of CYP3A4, such as mitotane. Taking these drugs together may significantly decrease voxilaprevir plasma concentrations, potentially resulting in loss of antiviral efficacy.
    Solifenacin: (Moderate) Use caution if mitotane and solifenacin are used concomitantly, and monitor for decreased efficacy of solifenacin and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and solifenacin is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of solifenacin.
    Sonidegib: (Major) Avoid the concomitant use of mitotane with sonidegib due to decreased sonidegib exposure and possible decreases in efficacy. Mitotane is a strong CYP3A4 inducer and sonidegib is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of sonidegib. Coadministration of a strong CYP3A4 inducer decreased the geometric mean Cmax and AUC of sonidegib by 54% and 72%, respectively.
    Sorafenib: (Major) Avoid coadministration of sorafenib with mitotane due to decreased plasma concentrations of sorafenib. Sorafenib is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Concomitant use with another strong CYP3A4 inducer decreased sorafenib exposure by 37%.
    Sotorasib: (Major) Avoid concurrent use of sotorasib and mitotane. Coadministration may decrease sotorasib exposure resulting in decreased efficacy. Sotorasib is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC of sotorasib by 51%.
    Sparsentan: (Major) Avoid concomitant use of sparsentan and mitotane due to the risk for decreased sparsentan exposure which may reduce its efficacy. Sparsentan is a CYP3A substrate and mitotane is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer is predicted to decrease sparsentan overall exposure by 47%.
    Spironolactone: (Moderate) An isolated case report indicated that mitotane activity might be antagonized by the concurrent administration of spironolactone. Until more data are available to confirm an interaction, the use of spironolactone with mitotane should be approached with caution.
    Spironolactone; Hydrochlorothiazide, HCTZ: (Moderate) An isolated case report indicated that mitotane activity might be antagonized by the concurrent administration of spironolactone. Until more data are available to confirm an interaction, the use of spironolactone with mitotane should be approached with caution.
    Stiripentol: (Major) Avoid coadministration of stiripentol with mitotane. If concurrent use is necessary, increase the dose of stiripentol. Coadministration may decrease stiripentol plasma concentrations resulting in a decrease in efficacy. Stiripentol is metabolized by CYP3A4; mitotane is a strong inducer of CYP3A4.
    Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if mitotane must be administered. Monitor for reduced efficacy of sufentanil injection and signs of opioid withdrawal if coadministration with mitotane is necessary; consider increasing the dose of sufentanil injection as needed. If mitotane is discontinued, consider a dose reduction of sufentanil injection and frequently monitor for signs or respiratory depression and sedation. Sufentanil is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease sufentanil concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Sunitinib: (Major) Avoid coadministration of mitotane with sunitinib if possible due to decreased exposure to sunitinib which could decrease efficacy. If concomitant use is unavoidable, consider increasing the daily dose of sunitinib to a maximum of 87.5 mg for patients with GIST or RCC, and to a maximum of 62.5 mg for patients with pNET; monitor carefully for toxicity. Sunitinib is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased exposure to sunitinib and its primary active metabolite by 46%.
    Suvorexant: (Moderate) Monitor for decreased efficacy of suvorexant if coadministration with mitotane is necessary. Suvorexant is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased suvorexant exposure by 77% to 88%.
    Tacrolimus: (Major) Use caution if mitotane and tacrolimus are used concomitantly, and monitor for decreased efficacy of tacrolimus and a possible change in dosage requirements. Monitor tacrolimus whole blood trough concentrations and adjust the dose of tacrolimus as necessary. Mitotane is a strong CYP3A4 inducer and tacrolimus is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of tacrolimus. Concomitant administration of immediate-release tacrolimus and another strong CYP3A inducer, rifampin, resulted in a significant decrease in the mean tacrolimus bioavailability (from 14% to 7%) and a significant increase in the mean tacrolimus clearance (from 0.035 L/hr/kg to 0.053 L/hr/kg) compared with tacrolimus alone in 6 healthy subjects. In another pharmacokinetic study in 22 healthy male subjects, the administration of a single 10 mg dose of extended-release tacrolimus (Astagraf XL) following 12 days of rifampin 600 mg/day decreased mean tacrolimus AUC and Cmax values by 56% and 46%, respectively.
    Tadalafil: (Major) Avoid coadministration of tadalafil with mitotane in patients with pulmonary hypertension due to decreased plasma concentrations of tadalafil. In patients with erectile dysfunction and/or benign prostatic hyperplasia, consider the potential for loss of efficacy of tadalafil during concurrent administration of mitotane due to reduced tadalafil exposure. Tadalafil is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased tadalafil exposure by 88%.
    Tamoxifen: (Major) Avoid coadministration of mitotane with tamoxifen due to decreased exposure to tamoxifen which may affect efficacy. Tamoxifen is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of tamoxifen by 86% and 55%, respectively.
    Tamsulosin: (Moderate) Use caution if mitotane and tamsulosin are used concomitantly, and monitor for decreased efficacy of tamsulosin and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and tamsulosin is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of tamsulosin.
    Tasimelteon: (Major) Avoid the concomitant use of mitotane with tasimelteon due to decreased tasimelteon exposure and possible decreases in efficacy. Mitotane is a strong CYP3A4 inducer and tasimelteon is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of tasimelteon. During administration of tasimelteon with another potent inducer of CYP3A4, tasimelteon exposure decreased by about 90%.
    Tazemetostat: (Major) Avoid coadministration of tazemetostat with mitotane as concurrent use may decrease tazemetostat exposure, which may reduce its efficacy. Tazemetostat is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer.
    Telmisartan; Amlodipine: (Moderate) Use caution if mitotane and amlodipine are used concomitantly, and monitor for decreased efficacy of amlodipine and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and amlodipine is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of amlodipine.
    Temsirolimus: (Major) Avoid coadministration of temsirolimus with mitotane due to the risk of decreased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus). If concomitant use is unavoidable, consider increasing the dose of temsirolimus from 25 mg per week up to 50 mg per week. If mitotane is discontinued, decrease the dose of temsirolimus to the dose used before initiation of mitotane. Temsirolimus is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer had no significant effect on the AUC or Cmax of temsirolimus, but decreased the AUC and Cmax of the active metabolite, sirolimus, by 56% and 65%, respectively.
    Teniposide: (Moderate) Monitor patients for reduced efficacy of teniposide if coadministration with mitotane is necessary. Teniposide is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with other strong CYP3A4 inducers reduced plasma concentrations of teniposide.
    Tezacaftor; Ivacaftor: (Major) Coadministration of ivacaftor with mitotane is not recommended due to decreased plasma concentrations of ivacaftor. Ivacaftor is a sensitive CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer significantly decreased ivacaftor exposure by approximately 9-fold. (Major) Do not administer tezacaftor; ivacaftor and mitotane together; coadministration may reduce the efficacy of tezacaftor; ivacaftor. Exposure to ivacaftor is significantly decreased and exposure to tezacaftor may be reduced by the concomitant use of mitotane, a strong CYP3A inducer; both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate). Coadministration of ivacaftor with a strong CYP3A inducer decreased ivacaftor exposure 89%.
    Theophylline, Aminophylline: (Major) Use caution if mitotane and theophylline, aminophylline are used concomitantly, and monitor for decreased efficacy of theophylline and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and theophylline is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of theophylline. When administered with other moderate to strong CYP3A inducers, average steady-state theophylline concentrations decreased by 25 to 40%.
    Thiotepa: (Major) Avoid the concomitant use of thiotepa and mitotane if possible; increased metabolism to the active thiotepa metabolite may result in increased thiotepa toxicity (e.g., infection, bleeding, skin toxicity). Consider an alternative agent with no or minimal potential to induce CYP3A4. If coadministration is necessary, monitor patients for signs and symptoms of thiotepa toxicity. In vitro, thiotepa is metabolized via CYP3A4 to the active metabolite, TEPA; mitotane is a strong CYP3A4 inducer.
    Tiagabine: (Major) Use caution if mitotane and tiagabine are used concomitantly, and monitor for decreased efficacy of tiagabine and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and tiagabine is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of tiagabine.
    Ticagrelor: (Major) Avoid the concomitant use of mitotane with ticagrelor due to decreased ticagrelor exposure and efficacy. Mitotane is a strong CYP3A4 inducer and ticagrelor is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of ticagrelor.
    Tinidazole: (Major) Use caution if mitotane and tinidazole are used concomitantly, and monitor for decreased efficacy of tinidazole and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and tinidazole is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of tinidazole.
    Tipranavir: (Contraindicated) Tipranavir is contraindicated for use with mitotane. Mitotane is a strong CYP3A4 inducer and tipranavir is a CYP3A4 substrate; coadministration significantly reduces plasma concentrations of tipranavir, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance.
    Tivozanib: (Major) Avoid concomitant use of tivozanib with mitotane due to decreased plasma concentrations of tivozanib, which may reduce its efficacy. Tivozanib is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the overall exposure of tivozanib by 52%.
    Tofacitinib: (Major) Coadministration of tofacitinib and mitotane is not recommended due to the potential for a loss of response or reduced clinical response to tofacitinib. Tofacitinib is a CYP3A4 substrate; mitotane is a strong CYP3A4 inducer. Tofacitinib exposure is decreased when coadministered with strong CYP3A4 inducers. In one study, the mean AUC and Cmax of tofacitinib were decreased by 84% and 74%, respectively when administered with another strong CYP3A4 inducer.
    Tolterodine: (Moderate) Use caution if mitotane and tolterodine are used concomitantly, and monitor for decreased efficacy of tolterodine and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer. CYP2D6 is primarily responsible for converting tolterodine to its active metabolite is CYP2D6; however, in the roughly 7% of the Caucasian population devoid of this isozyme ('poor metabolizers'), the drug is metabolized via CYP3A4 to N-dealkylated tolterodine. Coadministration could result in decreased plasma concentrations of tolterodine.
    Tolvaptan: (Major) Avoid concurrent use of tolvaptan and mitotane due to the risk for decreased tolvaptan plasma concentrations and reduced efficacy. Tolvaptan is a sensitive CYP3A substrate and mitotane is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased tolvaptan exposure by 85%.
    Toremifene: (Major) Avoid coadministration of mitotane with toremifene due to decreased plasma concentrations of toremifene which may result in decreased efficacy. Toremifene is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with strong CYP3A4 inducers lowers steady-state serum concentrations of toremifene.
    Trabectedin: (Major) Avoid the concomitant use of trabectedin with mitotane due to the risk of decreased trabectedin exposure. Trabectedin is a CYP3A substrate and mitotane is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased the systemic exposure of a single dose of trabectedin by 31% compared to a single dose of trabectedin given alone.
    Tramadol: (Major) Use caution if mitotane and tramadol are used concomitantly, and monitor for decreased efficacy of tramadol and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer. The metabolism of tramadol is stereoselective; the (+) enantiomer preferentially undergoes N-demethylation, mediated by CYP3A4 and CYP2B6, and the (-) enantiomer undergoes O-demethylation via CYP2D6. O-demethylation leads to the production of the active metabolite M1, which is critical to tramadol activity. Because of the role of CYP3A4 in tramadol metabolism, coadministration with mitotane may affect patient response to tramadol.
    Tramadol; Acetaminophen: (Major) Use caution if mitotane and tramadol are used concomitantly, and monitor for decreased efficacy of tramadol and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer. The metabolism of tramadol is stereoselective; the (+) enantiomer preferentially undergoes N-demethylation, mediated by CYP3A4 and CYP2B6, and the (-) enantiomer undergoes O-demethylation via CYP2D6. O-demethylation leads to the production of the active metabolite M1, which is critical to tramadol activity. Because of the role of CYP3A4 in tramadol metabolism, coadministration with mitotane may affect patient response to tramadol. (Minor) Use caution if mitotane and acetaminophen are used concomitantly, and monitor for decreased efficacy of acetaminophen. Mitotane is a strong CYP3A4 inducer and acetaminophen is a minor (10% to 15%) CYP3A4 substrate; coadministration may result in decreased plasma concentrations of acetaminophen.
    Trandolapril; Verapamil: (Moderate) Use caution if mitotane and verapamil are used concomitantly, and monitor for decreased efficacy of verapamil and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and verapamil is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of verapamil.
    Trazodone: (Moderate) Consider increasing the trazodone dose based on therapeutic response when coadministered with mitotane. Concurrent use may decrease trazodone exposure. Trazodone is a CYP3A4 substrate; mitotane is a strong CYP3A4 inducer. Coadministration with other strong CYP3A4 inducers decreased the exposure of trazodone compared to the use of trazodone alone.
    Triazolam: (Moderate) Use caution if mitotane and triazolam are used concomitantly, and monitor for decreased efficacy of triazolam and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and triazolam is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of triazolam. Additionally, mitotane can cause sedation, lethargy, vertigo, and other CNS adverse reactions; additive CNS effects may occur initially when mitotane is given concurrently with triazolam.
    Triprolidine: (Moderate) Mitotane can cause sedation, lethargy, vertigo, and other CNS side effects. Concomitant administration of mitotane and CNS depressants, including sedating h1-blockers, may cause additive CNS effects.
    Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
    Tucatinib: (Major) Avoid coadministration of tucatinib and mitotane due to the risk of decreased tucatinib exposure which may reduce its efficacy. Tucatinib is a CYP3A4 and CYP2C8 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with a strong CYP3A4/moderate CYP2C8 inducer decreased tucatinib exposure by 50%.
    Ubrogepant: (Major) Avoid the coadministration of ubrogepant and mitotane as concurrent use may decrease ubrogepant exposure and reduce the efficacy. Ubrogepant is a CYP3A4 substrate; mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer resulted in an 80% reduction in ubrogepant exposure.
    Ulipristal: (Major) Avoid administration of ulipristal with drugs that induce CYP3A4. Ulipristal is a substrate of CYP3A4 and mitotane is a CYP3A4 inducer. Concomitant use may decrease the plasma concentration and effectiveness of ulipristal.
    Umeclidinium; Vilanterol: (Moderate) Use caution if mitotane and vilanterol are used concomitantly (including combination products fluticasone; vilanterol and umeclidinium; vilanterol), and monitor for decreased efficacy of vilanterol and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and vilanterol is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of vilanterol.
    Upadacitinib: (Major) Coadministration of upadacitinib with mitotane is not recommended as upadacitinib exposure may be decreased leading to reduced therapeutic effect. Upadacitinib is CYP3A4 substrate; mitotane is a strong CYP3A4 inducer. Concurrent use of a strong CYP3A4 inducer decreased upadacitinib exposure by 61%.
    Valbenazine: (Major) Co-administration of strong CYP3A4 inducers, such as mitotane, and valbenazine, a CYP3A4 substrate, is not recommended. Strong CYP3A4 inducers can decrease systemic exposure of valbenazine and its active metabolite compared to the use of valbenazine alone. Reduced exposure of valbenazine and its active metabolite may reduce efficacy.
    Vandetanib: (Major) Avoid coadministration of vandetanib with mitotane due to decreased plasma concentrations of vandetanib and increased concentrations of the active metabolite. Vandetanib is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Concomitant use with another strong CYP3A4 inducer decreased the geometric mean AUC of vandetanib by 40%; the geometric mean AUC and Cmax of N-desmethylvandetanib increased by 266% and 414%, respectively.
    Vemurafenib: (Major) Avoid the concomitant use of vemurafenib and mitotane; significantly decreased vemurafenib exposure may occur resulting in reduced vemurafenib efficacy. Consider the use of an alternative agent. If use with mitotane cannot be avoided, increase the vemurafenib dose by 240 mg (as tolerated). If mitotane is discontinued, the previous (lower) vemurafenib dose may be resumed 2 weeks after the last mitotane dose. Vemurafenib is a CYP3A4 substrate; mitotane is a strong CYP3A4 inducer. In a drug interaction study, the vemurafenib AUC value decreased by 40% (90% CI, 24% to 53%) when a single 960-mg vemurafenib dose was administered with another strong CYP3A4 inducer; the vemurafenib Cmax was not changed.
    Venetoclax: (Major) Avoid the concomitant use of venetoclax and mitotane; venetoclax levels may be significantly decreased and its efficacy reduced. Venetoclax is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Consider alternative agents. In a drug interaction study in healthy subjects (n = 10), the venetoclax Cmax and AUC values were decreased by 42% and 71%, respectively, following the co-administration of multiple doses of a strong CYP3A4 inducer.
    Venlafaxine: (Moderate) Use caution if mitotane and venlafaxine are used concomitantly, and monitor for decreased efficacy of venlafaxine and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and venlafaxine is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of venlafaxine.
    Verapamil: (Moderate) Use caution if mitotane and verapamil are used concomitantly, and monitor for decreased efficacy of verapamil and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and verapamil is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of verapamil.
    Vilazodone: (Moderate) Consider increasing the dose of vilazodone up to 2-fold over 1 to 2 weeks (maximum, 80 mg per day) based on clinical response if coadministration with mitotane is necessary for more than 14 days. After discontinuation of mitotane, resume the previous vilazodone dose over 1 to 2 weeks. Vilazodone is primarily metabolized by CYP3A4 and mitotane is a strong CYP3A4 inducer. Decreased plasma concentrations of vilazodone are expected if vilazodone is used concomitantly with strong CYP3A4 inducers.
    Vincristine Liposomal: (Major) Concomitant use of mitotane with vincristine should be undertaken with caution as it could result in decreased plasma concentrations of vincristine, leading to reduced efficacy. Mitotane is a strong CYP3A4 inducer and vincristine is a CYP3A4 substrate.
    Vincristine: (Major) Concomitant use of mitotane with vincristine should be undertaken with caution as it could result in decreased plasma concentrations of vincristine, leading to reduced efficacy. Mitotane is a strong CYP3A4 inducer and vincristine is a CYP3A4 substrate.
    Voclosporin: (Major) Avoid coadministration of voclosporin with mitotane. Coadministration may decrease voclosporin exposure resulting in decreased efficacy. Voclosporin is a sensitive CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased voclosporin exposure by 87%.
    Vonoprazan; Amoxicillin: (Major) Avoid concomitant use of vonoprazan and mitotane due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and mitotane is a strong CYP3A inducer. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer.
    Vonoprazan; Amoxicillin; Clarithromycin: (Major) Avoid concomitant use of vonoprazan and mitotane due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and mitotane is a strong CYP3A inducer. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer. (Major) Coadministration of mitotane and clarithromycin may decrease clarithromycin serum concentrations due to CYP3A4 enzyme induction. While the 14-OH-clarithromycin active metabolite concentrations are increased, this metabolite has different antimicrobial activity compared to clarithromycin. The intended therapeutic effect of clarithromycin could be decreased. It is not clear if clarithromycin activity against other organisms would be reduced, but reduced efficacy is possible. Alternatives to clarithromycin should be considered in patients who are taking potent CYP3A4 inducers.
    Vorapaxar: (Major) Avoid the concomitant use of mitotane with vorapaxar; if coadministration cannot be avoided, monitor for decreased efficacy of vorapaxar. Mitotane is a strong CYP3A4 inducer and vorapaxar is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of vorapaxar.
    Voriconazole: (Major) Avoid the concomitant use of mitotane with voriconazole. Mitotane is a strong CYP3A4 inducer and voriconazole is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of voriconazole. Coadministration with other strong CYP3A inducers is either contraindicated (i.e., carbamazepine, rifampin, efavirenz, St. John's Wort, long-acting barbiturates) or requires an increased dose of voriconazole (i.e., phenytoin); specific recommendations are not available for use with mitotane or strong CYP3A inducers generally.
    Vortioxetine: (Major) Vortioxetine is extensively metabolized by CYP isoenzymes, primarily CYP2D6 and by CYP3A4 and other isoenzymes to a lesser extent. Therefore, the manufacturer recommends that the practitioner consider an increase in dose of vortioxetine when a strong CYP inducer, such as mitotane, is co-administered for more than 14 days. In such cases, the maximum recommended dose of vortioxetine should not exceed three times the original dose. When the inducer is discontinued, the dose of vortioxetine should be reduced to the original level within 14 days.
    Voxelotor: (Major) Avoid coadministration of voxelotor and mitotane as concurrent use may decrease voxelotor exposure and lead to reduced efficacy. If coadministration is unavoidable, increase voxelotor dosage to 2,500 mg PO once daily in patients 12 years and older. In patients 4 to 11 years old, weight-based dosage adjustments are recommended; consult product labeling for specific recommendations. Voxelotor is a substrate of CYP3A; mitotane is a strong CYP3A inducer. Coadministration of voxelotor with a strong CYP3A inducer is predicted to decrease voxelotor exposure by up to 40%.
    Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with mitotane is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. Mitotane is a strong CYP3A4 inducer and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
    Zaleplon: (Moderate) Monitor for decreased efficacy of zaleplon if coadministration with mitotane is necessary. Zaleplon is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Although CYP3A4 is normally a minor metabolizing enzyme of zaleplon, coadministration with another strong CYP3A4 inducer reduced zaleplon exposure by approximately 80%. Coadministration with mitotane could lead to ineffectiveness of zaleplon.
    Zanubrutinib: (Major) Avoid the concomitant use of zanubrutinib and mitotane. Coadministration may result in decreased zanubrutinib exposure and reduced efficacy. Zanubrutinib is a CYP3A4 substrate; mitotane is a strong CYP3A4 inducer. The AUC of zanubrutinib was decreased by 93% when coadministered with another strong CYP3A4 inducer.
    Zileuton: (Moderate) Use caution if mitotane and zileuton are used concomitantly, and monitor for decreased efficacy of zileuton and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and zileuton is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of zileuton.
    Ziprasidone: (Major) Use caution if mitotane and ziprasidone are used concomitantly, and monitor for decreased efficacy of ziprasidone and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and ziprasidone is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of ziprasidone. The concurrent use of ziprasidone with carbamazepine, a potent CYP3A4 inducer, causes a 35% decrease in the AUC of ziprasidone. Additionally, mitotane can cause sedation, lethargy, vertigo, and other CNS adverse reactions; additive CNS effects may occur initially when mitotane is given concurrently with ziprasidone.
    Zolmitriptan: (Minor) Use caution if mitotane and zolmitriptan are used concomitantly, and monitor for decreased efficacy of zolmitriptan and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and zolmitriptan is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of zolmitriptan. Another strong CYP3A inducer, rifampin, results in small decreases in zolmitriptan peak plasma concentrations (decreased 15%) and AUC (decreased 18%), as well as decreased plasma concentrations of a metabolite of zolmitriptan. This interaction is not likely to be clinically significant.
    Zolpidem: (Major) Concurrent use of zolpidem with potent CYP3A4 inducers, such as mitotane, should be avoided if possible because decreased plasma concentrations of zolpidem are possible and efficacy may be reduced. CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism, and there is evidence of significant decreases in systemic exposure and pharmacodynamics effects of zolpidem during co-administration of rifampin, a potent CYP3A4 inducer. Additionally, mitotane can cause sedation, lethargy, vertigo, and other CNS adverse reactions; additive CNS effects may occur when mitotane is given with zolpidem.
    Zonisamide: (Major) Use caution if mitotane and zonisamide are used concomitantly, and monitor for decreased efficacy of zonisamide and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and zonisamide is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of zonisamide. Concomitant administration of other strong CYP3A inducerse, phenytoin and carbamazepine, increase zonisamide plasma clearance from 0.30 to 0.35 mL/min/kg to 0.35 to 0.5 mL/min/kg. The half-life of zonisamide is decreased to 27 hours by phenytoin, to 38 hours by phenobarbital and carbamazepine, and to 46 hours by valproate.

    PREGNANCY AND LACTATION

    Pregnancy

    Mitotane can cause fetal harm when administered to a pregnant woman. Abnormal pregnancy outcomes such as preterm births and early pregnancy loss have been reported in limited post-marketing reports of human patients exposed to mitotane during pregnancy. Animal reproduction studies have not been conducted. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Women of childbearing potential are advised to use effective contraception during treatment and after discontinuation of treatment for as long as mitotane plasma levels are detectable.

    Mitotane has been detected in breast milk. Because of the potential for serious adverse reactions in a nursing infant from mitotane, advise women to discontinue breast-feeding during mitotane therapy and after treatment discontinuation for as long as mitotane plasma levels are detectable.

    MECHANISM OF ACTION

    Mechanism of Action: Mitotane's mechanism of action is unclear. It appears that the drug selectively inhibits certain functions of the adrenal cortex by binding to mitochondrial proteins. Steroid synthesis is disturbed, leading to adrenal atrophy and tumor death. The drug causes atrophy in the zona fasciculata and the reticularis regions of the adrenal cortex. The site of aldosterone biosynthesis (zona glomerulosa) is only minimally damaged by mitotane therapy, except in cases of prolonged therapy, which can cause extensive degeneration of this area. Mitotane inhibits production of corticosteroids and changes the extraadrenal metabolism of endogenous and exogenous steroids. The drug can have a suppressive effect on the pituitary corticotropin-secreting cells.

    PHARMACOKINETICS

    Mitotane is administered orally. It is lipophilic and widely distributed throughout the body, primarily accumulating in adipose tissue. The median terminal half-life is 53 days (range, 18 to 59 days). Approximately 10% of a dose is recovered in the urine as a water-soluble metabolite, while 1% to 17% is excreted into the bile as this metabolite; no unchanged drug is found in the urine or bile.
     
    Affected cytochrome P450 isoenzymes and drug transporters:  CYP3A4
    Mitotane is a strong CYP3A4 inducer; if coadministration of CYP3A4 substrates is necessary, monitor for a change in dosing requirements.

    Oral Route

    The bioavailability of mitotane is 40% after oral administration.