FERTOLET Tablets (Letrozole)

Table of Content

Composition

Each film-coated tablet contains:

Letrozole, IP…… 2.5 mg

Dosage Form

Tablets for oral use

Pharmacology

Pharmacodynamics

Letrozole is a specific nonsteroidal aromatase inhibitor. It inhibits the aromatase enzyme by competitively binding to the haem of the cytochrome (CY) P450 subunit of the enzyme, resulting in a reduction of oestrogen biosynthesis in all tissues. 

Induction of Ovulation in Anovulatory Infertility

Oestrogen exerts a negative feedback on the hypothalamic-pituitary axis and decreases the release of FSH from the pituitary gland. In infertile women, administration of letrozole during the early phase of the menstrual cycle blocks oestrogen production and, thereby, releases the hypothalamic-pituitary axis from oestrogenic negative feedback. This causes release of gonadotropins, which, in turn, leads to folliculogenesis and successful ovulation in anovulatory women.

Letrozole does not deplete the oestrogen receptor or produce a negative effect on the endometrium.

Letrozole has a half-life of 45 hours and absence of anti-oestrogenic activity. Since the drug is rapidly eliminated from the body, it is free from exerting any deleterious effects on the final stages of follicle development, oocyte maturation or on the early embryo.

Addition of letrozole to gonadotropins decreases gonadotropin requirements, increases the number of preovulatory follicles, and decreases endometrial thickness without a negative effect on pregnancy rates.

Since letrozole is to be used only for 5 days (D3 - D7 of the menstrual cycle) in a month for induction of ovulation, the possibility of side effects is less compared to its use in breast cancer.

In clinical studies, letrozole has been used as the first-line treatment for women with anovulatory infertility and for augmentation of ovulation in anovulatory infertility. Letrozole has been used for stimulating follicular development. When letrozole was added to gonadotropin regimens, it lead to less gonadotropin requirement and a pregnancy rate that was comparable to that with gonadotropin-only treatment.

Breast Cancer

Letrozole exerts its antitumour effect by depriving oestrogen-dependent breast cancer cells of their growth stimulus. In postmenopausal women, oestrogens are derived mainly from the action of the aromatase enzyme, which converts adrenal androgens, primarily androstenedione and testosterone, to oestrone. The suppression of oestrogen biosynthesis in the peripheral tissues and the malignant tissues can be achieved by specifically inhibiting the aromatase enzyme.

In healthy postmenopausal women, single doses of 0.1, 0.5 and 2.5 mg letrozole suppresses serum oestrone and oestradiol by 75 - 78% and 78% from baseline, respectively. Maximum suppression is achieved in 48 - 78 hours. In postmenopausal patients with advanced breast cancer, daily doses of 0.1 - 5 mg suppress plasma concentration of oestradiol, oestrone, and oestron sulphate by 78 - 95% from baseline in all patients treated.

Letrozole had no effect on plasma androgen concentrations (androstenedione and testosterone) among healthy women after single doses of 0.1, 0.5 and 2.5 mg indicating that the blockade of oestrogen biosynthesis does not lead to accumulation of androgenic precursors. Impairment of adrenal steroidogenesis has not been observed. 

Pharmacokinetics

Absorption and Distribution

Letrozole is rapidly and completely absorbed from the gastrointestinal tract and absorption is not affected by food. It is metabolized slowly to an inactive metabolite whose glucuronide conjugate is excreted renally, representing the major clearance pathway. About 90% of radiolabelled letrozole is recovered in urine. The terminal elimination half-life of letrozole is about 2 days and steady-state plasma concentration after daily 2.5 mg dosing is reached in 2 - 6 weeks. Plasma concentrations at steady state are 1.5 - 2 times higher than predicted from the concentrations measured after a single dose, indicating a slight non-linearity in the pharmacokinetics of letrozole upon daily administration of 2.5 mg. These steady-state levels are maintained over extended periods, however, and continuous accumulation of letrozole does not occur. Letrozole is weakly protein-bound and has a large volume of distribution (approximately 1.9 L/kg).

Metabolism and Excretion

Metabolism to a pharmacologically-inactive carbinol metabolite (4,4′-methanol-bisbenzonitrile) and renal excretion of the glucuronide conjugate of this metabolite is the major pathway of letrozole clearance. Of the radiolabel recovered in urine, at least 75% was the glucuronide of the carbinol metabolite, about 9% was two unidentified metabolites, and 6% was unchanged letrozole.

In human microsomes with specific CYP isozyme activity, CYP3A4 metabolized letrozole to the carbinol metabolite while CYP2A6 formed both this metabolite and its ketone analogue. In human liver microsomes, letrozole strongly inhibited CYP2A6 and moderately inhibited CYP2C19.

In a study of volunteers with varying renal function (24-hour creatinine clearance: 9 - 116ml/min), no effect of renal function on the pharmacokinetics of single doses of 2.5 mg of letrozole was found. In addition, in a study of 347 patients with advanced breast cancer, about half of whom received 2.5 mg letrozole and half 0.5 mg letrozole, renal impairment (calculated creatinine clearance: 20 - 50 ml/min) did not affect steady-state plasma letrozole concentration.

In a study of subjects with mild-to-moderate non-metastatic hepatic dysfunction (e.g. cirrhosis, Child-Pugh classification A and B), the mean AUC values of the volunteers with moderate hepatic impairment were 37% higher than in normal subjects, but still within the range seen in subjects without impaired function. In a pharmacokinetics study, subjects with liver cirrhosis and severe hepatic impairment (Child-Pugh classification C, which included bilirubin about 2 - 11 times the ULN with minimal-to-severe ascites) had a 2-fold increase in exposure (AUC) and a 47% reduction in systemic clearance. Breast cancer patients with severe hepatic impairment are, thus, expected to be exposed to higher levels of letrozole. That patients with normal liver function receiving similar doses of this drug.

In the study populations (adults ranging in age from 35 to >80 years), no change in pharmacokinetic parameters was observed with increasing age. Differences in letrozole pharmacokinetics between adult and paediatric populations have not been studied. Differences in letrozole pharmacokinetics due to race have not been studied.

Indications

Letrozole is indicated for the following: 

Induction of Ovulation in Anovulatory Infertility: for the induction of ovulation in women with anovulatory infertility.

Breast Cancer: for the treatment of advanced/metastatic breast cancer (hormone receptor-positive or receptor status unknown) in postmenopausal women as first-line treatment. 

Dosage and Administration

Induction of Ovulation in Anovulatory Infertility

For women of reproductive age with anovulatory infertility, the recommended dosage is 2.5 mg once daily for 5 days (days 3 - 7 of the menstrual cycle); for 3 consecutive cycles or till occurrence of pregnancy whichever is earlier.

If ovulation appears not to have occurred after the first course of therapy, a second course of 2.5 mg daily for 5 days should be given. This course may be started as early as 30 days after the previous one. Increase of the dosage or duration of therapy beyond 2.5 mg/day for 5 days should not be undertaken.

The patient should be examined carefully to exclude pregnancy, ovarian enlargement, or ovarian cyst formation between each treatment cycle.

The majority of patients who are going to respond will do so within three courses of therapy. If ovulation does not occur after three courses of therapy, further treatment with letrozole is not recommended and the patient should be reevaluated. If menses have not occurred after an ovulatory response, the patient should be reevaluated. If three ovulatory responses occur but pregnancy has not been achieved, further treatment is not recommended. As soon as pregnancy is detected, the drug should be discontinued. 

Breast Cancer

The recommended dose is 2.5 mg once daily. Treatment should continue as long as tumour response is seen. The drug should be discontinued if tumour stops responding as judged by tumour progression,

Contraindications

  • Known or suspected hypersensitivity to letrozole, other aromatase inhibitors, or to any of their ingredients
  • Pregnancy
  • Lactation
  • Severe hepatic dysfunction
  • In the presence of an ovarian cyst, except polycystic ovary, since further enlargement of the cyst may occur
  • In patients with abnormal uterine bleeding of undetermined origin.
  • Patients with uncontrolled thyroid or adrenal dysfunction or in the presence of an organic intracranial lesion such as pituitary tumour

Warnings and Precautions

General

Since fatigue and dizziness have been observed with the use of letrozole and somnolence was uncommonly reported, caution is advised since the patient’s physical and/or mental abilities required for operating machinery or driving a car may be impaired.

No dose-related effect of letrozole on any haematologic or clinical chemistry parameter was evident in studies. Moderate decreases in lymphocyte counts, of uncertain clinical significance, were observed in some patients receiving letrozole 2.5 mg. This depression was transient in about half of those affected. Increases in SGOT, SGPT and gamma glutamyl transferase (GGT) >5 times the upper limit of normal (ULN) and of bilirubin >1.5 times the ULN were most often associated with metastatic disease in the liver. About 3% of study participants receiving letrozole had abnormalities in liver chemistries not associated with documented metastases; these abnormalities may have been related to study drug therapy.

As letrozole is a potent oestrogen-lowering agent, reductions in bone mineral density can be anticipated. The impact of letrozole on long-term fracture risk remains undetermined. During adjuvant treatment with letrozole, women with osteoporosis or at risk of osteoporosis should have their bone mineral density formally assessed by bone densitometry, e.g. DEXA scanning at the commencement of treatment. Although adequate data to show the effects of therapy in the treatment of the bone mineral density loss caused by letrozole are not available, treatment for osteoporosis should be initiated as appropriate and patients treated with letrozole should be carefully monitored.

Induction of Ovulation in Anovulatory Infertility

Patient selection for the treatment of infertility should be done with care. The workup and treatment of candidates for letrozole therapy should be supervised by physicians experienced in the management of gynaecologic or endocrine disorders. Patients should be chosen for therapy with letrozole only after careful diagnostic evaluation. The plan of therapy should be outlined in advance. Impediments to achieving goals of therapy must be excluded or adequately treated before beginning letrozole. The therapeutic objective should be balanced with potential risks and discussed with the patient and others involved in the achievement of pregnancy. Coitus should be timed to coincide with the expected time of ovulation. Appropriate tests to determine ovulation may be useful during this time. Pelvic examination should be performed prior to letrozole administration and before each subsequent course. The patient should be instructed to inform the doctor of any abdominal or pelvic pain, weight gain or discomfort.

Causes of infertility other than ovarian dysfunction should be excluded before the start of the treatment.

The assumed risk of any pregnancy should be explained whether the ovulation was induced with the aid of letrozole or occurred naturally. The patient should be informed of the greater pregnancy risks associated with certain characteristics or conditions of any pregnant woman, e.g. age of female and male partner, history of spontaneous abortions, Rh genotype, abnormal menstrual history, infertility history (regardless of the cause), organic heart disease, diabetes, exposure to infectious agents such as rubella, familial history of birth anomaly, and other risk factors that may be pertinent to the patient for whom this treatment is being considered. Based upon the evaluation of the patient, genetic counselling may be indicated.   

The incidence of congenital malformations among offspring of mothers who conceived with clomiphene citrate (CC) or letrozole was evaluated in a clinical study. Overall, congenital malformations and chromosomal abnormalities were found in 14 of 514 newborns in the letrozole group (2.4%) and in 19 of 397 newborns in the CC group (4.8%). The major malformation rate in the letrozole group was 1.2% (6/514) and in the CC group was 3.0% (12/397). One newborn in the letrozole group was found to have a ventricular septal defect (0.2%) compared to 4 newborns in the CC group (1.0%). There was no difference in the overall rates of major and minor congenital malformations among newborns from mothers who conceived after letrozole or CC treatments.

There have been rare reports of ovarian cancer with fertility drugs; infertility itself is a primary risk factor. Therefore, the recommended duration of treatment should not be exceeded.

Patients should have adequate levels of endogenous oestrogen (as estimated form vaginal smears, endometrial biopsy, assay of urinary oestrogen or from bleeding in response to progesterone). Reduced oestrogen levels, while less favourable, do not preclude successful therapy.

Letrozole therapy cannot be expected to substitute for specific treatment of other causes of ovulatory failure such as primary pituitary or ovarian failure. The incidence of endometriosis and endometrial carcinoma increases with age as does the incidence of ovulatory disorders. Endometrial biopsy should always be performed prior to letrozole therapy in this population.

Impediments to pregnancy can include thyroid disorders, adrenal disorders, hyperprolactinaemia, and male factor infertility.

Caution should be exercised when using letrozole in patients with uterine fibroids due to the potential for further enlargement of the fibroids.

Drug Interactions

Clinical interaction studies with cimetidine and warfarin indicated that the co-administration of letrozole with these drugs does not result in clinically significant drug reactions, even though cimetidine is a known inhibitor of one of the CYP450 isoenzymes capable of metabolizing letrozole in vitro.

Letrozole inhibits in vitro the CYP450 isoenzyme 2A6, and, moderately, 2C19; however, CYP2A6 does not play a major role in drug metabolism. In in vitro experiments, letrozole was not able to substantially inhibit the metabolism of diazepam (a substrate if CYP2C19) at concentrations ~100-fold higher than those observed in plasma at steady state. Thus, clinically relevant interactions with CYP2C19 are unlikely to occur. Nevertheless, caution should be used in the concomitant administration of drugs whose disposition is mainly dependent on these isoenzymes and whose therapeutic index is narrow.

Co-administration of letrozole and tamoxifen 20 mg daily resulted in a reduction of letrozole plasma levels of 38% on average. Clinical experience in the second-line breast cancer pivotal trials indicates that the therapeutic effect of letrozole therapy is not impaired if letrozole is administered immediately after tamoxifen. There is no clinical experience to date on the use of letrozole in combination with other anti-cancer agents.

There was no evidence of other clinically relevant interaction in patients receiving other commonly prescribed drugs (e.g. benzodiazepines; barbiturates; NSAIDs such as diclofenac sodium, ibuprofen; paracetamol; furosemide; omeprazole).

In many clinical studies, letrozole has been safely co-administered and/or sequentially with gonadotropins including FSH and HMG. No untoward interactions were observed. Letrozole has also been safely co-administered with metformin without any untoward interaction reported.

Renal Impairment

No dosage adjustment is required for patients with renal impairment if creatinine clearance is >10 ml/min.

Hepatic Impairment

No dosage adjustment is recommended for patients with mild-to-moderate hepatic impairment, although letrozole blood concentrations were modestly increased in subjects with moderate hepatic impairment due to cirrhosis. The dose of letrozole in patients with cirrhosis and severe hepatic dysfunction should be reduced by 50%. The recommended dose of letrozole for such patients is 2.5 mg administered every other day. The effect of hepatic impairment on letrozole exposure in non-cirrhotic cancer patients with elevated bilirubin levels has not been determined. caution is recommended since letrozole elimination depends mainly on intrinsic metabolic clearance.

Pregnancy

Letrozole may cause foetal harm when administered to pregnant women.  Studies in rats or doses equal to or greater than 0.003 mg/kg (about 1/100 the daily maximum recommended human dose on a mg/m basis) administered during the period of organogenesis, have shown that letrozole is embryotoxic and foetotoxic, as indicated by intrauterine mortality, increased resorption, increased post-implantation loss, decreased numbers of live foetuses and foetal anomalies, including absence and shortening of renal papilla, dilation of the ureter, oedema, and incomplete ossification of front skull and metatarsals. Letrozole was teratogenic in rats. A 0.03 mg/kg dose (about one tenth the daily maximum recommended human dose on a mg/m2 basis) caused foetal domed head and cervical/centrum vertebral fusion.

Letrozole is embryotoxic at doses > 0.002 mg/kg and fetotoxic when administered to rabbits at 0.02 mg/kg (about 1/100,000 and 1/10,000 the daily maximum recommended human dose on a mg/m2 basis, respectively). Foetal anomalies included incomplete ossification of the skull, sternebrae and fore- and hindlegs.

There are no studies in pregnant women. If there is exposure to letrozole during pregnancy, the patient should be apprised of the potential hazard to the foetus and potential risk for loss of the pregnancy. The use of letrozole is contraindicated during pregnancy.

When being used in the treatment of infertility, to avoid inadvertent letrozole administration during early pregnancy, appropriate tests should be utilized during each treatment cycle to determine whether ovulation occurs. The patient should be evaluated carefully to exclude pregnancy, ovarian enlargement, or ovarian cyst formation between each treatment cycle. The next course of therapy should be delayed until these conditions have been excluded.

When pregnancy is detected, the drug should be immediately discontinued.

Lactation

It is not known whether letrozole is excreted in human milk. Because many drugs are excreted in human milk, letrozole should not be administered to a nursing mother.

Paediatric Use

Safety and effectiveness has not been established. 

Geriatric Use

For the treatment of breast cancer, no modification of the normal adult dosage regimen is necessary. Not intended for elderly patients for induction of ovulation.

Undesirable Effects

Adverse events associated with letrozole are generally mild to moderate and rarely severe enough to require discontinuation. The most commonly reported adverse effects with letrozole include arthralgia, hot flushes, gastrointestinal discomfort, nausea, vomiting, leg cramps, fatigue, lethargy, malaise, asthenia, headache, backache, premenstrual syndrome-type symptoms and others.

Other reported adverse events are musculoskeletal pain, gastrointestinal disturbances (constipation, vomiting, diarrhoea, abdominal pain), peripheral oedema, coughing, chest pain, insomnia, dyspnoea, increase in appetite, rash, dyspepsia, myalgia, bone pain, osteoporosis, bone fractures, alopecia, increased sweating, breast pain, vaginal bleeding, vaginal irritation, vulvovaginal dryness, anorexia, dizziness and weight increase, and pruritus.

Thromboembolic event, cataract, endometrial hyperplasia or cancer, myocardial infarction, ovarian cyst, cardiac failure, hypertension, cerebrovascular accident, hypercholesterolemia, urinary tract infection, influenza, angina pectoris (new or worsening) and viral infection are other frequently reported adverse events.

Overdosage

There is no clinical evidence for a particular dose of letrozole resulting in life-threatening symptoms. Isolated cases of letrozole overdose have been reported.  In these instances, the highest single dose ingested was 6.2 mg or 25 tablets.  While no serious adverse events were reported in these cases, because of the limited data available, no firm recommendations for treatment can be made.  There is no specific antidote to letrozole. However, emesis could be induced if the patient is alert. In general, supportive care and frequent monitoring of vital signs are also appropriate. Since letrozole is not highly protein-bound, dialysis may be helpful. 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.

Shelf Life

36 months

Storage and Handling Instructions

Store in a cool, dry place, protected from light. Keep out of the reach of children.

Packaging Information

FERTOLET is available in a blister pack of 5 tablets.

Manufacturer

Cipla Ltd.

Verna Indl Estate, Goa 403722

India

Last Updated: March 2017

Last Reviewed: March 2017