LETRODEX

Letrozole, or CGS 20267, is an oral non-steroidal type II aromatase inhibitor first described in the literature in 1990. 1, 5, 9, 10 It is a third generation aromatase inhibitor like exemestane and anastrozole, meaning it does not significantly affect cortisol, aldosterone, and thyroxine.

Letrozole was granted

FDA approval on 25 July 1997.

Letrozole is indicated to treat postmenopausal women with hormone receptor (HR) positive early breast cancer, postmenopausal women with early breast cancer who have periviously been treated with tamoxifen, and postmenopausal women with HR+ or unknown advanced breast cancer.

Letrozole, given with ribociclib, is indicated to treat pre, peri, and postmenopausal women with HR+ and human epidermal growth factor 2 (HER2) negative advanced or metastatic breast cancer.

Letrozole is an aromatase inhibitor used in the treatment of breast cancer.

Aromatase inhibitors work by inhibiting the action of the enzyme aromatase, which converts androgens into estrogens by a process called aromatization.

As breast tissue is stimulated by estrogens, decreasing their production is a way of suppressing recurrence of the breast tumor tissue.

Letrozole is a third generation type

II aromatase inhibitor used to treat estrogen dependant breast cancers.

It has a long duration of action as it has a half life of over 42 hours in breast cancer patients. 2, 4, 9 Patients should be counselled regarding the risk of interstitial lung disease, pneumonitis, QT prolongation, elevated transaminase levels, neutropenia, and embryo-fetal toxicity.

Letrozole is 99.9% Oral bioavailable.

A 2.5 mg oral dose reaches a C max of 104nmol/L with a T max of 8.10h, and an AUC of 7387nmol*h/L.

The volume of distribution of letrozole is 1.87 L/kg.

Letrozole is metabolized by

CYP2A6 to a ketone analog metabolite, which is further metabolized by CYP3A4 and CYP2A6 to 4,4'-(hydroxymethylene)dibenzonitrile. 8 4,4'-(hydroxymethylene)dibenzonitrile is glucuronidated by UGT2B7.

Hover over products below to view reaction partners Letrozole Letrozole ketone analog metabolite 4,4'-methanol-bisbenzonitrile Letrozole carbinol glucuronide metabolite.

Letrozole is 90% eliminated in the urine. 9 75% of the dose is recovered as a glucuronide metabolite, 9% is in the form of the ketone and carbinol metabolites, and 6% is recovered in urine as unchanged letrozole. 8, 9.

The terminal elimination half life of letrozole is approximately 42h in healthy volunteers, but longer in breast cancer patients. 2, 4, 9.

The average clearance after a single dose of letrozole was 1.52 L/h and at steady state was 1.20 L/h.

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Overdose data in humans is not readily available, however 1 reported case was not associated with serious adverse reactions.

Animal studies do not report serious adverse effects with high dose treatment.

Patients experiencing and overdose should be treated with symptomatic and supportive measures.

Oral doses over 2000 mg/kg were associated with reduced motor activity, ataxia, dyspnea, and death in mice and rats.

Letrozole can cause fetal harm.

Known hypersensitivity to the active substance, or to any of the excipients.

Letrozole tablets are taken orally without regard to meals: Recommended dose: 2.5.mg once daily Patients with cirrhosis or severe hepatic impairment: 2.5 mg every other day 2.1 Recommended Dose The recommended dose of letrozole tablet is one 2.5 mg tablet administered once a day, without regard to meals. 2.2 Use in Adjuvant Treatment of Early Breast Cancer In the adjuvant setting, the optimal duration of treatment with letrozole is unknown.

In both the adjuvant study and the post approval adjuvant study, median treatment duration was 5 years.

Treatment should be discontinued at relapse. 2.3 Use in Extended Adjuvant Treatment of Early Breast Cancer In the extended adjuvant setting, the optimal treatment duration with letrozole tablet is not known.

The planned duration of treatment in the study was 5 years.

In the final updated analysis, conducted at a median follow-up of 62 months, the median treatment duration for letrozole tablets was 60 months.

Seventy-one (71%) percent of patients were treated for at least 3 years and 58% of patients completed at least 4.5 years of extended adjuvant treatment.

The treatment should be discontinued at tumor relapse. 2.4 Use in First and Second-Line Treatment of Advanced Breast Cancer In patients with advanced disease, treatment with letrozole tablets should continue until tumor progression is evident. 2.5 Use in Hepatic Impairment No dosage adjustment is recommended for patients with mild to moderate hepatic impairment, although letrozole tablets blood concentrations were modestly increased in subjects with moderate hepatic impairment due to cirrhosis.

The dose of letrozole tablets in patients with cirrhosis and severe hepatic dysfunction should be reduced by 50% .

The recommended dose of letrozole tablets for such patients is 2.5 mg administered every other day. The effect of hepatic impairment on letrozole tablets exposure in noncirrhotic cancer patients with elevated bilirubin levels has not been determined. 2.6 Use in Renal Impairment No dosage adjustment is required for patients with renal impairment if creatinine clearance is greater than or equal to 10 mL/min.

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Based on postmarketing reports, findings from animal studies and the mechanism of action, letrozole can cause fetal harm and is contraindicated for use in pregnant women.

In post-marketing 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.

In animal reproduction studies, administration of letrozole to pregnant animals during organogenesis resulted in increased post-implantation pregnancy loss and resorption, fewer live fetuses, and fetal malformation affecting the renal and skeletal systems in rats and rabbits at doses approximately 0.1 times the daily maximum recommended human dose (MRHD) on a mg/m 2 basis.

The background risk of major birth defects and miscarriage for the indicated population is unknown.

However, the background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies.

In a fertility and early embryonic development toxicity study in female rats, oral administration of letrozole starting 2 weeks before mating until pregnancy day 6 resulted in an increase in pre-implantation loss at doses ≥ 0.003 mg/kg/day (approximately 0.01 times the maximum recommended human dose on a mg/m 2 basis).

In an embryo-fetal developmental toxicity study in rats, daily administration of oral letrozole during the period of organogenesis at doses ≥ 0.003 mg/kg (approximately 0.01 time the maximum recommended human dose on a mg/m 2 basis) resulted in embryo-fetal 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 teratogenic to rats at a dose of 0.03 mg/kg (approximately 0.01 times the maximum recommended human dose on a mg/m 2 basis) and caused fetal domed head and cervical/centrum vertebral fusion.

In the embryo-fetal development toxicity study in rabbits, daily administration of oral letrozole during the period of organogenesis at doses ≥ 0.002 mg/kg (approximately 0.01 times the maximum recommended human dose on a mg/m 2 basis) resulted in embryo-fetal toxicity including 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.

The safety and effectiveness in pediatric patients have not been established.

Letrozole administration to young (postnatal day 7) rats for 12 weeks duration at 0.003, 0.03, 0.3 mg/kg/day by oral gavage resulted in adverse skeletal/growth effects (bone maturation, bone mineral density) and neuroendocrine and reproductive developmental perturbations of the hypothalamic-pituitary axis.

Administration of 0.3 mg/kg/day resulted in AUC values that were similar to the AUC in adult patients receiving the recommended dose of 2.5 mg/day. 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.

Young rats in this study were allowed to recover following discontinuation of letrozole treatment for 42 days.

Histopathological changes were not reversible at clinically relevant exposures.

The median age of patients in all studies of first-line and second-line treatment of metastatic breast cancer was to 65 years.

About 1/3 of the patients were greater than or equal to 70 years old.

In the first-line study, patients greater than or equal to 70 years of age experienced longer time to tumor progression and higher response rates than patients less than 70.

For the extended adjuvant setting (MA-17), more than 5,100 postmenopausal women were enrolled in the clinical study.

In total, 41% of patients were aged 65 years or older at enrollment, while 12% were 75 or older.

In the extended adjuvant setting, no overall differences in safety or efficacy were observed between these older patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

In the adjuvant setting (BIG 1-98), more than 8,000 postmenopausal women were enrolled in the clinical study.

In total, 36 % of patients were aged 65 years or older at enrollment, while 12% were 75 or older.

More adverse reactions were generally reported in elderly patients irrespective of study treatment allocation.

However, in comparison to tamoxifen, no overall differences with regards to the safety and efficacy profiles were observed between elderly patients and younger patients.