LETROZOLE (Page 6 of 12)

6.6 First and Second-Line Treatment of Advanced Breast Cancer

In the combined analysis of the first- and second-line metastatic trials and post-marketing experiences other adverse reactions that were reported were cataract, eye irritation, palpitations, cardiac failure, tachycardia, dysesthesia (including hypesthesia/paresthesia), arterial thrombosis, memory impairment, irritability, nervousness, urticaria, increased urinary frequency, leukopenia, stomatitis cancer pain, pyrexia, vaginal discharge, appetite increase, dryness of skin and mucosa (including dry mouth), and disturbances of taste and thirst.

6.7 Postmarketing Experience

Cases of blurred vision, increased hepatic enzymes, angioedema, anaphylactic reactions, toxic epidermal necrolysis, erythema multiforme, and hepatitis have been reported. Cases of carpal tunnel syndrome and trigger .nger have been identied during post approval use of Letrozole tablets.

7 DRUG INTERACTIONS

Tamoxifen
Coadministration of Letrozole Tablets and tamoxifen 20 mg daily resulted in a reduction of letrazole plasma levels of 38% on average. Clinical experience in the second-line breast cancer trials indicates that the therapeutic effect of Letrozole Tablets therapy is not impaired if Letrozole Tablets is administered immediately after tamoxifen.

Cimetidine
A pharmacokinetic interaction study with cimetidine showed no clinically significant effect on letrazole pharmacokinetics.

Warfarin
An interaction study with warfarin showed no clinically significant effect of letrozole on warfarin pharmacokinetics.

Other anticancer agents
There is no clinical experience to date on the use of Letrozole Tablets in combination with other anticancer agents.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

P r e g n a n c y Ca te g o r y X [s e e C ontraindi c ations ( 4) ] . Letrozole Tablets may cause fetal harm when administered to a pregnant woman and the clinical benefit to premenopausal women with breast cancer has not been demonstrated. Letrozole Tablets is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

Letrozole Tablets caused adverse pregnancy outcomes, including congenital malformations, in rats and rabbits at doses much smaller than the daily maximum recommended human dose (MRHD) on a mg/m2 basis. Effects included increased post-implantation pregnancy loss and resorptions, fewer live fetuses, and fetal malformations affecting the renal and skeletal systems. Animal data and letrozole’s mechanism of action raise concerns that letrozole could be a human teratogen as well.

Reproduction studies in rats showed embryo and fetal toxicity at letrozole doses during organogenesis equal to or greater than 1/100 the daily maximum recommended human dose (MHRD) (mg/m2 basis). Adverse effects included: 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 doses 1/10 the daily MHRD (mg/m2 basis) caused fetal domed head and cervical/centrum vertebral fusion. In rabbits, letrozole caused embryo and fetal toxicity at doses about 1/100,000 and 1/10,000 the daily MHRD respectively (mg/m2 basis). Fetal anomalies included incomplete ossification of the skull, sternebrae, and fore- and hind legs. [s e e N on c lini c al T o x i c ology ( 13.2) ] . Physicians should discuss the need for adequate contraception with women who are recently menopausal. Contraception should be used until postmenopausal status is clinically well established.

8.3 Nursing Mothers

It is not known if letrozole is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from letrozole, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

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

8.5 Geriatric Use

The median age of patients in all studies of first-line and second-line treatment of metastatic breast cancer was 64-65 years. About 1/3 of the patients were ≥70 years old. In the first-line study, patients ≥70 years of age experienced longer time to tumor progression and higher response rates than patients <70. For the extended adjuvant setting, 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, 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.

10 OVERDOSAGE

Isolated cases of Letrozole Tablets overdose have been reported. In these instances, the highest single dose ingested was 62.5 mg or 25 Tablets. While no serious adverse reactions were reported in these cases, because of the limited data available, no firm recommendations for treatment can be made. However, emesis could be induced if the patient is alert. In general, supportive care and frequent monitoring of vital signs are also appropriate. In single-dose studies, the highest dose used was 30 mg, which was well tolerated; in multiple-dose trials, the largest dose of 10 mg was well tolerated.

Lethality was observed in mice and rats following single oral doses that were equal to or greater than 2,000 mg/kg (about 4,000 to 8,000 times the daily maximum recommended human dose on a mg/m2 basis); death was associated with reduced motor activity, ataxia and dyspnea. Lethality was observed in cats following single IV doses that were equal to or greater than 10 mg/kg (about 50 times the daily maximum recommended human dose on a mg/m2 basis); death was preceded by depressed blood pressure and arrhythmias.

11 DESCRIPTION

Letrozole Tablets for oral administration contain 2.5 mg of letrozole, a nonsteroidal aromatase inhibitor (inhibitor of estrogen synthesis). It is chemically described as 4,4′-(1H-1,2,4-Triazol– ylmethylene)bisbenzonitrile, and its structural formula is

structural formula

Letrozole is a white to yellowish crystalline powder, practically odorless, freely soluble in dichloromethane, slightly soluble in ethanol, and practically insoluble in water. It has a molecular weight of 285.31, empirical formula C17 H1 1 N5 , and a melting range of 184°C-185°C. Letrozole Tablets are available as 2.5 mg tablets for oral administration.

I na c ti v e I ng r e di e nts: Lactose Monohydrate, Corn Starch 826, Sodium Starch Glycolate (Primojel), Silicified Microcrystalline Cellulose (Prosolv HD 90), magnesium stearate, Polyvinyl Alcohol-Part Hydrolyzed, Macrogol, Titanium Dioxide, Talc, Iron Oxide Yellow, FD&C Yellow #6/Sunset Yellow FCF Aluminum Lake.

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