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  • CLASSES

    Cytostatic Aromatase Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    Non-steroidal oral aromatase inhibitor; used in postmenopausal women with advanced breast cancer who have failed prior anti-estrogen therapy; first-line treatment for advanced or metastatic breast cancer; also used as initial or extended adjuvant treatment in women with early breast cancer; used off-label for infertility.

    COMMON BRAND NAMES

    Femara

    HOW SUPPLIED

    Femara/Letrozole Oral Tab: 2.5mg

    DOSAGE & INDICATIONS

    For the treatment of breast cancer.
    NOTE: The American Society of Clinical Oncology recommends that all postmenopausal women with hormone receptor-positive early breast cancer receive adjuvant aromatase inhibitor therapy. Options include 5 years of an aromatase inhibitor or sequential therapy with 2 to 3 years or 5 years of tamoxifen followed by 2 to 3 years or 5 years of an aromatase inhibitor. The optimal duration of therapy and regimen is not known.
    For adjuvant treatment of postmenopausal women with hormone receptor positive early breast cancer.
    Oral dosage

    NOTE: The effectiveness of letrozole in the adjuvant treatment of early breast cancer is based on an analysis of recurrence in patients treated for a median of 24 months. Further data are needed to determine long-term outcomes.

    Adult postmenopausal females

    2.5 mg PO once daily. 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 as compared to tamoxifen significantly reduced the risk of recurrent disease (HR 0.81, 95% CI 0.70 to 0.93, p = 0.003). The risk of distant recurrence was also significantly reduced with letrozole (HR 0.73, 95% CI 0.60 to 0.88, p = 0.001). In addition, according to a Novartis press release, an analysis presented at the European Society of Medical Oncology held in Istanbul, Turkey in October 2006 indicates that letrozole continues to decrease the risk of breast cancer after 4 years of continued therapy. After a median of 51 months, women taking letrozole, as compared to tamoxifen, experienced a reduced risk of breast cancer recurrence of 18% and a reduced risk of distant recurrence of 19% (p values or confidence intervals not provided). The majority of the data from these interim analyses are from patients that have received only letrozole or only tamoxifen. Further analyses will address the safety and efficacy of continuous letrozole or tamoxifen for 5 years or switching to the alternate endocrine therapy after 2 years.

    For extended treatment of early breast cancer in postmenopausal women who have received 5 years of adjuvant tamoxifen therapy.
    NOTE: The effectiveness of letrozole in extended adjuvant treatment of early breast cancer is based on an analysis of disease-free survival in patients treated for a median of 24 months. Further data are needed to determine long-term outcomes.
    Oral dosage
    Adult postmenopausal females

    2.5 mg PO once daily; the optimal duration of treatment in the adjuvant setting is not known. The planned duration of treatment in the pivotal trial was 5 years. However, at the time of the analysis, the median treatment duration was 24 months; 25% of patients were treated for at least 3 years, and less than 1% of patients were treated for the planned duration of 5 years. The median duration of follow-up was 28 months. Treatment should be discontinued at tumor relapse. In the trial used for accelerated approval, 5,187 postmenopausal women who had received 5 years of tamoxifen therapy within 3 months of starting the trial were randomized to treatment with letrozole or placebo. At the time of analysis, the frequency of disease-free survival (DFS) events was 4.7% in patients receiving letrozole versus 7.5% in patients receiving placebo (HR = 0.62, 95% CI 0.49, 0.78; p = 0.00003). The risk of distant metastasis was also significantly lower for letrozole than placebo (HR 0.61; 95% CI 0.44, 0.84; p = 0.003). Data on survival were not mature enough for analysis when the study was terminated.

    For first-line treatment of postmenopausal women with hormone receptor positive or hormone receptor status unknown with locally advanced or metastatic disease.
    Oral dosage
    Adult postmenopausal females

    2.5 mg PO once daily. In a large randomized trial, letrozole was superior to tamoxifen in time to progression (9.4 vs. 6 months, respectively) and rate of objective tumor response (30% vs. 20%, respectively) with a median follow-up of 18 months. No differences were seen in the duration of tumor response.

    For the treatment of advanced breast cancer in postmenopausal women with disease progression following antiestrogen therapy.
    Oral dosage
    Adult postmenopausal females

    The recommended dose is 2.5 mg PO once daily. Treatment should continue until tumor progression is evident.

    For the treatment of postmenopausal women with hormone receptor positive metastatic breast cancer that overexpresses the HER2 receptor for whom hormonal therapy is indicated in combination with lapatinib.
    Oral dosage
    Adult postmenopausal females

    2.5 mg PO once daily in combination with lapatinib (1,500 mg PO once daily). Treatment is administered continuously.

    For the treatment of infertility† in women due to anovulation, irregular ovulation, or luteal phase defects, including women with polycystic ovary syndrome (PCOS).
    NOTE: Ensure that patients are not pregnant prior to initiating letrozole. 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 , the manufacturer of letrozole urges physicians to ensure that letrozole is not used in women who may become or are pregnant; birth defects have been reported in the children of women who were receiving letrozole during pregnancy.
    Oral dosage
    Adult premenopausal females

    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.

    For an increase in height in boys with idiopathic short stature† or constitutional delayed puberty†.
    For boys with idiopathic short stature†.
    Oral dosage
    Male Children >= 9 years and Adolescents

    Limited studies suggest that 2.5 mg PO once daily is effective in increasing predicted adult height in boys with idiopathic short stature who are not growth hormone deficient. In a study of 31 boys (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 increased predicted adult height by 5.9 cm vs. no change in boys taking placebo (p < 0.0001). Additionally, in boys taking letrozole, bone age increased by 0.7 SD vs. no change in boys taking placebo (p < 0.0001). No adverse effects on bone mineralization were identified after 2 years of treatment.

    For boys with constitutional delayed puberty†.
    Oral dosage
    Male Adolescents

    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 increased near-final adult height as compared to placebo (175.8 cm vs. 169.1 cm, respectively, p = 0.04). 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 lower in males taking placebo (169.1 cm vs. 173.9 cm, p = 0.007). Adverse effects on bone mineralization, testes size, or markers for spermatogenesis were not seen.

    For the treatment of endometriosis† refractory to other medical or surgical treatments.
    Oral dosage
    Adult females

    2.5 mg/day PO 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 women with pain associated with rectovaginal endometriosis, refractory to other medical or surgical treatment.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    2.5 mg/day PO for breast cancer: single doses of 20 mg PO or doses of 7.5 mg/day PO have been used off-label for infertility.

    Elderly

    2.5 mg/day PO for breast cancer: single doses of 20 mg PO or doses of 7.5 mg/day PO have been used off-label for infertility.

    Adolescents

    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.

    Children

    >= 9 years: Safe and effective use has not been established; however, 2.5 mg/day PO has been used in males with idiopathic short stature.
    < 9 years: Safe and effective use has not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Baseline Hepatic Impairment:
    Mild to moderate impairment (Child-Pugh Class A and B): No dosage adjustment is recommended.
    Severe impairment (Child-Pugh Class C): Reduce the dose of letrozole by 50%; administer letrozole 2.5 mg PO every other day.

    Renal Impairment

    No dosage adjustment is necessary for patients with CrCL greater than or equal to 10 mL/min.

    ADMINISTRATION

    Oral Administration

    May be administered without regard to meals.

    STORAGE

    Femara:
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Biliary cirrhosis, hepatic disease

    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.

    Osteoporosis

    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.

    Hypercholesterolemia

    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.

    Children

    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.

    Pregnancy

    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.

    Contraception requirements, infertility, pregnancy testing, reproductive risk

    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.

    Breast-feeding

    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.

    ADVERSE REACTIONS

    Severe

    bone fractures / Delayed / 0-13.8
    pleural effusion / Delayed / 0-5.0
    thromboembolism / Delayed / 0.6-2.9
    thrombosis / Delayed / 0-2.0
    stroke / Early / 0-2.0
    pulmonary embolism / Delayed / 0-2.0
    myocardial infarction / Delayed / 1.0-1.5
    diarrhea / Early / 0.5-0.5
    heart failure / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    teratogenesis / Delayed / Incidence not known

    Moderate

    hypercholesterolemia / Delayed / 3.0-52.3
    hot flashes / Early / 5.0-33.5
    bone pain / Delayed / 5.0-22.0
    edema / Delayed / 6.7-18.4
    dyspnea / Early / 5.5-18.0
    osteoporosis / Delayed / 5.1-14.5
    constipation / Delayed / 2.0-11.3
    hypertension / Early / 5.0-8.0
    chest pain (unspecified) / Early / 3.0-8.0
    vaginal bleeding / Delayed / 0.3-5.2
    peripheral edema / Delayed / 5.0-5.0
    hypercalcemia / Delayed / 0-5.0
    depression / Delayed / 4.9-4.9
    secondary malignancy / Delayed / 2.2-4.2
    osteopenia / Delayed / 3.6-3.6
    elevated hepatic enzymes / Delayed / 3.0-3.0
    phlebitis / Rapid / 0-2.0
    cataracts / Delayed / 2.0-2.0
    angina / Early / 1.1-1.3
    sinus tachycardia / Rapid / Incidence not known
    palpitations / Early / Incidence not known
    hepatitis / Delayed / Incidence not known
    stomatitis / Delayed / Incidence not known
    memory impairment / Delayed / Incidence not known
    psoriaform rash / Delayed / Incidence not known
    erythema / Early / Incidence not known
    blurred vision / Early / Incidence not known
    thrombocytopenia / Delayed / Incidence not known
    lymphopenia / Delayed / Incidence not known
    leukopenia / Delayed / Incidence not known

    Mild

    asthenia / Delayed / 4.0-33.6
    arthralgia / Delayed / 8.0-25.2
    musculoskeletal pain / Early / 21.0-22.0
    headache / Early / 4.3-20.1
    back pain / Delayed / 5.0-18.0
    nausea / Early / 8.6-17.0
    night sweats / Early / 14.6-14.6
    dizziness / Early / 3.0-14.2
    cough / Delayed / 5.0-13.0
    fatigue / Early / 6.0-13.0
    weight gain / Delayed / 2.0-12.9
    malaise / Early / 9.6-9.6
    lethargy / Early / 9.6-9.6
    myalgia / Early / 6.7-8.9
    weight loss / Delayed / 5.7-7.0
    vomiting / Early / 3.3-7.0
    insomnia / Early / 5.8-7.0
    infection / Delayed / 6.5-6.5
    abdominal pain / Early / 5.0-6.0
    weakness / Early / 6.0-6.0
    influenza / Delayed / 6.0-6.0
    anorexia / Delayed / 0.8-5.0
    anxiety / Delayed / 0-5.0
    vertigo / Early / 0-5.0
    rash (unspecified) / Early / 4.0-5.0
    vaginal irritation / Early / 4.5-4.5
    dyspepsia / Early / 3.0-4.0
    alopecia / Delayed / 3.4-3.4
    drowsiness / Early / 2.0-3.0
    pruritus / Rapid / 1.0-2.0
    dysgeusia / Early / Incidence not known
    appetite stimulation / Delayed / Incidence not known
    xerostomia / Early / Incidence not known
    polydipsia / Early / Incidence not known
    dysesthesia / Delayed / Incidence not known
    paresthesias / Delayed / Incidence not known
    irritability / Delayed / Incidence not known
    urticaria / Rapid / Incidence not known
    xerosis / Delayed / Incidence not known
    vesicular rash / Delayed / Incidence not known
    maculopapular rash / Early / Incidence not known
    vaginal discharge / Delayed / Incidence not known
    ocular irritation / Rapid / Incidence not known
    fever / Early / Incidence not known
    increased urinary frequency / Early / Incidence not known

    DRUG INTERACTIONS

    Estrogens: (Severe) 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) Letrozole should not be given concurrently with tamoxifen; when administered together, there is an average 38% reduction in letrozole plasma concentrations. Letrozole therapy after the completion of standard tamoxifen treatment is not associated with impaired effects of letrozole.

    PREGNANCY AND LACTATION

    Pregnancy

    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.

    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.

    MECHANISM OF ACTION

    Mechanism of Action: Letrozole inhibits aromatase, the enzyme that catalyzes the final step in estrogen production. Letrozole competitively binds to the heme of the cytochrome P450 subunit of aromatase. The formation of adrenal corticosteroids, aldosterone, or thyroid hormones is not affected by letrozole; only serum estradiol concentrations are affected by letrozole•Actions in post-menopausal women: In postmenopausal women, the principal source of circulating estrogens is from the conversion of adrenal and ovarian androgens (androstenedione and testosterone) to estrogens (estrone and estradiol) by aromatase in peripheral tissues. Inhibition of aromatase may result in a more complete estrogen block than surgical ablation. Extraglandular sites are more amenable to aromatase inhibition by letrozole than are premenopausal ovaries. Inhibiting the biosynthesis of estrogens is one way to deprive the tumor of estrogens and to restrict tumor growth. Letrozole can reduce circulating estrogen concentrations by 75—95% from the baseline within 2—3 days. Serum lutenizing hormone (LH) or follicle-stimulating hormone (FSH) levels are not affected by letrozole. Aromatase inhibitors might also inhibit estrogen production at the tumor cell. However, tumor production of estradiol may be insignificant because aromatase activity appears to be low.•Actions in pre-menopausal women -ovarian stimulation: Normally, through negative feedback, estrogens decrease the release of FSH from the pituitary gland; it is hypothesized that by blocking estradiol production through inhibiting aromatase, letrozole may increase the release of FSH and induce ovulation. It is also theorized that the androgens, which would normally be converted to estrogens, may accumulate in the ovaries thereby increasing the senstivity 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.

    PHARMACOKINETICS

    Letrozole is administered orally. It is weakly protein bound and has a large volume of distribution. Metabolism is via cytochrome P450 (CYP) enzymes. Specifically, CYP 3A4 metabolizes letrozole to an inactive carbinol metabolite (4,4'-methanol-bisbenzonitrile); CYP 2A6 formed the same metabolite and its ketone analog. In liver microsomes, letrozole strongly inhibited CYP2A6 and moderately inhibited CYP2C19. The inactive metabolites are further metabolized the glucuronide conjugate. Urinary excretion is the major route of elimination. Based on radiolabeled studies, at least 75% is excreted as the glucuronide of the carbinol metabolite, about 9% as two unidentified metabolites, and 6% as unchanged drug. Letrozole has a terminal elimination half-life of about 2 days.

    Oral Route

    Letrozole is rapidly and completely absorbed from the gastrointestinal tract; absorption is not affected by food. Steady-state plasma concentrations are reached in 2—6 weeks and are 1.5 to 2 times higher than predicted from the concentrations measured after a single dose, indicating a slight non-linearity in the pharmacokinetics of the drug upon daily administration; accumulation of letrozole does not occur.