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Cytostatic Aromatase Inhibitors
Nonsteroidal oral aromatase inhibitorUsed in postmenopausal women as adjuvant therapy for early breast cancer, extended adjuvant therapy after completion of 5 years of tamoxifen, and for advanced breast cancer; used off-label for infertility, idiopathic short stature in boys, and delayed puberty in boysContraindicated in pregnancy; consider bone mineral density monitoring and cholesterol monitoring
Femara/Letrozole Oral Tab: 2.5mg
2.5 mg PO once daily. The optimal duration of treatment is unknown, but the median treatment duration in clinical trials was 5 years; discontinue therapy at relapse. The Breast International Group (BIG) 1-98 study, which enrolled more than 8,000 patients, compared 4 study arms: letrozole for 5 years, tamoxifen for 5 years, letrozole for 2 years followed by tamoxifen (total 5 years of therapy), or tamoxifen for 2 years followed by letrozole (total 5 years of therapy). After a median follow-up of 25.8 months, letrozole significantly reduced the risk of recurrent disease compared with tamoxifen; the 5-year rate of disease-free survival was 87.4% versus 84.7%. The impact on overall survival was not statistically significant (91.8% vs. 90.9%).
2.5 mg PO once daily. The optimal duration of treatment in the extended adjuvant setting is not known, however the median duration of treatment in clinical trials was 5 years; discontinue treatment at tumor relapse. In a randomized, double-blind clinical trial (n = 5,100), treatment with letrozole for a median duration of 60 months significantly reduced the risk of breast cancer recurrence or contralateral breast cancer compared with placebo in postmenopausal women with receptor-positive or unknown primary breast cancer who were disease-free after 5 years of adjuvant treatment with tamoxifen. There was no significant difference in overall survival.
2.5 mg PO once daily until disease progression or unacceptable toxicity. In a large randomized, double-blind clinical trial, treatment with letrozole (n = 458) significantly improved median time to progression (9.4 months vs. 6 months) and objective response rate (32% vs. 21%) compared with tamoxifen (n = 454) in postmenopausal patients with locally advanced or metastatic breast cancer. The median duration of response was 18 months compared with 16 months, and overall survival was 35 months vs. 32 months, respectively. The improvement in median time to progression remained significant in patients who had received prior antiestrogen adjuvant therapy (8.9 months vs. 5.9 months) with an objective response rate of 26% compared with 8%, respectively.
2.5 mg PO once daily until disease progression or unacceptable toxicity. In 6 small, noncomparative trials, 20% of advanced breast cancer patients, previously treated with at least antiestrogen therapy, who received letrozole 2.5 mg daily (n = 40) achieved an objective tumor response (complete or partial response). In a randomized controlled trial, patients with advanced breast cancer who had progressed on antiestrogen therapy and received letrozole 2.5 mg daily (n = 174) had an objective response rate (ORR) of 23.6% for a median duration not reached, compared with an ORR of 16.3% and a median duration of 561 days for megestrol acetate (n = 190); median survival was 730 days compared with 659 days, respectively. The ORR for letrozole (n = 185) was 18.4% for a median of 706 days compared with 12.3% for a median of 450 days for aminoglutethimide (n = 179) in a separate trial; median survival was 792 days versus 592 days, respectively.
2.5 mg PO once daily in combination with lapatinib (1,500 mg PO once daily). In a randomized, double-blind clinical trial, treatment with lapatinib plus letrozole significantly improved median progression-free survival (PFS) compared with letrozole alone in postmenopausal patients with hormone receptor-positive, HER2-positive metastatic breast cancer (35.4 weeks vs. 13 weeks); the response rate was 27.9% versus 14.8%, respectively.
Limited studies indicate that 2.5 mg, 5 mg, or 7.5 mg PO once daily for 5 days, typically given on days 3 through 7 of the menstrual cycle, may be effective; in a study comparing 2.5 mg letrozole (n = 34) to 5 mg letrozole (n = 38) PO daily for 5 days, pregnancy rates per cycle were significantly higher in patients treated with the higher dosage (26% vs. 6%, p < 0.05). Alternatively, a single dose of letrozole 20 mg PO on day 3 of the menstrual cycle has been shown to be as effective as 2.5 mg PO once daily for 5 days in a nonrandomized study , although more data are needed before a single dose can be recommended. In general, ovulation and pregnancy rates are comparable to those with clomiphene (pregnancy rates per cycle of 9% to 27% for letrozole vs. 5.6% to 26% for clomiphene). Efficacy has also been demonstrated in patients with PCOS; ovulation occurred in 66% (65 of 99) of letrozole cycles vs. 75% (71 of 95) of clomiphene cycles, with pregnancy rates per cycle of 9% vs. 7%, respectively. In addition, successful pregnancies have occurred when letrozole is administered to patients who do not respond to clomiphene (lack of ovulation or insufficient endometrial thickness). In 30 patients that were treated with clomiphene 100 to 150 mg/day for 6 to 24 cycles, the administration of letrozole 2.5 mg (n = 4) or 5 mg PO (n = 26) PO once daily during menstrual cycle days 3 to 7 was associated with an ovulation rate of 90% and a pregnancy rate of 26%; pregnancy occurred during cycles 2 through 5 of letrozole therapy.
Limited studies suggest that 2.5 mg PO once daily is effective in increasing predicted adult height in male children and adolescents with idiopathic short stature who are not growth hormone deficient. In a study of 31 males (aged 9 to 14.5 years at study start) with idiopathic short stature randomized to letrozole 2.5 mg/day or placebo for 2 years, letrozole significantly increased predicted adult height by 5.9 cm compared with no change in patients taking placebo. Additionally, in patients taking letrozole, bone age significantly increased by 0.7 SD compared with no change in patients taking placebo. No adverse effects on bone mineralization were identified after 2 years of treatment.
Limited studies suggest that letrozole 2.5 mg PO once daily in combination with testosterone is effective in increasing near-final height in males with constitutional delayed puberty. In a study of 17 adolescent males (mean age 15 years at study start) with constitutional delayed puberty randomized to testosterone for 6 months plus placebo for 12 months or testosterone for 6 months plus letrozole for 12 months, letrozole significantly increased near-final adult height as compared to placebo (175.8 cm vs. 169.1 cm). Additionally, in males treated with letrozole, their near-final height did not differ significantly from their mid-parenteral target height (175.8 cm vs. 177.1 cm), while it was significantly lower in males taking placebo (169.1 cm vs. 173.9 cm). Adverse effects on bone mineralization, testes size, or markers for spermatogenesis were not seen.
2.5 mg PO once daily for up to 6 months, with or without other hormonal therapies, has been studied. According to treatment guidelines, aromatase inhibitors (e.g., letrozole) in combination with oral contraceptive pills, progestogens, or gonadotropin-releasing hormone analogs are recommended for patients with pain associated with rectovaginal endometriosis, refractory to other medical or surgical treatment.
†Indicates off-label use
2.5 mg/day PO per FDA-approved product labeling; however, single doses of 20 mg PO or doses of 7.5 mg/day PO have been used off-label for infertility.
2.5 mg/day PO for breast cancer.
Safe and effective use has not been established; however, 2.5 mg/day PO has been used in males with idiopathic short stature or constitutional delayed puberty.
Younger than 9 years: Safe and effective use has not been established.9 years and older: Safe and effective use has not been established; however, 2.5 mg/day PO has been used in males with idiopathic short stature.
Baseline Hepatic Impairment:Mild to moderate hepatic impairment (Child-Pugh Class A and B): No dosage adjustment is recommended.Severe hepatic impairment (Child-Pugh Class C) and cirrhosis: Reduce the dose of letrozole by 50%; administer letrozole 2.5 mg PO every other day.
No dosage adjustment is necessary for patients with CrCL greater than or equal to 10 mL/min.
Hazardous Drugs ClassificationNIOSH 2016 List: Group 1 NIOSH (Draft) 2020 List: Table 2Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure.
May be administered without regard to meals.
Femara:- Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
Use letrozole with caution in patients with pre-existing cirrhotic hepatic disease; a dose reduction may be necessary. Exposure to letrozole was approximately doubled in subjects with biliary cirrhosis and severe hepatic impairment compared with healthy volunteers with normal liver function; the effect of hepatic impairment on letrozole exposure in noncirrhotic cancer patients with elevated bilirubin levels has not been determined.
Use letrozole with caution in patients with pre-existing osteoporosis, as use of letrozole has been associated with decreases in bone mineral density (BMD). Consider monitoring patients for signs and symptoms of osteoporosis, including decreased bone mineral density (BMD), during treatment with letrozole. Adjuvant treatment with letrozole resulted in a significantly larger decrease in lumbar spine (L2 to L4) BMD compared to tamoxifen in a safety study. The incidence of fractures and osteoporosis was also greater in the letrozole group compared with the tamoxifen group in the adjuvant treatment trial (BIG 1-98). In a separate BMD sub-study of the extended adjuvant trial (MA-17B), there was not a significant difference in the change from baseline in lumbar spine BMD in letrozole and placebo treated groups. However, the incidence of bone fractures and new osteoporosis was greater in patients treated with letrozole compared with placebo.
Use letrozole with caution in patients with pre-existing hypercholesterolemia; consider monitoring serum cholesterol levels during treatment. Hypercholesterolemia requiring lipid lowering therapy was reported more often in patients treated with letrozole compared with tamoxifen in the adjuvant therapy trial (BIG 1-98). An increase of greater than or equal to 1.5 times the upper limit of normal (ULN) in total cholesterol was also observed more often in letrozole-treated patients who had baseline total serum cholesterol within the normal range compared with those who received tamoxifen.
The safety and effectiveness of letrozole in children has not been established; however, letrozole has been used for 1 to 2 years to increase height in male children and adolescents with either idiopathic short stature or constitutional delayed puberty. In animal studies, letrozole administration for 12 weeks at exposures similar to the AUC in adult patients receiving the FDA-approved dose of 2.5 mg per day resulted in adverse skeletal / growth effects (bone maturation, bone mineral density) and neuroendocrine and reproductive developmental perturbations of the hypothalamic-pituitary axis in young (postnatal day 7) rats. Additionally, decreased fertility was accompanied by hypertrophy of the hypophysis and testicular changes that included degeneration of the seminiferous tubular epithelium and atrophy of the female reproductive tract. These changes were not reversible at clinically relevant exposures within 42 months of discontinuation.
Treatment with letrozole is contraindicated for use during pregnancy. Letrozole has been prescribed off-label as a fertility treatment because it suppresses estrogen and can promote ovulation; while the outcomes of pregnancies in one cohort study demonstrate a similar rate of miscarriage and ectopic pregnancy in women who took letrozole versus other drugs for ovarian stimulation, pregnancy should be avoided by females of reproductive potential during letrozole treatment and for at least 3 weeks after the last dose. Although there are no adequately controlled studies in pregnant women, letrozole can cause fetal harm or death when administered during pregnancy based on postmarketing reports, animal studies, and its mechanism of action. Women who are pregnant or who become pregnant while receiving letrozole should be apprised of the potential hazard to the fetus. In postmarketing reports, use of letrozole during pregnancy resulted in cases of spontaneous abortions and congenital birth defects; however, the data are insufficient to inform a drug-associated risk. Daily administration of letrozole to rats during organogenesis at doses approximately 0.01 times the maximum recommended human dose on a mg/m2 basis resulted in embryofetal toxicity including intrauterine mortality, increased resorptions and postimplantation loss, decreased numbers of live fetuses and fetal anomalies including absence and shortening of renal papilla, dilation of ureter, edema and incomplete ossification of frontal skull and metatarsals. Letrozole was also teratogenic to rats at the same dose, causing fetal domed head and cervical/centrum vertebral fusion. In rabbits, the same dose level resulted in intrauterine mortality, increased resorption, increased postimplantation loss, and decreased numbers of live fetuses. Fetal anomalies included incomplete ossification of the skull, sternebrae, and fore- and hind legs.
Counsel patients about the reproductive risk and contraception requirements during letrozole treatment. Letrozole can be teratogenic if taken by the mother during pregnancy. Females of reproductive potential should avoid pregnancy and use effective contraception during and for at least 3 weeks after treatment with letrozole. Females of reproductive potential should undergo pregnancy testing prior to initiation of letrozole. Women who become pregnant while receiving letrozole should be apprised of the potential hazard to the fetus. Although there are no data regarding the effect of letrozole on human fertility, male and female infertility has been observed in animal studies.
Due to the potential for serious adverse reactions in nursing infants from letrozole, advise women to discontinue breast-feeding during treatment and for 3 weeks after the final dose. It is not known whether letrozole is present in human milk, although many drugs are excreted in human milk.
bone fractures / Delayed / 0-14.7new primary malignancy / Delayed / 0.3-5.3pleural effusion / Delayed / 0-5.0thromboembolism / Delayed / 0-3.2stroke / Early / 0-3.0myocardial infarction / Delayed / 0-2.0pulmonary embolism / Delayed / 0-2.0thrombosis / Delayed / 0-2.0heart failure / Delayed / 0-1.6infection / Delayed / 0-1.6hypertension / Early / 0-1.2weight gain / Delayed / 0-1.1dyspnea / Early / 0-0.8myalgia / Early / 0.3-0.8depression / Delayed / 0-0.8cataracts / Delayed / 0-0.7headache / Early / 0.1-0.7asthenia / Delayed / 0-0.6diarrhea / Early / 0-0.5bone pain / Delayed / 0.2-0.5back pain / Delayed / 0.3-0.5renal failure (unspecified) / Delayed / 0-0.5hypercholesterolemia / Delayed / 0-0.4osteoporosis / Delayed / 0.2-0.4dizziness / Early / 0-0.4fatigue / Early / 0.2-0.4hot flashes / Early / 0-0.4weight loss / Delayed / 0-0.3nausea / Early / 0.1-0.3musculoskeletal pain / Early / 0-0.3insomnia / Early / 0-0.3edema / Delayed / 0.1-0.2constipation / Delayed / 0.1-0.2lethargy / Early / 0-0.2malaise / Early / 0-0.2vomiting / Early / 0-0.1anorexia / Delayed / 0-0.1vaginal bleeding / Delayed / 0-0.1vaginal irritation / Early / 0-0.1flushing / Rapid / 0-0.1hyperhidrosis / Delayed / 0-0.1arthralgia / Delayed / 13.9erythema multiforme / Delayed / Incidence not knowntoxic epidermal necrolysis / Delayed / Incidence not knownteratogenesis / Delayed / Incidence not knownspontaneous fetal abortion / Delayed / Incidence not knownanaphylactoid reactions / Rapid / Incidence not knownangioedema / Rapid / Incidence not known
chest pain (unspecified) / Early / 0-8.0peripheral edema / Delayed / 0-5.0hyperbilirubinemia / Delayed / 0-5.0jaundice / Delayed / 0-5.0hypercalcemia / Delayed / 0-5.0angina / Early / 0-2.0paresis / Delayed / 0-2.0phlebitis / Rapid / 0-2.0endometrial hyperplasia / Delayed / 0-0.3osteopenia / Delayed / 0-0.2sinus tachycardia / Rapid / Incidence not knownpalpitations / Early / Incidence not knownhepatitis / Delayed / Incidence not knownelevated hepatic enzymes / Delayed / Incidence not knownstomatitis / Delayed / Incidence not knownmemory impairment / Delayed / Incidence not knownerythema / Early / Incidence not knownpsoriaform rash / Delayed / Incidence not knownblurred vision / Early / Incidence not knownlymphopenia / Delayed / Incidence not knownleukopenia / Delayed / Incidence not knownthrombocytopenia / Delayed / Incidence not known
cough / Delayed / 5.2-13.0alopecia / Delayed / 3.4-6.1abdominal pain / Early / 0-6.0influenza / Delayed / 0-6.0weakness / Early / 0-6.0anxiety / Delayed / 0-5.0rash / Early / 0-5.0vertigo / Early / 0-5.0drowsiness / Early / 0-5.0dyspepsia / Early / 0-3.0pruritus / Rapid / 0-1.0polydipsia / Early / Incidence not knowndysgeusia / Early / Incidence not knownxerostomia / Early / Incidence not knownappetite stimulation / Delayed / Incidence not knownirritability / Delayed / Incidence not knownparesthesias / Delayed / Incidence not knowndysesthesia / Delayed / Incidence not knownxerosis / Delayed / Incidence not knownvesicular rash / Delayed / Incidence not knownurticaria / Rapid / Incidence not knownmaculopapular rash / Early / Incidence not knownvaginal discharge / Delayed / Incidence not knownocular irritation / Rapid / Incidence not knownincreased urinary frequency / Early / Incidence not knownfever / Early / Incidence not knownnight sweats / Early / Incidence not knowncarpal tunnel syndrome / Delayed / Incidence not known
Estrogens: (Contraindicated) Estrogens, including hormonal contraceptives, could interfere competitively with the pharmacologic action of the aromatase inhibitors. The goal of aromatase inhibitor therapy is to decrease circulating estrogen concentrations and inhibit the growth of hormonally-responsive cancers. Estrogen therapy is not recommended during aromatase inhibitor treatment, due to opposing pharmacologic actions. Aromatase inhibitors (e.g., aminoglutethimide, anastrozole, exemestane, letrozole, testolactone, vorozole) exhibit their antiestrogenic effects by reducing the peripheral conversion of adrenally synthesized androgens (e.g., androstenedione) to estrogens through inhibition of the aromatase enzyme. Prasterone, Dehydroepiandrosterone, DHEA (Dietary Supplements): (Major) Prasterone, dehydroepiandrosterone, DHEA is converted via hydrosteroid dehydrogenases and aromatase into androstenedione, testosterone, and estradiol by peripheral tissues. Prasterone or DHEA supplements should not be given concurrently with any aromatase inhibitors, as DHEA could interfere with the pharmacologic action of the aromatase inhibitor and compromise aromatase inhibitor effectiveness. Conversely, aromatase inhibitors (e.g., aminoglutethimide, anastrozole, exemestane, letrozole, testolactone, vorozole) could interfere with biotransformation of DHEA. Prasterone, Dehydroepiandrosterone, DHEA (FDA-approved): (Major) Prasterone, dehydroepiandrosterone, DHEA is converted via hydrosteroid dehydrogenases and aromatase into androstenedione, testosterone, and estradiol by peripheral tissues. Prasterone or DHEA supplements should not be given concurrently with any aromatase inhibitors, as DHEA could interfere with the pharmacologic action of the aromatase inhibitor and compromise aromatase inhibitor effectiveness. Conversely, aromatase inhibitors (e.g., aminoglutethimide, anastrozole, exemestane, letrozole, testolactone, vorozole) could interfere with biotransformation of DHEA. Tamoxifen: (Major) Coadministration of letrozole with tamoxifen is not recommended because the efficacy of the combination in the treatment of breast cancer has not been established. Additionally, tamoxifen reduced the plasma concentration of letrozole by 38% when the drugs were coadministered.
Letrozole is a highly specific nonsteroidal aromatase inhibitor, preventing the conversion of androgens to estrogens by competitively binding to the heme of the CYP450 subunit of the aromatase enzyme, resulting in a reduction of estrogen biosynthesis in all tissues. In adult nontumor- and tumor-bearing female animals, letrozole is as effective as ovariectomy in reducing uterine weight, elevating serum LH, and causing regression of estrogen-dependent tumors; however, unlike ovariectomy, letrozole treatment did not increase serum FSH. It selectively inhibits gonadal steroidogenesis but has no significant effect on adrenal mineralocorticoid or glucocorticoid synthesis. No clinically relevant changes were found in the plasma concentrations of cortisol, aldosterone, 11-deoxycortisol, 17-hydroxy-progesterone, ACTH, or in plasma renin activity among postmenopausal patients receiving a daily dose of letrozole 0.1 mg to 5 mg. An ACTH stimulation test performed after 6 and 12 weeks of treatment did not indicate any attenuation of aldosterone or cortisol production; glucocorticoid or mineralocorticoid supplementation is not necessary. Blockade of estrogen biosynthesis by letrozole did not lead to accumulation of androgenic precursors in healthy postmenopausal women. Plasma levels of LH and FSH were not affected by letrozole in patients, nor was thyroid function as evaluated by TSH, T3 uptake, and T4 levels.In postmenopausal women, the principal source of circulating estrogens is from the conversion of adrenal and ovarian androgens (e.g., androstenedione and testosterone) to estrogens (estrone and estradiol) by aromatase. The suppression of estrogen biosynthesis in peripheral tissues and in the cancer tissue itself can thus be achieved by inhibiting the aromatase enzyme. Letrozole can reduce circulating estradiol, estrone, and estrone sulfate concentrations by 75% to 95% from baseline within 2 to 3 days.In premenopausal women when used for ovarian stimulation, the inhibition of aromatase by letrozole may increase the release of FSH by blocking estradiol production. Normally, through negative feedback, estrogens decrease the release of FSH from the pituitary gland It is also theorized that the androgens, which would normally be converted to estrogens, may accumulate in the ovaries thereby increasing the sensitivity of ovarian follicles to FSH. Unlike clomiphene, letrozole does not deplete estrogen receptors, which may be important for inducing mono-ovulation and also for preventing the negative changes in the endometrium and cervical mucus associated with clomiphene therapy.
Letrozole is administered orally. It is weakly protein bound and has a large volume of distribution (approximately 1.9 L/kg). The major clearance pathway is slow metabolism to an inactive carbinol metabolite (4,4'-methanol-bisbenzonitrile), whose glucuronide conjugate is renally excreted. Approximately 90% of radiolabeled letrozole is recovered in urine: at least 75% as the glucuronide of the carbinol metabolite, about 9% as 2 unidentified metabolites, and 6% as unchanged drug. The terminal elimination half-life is about 2 days. Affected cytochrome P450 isoenzymes: CYP3A4, CYP2A6Letrozole is metabolized in human microsomes by CYP3A4 to the carbinol metabolite, while CYP2A6 formed both this metabolite and its ketone analog. In human liver microsomes, letrozole inhibited CYP2A6 and CYP2C19; however, the clinical significance of these findings is unknown.
Letrozole is rapidly and completely absorbed from the gastrointestinal tract; absorption is not affected by food. Steady-state plasma concentrations are reached in 2 to 6 weeks, and are 1.5 to 2 times higher than predicted from the concentrations measured after a single dose, indicating a slight nonlinearity in the pharmacokinetics of the drug upon daily administration. These steady-state levels are maintained over extended periods, however, and continuous accumulation of letrozole does not occur. Daily doses of 0.1 mg to 5 mg of letrozole suppress plasma concentrations of estradiol, estrone, and estrone sulfate by 75% to 95% from baseline, with maximal suppression within 2 to 3 days. Suppression is dose related; estrogen suppression was maintained throughout treatment in all patients receiving greater than 0.5 mg.