CONTRAINDICATIONS / PRECAUTIONS
General Information
NOTE: This monograph discusses the use of aspirin; ASA; butalbital; caffeine combination products. Clinicians may wish to consult the individual monographs for more information about the specific contraindications and precautions for each agent.
Acute bronchospasm, angioedema, asthma, barbiturate hypersensitivity, carbamazepine hypersensitivity, hydantoin hypersensitivity, nasal polyps, NSAID hypersensitivity, salicylate hypersensitivity, tartrazine dye hypersensitivity, urticaria
Aspirin; ASA; butalbital; caffeine is contraindicated in patients with caffeine hypersensitivity, barbiturate hypersensitivity, salicylate hypersensitivity, NSAID hypersensitivity, or hypersensitivity to any of the other product components. Some product formulations may contain tartrazine; do not use such products in patients with tartrazine dye hypersensitivity. The risk of cross-sensitivity with other nonsteroidal antiinflammatory drugs is significantly greater with aspirin than other salicylates. Salicylate or NSAID hypersensitivity may exhibit as drug-induced angioedema, urticaria, nasal polyps, acute bronchospasm, and/or asthma activation after taking aspirin or other NSAIDs. Aspirin-containing products should be used with caution in patients with preexisting asthma since there is a higher risk for aspirin sensitivity (aspirin triad). The risk of hypersensitivity reactions to barbiturates may be higher in patients who previously experienced hydantoin hypersensitivity (e.g., phenytoin) or carbamazepine hypersensitivity as compared to the general population. Estimates of cross-sensitivity vary, but may range from 30—80%. There is no way to predict with certainty which patients will exhibit cross-sensitivity.
Porphyria
Aspirin; ASA; butalbital; caffeine should not be used in patients with porphyria because it may trigger symptoms of the disease. Barbiturates can stimulate the accumulation of porphyrin precursors.
Acute myocardial infarction, angina, cardiac arrhythmias, cardiac disease, depression, hypertension, hypotension, mental status changes, suicidal ideation
Aspirin; ASA; butalbital; caffeine should be used with caution in patient with mental status changes such as major depression or suicidal ideation due to potential exacerbation of these conditions by the CNS depressant effects or butalbital. Aspirin; ASA; butalbital; caffeine should be prescribed cautiously to certain high risk patients such as the elderly or debilitated patients, patients with cardiac disease (e.g., angina, cardiac arrhythmias, hypertension, hypotension, or immediately following an acute myocardial infarction) because of possible adverse hemodynamic effects.
Acid/base imbalance, chronic obstructive pulmonary disease (COPD), metabolic acidosis, metabolic alkalosis, pulmonary disease, respiratory acidosis, respiratory alkalosis, respiratory depression, sleep apnea, status asthmaticus
The respiratory effects of salicylates may contribute to serious acid/base imbalance in patients with underlying acid/base disorders (e.g., metabolic acidosis, metabolic alkalosis, respiratory acidosis, or respiratory alkalosis) or in overdose situations. Patients who are unable to compensate for salicylate-induced metabolic acidosis (i.e., respiratory response to CO2 is depressed) will develop respiratory acidosis and increased levels of plasma CO2. Because butalbital can cause dose-dependent respiratory depression, it should be used cautiously in patients with pulmonary disease states causing respiratory depression, dyspnea, severe pulmonary insufficiency or airway obstruction. Barbiturates should be avoided in patients with bronchopneumonia. Use with close supervision in patients with sleep apnea or chronic obstructive pulmonary disease (COPD) asthmatic disease or status asthmaticus.
Diabetes mellitus, hypothyroidism, prostatic hypertrophy, renal disease, renal failure, renal impairment, systemic lupus erythematosus (SLE), thyroid disease, urethral stricture
Aspirin; ASA; butalbital; caffeine should be used carefully in patients with diabetes mellitus, inflammatory bowel disease, prostatic hypertrophy, urethral stricture or thyroid disease (i.e., hypothyroidism). Aspirin; butalbital; caffeine should be used with caution in patients with renal disease, renal impairment and with extreme caution, if at all, in patients with advanced, chronic renal failure since metabolites of aspirin, including salicylic acid, are renally excreted. In addition, these patients may be at increased risk of developing salicylate-induced nephrotoxicity. Aspirin; butalbital; caffeine should be used cautiously in patients with renal disease or systemic lupus erythematosus (SLE) due to the risk of decreased glomerular filtration rate in these patients.
Anticoagulant therapy, thrombolytic therapy
Since aspirin inhibits platelet aggregation and increases bleeding time, aspirin, ASA; butalbital; caffeine may interact with anticoagulant therapy or thrombolytic therapy. Butalbital may decrease the effect of oral coumarin anticoagulants (e.g., warfarin) and necessitate coumarin dosage adjustment for optimal effect. Conversely, when the drug is discontinued, the dose of the anticoagulant may have to be decreased.
Agranulocytosis, anemia, coagulopathy, hematological disease, hemophilia, hypoprothrombinemia, thrombocytopenia, thrombotic thrombocytopenic purpura (TTP), vitamin K deficiency, von Willebrand's disease
Since aspirin inhibits platelet aggregation and increases bleeding time, aspirin, ASA; butalbital; caffeine use is contraindicated in patients with hematological disease, including coagulopathy, hemophilia, hypoprothrombinemia, von Willebrand's disease, thrombocytopenia, severe liver disease, vitamin K deficiency, aplastic anemia, agranulocytosis, pancytopenia, or thrombotic thrombocytopenic purpura (TTP).
Bone marrow suppression, immunosuppression, infection, neutropenia, pain
Aspirin, ASA; butalbital; caffeine should be used with caution in patients with immunosuppression or neutropenia following myelosuppressive chemotherapy. Aspirin may mask signs of infection, such as fever and pain, in patients with bone marrow suppression or immunosuppression.
Hepatic disease, hepatic encephalopathy, hepatitis
Since aspirin inhibits platelet aggregation and increases bleeding time, aspirin, ASA; butalbital; caffeine is contraindicated in patients with severe hepatic disease; use with caution, if at all, in patients with hepatitis. Because barbiturates may impair the ability of the liver to metabolize ammonia, barbiturates are best avoided in patients with hepatic encephalopathy. Note that barbiturates are hepatic enzyme inducers and patients should be monitored for altered drug levels and therapeutic effects as indicated.
Alcoholism, bleeding, esophagitis, gastritis, GI bleeding, peptic ulcer disease, surgery, tobacco smoking
Aspirin inhibits platelet aggregation and can increase the risk for bleeding. Aspirin can induce gastric or intestinal ulceration that can occasionally be accompanied by iron-deficiency anemia or other anemia from the resultant blood loss. Aspirin; butalbital; caffeine should not be used in patients with known peptic ulcer disease and should be used cautiously, if at all, in patients with a history of or active GI disease including erosive gastritis, esophagitis, GI bleeding, or previous NSAID-induced bleeding. Such patients should be monitored closely. Risk factors for peptic ulcer disease include tobacco smoking and patients with alcoholism. The risk of an aspirin-induced GI bleed is greater in the elderly. All patients receiving chronic aspirin treatment should be routinely monitored for potential GI ulceration and bleeding. Aspirin; butalbital; caffeine should generally be discontinued at least 1 week before surgery to minimize postoperative bleeding.
G6PD deficiency
Because salicylates may cause or aggravate hemolysis in patients with G6PD deficiency, some reference texts state that aspirin should be used cautiously in these patients. If hemolytic anemia occurs in patients receiving aspirin, it almost always occurs in G6PD-deficient individuals. Otherwise, hemolysis only occurs at high concentrations.
CNS depression, coadministration with other CNS depressants, driving or operating machinery
Aspirin; butalbital; caffeine may cause drowsiness or dizziness, consistent with the central nervous system (CNS) effects of butalbital. This product may impair mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving or operating machinery. Such tasks should be avoided while taking this product. Alcohol and other CNS depressants may produce an additive CNS depression with aspirin; butalbital; caffeine and coadministration with other CNS depressants should be avoided. Because butalbital can cause drowsiness and a decreased level of consciousness, there is a higher risk of falls, particularly in the elderly, with the potential for subsequent severe injuries.
Children, infants, influenza, neonates, Reye's syndrome, varicella, viral infection
Aspirin has been associated with the occurrence of Reye's syndrome when given to children with varicella (i.e., chickenpox) or influenza. Although a causal relationship has not been confirmed, most authorities advise against the use of aspirin in neonates, infants, or children with varicella, influenza, or other viral infection. If children are receiving chronic aspirin therapy, aspirin should be discontinued immediately if a fever develops and not resumed until diagnosis confirms that the febrile viral illness has run its course and the absence of Reye's syndrome. After varicella vaccination, aspirin use should generally be avoided for 6 weeks. Children receiving long-term aspirin therapy should receive the annual influenza vaccine.
Abrupt discontinuation, substance abuse
Butalbital is habit-forming, and there is the potential for substance abuse. Tolerance, psychological dependence, and physical dependence may occur especially after prolonged use. Consequently, extended use of aspirin; butalbital; caffeine is not recommended. Abrupt discontinuation of prolonged butalbital therapy can result in withdrawal symptoms. Gradually taper patients off butalbital to avoid a withdrawal reaction. Barbiturate-dependent patients can be withdrawn by using a number of different withdrawal regimens; consider gradually decreasing the daily dosage as tolerated by the patient.
Gout
In patients with gout, salicylates such as aspirin may increase serum uric acid concentrations, resulting in hyperuricemia, and interfere with the efficacy of uricosuric agents.
Ascites, dehydration, heart failure, hypovolemia, sodium restriction
Caution is advised with aspirin use in patients requiring sodium restriction or patients with hypovolemic states (e.g., ascites, dehydration, heart failure, hypertension, or hypovolemia) as they may be more susceptible to adverse renal effects of salicylate therapy. Patients with sodium-retaining states, such as congestive heart failure or renal failure, should avoid sodium-containing buffered aspirin preparations because of their high sodium content.
Geriatric
Aspirin; ASA; butalbital; caffeine should be used with caution in certain high-risk patients such as geriatric or debilitated patients because of the risk for central nervous system (CNS), respiratory depressant, and hemodynamic effects to barbiturates. Because butalbital can cause drowsiness and a decreased level of consciousness, there is a higher risk of falls, particularly in the elderly, with the potential for subsequent severe injuries. The risk of an aspirin-induced gastrointestinal (GI) side effects and GI bleed is greater in the elderly.[28502] According to the Beers Criteria, barbiturates are potentially inappropriate medications (PIMs) in geriatric patients; avoid use due to the high rate of physical dependence, tolerance to sedative effects, and risk of overdose at low dosages. Aspirin is also a PIM in selected geriatric patients. Aspirin may cause new or worsening gastric or duodenal ulcers, and there is an increased risk of GI bleeding and peptic ulcer disease in high-risk groups including those above 75 years of age, or those taking oral or parenteral corticosteroids, anticoagulants, or antiplatelet medications. The risk of ulcers, gross bleeding, or perforation is cumulative with continued use. The Beers panel recommends avoiding chronic use of aspirin doses above 325 mg/day in high-risk patients unless other alternatives are not effective and a gastroprotective agent can be used. Also, aspirin doses above 325 mg/day should be avoided in patients with a history of gastric or duodenal ulcers, unless other alternatives are not effective and the patient can take a gastroprotective agent. Gastroprotection reduces but does not eliminate GI risks.[63923] The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs); barbiturates generally should not be used since they are highly addictive and can cause multiple adverse effects in the elderly and may increase the metabolism of other necessary chronic medications and lessen their effectiveness.
Labor, obstetric delivery, pregnancy
Avoid aspirin use during the third trimester of pregnancy (starting at 30 weeks of gestation) due to the risk of premature closure of the fetal ductus arteriosus and persistent pulmonary hypertension in the neonate. If NSAID treatment is deemed necessary between 20 to 30 weeks of pregnancy, limit use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if NSAID treatment extends beyond 48 hours. Discontinue the NSAID if oligohydramnios occurs and follow up according to clinical practice. These recommendations do not apply to low-dose 81 mg aspirin prescribed for certain conditions in pregnancy. Use of NSAIDs around 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. Salicylates have also been associated with alterations in maternal and neonatal hemostasis mechanisms, decreased birth weight, and perinatal mortality. Avoid aspirin 1 week prior to and during labor and obstetric delivery because it can result in excessive blood loss at delivery. Prolonged gestation and labor due to prostaglandin inhibition have been reported. Withdrawal seizures were reported in a 2-day-old male infant whose mother had taken a butalbital-containing drug during the last 2 months of pregnancy. Butalbital was found in the infant's serum. The infant was given phenobarbital 5 mg/kg, which was tapered without further seizure or other withdrawal symptoms. Limit the use of caffeine-containing medications during pregnancy only when absolutely necessary. Neonatal arrhythmias (e.g., tachycardia, premature atrial contractions) and tachypnea have been reported when caffeine was consumed during pregnancy in amounts more than 500 mg/day. Caffeine withdrawal in the neonate after birth may account for these symptoms.[47012]Â [47014]
Breast-feeding
Aspirin, butalbital, and caffeine are all excreted in breast milk in small amounts. Because of potential for serious adverse reactions in nursing infants from aspirin; butalbital; caffeine, discontinue breast-feeding or discontinue the drug, taking into account the importance of the drug to the mother. Aspirin may cause adverse hematologic effects in newborns. Mean peak breast milk concentrations of salicylate in 6 nursing mothers after aspirin doses of 500, 1,000, and 1,500 mg were 5.8, 15.8, and 38.8 mg/L, respectively. Salicylate concentrations were detectable in breast milk within 1 hour of dosing and reached maximum concentration within 2 to 6 hours. Chronic barbiturate use while breast-feeding may cause dependence in the neonate. Cytochrome P450 metabolism of caffeine is inhibited in infants who are breast-fed; formula feeding does not appear to affect the pharmacokinetics of caffeine in infants.[47039] Peak caffeine milk concentrations usually occur within 1 hour after the maternal ingestion of a caffeinated beverage; with milk:plasma ratios of 0.5 to 0.7 reported.[47040] [47041] Although only small amounts are secreted in breast milk, caffeine can accumulate in the neonate if maternal ingestion is moderate to high. Higher caffeine intake (more than 500 mg/day) by a nursing mother may cause irritability or poor sleeping patterns in the infant who is breast-feeding.[47042] Alternative analgesics considered to be usually compatible with breast-feeding by previous American Academy of Pediatrics (AAP) recommendations include acetaminophen and ibuprofen.
DRUG INTERACTIONS
Abciximab: (Moderate) Unless contraindicated, aspirin is used in combination with abciximab. However, both drugs are associated with bleeding. Monitor for bleeding during concomitant therapy.
Abemaciclib: (Major) Avoid coadministration of butalbital 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 butalbital is a moderate CYP3A4 inducer. Coadministration with moderate CYP3A4 inducers is predicted to decrease the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by 53%, 41%, and 29% respectively.
Abrocitinib: (Contraindicated) Concurrent use with daily aspirin doses higher than 81 mg is contraindicated during the first 3 months of abrocitinib therapy due to an increased risk of bleeding with thrombocytopenia.
Acetaminophen: (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as barbiturates. An enhanced effect of the displaced drug may occur. (Minor) Caffeine has been reported to increase the metabolism of aspirin. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Acetaminophen; Aspirin: (Moderate) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as barbiturates. An enhanced effect of the displaced drug may occur. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Acetaminophen; Aspirin; Diphenhydramine: (Major) Because diphenhydramine can cause pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as barbiturates. (Moderate) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as barbiturates. An enhanced effect of the displaced drug may occur. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Acetaminophen; Caffeine: (Minor) Caffeine has been reported to increase the metabolism of aspirin. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Acetaminophen; Caffeine; Dihydrocodeine: (Major) Concomitant use of dihydrocodeine with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. It is recommended to avoid this combination when dihydrocodeine is being used for cough. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concomitant use of dihydrocodeine with a barbiturate can decrease dihydrocodeine concentrations, 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. Monitor for reduced efficacy of dihydrocodeine and signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine. (Minor) Caffeine has been reported to increase the metabolism of aspirin. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Acetaminophen; Caffeine; Pyrilamine: (Minor) Caffeine has been reported to increase the metabolism of aspirin. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Acetaminophen; Chlorpheniramine: (Moderate) Additive CNS depression may occur if barbiturates are co-used with sedating antihistamines, such as chlorpheniramine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Acetaminophen; Chlorpheniramine; Dextromethorphan: (Moderate) Additive CNS depression may occur if barbiturates are co-used with sedating antihistamines, such as chlorpheniramine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Additive CNS depression may occur if barbiturates are co-used with sedating antihistamines, such as chlorpheniramine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities. (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants like phenylephrine; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Additive CNS depression may occur if barbiturates are co-used with sedating antihistamines, such as chlorpheniramine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities. (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Acetaminophen; Chlorpheniramine; Phenylephrine : (Moderate) Additive CNS depression may occur if barbiturates are co-used with sedating antihistamines, such as chlorpheniramine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities. (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants like phenylephrine; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Acetaminophen; Codeine: (Major) Concomitant use of codeine with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. It is recommended to avoid this combination when codeine is being used for cough. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concomitant use of codeine with a barbiturate can decrease codeine concentrations, 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. Monitor for reduced efficacy of codeine and signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Acetaminophen; Dextromethorphan: (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Because doxylamine can cause pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as barbiturates. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants like phenylephrine; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Acetaminophen; Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants like phenylephrine; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Acetaminophen; Dextromethorphan; Pseudoephedrine: (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Acetaminophen; Dichloralphenazone; Isometheptene: (Major) Additive CNS depression may occur if barbiturates are used concomitantly with dichloralphenazone. (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Acetaminophen; Diphenhydramine: (Major) Because diphenhydramine can cause pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as barbiturates. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Acetaminophen; Guaifenesin; Phenylephrine: (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants like phenylephrine; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Acetaminophen; Hydrocodone: (Major) Concomitant use of hydrocodone with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. It is recommended to avoid this combination when hydrocodone is being used for cough. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concomitant use of hydrocodone with a barbiturate can decrease hydrocodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; hydrocodone is a CYP3A4 substrate. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Acetaminophen; Oxycodone: (Major) Concomitant use of oxycodone with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concurrent use of oxycodone with a barbiturate may decrease oxycodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. Monitor for signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; oxycodone is a CYP3A4 substrate. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Acetaminophen; Pamabrom; Pyrilamine: (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Acetaminophen; Pentazocine: (Moderate) Concomitant use of pentazocine with other CNS depressants can potentiate respiratory depression, CNS depression, and sedation. Pentazocine should be used cautiously in any patient receiving these agents, which may include barbiturates. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Acetaminophen; Pseudoephedrine: (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Acetazolamide: (Major) Avoid the coadministration of high-dose salicylates and carbonic anhydrase inhibitors whenever possible. There were reports of anorexia, tachypnea, lethargy, metabolic acidosis, coma, and death with high-dose aspirin and acetazolamide. Two mechanisms could cause increased acetazolamide concentrations, resulting in CNS depression and metabolic acidosis: first, competition with aspirin for renal tubular secretion and, second, displacement by salicylates from plasma protein binding sites. Additionally, carbonic anhydrase inhibitors alkalinize urine and increase the excretion of normal doses of salicylates; decreased plasma salicylate concentrations may or may not be clinically significant. (Minor) Acetazolamide can induce osteomalacia in patients treated chronically with barbiturates. Potential mechanisms for this interaction include a carbonic anhydrase inhibitor induced increase in the urinary excretion of calcium and an increase in barbiturate effects resulting from metabolic acidosis. Acetazolamide can also increase the rate of excretion of weakly acidic drugs, such as barbiturates.
Acetohexamide: (Moderate) Monitor blood glucose during concomitant sulfonylurea and aspirin use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Acidifying Agents: (Moderate) Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.
Aclidinium; Formoterol: (Moderate) Caffeine may enhance the cardiac inotropic effects of beta-agonists.
Acrivastine; Pseudoephedrine: (Moderate) Additive CNS depression may occur if barbiturates are used concomitantly with acrivastine. (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Adagrasib: (Major) Avoid concurrent use of adagrasib and barbiturates due to the risk of decreased adagrasib exposure which may reduce its efficacy. Adagrasib is a CYP3A substrate and barbiturates is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced adagrasib exposure by more than 66%.
Adenosine: (Major) Larger doses of adenosine may be required or adenosine may not be effective in the presence of methylxanthines. The effects of adenosine are antagonized by methylxanthines. When used for diagnostic purposes, instruct patients to avoid consumption of methylxanthine-containing products, including caffeinated beverages, for at least 5 half-lives prior to the imaging study.
Ado-Trastuzumab emtansine: (Moderate) Use caution if coadministration of aspirin with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding, with ado-trastuzumab emtansine therapy. Consider additional monitoring when concomitant use is medically necessary. While some patients who experienced bleeding during ado-trastuzumab therapy were also receiving anticoagulation therapy, others had no known additional risk factors
Albuterol: (Moderate) Caffeine may enhance the cardiac inotropic effects of beta-agonists.
Aldesleukin, IL-2: (Moderate) Aldesleukin, IL-2 may affect CNS function significantly. Therefore, psychotropic pharmacodynamic interactions could occur following concomitant administration of drugs with significant CNS activity. Use with caution.
Alendronate: (Minor) Monitor for gastrointestinal adverse events during concurrent use of alendronate and aspirin. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Alendronate; Cholecalciferol: (Minor) Monitor for gastrointestinal adverse events during concurrent use of alendronate and aspirin. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Alfentanil: (Major) Concomitant use of alfentanil with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concurrent use of alfentanil with a barbiturate may decrease alfentanil plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. Monitor for signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; alfentanil is a CYP3A4 substrate.
Aliskiren; Amlodipine: (Major) Barbiturates may induce the CYP3A4 metabolism of calcium-channel blockers such as amlodipine, and thereby reduce their oral bioavailability. The dosage requirements of amlodipine may be increased in patients receiving concurrent enzyme inducers; monitor blood pressure closely.
Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Major) Barbiturates may induce the CYP3A4 metabolism of calcium-channel blockers such as amlodipine, and thereby reduce their oral bioavailability. The dosage requirements of amlodipine may be increased in patients receiving concurrent enzyme inducers; monitor blood pressure closely. (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics. (Moderate) Monitor blood pressure as well as for signs of worsening renal function and loss of diuretic efficacy, including antihypertensive effects, during concomitant thiazide diuretic and salicylate use. Salicylate use decreases glomerular filtration rate and renal blood flow, and concomitant diuretic use may increase the risk of this reaction. Salicylates may diminish the effectiveness of diuretics due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention.
Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics. (Moderate) Monitor blood pressure as well as for signs of worsening renal function and loss of diuretic efficacy, including antihypertensive effects, during concomitant thiazide diuretic and salicylate use. Salicylate use decreases glomerular filtration rate and renal blood flow, and concomitant diuretic use may increase the risk of this reaction. Salicylates may diminish the effectiveness of diuretics due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention.
Alkalinizing Agents: (Moderate) Concurrent administration of high doses of alkalinizing agents may increase urine pH and decrease serum salicylate levels by decreasing renal tubular reabsorption of salicylic acid.
Alogliptin: (Moderate) Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. After acute overdose, aspirin can cause either hypo- or hyperglycemia. Large doses of aspirin should be used cautiously in patients receiving antidiabetic agents.
Alogliptin; Metformin: (Moderate) Monitor blood glucose during concomitant metformin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. After acute overdose, aspirin can cause either hypo- or hyperglycemia. Large doses of aspirin should be used cautiously in patients receiving antidiabetic agents.
Alogliptin; Pioglitazone: (Moderate) Monitor blood glucose during concomitant thiazolidinedione and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. After acute overdose, aspirin can cause either hypo- or hyperglycemia. Large doses of aspirin should be used cautiously in patients receiving antidiabetic agents.
Alpha-glucosidase Inhibitors: (Moderate) Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood sugar. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. After acute overdose, aspirin can cause either hypo- or hyperglycemia. Large doses of aspirin should be used cautiously in patients receiving antidiabetic agents.
Alprazolam: (Moderate) Monitor for reduced efficacy of alprazolam and signs of benzodiazepine withdrawal if coadministration with barbiturates is necessary. Alprazolam is a CYP3A4 substrate and barbiturates are strong CYP3A4 inducers. 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 barbiturates. Concurrent use may result in additive CNS depression.
Altretamine: (Minor) Because altretamine undergoes significant metabolism by the cytochrome P450 system, agents that stimulate CYP450 enzymes, such as barbiturates, increase the metabolism of altretamine and may result in decreased therapeutic effects.
Amantadine: (Major) Amantadine used concomitantly with psychostimulants, such as caffeine, can result in increased stimulant effects, such as nervousness, irritability, or insomnia, and can lead to seizures or cardiac arrhythmias. Close monitoring of the patient is recommended.
Amiloride: (Moderate) Salicylates can increase the risk of renal insufficiency in patients receiving diuretics, secondary to effects on renal blood flow. Salicylates inhibit renal prostaglandin production, which causes salt and water retention and decreased renal blood flow. Coadministration may cause hyperkalemia.
Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics. (Moderate) Monitor blood pressure as well as for signs of worsening renal function and loss of diuretic efficacy, including antihypertensive effects, during concomitant thiazide diuretic and salicylate use. Salicylate use decreases glomerular filtration rate and renal blood flow, and concomitant diuretic use may increase the risk of this reaction. Salicylates may diminish the effectiveness of diuretics due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention. (Moderate) Salicylates can increase the risk of renal insufficiency in patients receiving diuretics, secondary to effects on renal blood flow. Salicylates inhibit renal prostaglandin production, which causes salt and water retention and decreased renal blood flow. Coadministration may cause hyperkalemia.
Aminoglycosides: (Minor) Due to the inhibition of renal prostaglandins by salicylates, concurrent use of salicylates and other nephrotoxic agents like the aminoglycosides may lead to additive nephrotoxicity.
Aminosalicylate sodium, Aminosalicylic acid: (Moderate) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as barbiturates. An enhanced effect of the displaced drug may occur.
Amiodarone: (Minor) Amiodarone is an inhibitor of CYP1A2 isoenzymes, and could theoretically reduce CYP1A2-mediated caffeine metabolism. The clinical significance of this potential interaction is not known.
Amlodipine: (Major) Barbiturates may induce the CYP3A4 metabolism of calcium-channel blockers such as amlodipine, and thereby reduce their oral bioavailability. The dosage requirements of amlodipine may be increased in patients receiving concurrent enzyme inducers; monitor blood pressure closely.
Amlodipine; Atorvastatin: (Major) Barbiturates may induce the CYP3A4 metabolism of calcium-channel blockers such as amlodipine, and thereby reduce their oral bioavailability. The dosage requirements of amlodipine may be increased in patients receiving concurrent enzyme inducers; monitor blood pressure closely. (Minor) CYP3A4 inducers like the barbiturates may decrease the efficacy of atorvastatin, a CYP3A4 substrate. Monitor for potential reduced cholesterol-lowering efficacy when these drugs are co-administered.
Amlodipine; Benazepril: (Major) Barbiturates may induce the CYP3A4 metabolism of calcium-channel blockers such as amlodipine, and thereby reduce their oral bioavailability. The dosage requirements of amlodipine may be increased in patients receiving concurrent enzyme inducers; monitor blood pressure closely. (Moderate) Aspirin, ASA may reduce the vasodilatory efficacy of ACE inhibitors by inhibiting the synthesis of vasodilatory prostaglandins. This interaction has been documented primarily in heart failure patients. However, the established benefits of using aspirin in combination with an ACE inhibitor in patients with ischemic heart disease and left ventricular dysfunction generally outweigh this concern. Patients receiving concurrent salicylates and ACE inhibitor therapy should be monitored for antihypertensive or vasodilatory efficacy; the dose of the ACE inhibitor can be adjusted if indicated based on clinical evaluation.
Amlodipine; Celecoxib: (Major) Barbiturates may induce the CYP3A4 metabolism of calcium-channel blockers such as amlodipine, and thereby reduce their oral bioavailability. The dosage requirements of amlodipine may be increased in patients receiving concurrent enzyme inducers; monitor blood pressure closely. (Major) Concomitant use of analgesic doses of aspirin and celecoxib is generally not recommended due to the increased risk of bleeding. Concurrent use of analgesic doses of aspirin with NSAIDs does not produce a greater therapeutic effect compared to the use of NSAIDs alone. Celecoxib (200 to 400 mg/day) did not interfere with the cardioprotective antiplatelet effect of aspirin (100 to 325 mg) in 2 studies in healthy volunteers and in patients with osteoarthritis and established heart disease. Celecoxib is not a substitute for low dose aspirin for cardiovascular protection.
Amlodipine; Olmesartan: (Major) Barbiturates may induce the CYP3A4 metabolism of calcium-channel blockers such as amlodipine, and thereby reduce their oral bioavailability. The dosage requirements of amlodipine may be increased in patients receiving concurrent enzyme inducers; monitor blood pressure closely.
Amlodipine; Valsartan: (Major) Barbiturates may induce the CYP3A4 metabolism of calcium-channel blockers such as amlodipine, and thereby reduce their oral bioavailability. The dosage requirements of amlodipine may be increased in patients receiving concurrent enzyme inducers; monitor blood pressure closely.
Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Major) Barbiturates may induce the CYP3A4 metabolism of calcium-channel blockers such as amlodipine, and thereby reduce their oral bioavailability. The dosage requirements of amlodipine may be increased in patients receiving concurrent enzyme inducers; monitor blood pressure closely. (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics. (Moderate) Monitor blood pressure as well as for signs of worsening renal function and loss of diuretic efficacy, including antihypertensive effects, during concomitant thiazide diuretic and salicylate use. Salicylate use decreases glomerular filtration rate and renal blood flow, and concomitant diuretic use may increase the risk of this reaction. Salicylates may diminish the effectiveness of diuretics due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention.
Amobarbital: (Moderate) Caffeine has been reported to increase the metabolism of barbiturates, and barbiturates increase caffeine elimination. Higher caffeine doses may be needed after barbiturate administration.
Amoxapine: (Major) Monitor for excessive sedation and somnolence during coadministration of amoxapine and barbiturates. Concurrent use may result in additive CNS depression.
Amoxicillin: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid coadministration of omeprazole with barbiturates because it can result in decreased efficacy of omeprazole. Omeprazole is extensively metabolized in the liver by CYP2C19 and CYP3A4. Barbiturates induce CYP3A4 and CYP2C19. (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
Amoxicillin; Clavulanic Acid: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
Amphetamine: (Moderate) Avoid excessive caffeine intake during use of the amphetamine salts. Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. Excessive caffeine ingestion (via medicines, foods like chocolate, dietary supplements, or beverages including coffee, green tea, other teas, colas) may contribute to side effects like nervousness, irritability, nausea, insomnia, or tremor. Patients should avoid medications and dietary supplements which contain high amounts of caffeine.
Amphetamine; Dextroamphetamine Salts: (Moderate) Avoid excessive caffeine intake during use of the amphetamine salts. Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. Excessive caffeine ingestion (via medicines, foods like chocolate, dietary supplements, or beverages including coffee, green tea, other teas, colas) may contribute to side effects like nervousness, irritability, nausea, insomnia, or tremor. Patients should avoid medications and dietary supplements which contain high amounts of caffeine.
Amphetamine; Dextroamphetamine: (Moderate) Avoid excessive caffeine intake during use of the amphetamine salts. Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. Excessive caffeine ingestion (via medicines, foods like chocolate, dietary supplements, or beverages including coffee, green tea, other teas, colas) may contribute to side effects like nervousness, irritability, nausea, insomnia, or tremor. Patients should avoid medications and dietary supplements which contain high amounts of caffeine.
Amphotericin B cholesteryl sulfate complex (ABCD): (Minor) Concurrent use of amphotericin B and other potentially nephrotoxic medications, like the salicylates, may enhance the potential for drug-induced renal toxicity.
Amphotericin B lipid complex (ABLC): (Minor) Concurrent use of amphotericin B and other potentially nephrotoxic medications, like the salicylates, may enhance the potential for drug-induced renal toxicity.
Amphotericin B liposomal (LAmB): (Minor) Concurrent use of amphotericin B and other potentially nephrotoxic medications, like the salicylates, may enhance the potential for drug-induced renal toxicity.
Amphotericin B: (Minor) Concurrent use of amphotericin B and other potentially nephrotoxic medications, like the salicylates, may enhance the potential for drug-induced renal toxicity.
Ampicillin: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
Ampicillin; Sulbactam: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
Anagrelide: (Moderate) Anagrelide has been shown to inhibit CYP1A2. In theory, coadministration of anagrelide with substrates of CYP1A2, including caffeine, could lead to increases in the serum concentrations of caffeine and, thus, adverse effects. (Moderate) Anagrelide is partially metabolized by CYP1A2. Coadministration of anagrelide with drugs that induce CYP1A2, such as barbiturates, could theoretically increase the elimination of anagrelide and decrease the efficacy of anagrelide. (Moderate) Use caution with the coadministration of aspirin and anagrelide. The coadministration of single or repeated doses of anagrelide and aspirin resulted in greater ex vivo anti-platelet aggregation effects than administration of aspirin alone. In an observational study, the concomitant use of anagrelide and aspirin increased the rate of major hemorrhagic events compared to patients receiving other cytoreductive therapy. Assess the risks and benefits of concomitant aspirin and anagrelide use, particularly in patients at high risk for hemorrhage. Monitor for bleeding during concomitant therapy.
Angiotensin-converting enzyme inhibitors: (Moderate) Aspirin, ASA may reduce the vasodilatory efficacy of ACE inhibitors by inhibiting the synthesis of vasodilatory prostaglandins. This interaction has been documented primarily in heart failure patients. However, the established benefits of using aspirin in combination with an ACE inhibitor in patients with ischemic heart disease and left ventricular dysfunction generally outweigh this concern. Patients receiving concurrent salicylates and ACE inhibitor therapy should be monitored for antihypertensive or vasodilatory efficacy; the dose of the ACE inhibitor can be adjusted if indicated based on clinical evaluation.
Antithrombin III: (Moderate) Large doses of salicylates (more than 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and antithrombin III should be monitored closely for bleeding.
Apixaban: (Major) Large doses of salicylates (3 to 4 g/day or more) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and apixaban should be monitored closely for bleeding.
Apomorphine: (Moderate) Apomorphine causes significant somnolence. Concomitant administration of apomorphine and CNS depressants could result in additive depressant effects.
Apraclonidine: (Minor) No specific drug interactions were identified with systemic agents and apraclonidine during clinical trials. Theoretically, apraclonidine might potentiate the effects of CNS depressant drugs such as the anxiolytics, sedatives, and hypnotics, including barbiturates or benzodiazepines.
Apremilast: (Major) The coadministration of apremilast and barbiturates is not recommended. Apremilast is metabolized primarily by CYP3A4, with minor metabolism by CYP1A2; barbiturates are strong CYP3A4 inducers and also induce CYP1A2. Coadministration of rifampin, another strong CYP3A4 inducer, with a single dose of apremilast resulted in a decrease in apremilast AUC and Cmax by 72% and 43%, respectively. A similar reduction in systemic exposure may be seen with coadministration of apremilast and barbiturates which may result in a loss of efficacy of apremilast.
Arformoterol: (Moderate) Caffeine may enhance the cardiac inotropic effects of beta-agonists.
Aripiprazole: (Major) Because aripiprazole is metabolized by CYP3A4, the manufacturer recommends that the oral aripiprazole dose be doubled over 1 to 2 weeks when strong CYP3A4 inducers, such as barbiturates, are added to aripiprazole therapy. If these agents are used in combination, the patient should be carefully monitored for a decrease in aripiprazole efficacy. When the CYP3A4 inducer is withdrawn from the combination therapy, the aripiprazole dose in adults should be reduced over 1 to 2 weeks to the original level. 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. Additive CNS effects are possible, including drowsiness or dizziness. Patients should report any unusual changes in moods or behaviors while taking this combination.
Armodafinil: (Major) It is not clear how armodafinil interacts with barbiturates like phenobarbital. Armodafinil is partially metabolized by CYP3A4 and combined use with CYP3A4 inducers such as phenobarbital and other barbiturates may result in decreased armodafinil efficacy. Barbiturates used for sleep could counteract the effect of armodafinil on wakefulness, and would not ordinarily be prescribed. The potential effects of combining armodafinil with anticonvulsant barbiturate medications are unclear. Many psychostimulants can reduce the seizure threshold, but it is not clear if armodafinil can affect seizure control. (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with armodafinil. Caffeine should be used cautiously with armodafinil. Intake of caffeine should be limited. Excessive intake may cause nervousness, irritability, insomnia, or other side effects.
Artemether; Lumefantrine: (Major) The barbiturates are inducers and both components of artemether; lumefantrine are substrates of the CYP3A4 isoenzyme; therefore, coadministration may lead to decreased artemether; lumefantrine concentrations. Concomitant use warrants caution due to a possible reduction in antimalarial activity.
Articaine; Epinephrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
Ascorbic Acid, Vitamin C: (Minor) Agents that acidify the urine should be avoided in patients receiving high-dose salicylates. Urinary pH changes can decrease salicylate excretion. However, if the urine is acidic prior to administration of an acidifying agent, the increase in salicylic acid concentrations should be minimal.
Asenapine: (Moderate) Barbiturates can cause CNS depression, and if used concomitantly with asenapine, may increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness.
Aspirin, ASA: (Moderate) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as barbiturates. An enhanced effect of the displaced drug may occur.
Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Concomitant use of codeine with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. It is recommended to avoid this combination when codeine is being used for cough. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concomitant use of codeine with a barbiturate can decrease codeine concentrations, 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. Monitor for reduced efficacy of codeine and signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. (Moderate) Caffeine has been reported to increase the metabolism of barbiturates, and barbiturates increase caffeine elimination. Higher caffeine doses may be needed after barbiturate administration. (Moderate) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as barbiturates. An enhanced effect of the displaced drug may occur. (Minor) Caffeine has been reported to increase the metabolism of aspirin.
Aspirin, ASA; Caffeine: (Moderate) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as barbiturates. An enhanced effect of the displaced drug may occur. (Minor) Caffeine has been reported to increase the metabolism of aspirin.
Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as barbiturates. An enhanced effect of the displaced drug may occur. (Minor) Caffeine has been reported to increase the metabolism of aspirin.
Aspirin, ASA; Carisoprodol: (Moderate) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as barbiturates. An enhanced effect of the displaced drug may occur.
Aspirin, ASA; Carisoprodol; Codeine: (Major) Concomitant use of codeine with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. It is recommended to avoid this combination when codeine is being used for cough. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concomitant use of codeine with a barbiturate can decrease codeine concentrations, 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. Monitor for reduced efficacy of codeine and signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. (Moderate) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as barbiturates. An enhanced effect of the displaced drug may occur.
Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Moderate) Concurrent administration of high doses of alkalinizing agents may increase urine pH and decrease serum salicylate levels by decreasing renal tubular reabsorption of salicylic acid. (Moderate) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as barbiturates. An enhanced effect of the displaced drug may occur.
Aspirin, ASA; Dipyridamole: (Major) Methylxanthines, through antagonism of adenosine and thus pharmacologic-induced coronary vasodilation, have been associated with false-negative results during dipyridamole-thallium 201 stress testing. It is recommended that methylxanthines (caffeine, caffeinated beverages and foods, theophylline, etc.) be discontinued for at least 24 hours prior to stress testing. An interaction is not expected when methylxanthines are used concomitantly with chronic dipyridamole therapy. (Moderate) Although aspirin may be used in combination with dipyridamole, both drugs are associated with bleeding. Monitor for bleeding during concomitant therapy. (Moderate) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as barbiturates. An enhanced effect of the displaced drug may occur.
Aspirin, ASA; Omeprazole: (Major) Avoid coadministration of omeprazole with barbiturates because it can result in decreased efficacy of omeprazole. Omeprazole is extensively metabolized in the liver by CYP2C19 and CYP3A4. Barbiturates induce CYP3A4 and CYP2C19. (Moderate) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as barbiturates. An enhanced effect of the displaced drug may occur.
Aspirin, ASA; Oxycodone: (Major) Concomitant use of oxycodone with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concurrent use of oxycodone with a barbiturate may decrease oxycodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. Monitor for signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; oxycodone is a CYP3A4 substrate. (Moderate) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as barbiturates. An enhanced effect of the displaced drug may occur.
Aspirin, ASA; Pravastatin: (Moderate) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as barbiturates. An enhanced effect of the displaced drug may occur.
Atazanavir: (Major) Coadministration of butalbital and atazanavir may increase the metabolism of atazanavir and lead to decreased atazanavir concentrations resulting in reduction of antiretroviral efficacy and development of viral resistance. If atazanavir and butalbital are used together, the patient must be closely monitored for antiviral efficacy.
Atazanavir; Cobicistat: (Major) Coadministration of butalbital and atazanavir may increase the metabolism of atazanavir and lead to decreased atazanavir concentrations resulting in reduction of antiretroviral efficacy and development of viral resistance. If atazanavir and butalbital are used together, the patient must be closely monitored for antiviral efficacy.
Atenolol; Chlorthalidone: (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics. (Moderate) Monitor blood pressure as well as for signs of worsening renal function and loss of diuretic efficacy, including antihypertensive effects, during concomitant thiazide diuretic and salicylate use. Salicylate use decreases glomerular filtration rate and renal blood flow, and concomitant diuretic use may increase the risk of this reaction. Salicylates may diminish the effectiveness of diuretics due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention.
Atogepant: (Major) Use an atogepant dose of 30 or 60 mg PO once daily if coadministered with barbiturates. Concurrent use may decrease atogepant exposure and reduce efficacy. Atogepant is a CYP3A substrate and barbiturates are strong CYP3A inducers. Coadministration with a strong CYP3A inducer resulted in a 60% reduction in atogepant exposure and a 30% reduction in atogepant peak concentration.
Atorvastatin: (Minor) CYP3A4 inducers like the barbiturates may decrease the efficacy of atorvastatin, a CYP3A4 substrate. Monitor for potential reduced cholesterol-lowering efficacy when these drugs are co-administered.
Atorvastatin; Ezetimibe: (Minor) CYP3A4 inducers like the barbiturates may decrease the efficacy of atorvastatin, a CYP3A4 substrate. Monitor for potential reduced cholesterol-lowering efficacy when these drugs are co-administered.
Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as barbiturates. An enhanced effect of the displaced drug may occur.
Atropine; Difenoxin: (Moderate) Concurrent administration of diphenoxylate/difenoxin with barbiturates can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration.
Avacopan: (Major) Avoid concomitant use of avacopan and barbiturates due to the risk of decreased avacopan exposure which may reduce its efficacy. Avacopan is a CYP3A substrate and barbiturates are strong CYP3A inducers. Concomitant use of another strong CYP3A inducer decreased avacopan overall exposure by 93%.
Avanafil: (Minor) Avanafil is a substrate of and primarily metabolized by CYP3A4. It can be expected that concomitant administration of CYP3A4 enzyme-inducers will decrease plasma levels of avanafil, however, no interaction studies have been performed. CYP3A4 inducers include barbiturates.
Avapritinib: (Major) Avoid coadministration of avapritinib with butalbital due to the risk of decreased avapritinib efficacy. Avapritinib is a CYP3A4 substrate and butalbital is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer is predicted to decrease the AUC and Cmax of avapritinib by 62% and 55%, respectively.
Avatrombopag: (Major) In patients with chronic immune thrombocytopenia (ITP), increase the starting dose of avatrombopag to 40 mg PO once daily when used concomitantly with barbiturates. In patients starting barbiturates while receiving avatrombopag, monitor platelet counts and adjust the avatrombopag dose as necessary. Dosage adjustments are not required for patients with chronic liver disease. Avatrombopag is a CYP2C9 and CYP3A4 substrate, and dual moderate or strong inducers such as barbiturates decrease avatrombopag exposure, which may reduce efficacy.
Axitinib: (Major) Avoid coadministration of axitinib with butalbital if possible 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 butalbital is a moderate CYP3A4 inducer.
Azelastine: (Moderate) An enhanced CNS depressant effect may occur when azelastine, an antihistamine, is combined with CNS depressants including the barbiturates.
Azelastine; Fluticasone: (Moderate) An enhanced CNS depressant effect may occur when azelastine, an antihistamine, is combined with CNS depressants including the barbiturates. (Moderate) Coadministration may result in decreased exposure to fluticasone. Butalbital is a CYP3A4 inducer; fluticasone is a CYP3A4 substrate. Monitor for decreased response to fluticasone during concurrent use.
Azilsartan; Chlorthalidone: (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics. (Moderate) Monitor blood pressure as well as for signs of worsening renal function and loss of diuretic efficacy, including antihypertensive effects, during concomitant thiazide diuretic and salicylate use. Salicylate use decreases glomerular filtration rate and renal blood flow, and concomitant diuretic use may increase the risk of this reaction. Salicylates may diminish the effectiveness of diuretics due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention.
Bacitracin: (Minor) Additive nephrotoxicity may occur with concurrent use of systemic bacitracin and other nephrotoxic agents, including salicylates. Topical administration of any preparation containing bacitracin, especially when applied to large surface areas, also should not be given with other drugs that have a nephrotoxic potential.
Barbiturates: (Moderate) Caffeine has been reported to increase the metabolism of barbiturates, and barbiturates increase caffeine elimination. Higher caffeine doses may be needed after barbiturate administration. (Moderate) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as barbiturates. An enhanced effect of the displaced drug may occur.
Bedaquiline: (Major) Avoid concurrent use of barbiturates with bedaquiline. Barbiturates may induce CYP3A4 metabolism resulting in decreased bedaquiline systemic exposure (AUC) and possibly reduced therapeutic effect.
Belladonna; Opium: (Major) Concomitant use of opium with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
Benazepril: (Moderate) Aspirin, ASA may reduce the vasodilatory efficacy of ACE inhibitors by inhibiting the synthesis of vasodilatory prostaglandins. This interaction has been documented primarily in heart failure patients. However, the established benefits of using aspirin in combination with an ACE inhibitor in patients with ischemic heart disease and left ventricular dysfunction generally outweigh this concern. Patients receiving concurrent salicylates and ACE inhibitor therapy should be monitored for antihypertensive or vasodilatory efficacy; the dose of the ACE inhibitor can be adjusted if indicated based on clinical evaluation.
Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) Aspirin, ASA may reduce the vasodilatory efficacy of ACE inhibitors by inhibiting the synthesis of vasodilatory prostaglandins. This interaction has been documented primarily in heart failure patients. However, the established benefits of using aspirin in combination with an ACE inhibitor in patients with ischemic heart disease and left ventricular dysfunction generally outweigh this concern. Patients receiving concurrent salicylates and ACE inhibitor therapy should be monitored for antihypertensive or vasodilatory efficacy; the dose of the ACE inhibitor can be adjusted if indicated based on clinical evaluation. (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics. (Moderate) Monitor blood pressure as well as for signs of worsening renal function and loss of diuretic efficacy, including antihypertensive effects, during concomitant thiazide diuretic and salicylate use. Salicylate use decreases glomerular filtration rate and renal blood flow, and concomitant diuretic use may increase the risk of this reaction. Salicylates may diminish the effectiveness of diuretics due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention.
Bendamustine: (Major) Consider the use of an alternative therapy if barbiturate treatment is needed in patients receiving bendamustine. Barbiturates may decrease bendamustine exposure, which may result in decreased efficacy. Bendamustine is a CYP1A2 substrate and barbiturates are CYP1A2 inducers.
Bendroflumethiazide; Nadolol: (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics. (Moderate) Monitor blood pressure as well as for signs of worsening renal function and loss of diuretic efficacy, including antihypertensive effects, during concomitant thiazide diuretic and salicylate use. Salicylate use decreases glomerular filtration rate and renal blood flow, and concomitant diuretic use may increase the risk of this reaction. Salicylates may diminish the effectiveness of diuretics due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention.
Benzhydrocodone; Acetaminophen: (Major) Concomitant use of benzhydrocodone with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concurrent use of benzhydrocodone with a barbiturate may decrease benzhydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. Monitor for signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; benzhydrocodone is a CYP3A4 substrate. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Benzodiazepines: (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as barbiturates. An enhanced effect of the displaced drug may occur.
Benzphetamine: (Moderate) Avoid excessive caffeine intake during use of benzphetamine. Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. Excessive caffeine ingestion (via medicines, foods like chocolate, dietary supplements, or beverages including coffee, green tea, other teas, colas) may contribute to side effects like nervousness, irritability, nausea, insomnia, or tremor. Patients should avoid medications and dietary supplements which contain high amounts of caffeine.
Benztropine: (Moderate) CNS depressants, such as anxiolytics, sedatives, and hypnotics, can increase the sedative effects of benztropine.
Beta-agonists: (Moderate) Caffeine may enhance the cardiac inotropic effects of beta-agonists.
Beta-blockers: (Moderate) Concurrent use of beta-blockers with aspirin and other salicylates may result in loss of antihypertensive activity due to inhibition of renal prostaglandins and thus, salt and water retention and decreased renal blood flow.
Betrixaban: (Major) Monitor patients closely and promptly evaluate any signs or symptoms of bleeding if betrixaban and aspirin are used concomitantly. Coadministration of betrixaban and aspirin may increase the risk of bleeding.
Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Minor) Barbiturates may decrease the half-life and plasma concentrations of metronidazole. The clinical significance of this effect is uncertain.
Bismuth Subsalicylate: (Moderate) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as barbiturates. An enhanced effect of the displaced drug may occur. (Moderate) Monitor for salicylate-related adverse effects, including salicylate toxicity, if concomitant use of aspirin and bismuth subsalicylate is necessary. Adverse reactions, such as bleeding, renal impairment, and tinnitus, may occur.
Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as barbiturates. An enhanced effect of the displaced drug may occur. (Moderate) Monitor for salicylate-related adverse effects, including salicylate toxicity, if concomitant use of aspirin and bismuth subsalicylate is necessary. Adverse reactions, such as bleeding, renal impairment, and tinnitus, may occur. (Minor) Barbiturates may decrease the half-life and plasma concentrations of metronidazole. The clinical significance of this effect is uncertain.
Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics. (Moderate) Monitor blood pressure as well as for signs of worsening renal function and loss of diuretic efficacy, including antihypertensive effects, during concomitant thiazide diuretic and salicylate use. Salicylate use decreases glomerular filtration rate and renal blood flow, and concomitant diuretic use may increase the risk of this reaction. Salicylates may diminish the effectiveness of diuretics due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention.
Bortezomib: (Moderate) Because bortezomib undergoes significant metabolism by the cytochrome P450 system, induction of CYP450 enzymes by the barbiturates may increase the clearance and metabolism of this drug and may result in decreased therapeutic effects.
Brexpiprazole: (Major) Because brexpiprazole is partially metabolized by CYP3A4, the manufacturer recommends that the brexpiprazole dose be doubled over 1 to 2 weeks when strong CYP3A4 inducers, such as barbiturates and primidone, are added to brexpiprazole therapy. If these agents are used in combination, the patient should be carefully monitored for a decrease in brexpiprazole efficacy. When the CYP3A4 inducer is withdrawn from the combination therapy, the brexpiprazole dose should be reduced over 1 to 2 weeks to the original level.
Brigatinib: (Major) Avoid coadministration of brigatinib with butalbital due to decreased plasma exposure to brigatinib which may result in decreased efficacy. If concomitant use is unavoidable, after 7 days of concomitant treatment with butalbital, increase the dose of brigatinib as tolerated in 30 mg increments to a maximum of twice the original brigatinib dose. After discontinuation of butalbital, resume the brigatinib dose that was tolerated prior to initiation of butalbital. Brigatinib is a CYP3A4 substrate and butalbital is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of brigatinib by approximately 50%.
Brimonidine: (Moderate) Based on the sedative effects of brimonidine in individual patients, brimonidine administration has potential to enhance the CNS depressants effects of the anxiolytics, sedatives, and hypnotics including barbiturates.
Brimonidine; Brinzolamide: (Moderate) Based on the sedative effects of brimonidine in individual patients, brimonidine administration has potential to enhance the CNS depressants effects of the anxiolytics, sedatives, and hypnotics including barbiturates.
Brimonidine; Timolol: (Moderate) Based on the sedative effects of brimonidine in individual patients, brimonidine administration has potential to enhance the CNS depressants effects of the anxiolytics, sedatives, and hypnotics including barbiturates.
Brivaracetam: (Minor) Plasma concentrations of brivaracetam may decrease during co-administration with barbiturates. A 19% decrease in the plasma concentration of brivaracetam was observed during co-administration with phenobarbital; however, no dose adjustment is recommended for brivaracetam during concomitant therapy.
Bromocriptine: (Moderate) Caution and close monitoring are advised if bromocriptine and butalbital 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; butalbital is a moderate inducer of CYP3A4. (Minor) Bromocriptine is highly bound (more than 90%) to serum proteins. Therefore, it may increase the unbound fraction of other highly protein-bound medications (e.g., aspirin and other salicylates), which may alter their effectiveness and risk for side effects.
Brompheniramine: (Moderate) Additive CNS depression may occur if barbiturates are co-used with sedating antihistamines, such as brompheniramine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities.
Brompheniramine; Carbetapentane; Phenylephrine: (Moderate) Additive CNS depression may occur if barbiturates are co-used with sedating antihistamines, such as brompheniramine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities. (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants like phenylephrine; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including barbiturates.
Brompheniramine; Dextromethorphan; Guaifenesin: (Moderate) Additive CNS depression may occur if barbiturates are co-used with sedating antihistamines, such as brompheniramine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities.
Brompheniramine; Dextromethorphan; Phenylephrine: (Moderate) Additive CNS depression may occur if barbiturates are co-used with sedating antihistamines, such as brompheniramine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities. (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants like phenylephrine; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Brompheniramine; Phenylephrine: (Moderate) Additive CNS depression may occur if barbiturates are co-used with sedating antihistamines, such as brompheniramine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities. (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants like phenylephrine; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Brompheniramine; Pseudoephedrine: (Moderate) Additive CNS depression may occur if barbiturates are co-used with sedating antihistamines, such as brompheniramine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities. (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Brompheniramine; Pseudoephedrine; Dextromethorphan: (Moderate) Additive CNS depression may occur if barbiturates are co-used with sedating antihistamines, such as brompheniramine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities. (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Budesonide: (Moderate) Coadministration may result in decreased exposure to budesonide. Butalbital is a CYP3A4 inducer; budesonide is a CYP3A4 substrate. Monitor for decreased response to budesonide during concurrent use.
Budesonide; Formoterol: (Moderate) Caffeine may enhance the cardiac inotropic effects of beta-agonists. (Moderate) Coadministration may result in decreased exposure to budesonide. Butalbital is a CYP3A4 inducer; budesonide is a CYP3A4 substrate. Monitor for decreased response to budesonide during concurrent use.
Budesonide; Glycopyrrolate; Formoterol: (Moderate) Caffeine may enhance the cardiac inotropic effects of beta-agonists. (Moderate) Coadministration may result in decreased exposure to budesonide. Butalbital is a CYP3A4 inducer; budesonide is a CYP3A4 substrate. Monitor for decreased response to budesonide during concurrent use.
Bumetanide: (Moderate) Salicylates may decrease the diuretic, natriuretic, and antihypertensive actions of diuretics, possibly through inhibition of renal prostaglandin synthesis. Patients receiving loop diuretics and salicylates should be monitored for changes in the effectiveness of their diuretic therapy.
Bupivacaine Liposomal: (Minor) Bupivacaine is metabolized by CYP3A4. Barbiturates induce these isoenzymes and if given concurrently with bupivacaine may decrease the efficacy of bupivacaine.
Bupivacaine: (Minor) Bupivacaine is metabolized by CYP3A4. Barbiturates induce these isoenzymes and if given concurrently with bupivacaine may decrease the efficacy of bupivacaine.
Bupivacaine; Epinephrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. (Minor) Bupivacaine is metabolized by CYP3A4. Barbiturates induce these isoenzymes and if given concurrently with bupivacaine may decrease the efficacy of bupivacaine.
Bupivacaine; Lidocaine: (Minor) Bupivacaine is metabolized by CYP3A4. Barbiturates induce these isoenzymes and if given concurrently with bupivacaine may decrease the efficacy of bupivacaine.
Bupivacaine; Meloxicam: (Major) Concomitant use of low dose aspirin or analgesic doses of aspirin and meloxicam is generally not recommended due to the increased risk of bleeding and renal impairment. Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone. Meloxicam is not a substitute for low dose aspirin for cardiovascular protection. (Minor) Bupivacaine is metabolized by CYP3A4. Barbiturates induce these isoenzymes and if given concurrently with bupivacaine may decrease the efficacy of bupivacaine.
Buprenorphine: (Moderate) Close monitoring of the patient is recommended if a CYP3A4 inducer is used with buprenorphine. Inducers of CYP3A4 such as phenobarbital may induce the hepatic metabolism of buprenorphine, which may lead to opiate withdrawal or inadequate pain control. It is likely that all barbiturates exert the same effect as phenobarbital. This interaction is most significant if the enzyme-inducing agent is added after buprenorphine therapy has begun. Buprenorphine doses may need to be increased if any of these agents are added. Conversely, buprenorphine doses may need to be decreased if these drugs are discontinued. Additive CNS depression may be the more important issue initially when barbiturates are given with buprenorphine; the induction of buprenorphine metabolism may take several days. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A dose reduction of one or both drugs may be warranted. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Buprenorphine; Naloxone: (Moderate) Close monitoring of the patient is recommended if a CYP3A4 inducer is used with buprenorphine. Inducers of CYP3A4 such as phenobarbital may induce the hepatic metabolism of buprenorphine, which may lead to opiate withdrawal or inadequate pain control. It is likely that all barbiturates exert the same effect as phenobarbital. This interaction is most significant if the enzyme-inducing agent is added after buprenorphine therapy has begun. Buprenorphine doses may need to be increased if any of these agents are added. Conversely, buprenorphine doses may need to be decreased if these drugs are discontinued. Additive CNS depression may be the more important issue initially when barbiturates are given with buprenorphine; the induction of buprenorphine metabolism may take several days. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A dose reduction of one or both drugs may be warranted. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Bupropion: (Moderate) Bupropion is associated with a dose-related risk of seizures. Excessive use of psychostimulants, including caffeine, is associated with an increased seizure risk and may increase this risk during the concurrent use of bupropion. Carefully consider a patient's caffeine intake from all sources, including medicines. Monitor for irritability, tremor, increased blood pressure, insomnia and seizures. Many non-prescription medicines and weight loss aids may contain caffeine and patients should read labels carefully. Examples of foods and beverages containing caffeine include coffee, teas, colas, energy drinks, chocolate, and some herbal or dietary supplements. Patients should be advised to limit excessive caffeine intake during bupropion therapy. (Moderate) Bupropion may interact with drugs that induce hepatic microsomal isoenzyme function via CYP2B6 such as the barbiturates. While not systematically studied, these drugs may induce the metabolism of bupropion and may decrease bupropion exposure. If bupropion is used concomitantly with a CYP inducer, it may be necessary to increase the dose of bupropion, but the maximum recommended dose should not be exceeded. Advise patients that until they are reasonably certain that the combination does not adversely affect their performance, they should refrain from driving an automobile or operating complex, hazardous machinery.
Bupropion; Naltrexone: (Moderate) Bupropion is associated with a dose-related risk of seizures. Excessive use of psychostimulants, including caffeine, is associated with an increased seizure risk and may increase this risk during the concurrent use of bupropion. Carefully consider a patient's caffeine intake from all sources, including medicines. Monitor for irritability, tremor, increased blood pressure, insomnia and seizures. Many non-prescription medicines and weight loss aids may contain caffeine and patients should read labels carefully. Examples of foods and beverages containing caffeine include coffee, teas, colas, energy drinks, chocolate, and some herbal or dietary supplements. Patients should be advised to limit excessive caffeine intake during bupropion therapy. (Moderate) Bupropion may interact with drugs that induce hepatic microsomal isoenzyme function via CYP2B6 such as the barbiturates. While not systematically studied, these drugs may induce the metabolism of bupropion and may decrease bupropion exposure. If bupropion is used concomitantly with a CYP inducer, it may be necessary to increase the dose of bupropion, but the maximum recommended dose should not be exceeded. Advise patients that until they are reasonably certain that the combination does not adversely affect their performance, they should refrain from driving an automobile or operating complex, hazardous machinery.
Buspirone: (Moderate) Monitor for reduced anxiolytic effect of buspirone. Potent inducers of CYP3A4, such as the barbiturates, may increase the rate of buspirone metabolism. If a patient has been titrated to a stable dosage on buspirone, a dose adjustment of buspirone may be necessary to maintain anxiolytic effect. There is also a risk of additive CNS depression (drowsiness) when buspirone is given concomitantly with barbiturates. In a study in healthy volunteers, co-administration of buspirone with a potent CYP3A4 inducer decreased the plasma concentrations (83.7% decrease in Cmax; 89.6% decrease in AUC) and pharmacodynamic effects of buspirone. (Minor) In vitro studies showed that therapeutic levels of aspirin, ASA increased the plasma concentrations of free buspirone by 23% through plasma protein binding displacement. In vivo interaction studies with these drugs have not been performed.
Butabarbital: (Moderate) Caffeine has been reported to increase the metabolism of barbiturates, and barbiturates increase caffeine elimination. Higher caffeine doses may be needed after barbiturate administration.
Butalbital; Acetaminophen: (Moderate) Caffeine has been reported to increase the metabolism of barbiturates, and barbiturates increase caffeine elimination. Higher caffeine doses may be needed after barbiturate administration. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Butalbital; Acetaminophen; Caffeine: (Moderate) Caffeine has been reported to increase the metabolism of barbiturates, and barbiturates increase caffeine elimination. Higher caffeine doses may be needed after barbiturate administration. (Minor) Caffeine has been reported to increase the metabolism of aspirin. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Concomitant use of codeine with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. It is recommended to avoid this combination when codeine is being used for cough. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concomitant use of codeine with a barbiturate can decrease codeine concentrations, 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. Monitor for reduced efficacy of codeine and signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. (Moderate) Caffeine has been reported to increase the metabolism of barbiturates, and barbiturates increase caffeine elimination. Higher caffeine doses may be needed after barbiturate administration. (Minor) Caffeine has been reported to increase the metabolism of aspirin. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Butorphanol: (Moderate) Concomitant use of butorphanol with other CNS depressants, such as barbiturates, can potentiate the effects of butorphanol on respiratory depression, CNS depression, and sedation.
Cabotegravir; Rilpivirine: (Moderate) Close clinical monitoring is advised when administering barbiturates with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Barbiturates are inducers of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
Caffeine: (Moderate) Caffeine has been reported to increase the metabolism of barbiturates, and barbiturates increase caffeine elimination. Higher caffeine doses may be needed after barbiturate administration. (Moderate) Certain foods that contain high amounts of caffeine or theobromine should be limited during the therapeutic use of caffeine in order to limit additive methylxanthine effects. While taking Caffeine-containing medicines, limit the use of foods, beverages (examples: coffee, tea, colas), herbs (examples: guarana, green tea) and other products that contain additional caffeine, such as chocolate and some non-prescription medications or dietary supplements for headache, insomnia, or weight loss. Too much Caffeine can cause effects like nausea, nervousness, or sleeplessness. Some drug products for adults that contain caffeine have about as much caffeine as a cup of coffee. (Minor) Caffeine has been reported to increase the metabolism of aspirin.
Caffeine; Sodium Benzoate: (Minor) Caffeine has been reported to increase the metabolism of aspirin.
Calcifediol: (Moderate) Dose adjustment of calcifediol may be necessary during coadministration with barbiturates. Additionally, serum 25-hydroxyvitamin D, intact PTH, and calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with barbiturates. Barbiturates stimulate microsomal hydroxylation and reduce the half-life of calcifediol. In rare cases, this has caused anticonvulsant-induced rickets and osteomalacia.
Calcitriol: (Moderate) Barbiturates can decrease the activity of vitamin D by increasing its metabolism. In rare cases, this has caused anticonvulsant-induced rickets and osteomalacia. Vitamin D supplementation may be required in patients with inadequate dietary intake of vitamin D who are receiving chronic treatment with barbiturates.
Calcium Carbonate; Risedronate: (Minor) Monitor for gastrointestinal adverse events during concurrent use of risedronate and aspirin. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Calcium, Magnesium, Potassium, Sodium Oxybates: (Contraindicated) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs. Specifically, sodium oxybate use is contraindicated in patients being treated with sedative hypnotic drugs. Sodium oxybate (GHB) has the potential to impair cognitive and motor skills. For example, the concomitant use of barbiturates and benzodiazepines increases sleep duration and may contribute to rapid onset, pronounced CNS depression, respiratory depression, or coma when combined with sodium oxybate. (Moderate) Caffeine should be avoided or used cautiously with oxybates. Monitor for potential side effects such as nervousness, irritability, insomnia, and/or cardiac arrhythmias.
Canagliflozin: (Moderate) Monitor blood glucose during concomitant canagliflozin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Canagliflozin; Metformin: (Moderate) Monitor blood glucose during concomitant canagliflozin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant metformin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Candesartan; Hydrochlorothiazide, HCTZ: (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics. (Moderate) Monitor blood pressure as well as for signs of worsening renal function and loss of diuretic efficacy, including antihypertensive effects, during concomitant thiazide diuretic and salicylate use. Salicylate use decreases glomerular filtration rate and renal blood flow, and concomitant diuretic use may increase the risk of this reaction. Salicylates may diminish the effectiveness of diuretics due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention.
Cannabidiol: (Moderate) Consider a dose reduction of caffeine as clinically appropriate, if adverse reactions occur when administered with cannabidiol. Increased caffeine exposure is possible. Caffeine is a CYP1A2 substrate and cannabidiol is a weak CYP1A2 inhibitor. (Moderate) Monitor for excessive sedation and somnolence during coadministration of cannabidiol and butalbital. CNS depressants can potentiate the effects of cannabidiol.
Caplacizumab: (Major) Avoid concomitant use of caplacizumab and aspirin when possible. Assess and monitor closely for bleeding if use together is necessary. Interrupt use of caplacizumab if clinically significant bleeding occurs.
Capmatinib: (Major) Avoid coadministration of capmatinib and butalbital due to the risk of decreased capmatinib exposure, which may reduce its efficacy. Capmatinib is a CYP3A substrate and butalbital is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased capmatinib exposure by 44%. (Moderate) Reduction or limitation of the caffeine dosage in medications or caffeine in beverages and food may be necessary during concurrent capmatinib therapy. Monitor for an increase in caffeine-related adverse reactions if coadministration with capmatinib is necessary. Caffeine is a sensitive CYP1A2 substrate and capmatinib is a weak CYP1A2 inhibitor. Coadministration with capmatinib increased caffeine exposure by 134%.
Capreomycin: (Major) Since capreomycin is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including salicylates, may increase serum concentrations of either drug. Theoretically, the chronic coadministration of these drugs may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Monitor patients for changes in renal function if these drugs are coadministered.
Captopril: (Moderate) Aspirin, ASA may reduce the vasodilatory efficacy of ACE inhibitors by inhibiting the synthesis of vasodilatory prostaglandins. This interaction has been documented primarily in heart failure patients. However, the established benefits of using aspirin in combination with an ACE inhibitor in patients with ischemic heart disease and left ventricular dysfunction generally outweigh this concern. Patients receiving concurrent salicylates and ACE inhibitor therapy should be monitored for antihypertensive or vasodilatory efficacy; the dose of the ACE inhibitor can be adjusted if indicated based on clinical evaluation.
Captopril; Hydrochlorothiazide, HCTZ: (Moderate) Aspirin, ASA may reduce the vasodilatory efficacy of ACE inhibitors by inhibiting the synthesis of vasodilatory prostaglandins. This interaction has been documented primarily in heart failure patients. However, the established benefits of using aspirin in combination with an ACE inhibitor in patients with ischemic heart disease and left ventricular dysfunction generally outweigh this concern. Patients receiving concurrent salicylates and ACE inhibitor therapy should be monitored for antihypertensive or vasodilatory efficacy; the dose of the ACE inhibitor can be adjusted if indicated based on clinical evaluation. (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics. (Moderate) Monitor blood pressure as well as for signs of worsening renal function and loss of diuretic efficacy, including antihypertensive effects, during concomitant thiazide diuretic and salicylate use. Salicylate use decreases glomerular filtration rate and renal blood flow, and concomitant diuretic use may increase the risk of this reaction. Salicylates may diminish the effectiveness of diuretics due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention.
Carbamazepine: (Moderate) Barbiturates can accelerate hepatic metabolism of carbamazepine due to induction of hepatic microsomal enzyme activity. Carbamazepine serum concentrations should be monitored closely if a barbiturate is added or discontinued during therapy. (Minor) Carbamazepine may induce caffeine metabolism via induction of the hepatic CYP1A2 isoenzyme.
Carbidopa; Levodopa; Entacapone: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, such as barbiturates, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should avoid driving or other hazardous tasks until the effects of the drug combination are known.
Carbinoxamine: (Moderate) Additive CNS depression may occur if barbiturates are co-used with sedating antihistamines, such as carbinoxamine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities.
Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Moderate) Additive CNS depression may occur if barbiturates are co-used with sedating antihistamines, such as carbinoxamine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities. (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Carbinoxamine; Phenylephrine: (Moderate) Additive CNS depression may occur if barbiturates are co-used with sedating antihistamines, such as carbinoxamine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities. (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants like phenylephrine; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Carbinoxamine; Pseudoephedrine: (Moderate) Additive CNS depression may occur if barbiturates are co-used with sedating antihistamines, such as carbinoxamine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities. (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Cardiac glycosides: (Moderate) Hepatic enzyme inducing drugs, such as barbiturates, can accelerate the metabolism of digoxin, decreasing its serum concentrations. It is recommended that digoxin concentrations be monitored if used with barbiturates.
Cariprazine: (Major) Concomitant use of cariprazine and barbiturates is not recommended because the net effect on cariprazine and its equipotent active metabolites is unclear. CYP3A is responsible for both the formation and elimination of cariprazine's major active metabolites. Barbiturates are CYP3A inducers, however, concurrent use of cariprazine with CYP3A inducers has not been evaluated, and the net effect is unclear. In addition, due to the CNS effects of cariprazine, caution should be used when cariprazine is given in combination with other centrally-acting medications including benzodiazepines and other anxiolytics, sedatives, and hypnotics.
Cefixime: (Minor) In vitro, salicylates have displaced cefixime from its protein-binding sites, resulting in a 50% increase in free cefixime levels. The clinical significance of this effect is unclear at this time.
Cefotetan: (Minor) Cefotetan has been associated with hypoprothrombinemia and may cause additive effects when given concurrently with salicylates.
Celecoxib: (Major) Concomitant use of analgesic doses of aspirin and celecoxib is generally not recommended due to the increased risk of bleeding. Concurrent use of analgesic doses of aspirin with NSAIDs does not produce a greater therapeutic effect compared to the use of NSAIDs alone. Celecoxib (200 to 400 mg/day) did not interfere with the cardioprotective antiplatelet effect of aspirin (100 to 325 mg) in 2 studies in healthy volunteers and in patients with osteoarthritis and established heart disease. Celecoxib is not a substitute for low dose aspirin for cardiovascular protection.
Celecoxib; Tramadol: (Major) Concomitant use of analgesic doses of aspirin and celecoxib is generally not recommended due to the increased risk of bleeding. Concurrent use of analgesic doses of aspirin with NSAIDs does not produce a greater therapeutic effect compared to the use of NSAIDs alone. Celecoxib (200 to 400 mg/day) did not interfere with the cardioprotective antiplatelet effect of aspirin (100 to 325 mg) in 2 studies in healthy volunteers and in patients with osteoarthritis and established heart disease. Celecoxib is not a substitute for low dose aspirin for cardiovascular protection. (Major) Concomitant use of tramadol with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concomitant use of tramadol with a barbiturate can decrease tramadol concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Monitor for reduced efficacy of tramadol and signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of seizures, serotonin syndrome, and the risk of opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; tramadol is a CYP3A4 substrate.
Cenobamate: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and butalbital. Concurrent use may result in additive CNS depression.
Cetirizine: (Moderate) Concurrent use of cetirizine/levocetirizine with barbiturates should generally be avoided. Coadministration may increase the risk of CNS depressant-related side effects. If concurrent use is necessary, monitor for excessive sedation and somnolence.
Cetirizine; Pseudoephedrine: (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor. (Moderate) Concurrent use of cetirizine/levocetirizine with barbiturates should generally be avoided. Coadministration may increase the risk of CNS depressant-related side effects. If concurrent use is necessary, monitor for excessive sedation and somnolence.
Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) Additive CNS depression may occur if barbiturates are co-used with sedating antihistamines, such as dexchlorpheniramine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities. (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Chlorambucil: (Minor) Barbiturates appear to increase the hepatic activation of chlorambucil to its active metabolite than to inactive metabolite. Clinicians should be alert for a potential increase in chlorambucil related activity and/or toxicity.
Chloramphenicol: (Moderate) Chloramphenicol inhibits the cytochrome P-450 enzyme system and can affect the hepatic metabolism of phenobarbital. Phenobarbital levels rise modestly. It is also possible that plasma concentrations of chloramphenicol can be reduced by concomitant use of barbiturates, agents that are known to stimulate hepatic microsomal enzymes responsible for chloramphenicol metabolism.
Chlordiazepoxide: (Moderate) Additive CNS and/or respiratory depression may occur. Additionally, barbiturates may increase the metabolism of chlordiazepoxide. Chlordiazepoxide is a CYP3A4 substrate. Barbiturates are CYP3A4 inducers.
Chlordiazepoxide; Amitriptyline: (Moderate) Additive CNS and/or respiratory depression may occur. Additionally, barbiturates may increase the metabolism of chlordiazepoxide. Chlordiazepoxide is a CYP3A4 substrate. Barbiturates are CYP3A4 inducers.
Chlordiazepoxide; Clidinium: (Moderate) Additive CNS and/or respiratory depression may occur. Additionally, barbiturates may increase the metabolism of chlordiazepoxide. Chlordiazepoxide is a CYP3A4 substrate. Barbiturates are CYP3A4 inducers.
Chlorothiazide: (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics. (Moderate) Monitor blood pressure as well as for signs of worsening renal function and loss of diuretic efficacy, including antihypertensive effects, during concomitant thiazide diuretic and salicylate use. Salicylate use decreases glomerular filtration rate and renal blood flow, and concomitant diuretic use may increase the risk of this reaction. Salicylates may diminish the effectiveness of diuretics due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention.
Chlorpheniramine: (Moderate) Additive CNS depression may occur if barbiturates are co-used with sedating antihistamines, such as chlorpheniramine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities.
Chlorpheniramine; Codeine: (Major) Concomitant use of codeine with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. It is recommended to avoid this combination when codeine is being used for cough. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concomitant use of codeine with a barbiturate can decrease codeine concentrations, 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. Monitor for reduced efficacy of codeine and signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. (Moderate) Additive CNS depression may occur if barbiturates are co-used with sedating antihistamines, such as chlorpheniramine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities.
Chlorpheniramine; Dextromethorphan: (Moderate) Additive CNS depression may occur if barbiturates are co-used with sedating antihistamines, such as chlorpheniramine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities.
Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Additive CNS depression may occur if barbiturates are co-used with sedating antihistamines, such as chlorpheniramine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities. (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants like phenylephrine; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Additive CNS depression may occur if barbiturates are co-used with sedating antihistamines, such as chlorpheniramine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities. (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Major) Concomitant use of dihydrocodeine with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. It is recommended to avoid this combination when dihydrocodeine is being used for cough. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concomitant use of dihydrocodeine with a barbiturate can decrease dihydrocodeine concentrations, 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. Monitor for reduced efficacy of dihydrocodeine and signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine. (Moderate) Additive CNS depression may occur if barbiturates are co-used with sedating antihistamines, such as chlorpheniramine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities. (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants like phenylephrine; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Chlorpheniramine; Hydrocodone: (Major) Concomitant use of hydrocodone with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. It is recommended to avoid this combination when hydrocodone is being used for cough. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concomitant use of hydrocodone with a barbiturate can decrease hydrocodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; hydrocodone is a CYP3A4 substrate. (Moderate) Additive CNS depression may occur if barbiturates are co-used with sedating antihistamines, such as chlorpheniramine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities.
Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Major) Concomitant use of analgesic doses of aspirin and ibuprofen is generally not recommended due to the increased risk of bleeding and renal impairment. Because there may be an increased risk of cardiovascular events due to the interference of ibuprofen with the antiplatelet effect of aspirin, for patients taking low-dose aspirin for cardioprotection who require analgesics, consider use of an NSAID that does not interfere with the antiplatelet effect of aspirin, or non-NSAID analgesics, as appropriate. Administer single doses of ibuprofen at least 2 to 4 hours or more after aspirin and wait 8 hours after ibuprofen administration before administering aspirin to avoid significant interference. Monitor for signs and symptoms of renal impairment. Pharmacodynamic studies have demonstrated interference with the antiplatelet activity of aspirin when ibuprofen 400 mg 3 times daily is administered with enteric-coated low-dose aspirin. The interaction exists even after ibuprofen 400 mg once daily, particularly when ibuprofen is dosed prior to aspirin. The interaction is alleviated if immediate-release low-dose aspirin is dosed at least 2 hours prior to a once daily regimen of ibuprofen; however, this finding cannot be extended to enteric-coated low-dose aspirin. A decrease in antiplatelet activity (53%) was observed when ibuprofen 400 mg once daily was administered 2 hours before low-dose immediate-release aspirin 81 mg/day for 6 days. An interaction was still observed, but minimized, when ibuprofen 400 mg once daily was administered as early as 8 hours before immediate-release aspirin (90.7%). There was no interaction with the antiplatelet activity of aspirin when ibuprofen 400 mg once daily was administered 2 hours after immediate-release aspirin (99.2%). In another study of low-dose immediate-release aspirin 81 mg/day and ibuprofen 400 mg 3 times daily (1, 7, and 13 hours post-aspirin dose) for 10 consecutive days, there was no interaction with the antiplatelet activity of aspirin (98.3%); however, there were individuals with aspirin antiplatelet activity below 95%, with the lowest being 90.2%. When a similarly designed study was conducted with enteric-coated aspirin 81 mg/day for 6 days and ibuprofen 400 mg 3 times daily (2, 7 and 12 h post-aspirin dose) for 6 days, there was an interaction with the antiplatelet activity at 24 hours after the day 6 aspirin dose (67%). Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone. Ibuprofen is not a substitute for low dose aspirin for cardiovascular protection. (Moderate) Additive CNS depression may occur if barbiturates are co-used with sedating antihistamines, such as chlorpheniramine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities. (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Chlorpheniramine; Phenylephrine: (Moderate) Additive CNS depression may occur if barbiturates are co-used with sedating antihistamines, such as chlorpheniramine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities. (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants like phenylephrine; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Chlorpheniramine; Pseudoephedrine: (Moderate) Additive CNS depression may occur if barbiturates are co-used with sedating antihistamines, such as chlorpheniramine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities. (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Chlorpropamide: (Moderate) Monitor blood glucose during concomitant sulfonylurea and aspirin use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Chlorthalidone: (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics. (Moderate) Monitor blood pressure as well as for signs of worsening renal function and loss of diuretic efficacy, including antihypertensive effects, during concomitant thiazide diuretic and salicylate use. Salicylate use decreases glomerular filtration rate and renal blood flow, and concomitant diuretic use may increase the risk of this reaction. Salicylates may diminish the effectiveness of diuretics due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention.
Chlorthalidone; Clonidine: (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics. (Moderate) Monitor blood pressure as well as for signs of worsening renal function and loss of diuretic efficacy, including antihypertensive effects, during concomitant thiazide diuretic and salicylate use. Salicylate use decreases glomerular filtration rate and renal blood flow, and concomitant diuretic use may increase the risk of this reaction. Salicylates may diminish the effectiveness of diuretics due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention.
Choline Salicylate; Magnesium Salicylate: (Moderate) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as barbiturates. An enhanced effect of the displaced drug may occur.
Cidofovir: (Contraindicated) The concomitant administration of cidofovir and NSAIDs, such as aspirin, is contraindicated due to the potential for increased nephrotoxicity. Aspirin should be discontinued 7 days prior to beginning cidofovir.
Cilostazol: (Moderate) Use caution with the coadministration of aspirin and cilostazol. Although the short-term (<= 4 days) coadministration of aspirin and cilostazol increased the inhibition of ADP-induced platelet aggregation by 22% to 37% compared to aspirin or cilostazol use alone, no clinically significant effect on PT, aPTT, or bleeding time was observed compared to aspirin alone. In clinical trials, there was no apparent increase in hemorrhagic adverse effects in patients taking cilostazol and aspirin compared to aspirin alone. The effects of long-term coadministration are unknown. Monitor for bleeding during concomitant therapy.
Cimetidine: (Minor) Inhibitors of CYP1A2, such as cimetidine, may inhibit the hepatic oxidative metabolism of caffeine. In patients who complain of caffeine-related side effects caffeine dosage or intake may need to be reduced.
Cinacalcet: (Moderate) Coadministration of cinacalcet with a CYP3A4 enzyme inducer, such as a barbiturate, may result in a decreased effect of cinacalcet.
Ciprofloxacin: (Moderate) Reduction or limitation of the caffeine dosage in medications and limitation of caffeine in beverages and food may be necessary during concurrent ciprofloxacin therapy. Ciprofloxacin can decrease the clearance of caffeine. Caffeine toxicity may occur and can manifest as nausea, vomiting, anxiety, tachycardia, or seizures. Ciprofloxacin is a CYP1A2 inhibitor and caffeine is a CYP1A2 substrate.
Citalopram: (Moderate) Monitor for decreased efficacy of citalopram if coadministration with barbiturates is necessary. Citalopram is a CYP3A4 and CYP2C19 substrate and barbiturates are moderate 2C19 inducers and strong CYP3A4 inducers. Coadministration with another strong CYP3A4 inducer did not affect citalopram plasma concentrations, but increased clearance of citalopram with strong CYP3A4 inducers is possible. (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
Citric Acid; Potassium Citrate; Sodium Citrate: (Moderate) Concurrent administration of high doses of alkalinizing agents may increase urine pH and decrease serum salicylate levels by decreasing renal tubular reabsorption of salicylic acid. (Moderate) Urinary alkalinizing agents, like potassium citrate, increase the excretion of salicylates by increasing renal clearance.
Clemastine: (Moderate) Additive CNS depression may occur if barbiturates are co-used with sedating antihistamines, such as clemastine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities.
Clobazam: (Moderate) Concomitant of clobazam with other CNS-depressant drugs including barbiturates can potentiate the CNS effects (i.e., increased sedation or respiratory depression) of either agent. The primary metabolic pathway of clobazam is CYP3A4, and to a lesser extent, CYP2C19 and CYP2B6. Metabolism of N-desmethylclobazam occurs primarily through CYP2C19. Results of a population pharmacokinetic analysis showed that concurrent use of phenobarbital, a CYP3A4 and CYP2C9 inducer, did not significantly alter the kinetics of clobazam or its active metabolite N-desmethylclobazam at steady-state. It should be noted that because clobazam is metabolized by multiple enzyme systems, induction of one pathway may not appreciably increase its clearance.
Clomipramine: (Moderate) Clomipramine may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. This may increase the risk for an upper GI bleed.
Clonazepam: (Moderate) Monitoring of clonazepam concentrations or dosage adjustment may be necessary if used concurrently with barbiturates due to decreased clonazepam concentrations. Clonazepam concentration decreases of approximately 38% have been reported when clonazepam is used with strong CYP3A4 inducers. Clonazepam is a CYP3A4 substrate. Barbiturates are strong CYP3A4 inducers. Additive CNS and/or respiratory depression may also occur.
Clopidogrel: (Moderate) Monitor for bleeding if aspirin and clopidogrel are used together as concomitant has an additive effect on platelet function.
Clorazepate: (Moderate) Additive CNS and/or respiratory depression may occur. Additionally, barbiturates may increase the metabolism of N-desmethyldiazepam, the active metabolite of clorazepate. N-desmethyldiazepam is a CYP3A4 and CYP2C19 substrate. Barbiturates are CYP3A4 and CYP2C19 inducers.
Clozapine: (Major) Caffeine may inhibit clozapine metabolism via CYP1A2. Clozapine clearance has been decreased by roughly 14 percent during coadministration of caffeine, and a documented increase in clozapine serum concentrations has occurred in selected patients. In addition, a single case report associates the appearance of psychiatric symptoms with caffeine ingestion in one patient taking clozapine. Until more data are available, caffeine consumption should be minimized during clozapine treatment. (Moderate) Patients on certain anticonvulsant therapies should receive clozapine with caution. Clozapine may interact with anticonvulsants in several ways; concurrent use of clozapine in patients on antiepileptic medications is not recommended in seizures that are not well controlled. Clozapine lowers the seizure threshold in a dose-dependent manner and thus may induce seizures; dosage adjustments of clozapine should be cautious. CYP1A2, CYP3A4, and CYP2D6 isoenzymes metabolize clozapine; anticonvulsant drugs known to induce one or more of these isoenzymes include barbiturates. Clinicians should monitor for reduced clozapine effectiveness during concurrent use of anticonvulsants that are weak to moderate CYP inducers. Additive sedation may be noted initially with concurrent clozapine and barbiturate use; enzyme induction by barbiturates takes several days to become clinically apparent.
Cobimetinib: (Major) Avoid the concurrent use of cobimetinib with butalbital due to decreased cobimetinib efficacy. Cobimetinib is a CYP3A substrate in vitro, and butalbital is a moderate inducer of CYP3A. Based on simulations, cobimetinib exposure would decrease by 73% when coadministered with a moderate CYP3A inducer.
Codeine: (Major) Concomitant use of codeine with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. It is recommended to avoid this combination when codeine is being used for cough. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concomitant use of codeine with a barbiturate can decrease codeine concentrations, 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. Monitor for reduced efficacy of codeine and signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties.
Codeine; Guaifenesin: (Major) Concomitant use of codeine with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. It is recommended to avoid this combination when codeine is being used for cough. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concomitant use of codeine with a barbiturate can decrease codeine concentrations, 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. Monitor for reduced efficacy of codeine and signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties.
Codeine; Guaifenesin; Pseudoephedrine: (Major) Concomitant use of codeine with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. It is recommended to avoid this combination when codeine is being used for cough. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concomitant use of codeine with a barbiturate can decrease codeine concentrations, 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. Monitor for reduced efficacy of codeine and signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Codeine; Phenylephrine; Promethazine: (Major) Concomitant use of codeine with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. It is recommended to avoid this combination when codeine is being used for cough. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concomitant use of codeine with a barbiturate can decrease codeine concentrations, 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. Monitor for reduced efficacy of codeine and signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants like phenylephrine; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Codeine; Promethazine: (Major) Concomitant use of codeine with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. It is recommended to avoid this combination when codeine is being used for cough. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concomitant use of codeine with a barbiturate can decrease codeine concentrations, 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. Monitor for reduced efficacy of codeine and signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties.
Colistimethate, Colistin, Polymyxin E: (Major) Theoretically, the chronic coadministration of these drugs may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Monitor patients for changes in renal function if these drugs are coadministered. Since colistimethate sodium is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including salicylates, may increase serum concentrations of either drug.
Colistin: (Major) Theoretically, the chronic coadministration of these drugs may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Monitor patients for changes in renal function if these drugs are coadministered. Since colistimethate sodium is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including salicylates, may increase serum concentrations of either drug.
Collagenase: (Moderate) Cautious use of injectable collagenase by patients taking more than 150 mg/day of aspirin is advised. The efficacy and safety of administering injectable collagenase to a patient taking more than 150 mg/day of aspirin within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
COMT inhibitors: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, such as barbiturates, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should avoid driving or other hazardous tasks until the effects of the drug combination are known.
Corticosteroids: (Moderate) Monitor for gastrointestinal toxicity during concurrent corticosteroid and salicylate use. Concomitant use increases the risk of GI bleeding. In patients receiving concomitant corticosteroids and chronic use of salicylates, withdrawal of corticosteroids may result in salicylism because corticosteroids enhance renal clearance of salicylates and their withdrawal is followed by return to normal rates of renal clearance.
Cyclosporine: (Major) Phenobarbital may induce cyclosporine metabolism, thereby increasing the clearance of cyclosporine. It is likely that other barbiturates would interact similarly with cyclosporine; however no supportive data are available. If phenobarbital is added to an existing cyclosporine regimen, monitor cyclosporine concentrations closely to avoid loss of clinical efficacy until a new steady-state concentration is achieved. Conversely, if phenobarbital is discontinued, cyclosporine concentrations could increase. (Minor) Due to the inhibition of renal prostaglandins by salicylates, concurrent use of salicylates and other nephrotoxic agents like cyclosporine may lead to additive nephrotoxicity.
Cyproheptadine: (Moderate) Additive CNS depression may occur if barbiturates are used concomitantly with cyproheptadine.
Dabigatran: (Major) Educate patients about the signs of increased bleeding and the need to report these signs to a healthcare provider immediately if coadministration of dabigatran and aspirin or another salicylate is necessary. Dabigatran can cause significant and, sometimes, fatal bleeding. This risk may be increased by concurrent use of chronic salicylate therapy.
Dalteparin: (Moderate) An additive risk of bleeding may be seen in patients receiving a low molecular weight heparin in combination with other agents known to increase the risk of bleeding such as salicylates. Monitor clinical and laboratory response closely during concurrent use.
Danazol: (Moderate) Danazol can decrease hepatic synthesis of procoagulant factors, increasing the possibility of bleeding when used concurrently with platelet inhibitors.
Dapagliflozin: (Moderate) Monitor blood glucose during concomitant dapagliflozin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Dapagliflozin; Metformin: (Moderate) Monitor blood glucose during concomitant dapagliflozin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant metformin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Dapagliflozin; Saxagliptin: (Moderate) Monitor blood glucose during concomitant dapagliflozin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant saxagliptin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Daratumumab; Hyaluronidase: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Daridorexant: (Major) Avoid concomitant use of daridorexant and butalbital. Coadministration may decrease daridorexant exposure which may reduce its efficacy. Additive CNS effects, such as sedation and psychomotor impairment, are also possible. Daridorexant is a CYP3A substrate and butalbital is a moderate CYP3A inducer. Concomitant use of another moderate CYP3A inducer decreased daridorexant overall exposure by over 50%.
Darifenacin: (Minor) Barbiturates (e.g., phenobarbital or primidone) may induce the CYP3A4 metabolism of darifenacin. The dosage requirements of darifenacin may be increased in patients receiving concurrent enzyme inducers. (Minor) Consuming > 400 mg/day caffeine has been associated with the development of urinary incontinence. Caffeine may aggravate bladder symptoms, increase urination, and counteract the effectiveness of darifenacin to some degree. Patients may wish to limit their intake of caffeinated drugs, dietary supplements (e.g., guarana), or beverages (e.g., green tea, other teas, coffee, colas).
Darunavir: (Major) Coadministration of darunavir with barbiturates is not recommended as there is a potential for decreased darunavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Darunavir is a CYP3A4 substrate; barbiturates as a class are CYP3A4 inducers. Most reports of clinically significant drug interactions occurring with the barbiturates have involved phenobarbital, a known potent CYP3A4 inducer.
Darunavir; Cobicistat: (Major) Coadministration of darunavir with barbiturates is not recommended as there is a potential for decreased darunavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Darunavir is a CYP3A4 substrate; barbiturates as a class are CYP3A4 inducers. Most reports of clinically significant drug interactions occurring with the barbiturates have involved phenobarbital, a known potent CYP3A4 inducer.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Coadministration of darunavir with barbiturates is not recommended as there is a potential for decreased darunavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Darunavir is a CYP3A4 substrate; barbiturates as a class are CYP3A4 inducers. Most reports of clinically significant drug interactions occurring with the barbiturates have involved phenobarbital, a known potent CYP3A4 inducer.
Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid concomitant use of ritonavir and barbiturates. Concomitant use may decrease the exposure of both drugs, resulting in reduced efficacy. If concomitant use is necessary, monitor for decreased virologic response and decreased efficacy of the barbiturate. A dose increase of the barbiturate may be necessary. Ritonavir is a CYP3A substrate and inducer and barbiturates are CYP3A inducers.
Deferasirox: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including salicylates.
Defibrotide: (Contraindicated) Coadministration of defibrotide with antithrombotic agents like aspirin is contraindicated. The pharmacodynamic activity and risk of hemorrhage with antithrombotic agents are increased if coadministered with defibrotide. If therapy with defibrotide is necessary, discontinue antithrombotic agents prior to initiation of defibrotide therapy. Consider delaying the onset of defibrotide treatment until the effects of the antithrombotic agent have abated.
Deflazacort: (Major) Avoid concomitant use of deflazacort and butalbital. Concurrent use may significantly decrease concentrations of 21-desDFZ, the active metabolite of deflazacort, resulting in loss of efficacy. Deflazacort is a CYP3A4 substrate; butalbital is a moderate 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) Barbiturates may increase the metabolism of delavirdine, lead to substantial reductions in delavirdine concentrations and efficacy. The manufacturer recommends that delavirdine not be given with barbiturates when used as anticonvulsants due to the potential for subtherapeutic antiretroviral activity and the subsequent possibility for the development of resistant mutations of HIV. In addition, delavirdine may inhibit the metabolism of the barbiturates. If used concomitantly, the patient should be observed for changes in the clinical efficacy and concentrations of the antiretroviral and anticonvulsant regimens.
Desloratadine; Pseudoephedrine: (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Desogestrel; Ethinyl Estradiol: (Minor) Serum concentrations of caffeine may be increased during concurrent administration with ethinyl estradiol. Patients may desire to limit products that contain high amounts of caffeine to minimize caffeine-related side effects such as nausea or tremors.
Deutetrabenazine: (Moderate) Advise patients that concurrent use of deutetrabenazine and drugs that can cause CNS depression, such as barbiturates, may have additive effects and worsen drowsiness or sedation.
Dexamethasone: (Moderate) Coadministration may result in decreased exposure to dexamethasone. Butalbital is a CYP3A4 inducer; dexamethasone is a CYP3A4 substrate. Monitor for decreased response to dexamethasone during concurrent use.
Dexbrompheniramine; Pseudoephedrine: (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Dexchlorpheniramine: (Moderate) Additive CNS depression may occur if barbiturates are co-used with sedating antihistamines, such as dexchlorpheniramine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities.
Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Additive CNS depression may occur if barbiturates are co-used with sedating antihistamines, such as dexchlorpheniramine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities. (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Dexmedetomidine: (Moderate) Co-administration of dexmedetomidine with barbiturates is likely to lead to an enhancement of CNS depression.
Dextroamphetamine: (Moderate) Avoid excessive caffeine intake during use of the amphetamine salts. Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. Excessive caffeine ingestion (via medicines, foods like chocolate, dietary supplements, or beverages including coffee, green tea, other teas, colas) may contribute to side effects like nervousness, irritability, nausea, insomnia, or tremor. Patients should avoid medications and dietary supplements which contain high amounts of caffeine.
Dextromethorphan; Bupropion: (Moderate) Bupropion is associated with a dose-related risk of seizures. Excessive use of psychostimulants, including caffeine, is associated with an increased seizure risk and may increase this risk during the concurrent use of bupropion. Carefully consider a patient's caffeine intake from all sources, including medicines. Monitor for irritability, tremor, increased blood pressure, insomnia and seizures. Many non-prescription medicines and weight loss aids may contain caffeine and patients should read labels carefully. Examples of foods and beverages containing caffeine include coffee, teas, colas, energy drinks, chocolate, and some herbal or dietary supplements. Patients should be advised to limit excessive caffeine intake during bupropion therapy. (Moderate) Bupropion may interact with drugs that induce hepatic microsomal isoenzyme function via CYP2B6 such as the barbiturates. While not systematically studied, these drugs may induce the metabolism of bupropion and may decrease bupropion exposure. If bupropion is used concomitantly with a CYP inducer, it may be necessary to increase the dose of bupropion, but the maximum recommended dose should not be exceeded. Advise patients that until they are reasonably certain that the combination does not adversely affect their performance, they should refrain from driving an automobile or operating complex, hazardous machinery.
Dextromethorphan; Diphenhydramine; Phenylephrine: (Major) Because diphenhydramine can cause pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as barbiturates. (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants like phenylephrine; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants like phenylephrine; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Dextromethorphan; Quinidine: (Major) Quinidine is eliminated primarily via hepatic metabolism, primarily by the CYP3A4 isoenzyme. Administration of other hepatic enzyme inducers, such as barbiturates, can accelerate quinidine elimination and decrease its serum concentrations. Phenobarbital may decrease quinidine half-life and corresponding AUC by about 50 to 60%. Quinidine concentrations should be monitored closely after one of these agents is added. No special precautions appear necessary if these agents are begun several weeks before quinidine is added but quinidine doses may require adjustment if one of these agents is added or discontinued during quinidine therapy.
Diazepam: (Moderate) Additive CNS and/or respiratory depression may occur. Additionally, barbiturates may increase the metabolism of diazepam. Diazepam is a CYP2C9, CYP2C19, and CYP3A4 substrate. Barbiturates are CYP2C9, CYP2C19, and CYP3A4 inducers.
Dichlorphenamide: (Major) Dichlorphenamide is contraindicated with the concomitant use of high dose aspirin, ASA and should be used cautiously in patients receiving low dose aspirin. Dichlorphenamide may cause an elevation in salicylate concentrations in patients receiving aspirin. Adverse reactions including anorexia, tachypnea, lethargy, and coma have been reported with the concomitant use of dichlorphenamide and high dose aspirin.
Diclofenac: (Major) Concomitant use of analgesic doses of aspirin and diclofenac is generally not recommended due to the increased risk of bleeding and renal impairment. Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone. Diclofenac is not a substitute for low dose aspirin for cardiovascular protection. (Moderate) Caution is advised when administering diclofenac with inducers of CYP2C9, such as barbiturates. When used together, the systemic exposure to diclofenac (a CYP2C9 substrate) may decrease, potentially resulting in impaired efficacy. Higher diclofenac doses may be needed. In addition, phenobarbital toxicity has been reported to have occurred in a patient on chronic phenobarbital treatment after diclofenac initiation.
Diclofenac; Misoprostol: (Major) Concomitant use of analgesic doses of aspirin and diclofenac is generally not recommended due to the increased risk of bleeding and renal impairment. Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone. Diclofenac is not a substitute for low dose aspirin for cardiovascular protection. (Moderate) Caution is advised when administering diclofenac with inducers of CYP2C9, such as barbiturates. When used together, the systemic exposure to diclofenac (a CYP2C9 substrate) may decrease, potentially resulting in impaired efficacy. Higher diclofenac doses may be needed. In addition, phenobarbital toxicity has been reported to have occurred in a patient on chronic phenobarbital treatment after diclofenac initiation.
Dicloxacillin: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
Diethylpropion: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
Difelikefalin: (Moderate) Monitor for dizziness, somnolence, mental status changes, and gait disturbances if concomitant use of difelikefalin with CNS depressants is necessary. Concomitant use may increase the risk for these adverse reactions.
Diflunisal: (Major) The concurrent use of diflunisal and salicylates is not recommended due to the increased risk of gastrointestinal toxicity with little or no increase in anti-inflammatory efficacy.
Diltiazem: (Major) Diltiazem is a CYP3A4 substrate. Coadministration of diltiazem with known CYP3A4 inducers, such as barbiturates, may significantly decrease the bioavailability of diltiazem. When possible, avoid coadministration of these drugs and consider alternative therapy. When an alternative therapy is not possible, patients should be monitored for the desired cardiovascular effects on heart rate, chest pain, or blood pressure.
Dimenhydrinate: (Moderate) Additive CNS depression may occur if barbiturates are used concomitantly with dimenhydrinate.
Diphenhydramine: (Major) Because diphenhydramine can cause pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as barbiturates.
Diphenhydramine; Ibuprofen: (Major) Because diphenhydramine can cause pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as barbiturates. (Major) Concomitant use of analgesic doses of aspirin and ibuprofen is generally not recommended due to the increased risk of bleeding and renal impairment. Because there may be an increased risk of cardiovascular events due to the interference of ibuprofen with the antiplatelet effect of aspirin, for patients taking low-dose aspirin for cardioprotection who require analgesics, consider use of an NSAID that does not interfere with the antiplatelet effect of aspirin, or non-NSAID analgesics, as appropriate. Administer single doses of ibuprofen at least 2 to 4 hours or more after aspirin and wait 8 hours after ibuprofen administration before administering aspirin to avoid significant interference. Monitor for signs and symptoms of renal impairment. Pharmacodynamic studies have demonstrated interference with the antiplatelet activity of aspirin when ibuprofen 400 mg 3 times daily is administered with enteric-coated low-dose aspirin. The interaction exists even after ibuprofen 400 mg once daily, particularly when ibuprofen is dosed prior to aspirin. The interaction is alleviated if immediate-release low-dose aspirin is dosed at least 2 hours prior to a once daily regimen of ibuprofen; however, this finding cannot be extended to enteric-coated low-dose aspirin. A decrease in antiplatelet activity (53%) was observed when ibuprofen 400 mg once daily was administered 2 hours before low-dose immediate-release aspirin 81 mg/day for 6 days. An interaction was still observed, but minimized, when ibuprofen 400 mg once daily was administered as early as 8 hours before immediate-release aspirin (90.7%). There was no interaction with the antiplatelet activity of aspirin when ibuprofen 400 mg once daily was administered 2 hours after immediate-release aspirin (99.2%). In another study of low-dose immediate-release aspirin 81 mg/day and ibuprofen 400 mg 3 times daily (1, 7, and 13 hours post-aspirin dose) for 10 consecutive days, there was no interaction with the antiplatelet activity of aspirin (98.3%); however, there were individuals with aspirin antiplatelet activity below 95%, with the lowest being 90.2%. When a similarly designed study was conducted with enteric-coated aspirin 81 mg/day for 6 days and ibuprofen 400 mg 3 times daily (2, 7 and 12 h post-aspirin dose) for 6 days, there was an interaction with the antiplatelet activity at 24 hours after the day 6 aspirin dose (67%). Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone. Ibuprofen is not a substitute for low dose aspirin for cardiovascular protection.
Diphenhydramine; Naproxen: (Major) Because diphenhydramine can cause pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as barbiturates. (Major) Concomitant use of analgesic doses of aspirin and naproxen is generally not recommended due to the increased risk of bleeding and renal impairment. Because there may be an increased risk of cardiovascular events after discontinuation of naproxen due to the interference with the antiplatelet effect of aspirin during the washout period, for patients taking low-dose aspirin for cardioprotection who require intermittent analgesics, consider use of an NSAID that does not interfere with the antiplatelet effect of aspirin, or non-NSAID analgesics as appropriate. A pharmacodynamic study demonstrated that lower dose naproxen (220mg/day or 220mg twice daily) interfered with the antiplatelet effect of low-dose immediate-release aspirin, with the interaction most marked during the washout period of naproxen. There is reason to expect that the interaction would be present with prescription doses of naproxen or with enteric-coated low-dose aspirin; however, the peak interference with aspirin function may be later than observed in the study due to the longer washout period. A decrease in antiplatelet activity was observed at 24 hours after 10 days of naproxen 220 mg/day with low-dose immediate-release aspirin 81 mg/day (93.1%) vs. aspirin alone (98.7%). The interaction was observed even after discontinuation of naproxen on day 11 while aspirin therapy continued but normalized by day 13. The interaction was greater when naproxen was given 30 minutes before aspirin (87.7% vs. 98.7%) and minimal when aspirin was administered 30 minutes before naproxen (95.4% vs. 98.7%). The interaction was minimal at 24 hours after day 10 when naproxen 220 mg twice daily was given 30 minutes before low-dose immediate-release aspirin (95.7% vs. 98.7%); however, the interaction was greater on day 11 after naproxen discontinuation (84.3% vs. 98.7%) and did not normalize by day 13 (90.7% vs. 98.5%). Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone. Naproxen is not a substitute for low dose aspirin for cardiovascular protection.
Diphenhydramine; Phenylephrine: (Major) Because diphenhydramine can cause pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as barbiturates. (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants like phenylephrine; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Diphenoxylate; Atropine: (Moderate) Concurrent administration of diphenoxylate/difenoxin with barbiturates can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration.
Dipyridamole: (Major) Methylxanthines, through antagonism of adenosine and thus pharmacologic-induced coronary vasodilation, have been associated with false-negative results during dipyridamole-thallium 201 stress testing. It is recommended that methylxanthines (caffeine, caffeinated beverages and foods, theophylline, etc.) be discontinued for at least 24 hours prior to stress testing. An interaction is not expected when methylxanthines are used concomitantly with chronic dipyridamole therapy. (Moderate) Although aspirin may be used in combination with dipyridamole, both drugs are associated with bleeding. Monitor for bleeding during concomitant therapy.
Disopyramide: (Moderate) Hepatic microsomal enzyme-inducing agents, such as barbiturates, have the potential to accelerate the hepatic metabolism of disopyramide, a CYP3A4 substrate. Serum disopyramide concentrations should be monitored closely if hepatic enzyme inducers are either added or discontinued during disopyramide therapy.
Disulfiram: (Moderate) Disulfiram has been shown to inhibit caffeine elimination. Caffeine elimination decreased by 30 percent in those patients that were not recovering alcoholics and by 24 percent in those patients that were recovering alcoholics. During disulfiram therapy, patients may need to limit their caffeine intake if nausea, nervousness, tremor, restlessness, palpitations, or insomnia complaints occur. Adverse events were not noted during this pharmacokinetic study, however, the decrease in caffeine clearance could be significant in some patients, including some patients with cardiovascular disease.
Dobutamine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
Dolutegravir; Rilpivirine: (Moderate) Close clinical monitoring is advised when administering barbiturates with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Barbiturates are inducers of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
Donepezil: (Moderate) The elimination of donepezil may be increased by concurrent administration of moderate to strong inducers of CYP2D6 and CYP3A4, such as barbiturates (including primidone). The clinical effect of this interaction on the efficacy of donepezil has not been determined. Observe patients for evidence of reduced donepezil efficacy if these agents are prescribed concurrently.
Donepezil; Memantine: (Moderate) The elimination of donepezil may be increased by concurrent administration of moderate to strong inducers of CYP2D6 and CYP3A4, such as barbiturates (including primidone). The clinical effect of this interaction on the efficacy of donepezil has not been determined. Observe patients for evidence of reduced donepezil efficacy if these agents are prescribed concurrently.
Dopamine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
Doravirine: (Moderate) Concurrent administration of doravirine and butalbital may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate; butalbital is a moderate CYP3A4 inducer.
Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Major) Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir disoproxil fumarate with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents, like salicylates should be carefully monitored for changes in serum creatinine and phosphorus. (Moderate) Concurrent administration of doravirine and butalbital may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate; butalbital is a moderate CYP3A4 inducer.
Doxapram: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants, like doxapram. CNS stimulants and sympathomimetics are associated with adverse effects such as nervousness, irritability, insomnia, and/or cardiac arrhythmias, and the concomitant use of these drugs increases the risk of developing such adverse reactions. Coadminsitration should be avoided or used cautiously.
Doxercalciferol: (Moderate) Although these interactions have not been specifically studied, hepatic enzyme inducers, such as barbiturates, may affect the 25-hydroxylation of doxercalciferol and may necessitate dosage adjustments of doxercalciferol.
Doxorubicin Liposomal: (Major) Barbiturates induce CYP3A4 and doxorubicin is a major substrate of CYP3A4. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of barbiturates and doxorubicin if possible. If not possible, monitor doxorubicin closely for efficacy.
Doxorubicin: (Major) Barbiturates induce CYP3A4 and doxorubicin is a major substrate of CYP3A4. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of barbiturates and doxorubicin if possible. If not possible, monitor doxorubicin closely for efficacy.
Doxycycline: (Major) Phenobarbital has been shown to affect the pharmacokinetics of doxycycline. Doxycycline half-life was decreased from 15.3 hours to 11.1 hours. It is likely that other barbiturates may exert the same effect. Clinicians should keep in mind that larger doses of doxycycline may be necessary in patients receiving barbiturates. This interaction may not apply to other tetracyclines since they are less dependent on hepatic metabolism for elimination.
Doxylamine: (Moderate) Because doxylamine can cause pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as barbiturates.
Doxylamine; Pyridoxine: (Moderate) Because doxylamine can cause pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as barbiturates.
Dronabinol: (Moderate) Use caution if coadministration of dronabinol with barbiturates is necessary, and monitor for an increase in barbiturate-related adverse reactions and a decrease in the efficacy of dronabinol. Additive dizziness, confusion, somnolence, and other CNS effects may also occur. Dronabinol is a CYP2C9 and 3A4 substrate; barbiturates are moderate or strong (phenobarbital) inducers of CYP3A4; additionally phenobarbital is a moderate CYP2C9 inducer. Concomitant use may result in decreased plasma concentrations of dronabinol. Decreased clearance of barbiturates has also been reported with dronabinol use, possibly by competitive inhibition of metabolism. Published data show an increase in the elimination half-life of pentobarbital by 4 hours when concomitantly dosed with dronabinol.
Dronedarone: (Major) The concomitant use of dronedarone and CYP3A4 inducers should be avoided. Dronedarone is metabolized by CYP3A. Barbiturates induce CYP3A4. Coadministration of CYP3A4 inducers, such as barbiturates, with dronedarone may result in reduced plasma concentration and subsequent reduced effectiveness of dronedarone therapy.
Droperidol: (Major) Central nervous system depressants, such as barbiturates, have additive or potentiating effects with droperidol. Following administration of droperidol, lower doses of the other CNS depressant should be used.
Drospirenone; Ethinyl Estradiol: (Minor) Serum concentrations of caffeine may be increased during concurrent administration with ethinyl estradiol. Patients may desire to limit products that contain high amounts of caffeine to minimize caffeine-related side effects such as nausea or tremors.
Drospirenone; Ethinyl Estradiol; Levomefolate: (Minor) Serum concentrations of caffeine may be increased during concurrent administration with ethinyl estradiol. Patients may desire to limit products that contain high amounts of caffeine to minimize caffeine-related side effects such as nausea or tremors.
Duvelisib: (Major) Avoid concomitant use of duvelisib with butalbital. Coadministration may decrease the exposure of duvelisib, which may reduce the efficacy of duvelisib. If concomitant use is necessary, increase the dose of duvelisib on day 12 of coadministration from 25 mg PO twice daily to 40 mg PO twice daily; or from 15 mg PO twice daily to 25 mg PO twice daily. When butalbital has been discontinued for at least 14 days, resume duvelisib at the dose taken prior to initiating treatment with butalbital. Duvelisib is a CYP3A substrate; butalbital is a moderate CYP3A inducer. Coadministration of duvelisib with another moderate CYP3A inducer for 12 days decreased duvelisib exposure by 35%.
Dyphylline: (Major) Due to the risk for additive adverse effects, avoid the concurrent administration of caffeine and dyphylline-containing products when possible. Concurrent administration can produce excessive xanthine-related adverse events such as nausea, irritability, nervousness, and insomnia. More severe adverse effects such as tremors, seizures, or cardiac arrhythmias are also possible with excessive dosages and in sensitive patients. In addition, counsel patients to limit dietary caffeine intake while taking dyphylline.
Dyphylline; Guaifenesin: (Major) Due to the risk for additive adverse effects, avoid the concurrent administration of caffeine and dyphylline-containing products when possible. Concurrent administration can produce excessive xanthine-related adverse events such as nausea, irritability, nervousness, and insomnia. More severe adverse effects such as tremors, seizures, or cardiac arrhythmias are also possible with excessive dosages and in sensitive patients. In addition, counsel patients to limit dietary caffeine intake while taking dyphylline.
Echinacea: (Moderate) Echinacea may inhibit the metabolism of caffeine. Echinacea reduces the oral clearance of caffeine by 27 percent and increases the mean AUC by 129 percent. Monitor patients for signs of increased caffeine serum concentrations if these drugs are coadministered until more data are available.
Edoxaban: (Major) Monitor for bleeding in patients who require chronic treatment with aspirin. Concomitant use of edoxaban with drugs that affect hemostasis, such as aspirin, may increase the risk of bleeding. The coadministration of aspirin (100 mg or 325 mg) and edoxaban increased bleeding time relative to that seen with either drug alone.
Efavirenz: (Major) Complex interactions may occur when barbiturates (e.g., phenobarbital) are administered to patients receiving treatment for HIV infection; if treating seizure disorder, a different anticonvulsant should be used whenever possible. If a barbiturate must be used in a patient being treated for HIV, the patient must be closely monitored for antiviral efficacy and seizure control; appropriate dose adjustments to the barbiturate or the antiretroviral medications are unknown. The combination regimens used to treat HIV often include substrates, inducers, and inhibitors of several CYP isoenzymes. Efavirenz is a substrate and inducer of CYP3A4 and an inhibitor of CYP2C9 and CYP2C19. Phenobarbital is an inducer of CYP3A4, and a substrate and inducer of CYP2C9 and CYP2C19. Use caution if these drugs are to be coadministered, with increased monitoring of both efavirenz and barbiturate concentrations.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Complex interactions may occur when barbiturates (e.g., phenobarbital) are administered to patients receiving treatment for HIV infection; if treating seizure disorder, a different anticonvulsant should be used whenever possible. If a barbiturate must be used in a patient being treated for HIV, the patient must be closely monitored for antiviral efficacy and seizure control; appropriate dose adjustments to the barbiturate or the antiretroviral medications are unknown. The combination regimens used to treat HIV often include substrates, inducers, and inhibitors of several CYP isoenzymes. Efavirenz is a substrate and inducer of CYP3A4 and an inhibitor of CYP2C9 and CYP2C19. Phenobarbital is an inducer of CYP3A4, and a substrate and inducer of CYP2C9 and CYP2C19. Use caution if these drugs are to be coadministered, with increased monitoring of both efavirenz and barbiturate concentrations. (Major) Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir disoproxil fumarate with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents, like salicylates should be carefully monitored for changes in serum creatinine and phosphorus.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Complex interactions may occur when barbiturates (e.g., phenobarbital) are administered to patients receiving treatment for HIV infection; if treating seizure disorder, a different anticonvulsant should be used whenever possible. If a barbiturate must be used in a patient being treated for HIV, the patient must be closely monitored for antiviral efficacy and seizure control; appropriate dose adjustments to the barbiturate or the antiretroviral medications are unknown. The combination regimens used to treat HIV often include substrates, inducers, and inhibitors of several CYP isoenzymes. Efavirenz is a substrate and inducer of CYP3A4 and an inhibitor of CYP2C9 and CYP2C19. Phenobarbital is an inducer of CYP3A4, and a substrate and inducer of CYP2C9 and CYP2C19. Use caution if these drugs are to be coadministered, with increased monitoring of both efavirenz and barbiturate concentrations. (Major) Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir disoproxil fumarate with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents, like salicylates should be carefully monitored for changes in serum creatinine and phosphorus.
Elacestrant: (Major) Avoid concurrent use of elacestrant and barbiturates due to the risk of decreased elacestrant exposure which may reduce its efficacy. Elacestrant is a CYP3A substrate and barbiturates is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced elacestrant overall exposure by 86%.
Elbasvir; Grazoprevir: (Contraindicated) Concurrent administration of barbiturates with elbasvir; grazoprevir is contraindicated. Barbiturates are strong CYP3A inducers, while both elbasvir and grazoprevir are substrates of CYP3A. Use of these drugs together is expected to significantly decrease the plasma concentrations of both elbasvir and grazoprevir, and may result in decreased virologic response.
Eltrombopag: (Moderate) Eltrombopag is metabolized by CYP1A2. The significance of administering inducers of CYP1A2, such as barbiturates, on the systemic exposure of eltrombopag has not been established. Monitor patients for a decrease in the efficacy of eltrombopag if these drugs are coadministered.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir disoproxil fumarate with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents, like salicylates should be carefully monitored for changes in serum creatinine and phosphorus.
Empagliflozin: (Moderate) Monitor blood glucose during concomitant empagliflozin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Empagliflozin; Linagliptin: (Major) Inducers of CYP3A4 (e.g., barbiturates) can decrease exposure to linagliptin to subtherapeutic and likely ineffective concentrations. For patients requiring use of such drugs, an alternative to linagliptin is strongly recommended. (Moderate) Monitor blood glucose during concomitant empagliflozin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant linagliptin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Empagliflozin; Linagliptin; Metformin: (Major) Inducers of CYP3A4 (e.g., barbiturates) can decrease exposure to linagliptin to subtherapeutic and likely ineffective concentrations. For patients requiring use of such drugs, an alternative to linagliptin is strongly recommended. (Moderate) Monitor blood glucose during concomitant empagliflozin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant linagliptin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant metformin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Empagliflozin; Metformin: (Moderate) Monitor blood glucose during concomitant empagliflozin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant metformin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Close clinical monitoring is advised when administering barbiturates with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Barbiturates are inducers of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Major) Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir disoproxil fumarate with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents, like salicylates should be carefully monitored for changes in serum creatinine and phosphorus. (Moderate) Close clinical monitoring is advised when administering barbiturates with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Barbiturates are inducers of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir disoproxil fumarate with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents, like salicylates should be carefully monitored for changes in serum creatinine and phosphorus.
Enalapril, Enalaprilat: (Moderate) Aspirin, ASA may reduce the vasodilatory efficacy of ACE inhibitors by inhibiting the synthesis of vasodilatory prostaglandins. This interaction has been documented primarily in heart failure patients. However, the established benefits of using aspirin in combination with an ACE inhibitor in patients with ischemic heart disease and left ventricular dysfunction generally outweigh this concern. Patients receiving concurrent salicylates and ACE inhibitor therapy should be monitored for antihypertensive or vasodilatory efficacy; the dose of the ACE inhibitor can be adjusted if indicated based on clinical evaluation.
Enalapril; Felodipine: (Major) Barbiturates (e.g., phenobarbital, primidone) may significantly reduce systemic exposure of felodipine; consider alternative therapy. If coadministration is necessary, monitor the patient closely for desired cardiovascular effects on heart rate, blood pressure, or chest pain. Felodipine is a CYP3A4 substrate, and these anticonvulsants are potent CYP3A4 inducers. In a pharmacokinetic study, felodipine's Cmax was considerably lower in epileptic patients on long-term anticonvulsant therapy than in healthy volunteers. In these patients, the mean AUC was reduced approximately 6% of that observed in healthy adults. (Moderate) Aspirin, ASA may reduce the vasodilatory efficacy of ACE inhibitors by inhibiting the synthesis of vasodilatory prostaglandins. This interaction has been documented primarily in heart failure patients. However, the established benefits of using aspirin in combination with an ACE inhibitor in patients with ischemic heart disease and left ventricular dysfunction generally outweigh this concern. Patients receiving concurrent salicylates and ACE inhibitor therapy should be monitored for antihypertensive or vasodilatory efficacy; the dose of the ACE inhibitor can be adjusted if indicated based on clinical evaluation.
Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) Aspirin, ASA may reduce the vasodilatory efficacy of ACE inhibitors by inhibiting the synthesis of vasodilatory prostaglandins. This interaction has been documented primarily in heart failure patients. However, the established benefits of using aspirin in combination with an ACE inhibitor in patients with ischemic heart disease and left ventricular dysfunction generally outweigh this concern. Patients receiving concurrent salicylates and ACE inhibitor therapy should be monitored for antihypertensive or vasodilatory efficacy; the dose of the ACE inhibitor can be adjusted if indicated based on clinical evaluation. (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics. (Moderate) Monitor blood pressure as well as for signs of worsening renal function and loss of diuretic efficacy, including antihypertensive effects, during concomitant thiazide diuretic and salicylate use. Salicylate use decreases glomerular filtration rate and renal blood flow, and concomitant diuretic use may increase the risk of this reaction. Salicylates may diminish the effectiveness of diuretics due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention.
Encorafenib: (Major) Avoid coadministration of encorafenib and butalbital due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; butalbital is a moderate 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.
Enoxaparin: (Moderate) An additive risk of bleeding may be seen in patients receiving a low molecular weight heparin in combination with other agents known to increase the risk of bleeding such as salicylates. Monitor clinical and laboratory response closely during concurrent use.
Entacapone: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, such as barbiturates, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should avoid driving or other hazardous tasks until the effects of the drug combination are known.
Entrectinib: (Major) Avoid coadministration of entrectinib with butalbital due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; butalbital is a moderate CYP3A4 inducer. Coadministration of a moderate CYP3A4 inducer is predicted to reduce the entrectinib AUC by 56%.
Ephedrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants like ephedrine. Adverse effects such as nervousness, irritability, insomnia, and/or cardiac arrhythmias are also possible when excessive dosages of caffeine are taken concurrently with ephedrine. Patients may also need to limit their intake of caffeine-containing beverages or foods (e.g., coffee, green tea, other teas, guarana, colas, or chocolate) to avoid caffeine-like side effects.
Ephedrine; Guaifenesin: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants like ephedrine. Adverse effects such as nervousness, irritability, insomnia, and/or cardiac arrhythmias are also possible when excessive dosages of caffeine are taken concurrently with ephedrine. Patients may also need to limit their intake of caffeine-containing beverages or foods (e.g., coffee, green tea, other teas, guarana, colas, or chocolate) to avoid caffeine-like side effects.
Epinephrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
Epoprostenol: (Moderate) When used concurrently with platelet inhibitors, epoprostenol may increase the risk of bleeding.
Eprosartan; Hydrochlorothiazide, HCTZ: (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics. (Moderate) Monitor blood pressure as well as for signs of worsening renal function and loss of diuretic efficacy, including antihypertensive effects, during concomitant thiazide diuretic and salicylate use. Salicylate use decreases glomerular filtration rate and renal blood flow, and concomitant diuretic use may increase the risk of this reaction. Salicylates may diminish the effectiveness of diuretics due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention.
Eptifibatide: (Moderate) Unless contraindicated, aspirin is used in combination with eptifibatide. However, both drugs are associated with bleeding. Monitor for bleeding during concomitant therapy.
Erdafitinib: (Major) If coadministration of erdafitinib and butalbital is necessary at the initiation of erdafitinib therapy, administer the dose of erdafitinib as recommended (8 mg once daily with potential to increase the dose to 9 mg on days 14 to 21 based on phosphate levels and tolerability). If butalbital must be added to erdafitinib therapy after the initial dose increase period (days 14 to 21), increase the dose of erdafitinib up to 9 mg. If butalbital is discontinued, continue erdafitinib at the same dose in the absence of drug-related toxicity. Erdafitinib is a CYP3A4 substrate and butalbital is a moderate CYP3A4 inducer.
Ergotamine; Caffeine: (Minor) Caffeine has been reported to increase the metabolism of aspirin.
Erlotinib: (Moderate) There may be a risk of reduced erlotinib efficacy when coadministered with butalbital; however, the risk has not been clearly defined. If coadministration is necessary, consider increasing the erlotinib dose by 50 mg increments at 2-week intervals as tolerated, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Butalbital is a CYP3A4 and 1A2 inducer. Coadministration may decrease plasma concentrations of erlotinib.
Ertugliflozin; Metformin: (Moderate) Monitor blood glucose during concomitant metformin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Ertugliflozin; Sitagliptin: (Moderate) Monitor blood glucose during concomitant sitagliptin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Erythromycin: (Moderate) Inhibitors of the hepatic CYP4501A2, such as erythromycin, may inhibit the hepatic oxidative metabolism of caffeine. No specific management is recommended except in patients who complain of caffeine related side effects. In such patients, the dosage of caffeine containing medications or the ingestion of caffeine containing products may need to be reduced.
Escitalopram: (Moderate) Escitalopram is metabolized by CYP2C19 and CYP3A4. Barbiturates can induce the metabolism of various CYP 450 isoenzymes, including those involved in escitalopram metabolism. Although no clinical data are available to support a clinically significant interaction, escitalopram may need to be administered in higher doses in patients chronically taking barbiturates. (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
Esketamine: (Major) Closely monitor blood pressure during concomitant use of esketamine and caffeine. Coadministration of psychostimulants, such as caffeine, with esketamine may increase blood pressure. (Major) Closely monitor patients receiving esketamine and barbiturates for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Eslicarbazepine: (Major) Barbiturates may induce the metabolism of eslicarbazepine resulting in decreased plasma concentrations of and potentially reduced efficacy of eslicarbazepine. An increased dose of eslicarbazepine may be necessary if these drugs are coadministered.
Esomeprazole: (Major) Avoid coadministration of esomeprazole with barbiturates because it can result in decreased efficacy of esomeprazole. Esomeprazole is extensively metabolized in the liver by CYP2C19 and CYP3A4. Barbiturates induce CYP3A4 and CYP2C19.
Estazolam: (Moderate) Additive CNS and/or respiratory depression may occur. Additionally, barbiturates may increase the metabolism of estazolam. Estazolam is a CYP3A4 substrate. Barbiturates are CYP3A4 inducers.
Estrogens affected by CYP3A inducers: (Major) Women taking both estrogens and barbiturates should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed barbiturates. 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 barbiturates. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on barbiturates, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and barbiturate are strong CYP3A4 inducers. Concurrent administration may increase estrogen elimination.
Eszopiclone: (Major) Barbiturates are potent inducers of CYP3A4 may increase the rate of eszopiclone metabolism. Additive CNS depression may also occur if barbiturates are used concomitantly with eszopiclone. Caution should be exercised during concomitant use of eszopiclone and any barbiturate; dosage reduction of one or both agents may be necessary. (Minor) Patients taking eszopiclone for sleep should avoid caffeine-containing medications, dietary supplements, foods, and beverages close to bedtime, as well as excessive total daily caffeine intake, as part of proper sleep hygiene, since caffeine intake can interfere with proper sleep. Limit use of caffeine-containing products including medications, dietary supplements (e.g., guarana), and beverages (e.g., coffee, green tea, other teas, or colas).
Ethacrynic Acid: (Moderate) Salicylates may decrease the diuretic, natriuretic, and antihypertensive actions of diuretics, possibly through inhibition of renal prostaglandin synthesis. Patients receiving loop diuretics and salicylates should be monitored for changes in the effectiveness of their diuretic therapy.
Ethanol: (Major) Advise patients to avoid alcohol consumption while taking CNS depressants. Alcohol consumption may result in additive CNS depression. (Major) Concomitant ingestion of alcohol with salicylates, especially aspirin, ASA, increases the risk of developing gastric irritation and GI mucosal bleeding. Alcohol and salicylates are mucosal irritants and aspirin decreases platelet aggregation. Routine ingestion of alcohol and aspirin can cause significant GI bleeding, which may or may not be overt. Even occasional concomitant use of salicylates and alcohol should be avoided. Chronic ingestion of alcohol is often associated with hypoprothrombinemia and this condition increases the risk of salicylate-induced bleeding. Patients should be warned regarding the potential for increased risk of GI bleeding if alcohol-containing beverages are taken concurrently with salicylates.
Ethinyl Estradiol: (Minor) Serum concentrations of caffeine may be increased during concurrent administration with ethinyl estradiol. Patients may desire to limit products that contain high amounts of caffeine to minimize caffeine-related side effects such as nausea or tremors.
Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Minor) Serum concentrations of caffeine may be increased during concurrent administration with ethinyl estradiol. Patients may desire to limit products that contain high amounts of caffeine to minimize caffeine-related side effects such as nausea or tremors.
Ethinyl Estradiol; Norelgestromin: (Minor) Serum concentrations of caffeine may be increased during concurrent administration with ethinyl estradiol. Patients may desire to limit products that contain high amounts of caffeine to minimize caffeine-related side effects such as nausea or tremors.
Ethinyl Estradiol; Norethindrone Acetate: (Minor) Serum concentrations of caffeine may be increased during concurrent administration with ethinyl estradiol. Patients may desire to limit products that contain high amounts of caffeine to minimize caffeine-related side effects such as nausea or tremors.
Ethinyl Estradiol; Norgestrel: (Minor) Serum concentrations of caffeine may be increased during concurrent administration with ethinyl estradiol. Patients may desire to limit products that contain high amounts of caffeine to minimize caffeine-related side effects such as nausea or tremors.
Ethosuximide: (Moderate) Barbiturates induce hepatic microsomal enzymes and increase the hepatic metabolism of ethosuximide, leading to a decrease in ethosuximide plasma concentrations and half-life. To maintain a therapeutic dosage, serum concentrations of ethosuximide should be measured, especially if barbiturate therapy is added to or withdrawn from ethosuximide therapy.
Ethotoin: (Minor) Large doses of salicylates can displace hydantoins from plasma protein-binding sites. Although increased serum concentrations of unbound phenytoin may lead to phenytoin toxicity, the liver may also more rapidly clear unbound drug.
Ethynodiol Diacetate; Ethinyl Estradiol: (Minor) Serum concentrations of caffeine may be increased during concurrent administration with ethinyl estradiol. Patients may desire to limit products that contain high amounts of caffeine to minimize caffeine-related side effects such as nausea or tremors.
Etidronate: (Minor) Monitor for gastrointestinal adverse events during concurrent use of etidronate and aspirin. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Etodolac: (Major) The concurrent use of aspirin with other NSAIDs should be avoided because this may increase bleeding or lead to decreased renal function. The use of salicylates together with NSAIDs can also lead to additive GI toxicity.
Etonogestrel; Ethinyl Estradiol: (Minor) Serum concentrations of caffeine may be increased during concurrent administration with ethinyl estradiol. Patients may desire to limit products that contain high amounts of caffeine to minimize caffeine-related side effects such as nausea or tremors.
Everolimus: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate if coadministration with butalbital is necessary. The dose of everolimus may need to be increased. Everolimus is a sensitive CYP3A4 substrate and butalbital is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers may increase the metabolism of everolimus and decrease everolimus blood concentrations.
Ezetimibe; Simvastatin: (Moderate) Barbiturates are significant hepatic CYP3A4 inducers. Monitor for potential reduced cholesterol-lowering efficacy when barbiturates are co-administered with simvastatin, which is metabolized by CYP3A4.
Fedratinib: (Major) Avoid coadministration of fedratinib with barbiturates as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; barbiturates are strong CYP3A4 inducers. Coadministration of fedratinib with another strong CYP3A4 inducer decreased the overall exposure of fedratinib by 81%.
Felodipine: (Major) Barbiturates (e.g., phenobarbital, primidone) may significantly reduce systemic exposure of felodipine; consider alternative therapy. If coadministration is necessary, monitor the patient closely for desired cardiovascular effects on heart rate, blood pressure, or chest pain. Felodipine is a CYP3A4 substrate, and these anticonvulsants are potent CYP3A4 inducers. In a pharmacokinetic study, felodipine's Cmax was considerably lower in epileptic patients on long-term anticonvulsant therapy than in healthy volunteers. In these patients, the mean AUC was reduced approximately 6% of that observed in healthy adults.
Fenfluramine: (Major) Avoid concurrent use of fenfluramine and barbiturates 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 barbiturates are discontinued during fenfluramine maintenance treatment, consider gradual reduction in the fenfluramine dosage to the dose administered prior to barbiturate initiation. Fenfluramine is a CYP3A substrate and barbiturates are strong CYP3A inducers.
Fenoprofen: (Major) The concurrent use of aspirin with other NSAIDs should be avoided because this may increase bleeding or lead to decreased renal function. The use of salicylates together with NSAIDs can also lead to additive GI toxicity. (Minor) Phenobarbital and possibly other barbiturates can decrease the plasma concentrations and half-life of fenoprofen. The clinical significance of this interaction has not been established, but dosage adjustments of fenoprofen may be necessary with concurrent administration of phenobarbital or following initiation or withdrawal of the drug.
Fentanyl: (Major) Concomitant use of fentanyl with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concurrent use of fentanyl with a barbiturate may decrease fentanyl plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. Monitor for signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; fentanyl is a CYP3A4 substrate.
Fesoterodine: (Minor) Beverages containing caffeine or ethanol may aggravate bladder symptoms and counteract the effectiveness of fesoterodine to some degree. Patients may wish to limit their intake of caffeinated drugs, dietary supplements (e.g., guarana), or beverages (e.g., green tea, other teas, coffee, colas) and alcoholic beverages.
Fexofenadine; Pseudoephedrine: (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Finerenone: (Major) Avoid concurrent use of finerenone and butalbital due to the risk for decreased finerenone exposure which may reduce its efficacy. Finerenone is a CYP3A substrate and butalbital is a moderate CYP3A inducer. Coadministration with another moderate CYP3A inducer decreased overall exposure to finerenone by 80%.
Fish Oil, Omega-3 Fatty Acids (Dietary Supplements): (Moderate) Because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with aspirin. Theoretically, the risk of bleeding may be increased.
Flavocoxid, Flavocoxid; Citrated Zinc Bisglycinate: (Major) Because flavocoxid has been associated with isolated cases of occult GI bleeding, additive pharmacodynamic effects may be seen in patients receiving salicylates. Avoid the concurrent use of flavocoxid with salicylates until further data are available.
Flibanserin: (Major) The concomitant use of flibanserin with CYP3A4 inducers significantly decreases flibanserin exposure compared to the use of flibanserin alone. Therefore, concurrent use of flibanserin and phenobarbital or other barbiturates, which are strong CYP3A4 inducers, is not recommended.
Fluconazole: (Moderate) Fluconazole has been shown to inhibit the clearance of caffeine by 25 percent. The clinical significance of these interactions has not been determined. (Minor) Barbiturates induce hepatic CYP enzymes including 3A4, 2C19 and 2C9 and may reduce effective serum concentrations of fluconazole. Be alert for lack of efficacy of fluconazole in concurrent use.
Fluoxetine: (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
Flurbiprofen: (Major) The concurrent use of aspirin with other NSAIDs should be avoided because this may increase bleeding or lead to decreased renal function. The use of salicylates together with NSAIDs can also lead to additive GI toxicity.
Fluticasone: (Moderate) Coadministration may result in decreased exposure to fluticasone. Butalbital is a CYP3A4 inducer; fluticasone is a CYP3A4 substrate. Monitor for decreased response to fluticasone during concurrent use.
Fluticasone; Salmeterol: (Moderate) Caffeine may enhance the cardiac inotropic effects of beta-agonists. (Moderate) Coadministration may result in decreased exposure to fluticasone. Butalbital is a CYP3A4 inducer; fluticasone is a CYP3A4 substrate. Monitor for decreased response to fluticasone during concurrent use.
Fluticasone; Umeclidinium; Vilanterol: (Moderate) Caffeine may enhance the cardiac inotropic effects of beta-agonists. (Moderate) Coadministration may result in decreased exposure to fluticasone. Butalbital is a CYP3A4 inducer; fluticasone is a CYP3A4 substrate. Monitor for decreased response to fluticasone during concurrent use.
Fluticasone; Vilanterol: (Moderate) Caffeine may enhance the cardiac inotropic effects of beta-agonists. (Moderate) Coadministration may result in decreased exposure to fluticasone. Butalbital is a CYP3A4 inducer; fluticasone is a CYP3A4 substrate. Monitor for decreased response to fluticasone during concurrent use.
Fluvoxamine: (Moderate) Strong inhibitors of CYP1A2, such as fluvoxamine, may inhibit the metabolism of caffeine. No specific management is recommended except in patients with caffeine-related side effects after initiating fluvoxamine. In such patients, the dosage of caffeine containing medications or the ingestion of caffeine containing products may need to be reduced. (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
Fondaparinux: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g. aspirin, ASA) in combination with fondaparinux. Data on the concomitant use of fondaparinux with aspirin are lacking; however, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Food: (Major) Advise patients to avoid cannabis use during barbiturate treatment due to the risk for additive CNS depression and other adverse reactions. Concomitant use may also decrease the concentration of some cannabinoids and alter their effects. The cannabinoids delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are CYP3A substrates and barbiturates are strong CYP3A inducers. 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.
Formoterol: (Moderate) Caffeine may enhance the cardiac inotropic effects of beta-agonists.
Formoterol; Mometasone: (Moderate) Caffeine may enhance the cardiac inotropic effects of beta-agonists.
Fosamprenavir: (Moderate) Monitor for decreased fosamprenavir efficacy if coadministered with barbiturates. 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 barbiturates are strong CYP3A inducers. Coadministration with another strong CYP3A inducer decreased the fosamprenavir overall exposure by 82%.
Foscarnet: (Minor) Due to the inhibition of renal prostaglandins by salicylates, concurrent use of salicylates and other nephrotoxic agents, such as foscarnet, may lead to additive nephrotoxicity.
Fosinopril: (Moderate) Aspirin, ASA may reduce the vasodilatory efficacy of ACE inhibitors by inhibiting the synthesis of vasodilatory prostaglandins. This interaction has been documented primarily in heart failure patients. However, the established benefits of using aspirin in combination with an ACE inhibitor in patients with ischemic heart disease and left ventricular dysfunction generally outweigh this concern. Patients receiving concurrent salicylates and ACE inhibitor therapy should be monitored for antihypertensive or vasodilatory efficacy; the dose of the ACE inhibitor can be adjusted if indicated based on clinical evaluation.
Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) Aspirin, ASA may reduce the vasodilatory efficacy of ACE inhibitors by inhibiting the synthesis of vasodilatory prostaglandins. This interaction has been documented primarily in heart failure patients. However, the established benefits of using aspirin in combination with an ACE inhibitor in patients with ischemic heart disease and left ventricular dysfunction generally outweigh this concern. Patients receiving concurrent salicylates and ACE inhibitor therapy should be monitored for antihypertensive or vasodilatory efficacy; the dose of the ACE inhibitor can be adjusted if indicated based on clinical evaluation. (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics. (Moderate) Monitor blood pressure as well as for signs of worsening renal function and loss of diuretic efficacy, including antihypertensive effects, during concomitant thiazide diuretic and salicylate use. Salicylate use decreases glomerular filtration rate and renal blood flow, and concomitant diuretic use may increase the risk of this reaction. Salicylates may diminish the effectiveness of diuretics due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention.
Fosphenytoin: (Minor) Large doses of salicylates can displace phenytoin from plasma protein-binding sites. Although increased serum concentrations of unbound phenytoin may lead to phenytoin toxicity, the liver may also more rapidly clear unbound drug. Fosphenytoin is converted to phenytoin in vivo, so this interaction may also occur with fosphenytoin.
Furosemide: (Moderate) Salicylates may decrease the diuretic, natriuretic, and antihypertensive actions of diuretics, possibly through inhibition of renal prostaglandin synthesis. Patients receiving loop diuretics and salicylates should be monitored for changes in the effectiveness of their diuretic therapy.
Gabapentin: (Major) Concomitant use of barbiturates with gabapentin may cause excessive sedation, somnolence, and respiratory depression. If concurrent use is necessary, initiate gabapentin at the lowest recommended dose and monitor patients for symptoms of respiratory depression and sedation. Educate patients about the risks and symptoms of excessive CNS depression and respiratory depression.
Ganaxolone: (Major) Avoid concurrent use of ganaxolone and barbiturates 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 barbiturates are a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ganaxolone overall exposure by 68%.
Garlic, Allium sativum: (Moderate) Garlic, Allium sativum may produce clinically-significant antiplatelet effects; until more data are available, garlic should be used cautiously in patients receiving drugs with a potential risk for bleeding such as aspirin, ASA.
General anesthetics: (Moderate) Additive CNS depression may occur if general anesthetics are used concomitantly with barbiturates.
Ginger, Zingiber officinale: (Moderate) There may be an increased risk of bleeding in patients on aspirin therapy who take ginger as a supplement (i.e., usual dietary intake is not expected to pose a risk). Several pungent constituents of ginger, Zingiber officinale are reported to inhibit arachidonic acid induced platelet activation in human whole blood. Ginger-associated platelet inhibition may be related to a decrease in COX-1/Thromboxane synthase enzymatic activity. The increased risk of bleeding is theoretical; clinical data of an interaction are not available.
Ginkgo, Ginkgo biloba: (Moderate) Monitor for signs or symptoms of bleeding with coadministration of ginkgo biloba and aspirin as an increased bleeding risk may occur. Although data are mixed, ginkgo biloba is reported to inhibit platelet aggregation and several case reports describe bleeding complications with ginkgo biloba, with or without concomitant drug therapy.
Givosiran: (Major) Avoid concomitant use of givosiran and caffeine due to the risk of increased caffeine-related adverse reactions. If use is necessary, consider decreasing the caffeine dose. Caffeine is a sensitive CYP1A2 substrate. Givosiran may moderately reduce hepatic CYP1A2 enzyme activity because of its pharmacological effects on the hepatic heme biosynthesis pathway.
Glasdegib: (Major) Avoid coadministration of glasdegib and butalbital due to the potential for decreased glasdegib exposure and risk of decreased efficacy. If concurrent use cannot be avoided, increase the glasdegib dosage (i.e., from 100 mg PO daily to 200 mg PO daily; or from 50 mg PO daily to 100 mg PO daily). Resume the previous dose of glasdegib after butalbital has been discontinued for 7 days. Glasdegib is a CYP3A4 substrate; butalbital is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer was predicted to decrease the glasdegib AUC value by 55%.
Glimepiride: (Moderate) Monitor blood glucose during concomitant sulfonylurea and aspirin use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Minor) Barbiturates may induce the CYP2C9 metabolism of glimepiride. Blood glucose concentrations should be monitored and possible dose adjustments of glimepiride may need to be made.
Glimepiride; Rosiglitazone: (Moderate) Monitor blood glucose during concomitant sulfonylurea and aspirin use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant thiazolidinedione and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Minor) Barbiturates may induce the CYP2C9 metabolism of glimepiride. Blood glucose concentrations should be monitored and possible dose adjustments of glimepiride may need to be made.
Glipizide: (Moderate) Monitor blood glucose during concomitant sulfonylurea and aspirin use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Glipizide; Metformin: (Moderate) Monitor blood glucose during concomitant metformin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant sulfonylurea and aspirin use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Glyburide: (Moderate) Monitor blood glucose during concomitant sulfonylurea and aspirin use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Glyburide; Metformin: (Moderate) Monitor blood glucose during concomitant metformin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant sulfonylurea and aspirin use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Glycopyrrolate; Formoterol: (Moderate) Caffeine may enhance the cardiac inotropic effects of beta-agonists.
Grapefruit juice: (Minor) Data are limited and conflicting as to whether grapefruit juice significantly alters the serum concentrations and/or AUC of caffeine. Caffeine is primarily a CYP1A2 substrate, and grapefruit juice appears to have but a small effect on this enzyme in vivo. One report suggests that grapefruit juice decreases caffeine elimination by inhibition of flavin-containing monooxygenase, a P450 independent system. This interaction might increase caffeine levels and mildly potentiate the clinical effects and common side effects of caffeine. If side effects appear, patients may need to limit either caffeine or grapefruit juice intake.
Green Tea: (Moderate) Green tea should be used cautiously in patients taking aspirin; there may be an increased risk of bleeding. Monitoring clinical and/or laboratory parameters is warranted. Green tea has demonstrated antiplatelet and fibrinolytic actions in animals. (Moderate) Many green tea products contain caffeine. Due to the risk for adverse effects, avoid the concurrent administration of caffeine and green tea products that contain caffeine when possible. Concurrent administration can produce excessive caffeine-related adverse events such as nausea, irritability, nervousness, and insomnia. (Minor) Some green tea products contain caffeine. The metabolism of xanthines, such as caffeine, can be increased by concurrent use with barbiturates. The hypnotic effects of barbiturates can be reduced by caffeine administration.
Griseofulvin: (Moderate) Concurrent administration of griseofulvin with salicylates may result in decreased salicylate serum concentrations. Caution and close monitoring for changes in the effectiveness of the salicylate are recommended. (Minor) Barbiturates can impair the oral absorption of griseofulvin, resulting in decreased serum concentrations and, potentially, decreased antifungal efficacy. The clinical significance of this interaction is uncertain, but the manufacturer recommends that these drugs not be co-administered.
Guaifenesin; Hydrocodone: (Major) Concomitant use of hydrocodone with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. It is recommended to avoid this combination when hydrocodone is being used for cough. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concomitant use of hydrocodone with a barbiturate can decrease hydrocodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; hydrocodone is a CYP3A4 substrate.
Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of hydrocodone with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. It is recommended to avoid this combination when hydrocodone is being used for cough. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concomitant use of hydrocodone with a barbiturate can decrease hydrocodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; hydrocodone is a CYP3A4 substrate. (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Guaifenesin; Phenylephrine: (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants like phenylephrine; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Guaifenesin; Pseudoephedrine: (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Guanfacine: (Major) Monitor patients for guanfacine efficacy and for excess sedation during butalbital coadministration. Guanfacine plasma concentrations can be reduced by butalbital, by induction of CYP3A4 metabolism. Immediate-release guanfacine may require more frequent dosing to achieve or maintain desired hypotensive response; if it is discontinued, carefully taper the dose to prevent rebound hypertension. The extended-release guanfacine dose for attention deficit hyperactivity disorder (ADHD) may need to be doubled, per FDA-approved labeling; any dose change should occur over 1 to 2 weeks (e.g., dose increase when adding, or decrease when discontinuing, an enzyme inducer). Guanfacine is primarily metabolized by CYP3A4. Barbiturates (e.g., phenobarbital, primidone) are strong CYP3A4 inducers. Guanfacine plasma concentrations and elimination half-life were significantly reduced with coadministration of an enzyme inducer (e.g., phenobarbital, primidone, phenytoin, fosphenytoin) in two patients with renal impairment. Additionally, guanfacine has been associated with sedative effects and can potentiate the actions of CNS depressants, including barbiturates.
Haloperidol: (Moderate) Haloperidol can potentiate the actions of other CNS depressants such as barbiturates. Caution should be exercised with simultaneous use of these agents due to potential excessive CNS effects.
Hemin: (Major) Hemin works by inhibiting the enzyme (delta)-aminolevulinic acid synthetase. Drugs which increase the activity of this enzyme, such as barbiturates should not be used with hemin.
Heparin: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g. aspirin, ASA). Despite the potential drug-drug interaction between aspirin and heparin, heparin is frequently administered in combination with low-dose aspirin therapy to patients who have had an acute myocardial infarction and in other disease states. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Homatropine; Hydrocodone: (Major) Concomitant use of hydrocodone with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. It is recommended to avoid this combination when hydrocodone is being used for cough. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concomitant use of hydrocodone with a barbiturate can decrease hydrocodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; hydrocodone is a CYP3A4 substrate.
Hyaluronidase, Recombinant; Immune Globulin: (Moderate) Immune Globulin (IG) products have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephrosis, and death. Patients predisposed to acute renal failure include patients receiving known nephrotoxic drugs like nonsteroidal anti-inflammatory drugs (NSAIDs) and salicylates. Coadminister IG products at the minimum concentration available and the minimum rate of infusion practicable. Also, closely monitor renal function. (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Hyaluronidase: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Hydantoins: (Moderate) Barbiturates can stimulate the hydroxylating enzyme that metabolizes phenytoin or, conversely, may inhibit phenytoin (or fosphenytoin) metabolism. In general, therapeutic doses of phenobarbital induce the hepatic metabolism of phenytoin, producing lower phenytoin serum concentrations. Large doses of phenobarbital, however, tend to increase phenytoin serum concentrations due to competition for hepatic pathways. Thus, phenytoin serum concentrations can increase, decrease, or not change during concomitant therapy with barbiturates. Conversely, phenytoin can increase serum concentrations of the barbiturate, however this has not been as well studied. Similar interactions may occur with ethotoin, although specific data are lacking. (Moderate) Higher caffeine doses may be needed after hydantoin administration; hydantoins increase caffeine elimination.
Hydralazine; Hydrochlorothiazide, HCTZ: (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics. (Moderate) Monitor blood pressure as well as for signs of worsening renal function and loss of diuretic efficacy, including antihypertensive effects, during concomitant thiazide diuretic and salicylate use. Salicylate use decreases glomerular filtration rate and renal blood flow, and concomitant diuretic use may increase the risk of this reaction. Salicylates may diminish the effectiveness of diuretics due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention.
Hydrochlorothiazide, HCTZ: (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics. (Moderate) Monitor blood pressure as well as for signs of worsening renal function and loss of diuretic efficacy, including antihypertensive effects, during concomitant thiazide diuretic and salicylate use. Salicylate use decreases glomerular filtration rate and renal blood flow, and concomitant diuretic use may increase the risk of this reaction. Salicylates may diminish the effectiveness of diuretics due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention.
Hydrochlorothiazide, HCTZ; Methyldopa: (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics. (Moderate) Monitor blood pressure as well as for signs of worsening renal function and loss of diuretic efficacy, including antihypertensive effects, during concomitant thiazide diuretic and salicylate use. Salicylate use decreases glomerular filtration rate and renal blood flow, and concomitant diuretic use may increase the risk of this reaction. Salicylates may diminish the effectiveness of diuretics due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention.
Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) Aspirin, ASA may reduce the vasodilatory efficacy of ACE inhibitors by inhibiting the synthesis of vasodilatory prostaglandins. This interaction has been documented primarily in heart failure patients. However, the established benefits of using aspirin in combination with an ACE inhibitor in patients with ischemic heart disease and left ventricular dysfunction generally outweigh this concern. Patients receiving concurrent salicylates and ACE inhibitor therapy should be monitored for antihypertensive or vasodilatory efficacy; the dose of the ACE inhibitor can be adjusted if indicated based on clinical evaluation. (Moderate) Barbiturates may potentiate orthostatic hypotension when used concurrently with thiazide diuretics. (Moderate) Monitor blood pressure as well as for signs of worsening renal function and loss of diuretic efficacy, including antihypertensive effects, during concomitant thiazide diuretic and salicylate use. Salicylate use decreases glomerular filtration rate and renal blood flow, and concomitant diuretic use may increase the risk of this reaction. Salicylates may diminish the effectiveness of diuretics due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention.
Hydrocodone: (Major) Concomitant use of hydrocodone with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. It is recommended to avoid this combination when hydrocodone is being used for cough. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concomitant use of hydrocodone with a barbiturate can decrease hydrocodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; hydrocodone is a CYP3A4 substrate.
Hydrocodone; Ibuprofen: (Major) Concomitant use of analgesic doses of aspirin and ibuprofen is generally not recommended due to the increased risk of bleeding and renal impairment. Because there may be an increased risk of cardiovascular events due to the interference of ibuprofen with the antiplatelet effect of aspirin, for patients taking low-dose aspirin for cardioprotection who require analgesics, consider use of an NSAID that does not interfere with the antiplatelet effect of aspirin, or non-NSAID analgesics, as appropriate. Administer single doses of ibuprofen at least 2 to 4 hours or more after aspirin and wait 8 hours after ibuprofen administration before administering aspirin to avoid significant interference. Monitor for signs and symptoms of renal impairment. Pharmacodynamic studies have demonstrated interference with the antiplatelet activity of aspirin when ibuprofen 400 mg 3 times daily is administered with enteric-coated low-dose aspirin. The interaction exists even after ibuprofen 400 mg once daily, particularly when ibuprofen is dosed prior to aspirin. The interaction is alleviated if immediate-release low-dose aspirin is dosed at least 2 hours prior to a once daily regimen of ibuprofen; however, this finding cannot be extended to enteric-coated low-dose aspirin. A decrease in antiplatelet activity (53%) was observed when ibuprofen 400 mg once daily was administered 2 hours before low-dose immediate-release aspirin 81 mg/day for 6 days. An interaction was still observed, but minimized, when ibuprofen 400 mg once daily was administered as early as 8 hours before immediate-release aspirin (90.7%). There was no interaction with the antiplatelet activity of aspirin when ibuprofen 400 mg once daily was administered 2 hours after immediate-release aspirin (99.2%). In another study of low-dose immediate-release aspirin 81 mg/day and ibuprofen 400 mg 3 times daily (1, 7, and 13 hours post-aspirin dose) for 10 consecutive days, there was no interaction with the antiplatelet activity of aspirin (98.3%); however, there were individuals with aspirin antiplatelet activity below 95%, with the lowest being 90.2%. When a similarly designed study was conducted with enteric-coated aspirin 81 mg/day for 6 days and ibuprofen 400 mg 3 times daily (2, 7 and 12 h post-aspirin dose) for 6 days, there was an interaction with the antiplatelet activity at 24 hours after the day 6 aspirin dose (67%). Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone. Ibuprofen is not a substitute for low dose aspirin for cardiovascular protection. (Major) Concomitant use of hydrocodone with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. It is recommended to avoid this combination when hydrocodone is being used for cough. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concomitant use of hydrocodone with a barbiturate can decrease hydrocodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; hydrocodone is a CYP3A4 substrate.
Hydrocodone; Pseudoephedrine: (Major) Concomitant use of hydrocodone with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. It is recommended to avoid this combination when hydrocodone is being used for cough. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concomitant use of hydrocodone with a barbiturate can decrease hydrocodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; hydrocodone is a CYP3A4 substrate. (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Hydromorphone: (Major) Concomitant use of hydromorphone with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
Hydroxyzine: (Major) Because hydroxyzine can cause pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including barbiturates.
Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Moderate) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as barbiturates. An enhanced effect of the displaced drug may occur.
Ibandronate: (Moderate) Monitor renal function and for gastrointestinal adverse events during concurrent use of intravenous or oral ibandronate use, respectively, and aspirin. Acute renal failure has been observed with intravenous ibandronate and concomitant use of other nephrotoxic agents may increase this risk. Additionally, the oral formulations of both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients
Ibrexafungerp: (Major) Avoid concurrent administration of ibrexafungerp with barbiturates. Use of these drugs together is expected to significantly decrease ibrexafungerp exposure, which may reduce its efficacy. Ibrexafungerp is a CYP3A substrate and barbiturates are strong CYP3A inducers.
Ibritumomab Tiuxetan: (Major) During and after therapy, avoid the concomitant use of Yttrium (Y)-90 ibrutumomab tiuxetan with drugs that interfere with platelet function such as aspirin; the risk of bleeding may be increased. If coadministration with asprin is necessary, monitor platelet counts more frequently for evidence of thrombocytopenia. (Moderate) Agents that acidify the urine, like phosphate salts, should be avoided in patients receiving high-dose salicylates. Urine acidifying agents may increase renal tubular reabsorption of salicylic acid and possibly increase salicylic acid levels. (Moderate) Concurrent administration of high doses of alkalinizing agents may increase urine pH and decrease serum salicylate levels by decreasing renal tubular reabsorption of salicylic acid.
Ibrutinib: (Moderate) The concomitant use of ibrutinib and antiplatelet agents such as aspirin may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood. Also, aspirin may mask signs of infection such as fever and in patients following treatment with antineoplastic agents or immunosuppressives.
Ibuprofen: (Major) Concomitant use of analgesic doses of aspirin and ibuprofen is generally not recommended due to the increased risk of bleeding and renal impairment. Because there may be an increased risk of cardiovascular events due to the interference of ibuprofen with the antiplatelet effect of aspirin, for patients taking low-dose aspirin for cardioprotection who require analgesics, consider use of an NSAID that does not interfere with the antiplatelet effect of aspirin, or non-NSAID analgesics, as appropriate. Administer single doses of ibuprofen at least 2 to 4 hours or more after