Letrozole Tablets USP 2.5mg Taj Pharma

  1. Name of the medicinal product

Letrozole Tablets USP 2.5mg Taj Pharma

  1. Qualitative and quantitative composition

Letrozole Tablets USP 2.5mg Taj Pharma
Each film-coated tablet contains:
Letrozole USP 2.5mg
Excipients: Q.S.
Colours: Yellow Oxide of Iron, Titanium Dioxide USP, Red oxide of Iron and Tartarazine

Excipient with known effect

Each film-coated tablet contains 45mg of lactose monohydrate.
Each film-coated tablet contains 0.546mg of sodium.

For the full list of excipients, see section 6.1.

  1. Pharmaceutical form

Film-coated tablet,
Yellow Oxide of Iron, Titanium Dioxide USP, Red oxide of Iron and Tartarazine

  1. Clinical particulars

Therapeutic indications

Adjuvant treatment of postmenopausal women with hormone receptor positive invasive early breast cancer.

Extended adjuvant treatment of hormone-dependent early invasive breast cancer in postmenopausal women who have received prior standard adjuvant tamoxifen therapy for 5 years.

First-line treatment in postmenopausal women with hormone-dependent advanced breast cancer. Advanced breast cancer after relapse or disease progression, in women with natural or artificially induced postmenopausal endocrine status, who have previously been treated with antioestrogens. Neoadjuvant treatment of postmenopausal women with hormone receptor positive, HER-2 negative breast cancer where chemotherapy is not suitable and immediate surgery not indicated.

Efficacy has not been demonstrated in patients with hormone receptor negative breast cancer.

Posology and method of administration

Posology

Adult and elderly patients

The recommended dose of Letrozole Taj Pharma tablet is 2.5mg once daily.

In patients with advanced or metastatic breast cancer, treatment with Letrozole Taj Pharma tablets should continue until tumour progression is evident.

In the adjuvant and extended adjuvant setting, treatment with Letrozole Taj Pharma tablets should continue for 5 years or until tumour relapse occurs, whichever is first.

In the neoadjuvant setting, treatment with Letrozole Taj Pharma tablets could be continued for 4 to 8 months in order to establish optimal tumour reduction. If the response is not adequate, treatment with Letrozole Taj Pharma tablets should be discontinued and surgery scheduled and/or further treatment options discussed with the patient.

Following standard adjuvant tamoxifen therapy, treatment with Letrozole Taj Pharma tablets should continue for 5 years or until tumour relapse occurs, whichever comes first. In patients with metastatic disease, treatment with Letrozole Taj Pharma tablets should continue until tumour progression is evident. Regular monitoring to observe progression during the pre-operative treatment period is recommended (see section 5.1). No dose adjustment is required for elderly patients.

Paediatric population

Letrozole Taj Pharma tablets is not recommended for use in children and adolescents. The safety and efficacy of Letrozole Taj Pharma tablets in children and adolescents aged up to 17 years have not been established. Limited data are available and no recommendation on a posology can be made.

Renal impairment

No dosage adjustment of Letrozole Taj Pharma tablets is required for patients with renal insufficiency with creatinine clearance ≥10 ml/min. Insufficient data are available in cases of renal insufficiency with creatinine clearance lower than 10 ml/min (see sections 4.4 and 5.2).

Hepatic impairment

No dosage adjustment of Letrozole Taj Pharma tablets is required for patients with mild to moderate hepatic insufficiency (Child-Pugh grade A or B). Insufficient data are available for patients with severe hepatic impairment. Patients with severe hepatic impairment (Child-Pugh C) require close supervision (see sections 4.4 and 5.2).

Method of administration

Letrozole Taj Pharma tablets should be taken orally and can be taken with or without food.

A missed dose should be taken as soon as the patient remembers. However, if it is almost time for the next dose (within 2 or 3 hours), the missed dose should be skipped, and the patient should go back to her regular dosage schedule. Doses should not be doubled because with daily doses over the 2.5mg recommended dose, over-proportionality in systemic exposure was observed (see section 5.2).

Contraindications

  • Hypersensitivity to the active substance or to any of the excipients listed in section 6.1
  • Premenopausal endocrine status
  • Premenopausal, pregnant or lactating women (see section 4.6).

Special warnings and precautions for use

Menopausal status

In patients whose menopausal status is unclear, luteinising hormone (LH), follicle-stimulating hormone (FSH) and/or oestradiol levels should be measured before initiating treatment with Letrozole Taj Pharma. Only women of postmenopausal endocrine status should receive Letrozole Taj Pharma.

Paediatric population

Letrozole Taj Pharma tablets are not recommended for use in children as efficacy and safety in this patient group have not been assessed in clinical studies.

Male breast cancer

There are no efficacy data to support the use of Letrozole Taj Pharma in men with breast cancer.

Renal impairment

Letrozole Taj Pharma has not been investigated in a sufficient number of patients with a creatinine clearance lower than 10 ml/min. The potential risk/benefit to such patients should be carefully considered before administration of Letrozole Taj Pharma.

Hepatic impairment

In patients with severe hepatic impairment (Child-Pugh C), systemic exposure and terminal half-life were approximately doubled compared to healthy volunteers. Such patients should therefore be kept under close supervision (see section 5.2).

Bone effects

Women with a history of osteoporosis and/or fractures, or who are at increased risk of osteoporosis, should have their bone mineral density formally assessed prior to the commencement of adjuvant and extended adjuvant treatment and monitored during and following treatment with Letrozole Taj Pharma. In the adjuvant setting a sequential treatment schedule (Letrozole Taj Pharma 2 years followed by tamoxifen 3 years) could also be considered depending on the patient`s safety profile (see sections 4.2, 4.8 and 5.1).

As Letrozole Taj Pharma is a potent oestrogen lowering agent, reductions in bone mineral density can be anticipated. During adjuvant treatment with Letrozole Taj Pharma, 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. Treatment or prophylaxis for osteoporosis should be initiated as appropriate and patients treated with Letrozole Taj Pharma tablets should be carefully monitored (see sections 4.8 and 5.1).

Tendonitis and tendon rupture

Tendonitis and tendon ruptures (rare) may occur. Close monitoring of the patients and appropriate measures (e.g. immobilisation) must be initiated for the affected tendon (see section 4.8).

Other warnings

Co-administration of Letrozole Taj Pharma with tamoxifen, other anti-oestrogens or oestrogen-containing therapies should be avoided as these substances may diminish the pharmacological action of Letrozole Taj Pharma (see section 4.5).

Lactose

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Sodium

This medicine contains less than 1 mmol sodium (23mg) per tablet, that is to say essentially ‘sodium-free’.

  • Interaction with other medicinal products and other forms of interaction

Metabolism of Letrozole Taj Pharma is partly mediated via CYP2A6 and CYP3A4. Clinical interaction studies with cimetidine and warfarin indicated that the co-administration of Letrozole Taj Pharma with these drugs does not result in clinically significant drug interactions, even though cimetidine is a known weak inhibitor of one of the cytochrome P450 isoenzymes capable of metabolising Letrozole Taj Pharma in vitro (See section 5.2 Metabolism and elimination).

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).

There is no clinical experience to date on the use of Letrozole Taj Pharma in combination with oestrogens or other anticancer agents, other than tamoxifen. Tamoxifen, other anti-oestrogens or oestrogen-containing therapies may diminish the pharmacological action of Letrozole Taj Pharma. In addition, co-administration of tamoxifen with Letrozole Taj Pharma has been shown to substantially decrease plasma concentrations of Letrozole Taj Pharma. Co-administration of Letrozole Taj Pharma with tamoxifen, other anti-oestrogens or oestrogens should be avoided.

Letrozole Taj Pharma inhibits in vitro the cytochrome P450-isoenzymes 2A6 and moderately 2C19, however, CYP2A6 does not play a major role in drug metabolism. In in vitro experiments, Letrozole Taj Pharma was not able to substantially inhibit the metabolism of diazepam (a substrate of CYP2C19) at concentrations approximately 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 (e.g phenytoin, clopidrogel).

Fertility, pregnancy and lactation

Women of perimenopausal status or child-bearing potential

Letrozole Taj Pharma should only be used in women with a clearly established postmenopausal status (see section 4.4). As there are reports of women regaining ovarian function during treatment with Letrozole Taj Pharma despite a clear postmenopausal status at start of therapy, the physician needs to discuss adequate contraception when necessary.

Pregnancy

Based on human experience in which there have been isolated cases of birth defects (labial fusion, ambiguous genitalia), Letrozole Taj Pharma may cause congenital malformations when administered during pregnancy. Studies in animals have shown reproductive toxicity (see section 5.3).

Letrozole Taj Pharma is contraindicated during pregnancy (see section 4.3 and 5.3).

Breast-feeding

It is unknown whether Letrozole Taj Pharma and its metabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded.

Letrozole Taj Pharma is contraindicated during breast-feeding (see section 4.3).

Fertility

The pharmacological action of Letrozole Taj Pharma is to reduce oestrogen production by aromatase inhibition. In premenopausal women, the inhibition of oestrogen synthesis leads to feedback increases in gonadotropin (LH, FSH) levels. Increased FSH levels in turn stimulate follicular growth, and can induce ovulation.

Effects on ability to drive and use machines

Letrozole Taj Pharma has minor influence on the ability to drive and use machines. Since fatigue and dizziness have been observed with the use of Letrozole Taj Pharma and somnolence has been reported uncommonly, caution is advised when driving or using machines.

Undesirable effects

Letrozole Taj Pharma was generally well tolerated across all studies as first-line and second-line treatment for advanced breast cancer, as adjuvant treatment of early breast cancer as well as in the treatment of women who have received prior standard tamoxifen therapy. Approximately, one third of the patients treated with Letrozole Taj Pharma in the metastatic and neoadjuvant settings, and approximately 80% of the patients in the adjuvant setting (both Letrozole Taj Pharma and tamoxifen arms, at a median treatment duration of 60 months), and approximately 80% of the patients treated following standard adjuvant tamoxifen (both Letrozole Taj Pharma and placebo arms, at a median treatment duration of 60 months) experienced adverse reactions. Generally, the observed adverse reactions are mainly mild or moderate in nature, and most are associated with oestrogen deprivation.

The most frequently reported adverse reactions in clinical studies were hot flushes, hypercholesterolaemia, arthralgia, fatigue, increased sweating and nausea. Many adverse reactions can be attributed to the normal pharmacological consequences of oestrogen deprivation (e.g. hot flushes, alopecia and vaginal bleeding).

Important additional adverse reactions that may occur with Letrozole Taj Pharma are: skeletal events such as osteoporosis and/or bone fractures and cardiovascular events (including cerebrovascular and thromboembolic events). The frequency category for these adverse reactions is described in Table 1.

Tabulated listing of adverse reactions

The frequencies of adverse reactions for Letrozole Taj Pharma are mainly based on data collected from clinical trials.

The following adverse drug reactions, listed in Table 1, were reported from clinical studies and from post marketing experience with Letrozole Taj Pharma tablets.

Table 1

Adverse reactions are ranked under headings of frequency, the most frequent first, using the following convention: very common ≥ 10%; common ≥ 1% to < 10%; uncommon ≥ 0.1% to < 1%; rare ≥ 0.01% to < 0.1%; very rare < 0.01%, not known (cannot be estimated from the available data).

Frequency Very Common

(≥1/10)

Common

(≥1/100 to <1/10)

Uncommon

(≥1/1,000 to <1/100)

Rare

(≥1/10,000 to <1/1,000)

Very rare

(<1/10,000),

Not known (cannot be estimated from the available data)
Organ System
Infections and infestations Urinary tract infection
Neoplasms benign, malignant and unspecified (including cysts and polyps) Tumour pain6
Blood and lymphatic system disorders Leucopenia
Immune system disorders Angioedema Anaphylactic reactions
Metabolism and nutrition disorders Hypercholesterolaemia Anorexia, appetite increase, General oedema
Psychiatric disorders Depression Anxiety1, irritability
Nervous system disorders Headache, dizziness Somnolence, insomnia, memory impairment, dysaesthesia2, taste disturbance, cerebrovascular accident, carpal tunnel syndrome
Eye disorders Cataract, eye irritation, blurred vision
Cardiac disorders Palpitations6 Tachycardia, ischaemic cardiac events (including new or worsening angina, angina requiring surgery, myocardial infarction and myocardial ischaemia)
Vascular disorders Hot flushes Hypertension Thrombophlebitis3, ischemic cardiac events7, 8 Pulmonary embolism, arterial thrombosis, cerebrovascu-lar infarction
Respiratory, thoracic and mediastinal disorders Dyspnoea, cough
Gastrointestinal disorders Nausea, dyspepsia 6, constipation, abdominal pain, diarrhoea, vomiting Dry mouth, stomatitis6
Hepatobiliary disorders Increased hepatic enzymes, hyperbilirubinemia, jaundice. Hepatitis
Skin and subcutaneous tissue disorders Increased sweating Alopecia, rash4, dry skin Pruritus, urticaria Toxic epidermal necrolysis, erythema multiforme
Musculoskeletal and connective tissue disorders Arthralgia Myalgia, bone pain6, osteoporosis, bone fractures, arthritis. Tendonitis Tendon rupture Trigger finger
Renal and urinary disorders Increased urinary frequency
Reproductive system and breast disorders Vaginal bleeding Vaginal discharge, vaginal dryness, breast pain
General disorders and administration site conditions Fatigue5, hot flushes Peripheral oedema, chest pain. General oedema, pyrexia, mucosal dryness, thirst
Investigations Weight increase Weight loss

Including:

(1) nervousness, irritability

(2) paraesthesia, hypoaesthesia

(3) superficial and deep thrombophlebitis

(4) erythematous, maculopapular, psoriaform and vesicular rash

(5) aesthenia and malaise

(6) in metastatic/neoadjuvant setting only

(7) in the adjuvant setting, irrespective of causality, the following adverse events occurred in the Letrozole Taj Pharma and tamoxifen groups respectively: thromboembolic events (2.1% vs. 3.6%), angina pectoris (1.1% vs. 1.0%), myocardial infarction (1.0% vs. 0.5%), cardiac failure (0.8% vs. 0.5%) (see section 5.1).

(8) After standard adjuvant tamoxifen, at a median treatment duration of 60 months for Letrozole Taj Pharma and 37 months for placebo, the following AEs were reported for Letrozole Taj Pharma and placebo (excluding all switches to Letrozole Taj Pharma) respectively: new or worsening angina (1.4% vs. 1.0%); angina requiring surgery (0.8% vs. 0.6%); myocardial infarction (1.0% vs. 0.7%); thromboembolic event (0.9% vs. 0.3%); stroke/TIA (1.5% vs. 0.8%) (see section 5.1)

Table 2 presents the frequency of specific target adverse events, CTC grades 1-4 in the BIG 1-98 study, irrespective of causality, reported in patients receiving Letrozole Taj Pharma or tamoxifen monotherapy, at a median treatment duration of 60 months. The reporting period includes 30 days after cessation of trial therapy.

Table 2:

CTC grades 1-4 CTC grades 3-4
Pre-specified event Letrozole Taj Pharma

N = 2448

Tamoxifen

N – 2447

Letrozole Taj Pharma

N = 2448

Tamoxifen

N = 2447

n (%) n (%) n (%) n (%)
Hypercholesterolaemia 1280 (52.3) 700 (28.6) 11 (0.4) 6 (0.2)
Hot flashes / hot flushes 821 (33.5) 929 (38.0) 0 0
Arthralgia / arthritis 617 (25.2) 500 (20.4) 84 (3.4) 49 (2.0)
Night sweats 357 (14.6) 426 (17.4) 0 0
Nausea 283 (11.6) 277 (11.3) 6 (0.2) 9 (0.4)
Bone fractures 245 (10.0) 170 (6.9) 83 (3.4) 43 (1.8)
Fatigue (lethargy, malaise, asthenia) 235 (9.6) 250 (10.2) 6 (0.2) 7 (0.3)
Myalgia 217 (8.9) 212 (8.7) 18 (0.7) 14 (0.6)
Vaginal bleeding 128 (5.2) 320 (13.2) 1 (<0.1) 8 (0.3)
Oedema 164 (6.7) 160 (6.5) 3 (0.1) 1 (<0.1)
Headache 105 (4.3) 94 (3.8) 9 (0.4) 5 (0.2)
Osteoporosis 124 (5.1) 66 (2.7) 10 (0.4) 5 (0.2)
Vaginal irritation 111 (4.5) 77 (3.1) 2 (<0.1) 2 (<0.1)
Osteopaenia 87 (3.6) 74 (3.0) 0 2 (<0.1)
Dizziness / light-headedness 84 (3.4) 84 (3.4) 1 (<0.1) 6 (0.2)
Vomiting 80 (3.3) 80 (3.3) 3 (0.1) 5 (0.2)
Total serum cholesterol>1.5*ULN1 151/1843 (8.2) 57/1840 (3.1)
Thromboembolic event2 51 (2.1) 89 (3.6)
Constipation 49 (2.0) 71 (2.9) 3 (0.1) 1 (<0.1)
Cerebrovascular accident/ Transient ischaemic attack2, 3 52 (2.1) 46 (1.9)
Endometrial proliferation disorders 14 (0.6) 86 (3.5) 0 14 (0.6)
Cataract 49 (2.0) 54 (2.2) 16 (0.7) 17 (0.7)
Breast pain 37 (1.5) 43 (1.8) 1 (<0.1) 0
Endometrial hyperplasia or cancer4 6/1909 (0.3) 57/1943 (2.3)
Anorexia 20 (0.8) 20 (0.8) 1 (<0.1) 1 (<0.1)
Angina pectoris (new worsening, or requiring surgical intervention) 2 26 (1.1) 24 (1.0)
Cardiac failure 2 30 (1.2) 24 (1.0)
Myocardial infarction2 24 (1.0) 12 (0.5)
Ovarian cyst 11 (0.4) 18 (0.7) 4 (0.2) 4 (0.2)
1 Based on number of patients with normal serum cholesterol levels at baseline, and developing at least one value greater than 1.5 times the upper limit of normal in the laboratory measuring total serum cholesterol. Approximately 90% of the measured values were non-fasting measurements

2 All cardiovascular events (including cerebrovascular and thromboembolic events) assumed to be grades 3-5

3 Pre-printed term “CVA/TIA” without distinguishing between terms

4 Denominator is number of patients not having undergone hysterectomy at baseline

After standard adjuvant tamoxifen, the following adverse events irrespective of causality were reported significantly more often with Letrozole Taj Pharma than with placebo – hot flushes (Letrozole Taj Pharma, 61% versus placebo, 51%), arthralgia/arthritis (41% versus 27%), sweating (35% versus 30%), hypercholesterolaemia (24% versus 15%) and myalgia (18 % versus 9.4%). The majority of these adverse events were observed during the first year of treatment. In the 60% of patients in the placebo arm who switched to Letrozole Taj Pharma following a median duration of 31 months after completion of tamoxifen following unblinding of the study in 2003, a similar pattern of general adverse events was observed. The incidence of osteoporosis during treatment was significantly higher for Letrozole Taj Pharma than for placebo (12.2% versus 6.4%). The incidence of clinical fractures during treatment was significantly higher for Letrozole Taj Pharma than for placebo patients (10.4% versus 5.8%). In patients who switched to Letrozole Taj Pharma, newly diagnosed osteoporosis during treatment with Letrozole Taj Pharma was reported in 5.4% of patients while fractures were reported in 7.7% of patients. Irrespective of treatment, patients ≥ 65 years experienced more bone fractures and more osteoporosis.

Some adverse reactions have been reported with notably different frequencies in the adjuvant treatment setting. The following tables provide information on significant differences in Letrozole Taj Pharma versus tamoxifen monotherapy and in the Letrozole Taj Pharma-tamoxifen sequential treatment therapy:

Table 3 Adjuvant Letrozole Taj Pharma monotherapy versus tamoxifen monotherapy – adverse events with significant differences

Letrozole Taj Pharma, incidence rate Tamoxifen, incidence rate
N=2448 N=2447
During treatment (Median 5y) Any time after randomization (Median 8y) During treatment (Median 5y) Any time after randomization (Median 8y)
Bone fracture 10.2% 14.7% 7.2% 11.4%
Osteoporosis 5.1% 5.1% 2.7% 2.7%
Thromboembolic events 2.1% 3.2% 3.6% 4.6%
Myocardial infarction 1.0% 1.7% 0.5% 1.1%
Endometrial hyperplasia/endometrial cancer 0.2% 0.4% 2.3% 2.9%
Note: “During treatment” includes 30 days after last dose. “Any time” includes follow-up period after completion or discontinuation of study treatment.

Differences were based on risk ratios and 95% confidence intervals.

Table 4 Sequential treatment versus Letrozole Taj Pharma monotherapy – adverse events with significant differences

Letrozole Taj Pharma monotherapy Letrozole Taj Pharma->tamoxifen Tamoxifen->Letrozole Taj Pharma
N=1535 N=1527 N=1541
5 years 2 yrs-> 3y 2 yrs-> 3y
Bone fractures 10.0% 7.7%* 9.7%
Endometrial proliferative disorders 0.7% 3.4%** 1.7%*
Hypercholesterolaemia 52.5% 44.2%* 40.8%*
Hot flushes 37.6% 41.7%** 43.9%**
Vaginal bleeding 6.3% 9.6%** 12.7%**
* Significantly less than with Letrozole Taj Pharma monotherapy

** Significantly more than with Letrozole Taj Pharma monotherapy

Note: Reporting period is during treatment or within 30 days of stopping treatment

Description of selected adverse reactions

Cardiac adverse reactions

In the adjuvant setting, in addition to the data presented in Table 2, the following adverse events were reported for Letrozole Taj Pharma and tamoxifen, respectively (at median treatment duration of 60 months plus 30 days): angina requiring surgery (1.0% vs. 1.0%); cardiac failure (1.1% vs. 0.6%); hypertension (5.6% vs. 5.7%); cerebrovascular accident/transient ischaemic attack (2.1% vs. 1.9%).

In the extended adjuvant setting for Letrozole Taj Pharma (median duration of treatment 5 years) and placebo (median duration of treatment 3 years), respectively: angina requiring surgery (0.8% vs. 0.6%); new or worsening angina (1.4% vs. 1.0%); myocardial infarction (1.0% vs. 0.7%); thromboembolic event* (0.9% vs. 0.3%); stroke/transient ischaemic attack* (1.5% vs. 0.8%) were reported.

Events marked * were statistically significantly different in the two treatment arms.

Skeletal adverse reactions

For skeletal safety data from the adjuvant setting, please refer to Table 2.

In the extended adjuvant setting, significantly more patients treated with Letrozole Taj Pharma experienced bone fractures or osteoporosis (bone fractures, 10.4% and osteoporosis, 12.2%) than patients in the placebo arm (5.8% and 6.4%, respectively). Median duration of treatment was 5 years for Letrozole Taj Pharma, compared with 3 years for placebo.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

Overdose

There is no clinical experience of overdosage only isolated cases of overdose with Letrozole Taj Pharma have been reported. In animal studies, Letrozole Taj Pharma exhibits only a slight degree of acute toxicity. In clinical trials, the highest single and multiple dose tested in healthy volunteers was 30mg and 5mg, respectively, the latter also being the highest dose tested in postmenopausal breast cancer patients. Each of these doses was well tolerated. There is no clinical evidence for a particular dose of Letrozole Taj Pharma resulting in life-threatening symptoms.

There is no specific antidote to Letrozole Taj Pharma. In general, supportive care, symptomatic treatment and frequent monitoring of vital signs are appropriate.

  1. Pharmacological properties

Pharmacodynamic properties

Pharmacotherapeutic group: Endocrine therapy. Hormone antagonist and related agents: aromatase inhibitor; Letrozole Taj Pharma is a Non-steroidal aromatase inhibitor (inhibitor of oestrogen biosynthesis); antineoplastic agent.

Pharmacodynamic effects

The elimination of oestrogen-mediated growth stimulation is a prerequisite for tumour response in cases where the growth of tumour tissue depends on the presence of oestrogens and endocrine therapy is used. In postmenopausal women, oestrogens are mainly derived from the action of the aromatase enzyme, which converts adrenal androgens – primarily androstenedione and testosterone – to oestrone and oestradiol. The suppression of oestrogen biosynthesis in peripheral tissues and the cancer tissue itself can therefore be achieved by specifically inhibiting the aromatase enzyme.

Letrozole Taj Pharma is a non-steroidal aromatase inhibitor. It inhibits the aromatase enzyme by competitively binding to the haem of the aromatase cytochrome P450, resulting in a reduction of oestrogen biosynthesis in all tissues where present.

In healthy postmenopausal women, single doses of 0.1mg, 0.5mg and 2.5mg Letrozole Taj Pharma suppress 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 0.1mg to 5mg suppressed plasma concentration of oestradiol, oestrone, and oestrone sulphate by 75-95% from baseline in all patients treated. With doses of 0.5mg and higher, many values of oestrone and oestrone sulphate were below the limit of detection in the assays, indicating that higher oestrogen suppression is achieved with these doses. Oestrogen suppression was maintained throughout treatment in all these patients.

Letrozole Taj Pharma is highly specific in inhibiting aromatase activity. Impairment of adrenal steroidogenesis has not been observed. No clinically relevant changes were found in the plasma concentrations of cortisol, aldosterone, 11-deoxycortisol, 17-hydroxyprogesterone, and ACTH or in plasma renin activity among postmenopausal patients treated with a daily dose of Letrozole Taj Pharma 0.1 to 5mg. The ACTH stimulation test performed after 6 and 12 weeks of treatment with daily doses of 0.1mg, 0.25mg, 0.5mg, 1mg, 2.5mg, and 5mg did not indicate any attenuation of aldosterone or cortisol production. Thus, glucocorticoid and mineralocorticoid supplementation is not necessary.

No changes were noted in plasma concentrations of androgens (androstenedione and testosterone) among healthy postmenopausal women after 0.1mg, 0.5mg, and 2.5mg single doses of Letrozole Taj Pharma or in plasma concentrations of androstenedione among postmenopausal patients treated with daily doses of 0.1mg to 5mg, indicating that the blockade of oestrogen biosynthesis does not lead to accumulation of androgenic precursors. Plasma levels of LH and FSH are not affected by Letrozole Taj Pharma in patients, nor is thyroid function as evaluated by TSH, T4 and T3 uptake test.

Adjuvant treatment

Study BIG 1-98

BIG 1-98 was a multicentre, double-blind study in which over 8,000 postmenopausal women with hormone receptor-positive early breast cancer were randomised to one of the following treatments: A. tamoxifen for 5 years; B. Letrozole Taj Pharma for 5 years; C. tamoxifen for 2 years followed by Letrozole Taj Pharma for 3 years; D, Letrozole Taj Pharma for 2 years followed by tamoxifen for 3 years.

This study was designed to investigate two primary questions: whether Letrozole Taj Pharma for 5 years was superior to tamoxifen for 5 years (Primary Core Analysis and Monotherapy Arms Analysis) and whether switching endocrine treatments at 2 years was superior to continuing the same agent for a total of 5 years (Sequential Treatments Analysis).

The primary endpoint was disease-free survival (DFS); secondary efficacy endpoints were time to distant metastasis (TDM), distant disease free survival (DDFS), overall survival (OS), systemic disease-free survival (SDFS), invasive contralateral breast cancer and time to breast cancer recurrence.

Efficacy results at a median follow-up of 26 and 60 months

Data in Table 5 reflect the results of the Primary Core Analysis (PCA) based on data from the monotherapy arms (A and B) and from the two switching arms (C and D) at a median treatment duration of 24 months and a median follow-up of 26 months and at a median treatment duration of 32 months and a median follow-up of 60 months.

The 5-year DFS rates were 84% for Letrozole Taj Pharma and 81.4% for tamoxifen.

Table 5 Primary Core Analysis: Disease-free and overall survival, at a median follow-up of 26 months and at median follow-up of 60 months (ITT population)

Primary Core Analysis
Median follow-up 26 months Median follow-up 60 months
Letrozole Taj Pharma

N=4003

Tamoxifen

N=4007

HR1

(95% CI) P

Letrozole Taj Pharma

N=4003

Tamoxifen

N=4007

HR1

(95% CI) P

Disease-free survival (primary) events (protocol definition2) 351 428 0.81 (0.70, 0.93) 0.003 585 664 0.86 (0.77, 0.96) 0.008
Overall survival (secondary) Number of deaths 166 192 0.86 (0.70, 1.06) 330 374 0.87 (0.75, 1.01)

HR = Hazard ratio; CI = Confidence interval

1 Log rank test, stratified by randomisation option and use of chemotherapy (yes/no)

2 DFS events: loco-regional recurrence, distant metastasis, invasive contralateral breast cancer, second (non-breast) primary malignancy, death from any cause without a prior cancer event.

Results at a median follow-up of 96 months (monotherapy arms only)

The Monotherapy Arms Analysis (MAA) long-term update of the efficacy of Letrozole Taj Pharma monotherapy compared to tamoxifen monotherapy (median duration of adjuvant treatment: 5 years) is presented in Table 6.

The Monotherapy Arms Analysis (MAA) long-term update of the efficacy of Letrozole Taj Pharma monotherapy compared to tamoxifen monotherapy (median duration of adjuvant treatment: 5 years) is presented in Table 6.

Table 6 Monotherapy Arms Analysis: Disease-free and overall survival at a median follow-up of 96 months (ITT population)

Letrozole Taj Pharma

N=2463

Tamoxifen

N=2459

Hazard Ratio1 (95% CI) Value
Disease-free survival events (primary) 2 626 698 0.87 (0.78, 0.97) 0.01
Time to distant metastasis (secondary) 301 342 0.86 (0.74, 1.01) 0.06
Overall survival (secondary) deaths 393 436 0.89 (0.77, 1.02) 0.08
Censored analysis of DFS3 626 649 0.83 (0.74, 0.92)
Censored analysis of OS3 393 419 0.81 (0.70, 0.93)

1 Log rank test, stratified by randomisation option and use of chemotherapy (yes/no)

2 DFS events: loco-regional recurrence, distant metastasis, invasive contralateral breast cancer, second (non-breast) primary malignancy, death from any cause without a prior cancer event.

3 Observations in the tamoxifen arm censored at the date of selectively switching to Letrozole Taj Pharma

Sequential Treatments Analysis (STA)

The Sequential Treatments Analysis (STA) addresses the second primary question of BIG 1-98, namely whether sequencing of tamoxifen and Letrozole Taj Pharma would be superior to monotherapy. There were no significant differences in DFS, OS, SDFS, or DDFS from switch with respect to monotherapy (Table 7).

Table 7 Sequential treatments analysis of disease-free survival with Letrozole Taj Pharma as initial endocrine agent (STA switch population)

N Number of events1 Hazard ratio2 (97.5% confidence interval) Cox model P-value
[Letrozole Taj Pharma→] Tamoxifen 1460 254 1.03 (0.84, 1.26) 0.72
Letrozole Taj Pharma 1464 249

1 Protocol definition, including second non-breast primary malignancies, after switch / beyond two years

2 Adjusted by chemotherapy use

There were no significant differences in DFS, OS, SDFS or DDFS in any of the STA from randomisation pairwise comparisons (Table 7).

Table 8 Sequential Treatments Analyses from randomisation (STA-R) of disease-free survival (ITT STA-R population)

Letrozole Taj Pharma→Tamoxifen Letrozole Taj Pharma
Number of patients 1540 1546
Number of patients with DFS events (protocol definition) 330 319
Hazard ratio1 (99% CI) 1.04 (0.85, 1.27)
Letrozole Taj Pharma→Tamoxifen Tamoxifen2
Number of patients 1540 1548
Number of patients with DFS events (protocol definition) 330 353
Hazard ratio1 (99% CI) 0.92 (0.75, 1.12)

1 Adjusted by chemotherapy use (yes/no)

2 626 (40%) patients selectively crossed to Letrozole Taj Pharma after tamoxifen arm unblinded in 2005

Letrozole Taj Pharma was approved for the adjuvant treatment of early breast cancer on the basis of the Primary Core Analysis (PCA) results at a median follow-up of only 26 months (see Table 9). The updated analysis, using all data from the monotherapy arms (Monotherapy Arms Analysis, MAA) at a median follow-up of 73 months confirmed the superiority of Letrozole Taj Pharma over tamoxifen in reducing the risk of a disease-free survival event, including the risk of distant metastasis (Table 9).

The independent Data Monitoring Committee recommended unblinding the tamoxifen arms (other treatment arms remained blinded) and, in accordance with a formal protocol amendment, patients in the tamoxifen arms were allowed to cross over to Letrozole Taj Pharma to complete their adjuvant therapy (if they had received tamoxifen for 2 to 4.5 years) or to start further adjuvant therapy (if they had received tamoxifen for at least 4.5 years). Approximately 26% of patients (632 in total) in the tamoxifen monotherapy arms selectively crossed to Letrozole Taj Pharma or another aromatase inhibitor (12 patients), mostly to complete adjuvant therapy.

Table 9: Comparison of Letrozole Taj Pharma and tamoxifen monotherapy at a median follow-up of 26 months and of 73 months

PCA (median follow-up 26 months)

(PCA ITT population)

MAA (median follow-up 73 months)

(MAA ITT population)

Letrozole Taj Pharma Tamoxifen HR (95% CI) 1 Letrozole Taj Pharma Tamoxifen HR (95% CI) 1
N=4003 N=4007 P value N=4003 N=4007 P value
Disease-free survival (DFS) (protocol definition)2 (primary endpoint)
Events 351 428 0.81

(0.70, 0.93)

0.003

509 565 0.88

(0.78, 0.99)

0.03

5-year DFS rate 84.0% 81.4% 85.6% 82.6%
Time to distant metastases (TDM) (secondary endpoint)3
Events 184 249 0.73

(0.60, 0.88)

257 298 0.85

(0.72, 1.00)

Distant disease-free survival (DDFS) (secondary endpoint)4
Events 265 318 0.82

(0.70, 0.97)

385 432 0.87

(0.76, 1.00)

Overall survival (OS) (secondary endpoint)
Events 166 192 0.86

(0.70, 1.06)

303 343 0.87

(0.75, 1.02)

5-year OS rate 91.1% 89.7% 89.3% 88.1%
Censored analysis of DFS (protocol definition)5
Events 509 543 0.85

(0.75, 0.96)

Censored analysis of OS5
Events 303 338 0.82

(0.70, 0.96)

PCA = Primary Core Analysis; MAA = Monotherapy Arms Analysis; HR = Hazard ratio; CI = Confidence interval

1 Adjusted by stratification factors of randomisation option and use of adjuvant chemotherapy

2 Protocol definition of DFS events: loco-regional recurrence, distant metastasis, invasive contralateral breast cancer, second non-breast primary cancer, death from any cause without a prior cancer event

3 Time to distant metastasis. Note: In original analysis, this endpoint was erroneously labelled “distant disease-free survival” (DDFS)

4 DDFS events: Earlier event of either distant metastasis or death from any cause

5 Follow-up times censored at date of selectively crossing from tamoxifen to Letrozole Taj Pharma, after tamoxifen arm was unblinded following the PCA results

Note: P values are provided only for the primary endpoint; if the 95% CI does not include 1.0, the result may be regarded as “statistically significant” at face value

The Sequential Treatments Analyses from switch (STA-S) address the second primary question in BIG 1- 98, namely for a new patient, whether it was better to switch endocrine agents after approximately 2 years, or to continue with the same endocrine agent for a total of 5 years. Table 10 shows that there was no statistically significant difference between treatments. The safety profile of the sequential treatments should be considered in reviewing the efficacy results.

Table 10: Summary of sequential treatment analyses from switch (STA-S) (ITT population)

[Letrozole Taj Pharma 2y -] Tamoxifen vs Letrozole Taj Pharma 5y beyond 2 years 1 [Tamoxifen 2y -] Letrozole Taj Pharma vs Tamoxifen 5y beyond 2 years 1
Tamoxifen Letrozole Taj Pharma Letrozole Taj Pharma Tamoxifen 2
N=1460 N=1463 N=1446 N=1459
Disease-free survival (protocol definition) (primary endpoint)
Events 160 178 160 186
HR (97.5% CI) 3 0.92 (0.72, 1.17) 0.85 (0.67, 1.09)
P value 0.42 0.14
DFS censoring follow-up times at date of selective crossover in tamoxifen arm 2
Events 160 165
HR (97.5% CI) 3 0.76 (0.59, 0.97)
Overall survival (secondary endpoint)
Events 72 86 85 94
HR (97.5% CI) 3 0.85 (0.59, 1.22) 0.92 (0.66, 1.28)
OS censoring follow-up times at date of selective crossover in tamoxifen arm 2
Events 85 89
HR (97.5% CI) 3 0.73 (0.52, 1.02)
HR = Hazard ratio; CI = Confidence interval

1 Median follow-up beyond switch approximately 43 months

2 Approximately 43% of patients (624) in the tamoxifen 5 years arm selectively crossed to an aromatase inhibitor after the switch, mostly to complete adjuvant therapy

3 Adjusted by stratification factor of use of adjuvant chemotherapy

Adjuvant Therapy in Early Breast Cancer, Study D2407

Study D2407 is an open-label, randomised, multicentre post approval safety study designed to compare the effects of adjuvant treatment with Letrozole Taj Pharma and tamoxifen on bone mineral density (BMD) and serum lipid profiles. A total of 262 patients were assigned either Letrozole Taj Pharma for 5 years or tamoxifen for 2 years followed by Letrozole Taj Pharma for 3 years.

At 24 months, there was a statistically significant difference in the primary end-point; the lumbar spine BMD (L2-L4) showed a median decrease of 4.1% for Letrozole Taj Pharma compared to a median increase of 0.3% in the tamoxifen.

No patient with a normal BMD at baseline became osteoporotic during 2 years of treatment and only 1 patient with osteopenia at baseline (T score of -1.9) developed osteoporosis during the treatment period (assessment by central review).

The results for total hip BMD were similar to those for lumbar spine but less pronounced.

There was no significant difference between treatments in the rate of fractures – 15% in the Letrozole Taj Pharma arm, 17% in the tamoxifen arm.

Median total cholesterol levels in the tamoxifen arm were decreased by 16% after 6 months compared to baseline and this decrease was maintained at subsequent visits up to 24 months. In the Letrozole Taj Pharma arm, total cholesterol levels were relatively stable over time, giving a statistically significant difference in favour of tamoxifen at each time point.

Treatment after standard adjuvant tamoxifen, study CFEM345G MA-17

In a multicentre, double-blind, randomised, placebo-controlled study (MA-17), performed in over 5100 postmenopausal patients with receptor-positive or unknown primary breast cancer patients who had remained disease-free after completion of adjuvant treatment with tamoxifen (4.5 to 6 years) were randomly assigned either Letrozole Taj Pharma or placebo for 5 years.

The primary endpoint was disease-free survival, defined as the interval between randomisation and the earliest occurrence of loco-regional recurrence, distant metastasis, or contralateral breast cancer.

The primary analysis conducted at a median follow-up of around 28 months (25% of the patients being followed-up for up to 38 months) showed that Letrozole Taj Pharma reduced the risk of recurrence by 42% compared with placebo (hazard ratio 0.58; P = 0.00003), an absolute reduction of 2.4%. This statistically significant benefit in DFS in favour of Letrozole Taj Pharma was observed regardless of nodal status or prior chemotherapy.

There was no significant difference in overall survival: (Letrozole Taj Pharma 51 deaths; placebo 62; HR 0.82; 95% CI 0.56, 1.19).

The independent Data and Safety Monitoring Committee recommended that women who were disease free in the placebo arm be allowed to switch to Letrozole Taj Pharma for up to 5 years when the study was unblinded in 2003. In the updated, final analysis conducted in 2008, 1551 women (60% of those eligible to switch) switched from placebo to Letrozole Taj Pharma at a median 31 months after completion of adjuvant tamoxifen therapy. Median duration of Letrozole Taj Pharma after switch was 40 months.

The updated final analysis conducted at a median follow-up of 62 months confirmed the significant reduction in the risk of breast cancer recurrence with Letrozole Taj Pharma compared with placebo, despite 60% of eligible patients in the placebo arm switching to Letrozole Taj Pharma after the study was unblinded. In the Letrozole Taj Pharma arm, median duration of treatment was 60 months; in the placebo arm, median duration of treatment was 37 months. The protocol-specified 4-year DFS rate was identical in the Letrozole Taj Pharma arm for both the 2004 and the 2008 analyses, confirming the stability of the data and robust effectiveness of Letrozole Taj Pharma long-term. In the placebo arm, the increase in 4-year DFS rate at the updated analysis clearly reflects the impact of 60% of the patients having switched to Letrozole Taj Pharma. This switching also accounts for the apparent dilution in treatment difference.

In the original analysis, for the secondary endpoint overall survival (OS) a total 113 deaths were reported (51 Letrozole Taj Pharma, 62 placebo). Overall, there was no significant difference between treatments in OS (hazard ratio 0.82; P = 0.29). Table 11 summarises the results:

Table 11: Summary of results of study MA-17 after completion of adjuvant therapy with tamoxifen (Modified ITT population)

Initial analysis

Median follow-up 28 months

Updated analysis 1

Median follow-up 62 months

Letrozole Taj Pharma Placebo HR2 (95% CI) Letrozole Taj Pharma Placebo HR2 (95% CI)
N = 2582

n (%)

N = 2586

n (%)

P value N = 2582

n (%)

N = 2586

n (%)

P value
Disease-free survival (protocol definition)3
Events 92 (3.6) 155 (6.0) 0.58 (0.45, 0.76)

0.00003

209 (8.1) 286 (11.1) 0.75 (0.63, 0.89)

0.001

4-year DFS rate 94.4% 89.8% 94.4% 91.4%
Disease-free survival including deaths from any cause
Events 122 (4.7) 193 (7.5) 0.62 (0.49, 0.78) 344 (13.3) 402 (15.5) 0.89 (0.77, 1.03)
5-year DFS rate 90.5% 80.8% 88.8% 86.7%
Distant metastases
Events 57 (2.2) 93 (3.6) 0.61 (0.44, 0.84) 142 (5.5) 169 (6.5) 0.88 (0.70, 1.10)
Overall survival
Deaths 51 (2.0) 62 (2.4) 0.82 (0.56, 1.19) 236 (9.1) 232 (9.0) 1.13 (0.95, 1.36)
Deaths 4 236 (9.1) 5 170 (6.6) 6 0.78 (0.64, 0.96)
Contralateral breast cancer (invasive)
Events 15 (0.6) 25 (1.0) 0.60 7 (0.31, 1.14) 33 (1.3) 51 (2.0) 0.64 7 (0.41, 1.00)
HR = Hazards ratio; CI = Confidence interval

P values are given for the primary endpoint only, in view of multiple endpoints and multiple analyses. If both bounds of the 95% confidence interval are ≤ 1.00, the treatment difference may be regarded as “significant” at the 5% level at face value; values < 1.00 favour Letrozole Taj Pharma; values > 1.00 favour placebo

1 When the study was unblinded after the first interim analysis, 1551 patients in the randomised placebo arm (60% of those eligible to switch – i.e. who were disease-free) switched to Letrozole Taj Pharma at a median 31 months after randomisation. The analyses presented here ignore the switching under the ITT principle

2 Stratified by receptor status, nodal status and prior adjuvant chemotherapy

3 Protocol definition of disease-free survival events: loco-regional recurrence, distant metastasis or contralateral breast cancer

4 Exploratory analysis, censoring follow-up times at the date of switching (if a switch occurred) – see footnote 1.

5 Median follow-up 62 months

6 Median follow-up until switch (if it occurred) 37 months

7 Odds ratio and 95% CI for the odds ratio

In the updated quality of life substudy there were no significant differences between treatments in physical component summary score or mental component summary score, or in any domain score in the SF36 scale. In the MENQOL scale, significantly more women in the Letrozole Taj Pharma arm than in the placebo arm were most bothered (generally in the first year of treatment) by those symptoms deriving from oestrogen deprivation – hot flushes and vaginal dryness. The symptom that bothered most patients in both treatment arms was aching muscles, with a statistically significant difference in favour of placebo. According to the study protocol, patients who completed standard adjuvant treatment with tamoxifen not more than 3 months previously could enter the study. In the updated analysis of MA-17, however, analysis included data from patients who switched from placebo to Letrozole Taj Pharma (60% of eligible patients) at a median 31 months after completing tamoxifen. In the updated analysis, as shown in Table 11, there was a significant reduction in the odds of an invasive contralateral breast cancer with Letrozole Taj Pharma compared with placebo, despite 60% of the patients in the placebo arm having switched to Letrozole Taj Pharma. There was no significant difference in overall survival.

An exploratory analysis censoring follow-up times at the date of switch (if it occurred) showed a significant reduction in the risk of all-cause mortality with Letrozole Taj Pharma compared with placebo (Table 11).

There was no difference in safety and efficacy between patients aged < 65 versus ≥ 65 years.

The updated safety profile of Letrozole Taj Pharma did not reveal any new adverse event and was entirely consistent with the profile reported in 2004.

Updated results (median follow-up was 61 months) from the bone sub-study (n=226) demonstrated that, at 2 years, compared to baseline, patients receiving Letrozole Taj Pharma had a median decrease of 3.8 % in hip bone mineral density (BMD) compared to 2.0 % in the placebo group (P = 0.022). There was no significant difference between treatments in changes in lumbar spine BMD at any time. Concomitant calcium and vitamin D supplementation was mandatory in the BMD substudy. Updated results (median follow-up was approximately 62 months) from the lipid sub-study (n=347) showed for any of the lipid measurements no significant difference between the Letrozole Taj Pharma and placebo groups at any time. In the updated analysis, the incidence of cardiovascular events (including cerebrovascular and thromboembolic events) during treatment with Letrozole Taj Pharma versus placebo until switch was 9.8% vs. 7.0%, a statistically significant difference.

Amongst the pre-printed, check-listed terms during study treatment, the most frequently reported events were: stroke/transient ischemic attack (Letrozole Taj Pharma, 1.5%; placebo until switch, 0.8%); new or worsening angina (Letrozole Taj Pharma, 1.4%; placebo until switch, 1.0%); myocardial infarction (Letrozole Taj Pharma, 1.0%; placebo until switch, 0.7%); thromboembolic events (Letrozole Taj Pharma, 0.9%; placebo until switch, 0.3%).

The reported frequency of thromboembolic events as well as of stroke/transient ischaemic attack was significantly higher for Letrozole Taj Pharma than placebo until switch. The interpretation of safety results should consider that there was an imbalance in the median duration of treatment with Letrozole Taj Pharma (60 months) compared with placebo (37 months) due to the switch from placebo to Letrozole Taj Pharma which occurred in approximately 60% of the patients.

Neoadjuvant treatment

A double blind trial (P024) was conducted in 337 postmenopausal breast cancer patients randomly allocated either Letrozole Taj Pharma 2.5mg for 4 months or tamoxifen for 4 months. At baseline all patients had tumours stage T2T4c, N02, M0, ER and/or PgR positive and none of the patients would have qualified for breast-conserving surgery. Based on clinical assessment there were 55% objective responses in the Letrozole Taj Pharma arm versus 36% for the tamoxifen arm (P<0.001). This finding was consistently confirmed by ultrasound (Letrozole Taj Pharma 35% vs tamoxifen 25%, P=0.04) and mammography (Letrozole Taj Pharma 34% vs tamoxifen 16%, P<0.001). In total 45% of patients in the Letrozole Taj Pharma group versus 35% of patients in the tamoxifen group (P=0.02) underwent breast-conserving therapy). During the 4month preoperative treatment period, 12% of patients treated with Letrozole Taj Pharma and 17% of patients treated with tamoxifen had disease progression on clinical assessment.

First-line treatment

One large well-controlled double-blind trial was conducted comparing Letrozole Taj Pharma 2.5mg to tamoxifen 20mg daily as first-line therapy in postmenopausal women with locally advanced or metastatic breast cancer. In this trial of 907 women, Letrozole Taj Pharma was superior to tamoxifen in time to progression (primary endpoint) and in overall objective response, time to treatment failure and clinical benefit (CR+PR+NC ≥ 24 weeks).

The results are summarised in Table 12:

Table 12 Results at a median follow-up of 32 months

Variable Statis ic Letrozole Taj Pharma

N=453

Tamoxifen

N=454

Time of progression Median 9.4 months 6.0 months
(95% CI for median) (8.9, 11.6 months) (5.4, 6.3 months)
Hazard ratio (HR) 0.72
(95% CI for HR) (0.62, 0.83)
P <0.0001
Objective response rate (ORR) CR+PR 145 (32%) 95 (21%)
(95% CI for rate) (28, 36%) (17, 25%)
Odds ratio 1.78
(95% CI for oddsrate) (1.32, 2.40)
P=0.0002

Time to progression was significantly longer, and response rate significantly higher for Letrozole Taj Pharma irrespective of whether adjuvant anti-oestrogen therapy had been given or not. Time to progression was significantly longer for Letrozole Taj Pharma irrespective of dominant site of disease. Median time to progression was 12.1 months for Letrozole Taj Pharma and 6.4 months for tamoxifen in patients with soft tissue disease only and median 8.3 months for Letrozole Taj Pharma an 4.6 months for tamoxifen in patients with visceral metastases.

Study design allowed patients to cross over upon progression to the other therapy or discontinue from the study. Approximately 50% of patients crossed over to the opposite treatment arm and crossover was virtually completed by 36 months. The median time to crossover was 17 months (Letrozole Taj Pharma to tamoxifen) and 13 months (tamoxifen to Letrozole Taj Pharma).

Letrozole Taj Pharma treatment in the firstline therapy of advanced breast cancer resulted in a median overall survival of 34 months compared with 30 months for tamoxifen (logrank test P=0.53, not significant). The absence of an advantage for Letrozole Taj Pharma on overall survival could be explained by the crossover design of the study. As the study design allowed patients to cross-over upon progression to the other therapy the long-term survival could not be evaluated.

Pre-operative treatment

A double blind trial (P024) was conducted in 337 postmenopausal breast cancer patients randomly allocated either Letrozole Taj Pharma 2.5mg for 4 months or tamoxifen for 4 months. At baseline all patients had tumours stage T2-T4c, N0-2, M0, ER and/or PgR positive and none of the patients would have qualified for breast-conserving surgery. There were 55% objective responses in the Letrozole Taj Pharma treated patients versus 36% for the tamoxifen treated patients (p < 0.001) based on clinical assessment. This finding was consistently confirmed by ultrasound (p = 0.042) and mammography (p < 0.001) giving the most conservative assessment of response. This response was reflected in a statistically significantly higher number of patients in the Letrozole Taj Pharma group who became suitable for and underwent breast-conserving therapy (45% of patients in the Letrozole Taj Pharma group versus 35% of patients in the tamoxifen group, p = 0.022). During the 4 month pre-operative treatment period, 12% of patients treated with Letrozole Taj Pharma and 17% of patients treated with tamoxifen had disease progression on clinical assessment.

Second-line treatment

Two well-controlled clinical trials were conducted comparing two Letrozole Taj Pharma doses (0.5mg and 2.5mg) to megestrol acetate and to aminoglutethimide, respectively, in postmenopausal women with advanced breast cancer previously treated with anti-oestrogens.

Time to progression was not significantly different between Letrozole Taj Pharma 2.5mg and megestrol acetate (P=0.07). Statistically significant differences were observed in favour of Letrozole Taj Pharma 2.5mg compared to megestrol acetate in overall objective tumour response rate (24% vs 16%, P=0.04), and in time to treatment failure (P=0.04). Overall survival was not significantly different between the 2 arms (P=0.2).

In the second study, the response rate was not significantly different between Letrozole Taj Pharma 2.5mg and aminoglutethimide (P=0.06). Letrozole Taj Pharma 2.5mg was statistically superior to aminoglutethimide for time to progression (P=0.008), time to treatment failure (P=0.003) and overall survival (P=0.002).

Male breast cancer

Use of Letrozole Taj Pharma in men with breast cancer has not been studied.

Pharmacokinetic properties

Absorption

Letrozole Taj Pharma is rapidly and completely absorbed from the gastrointestinal tract (mean absolute bioavailability: 99.9%). Food slightly decreases the rate of absorption (median tmax 1 hour fasted versus 2 hours fed; and mean Cmax 129 ± 20.3 nmol/litre fasted versus 98.7 ± 18.6 nmol/litre fed) but the extent of absorption (AUC) is not changed. The minor effect on the absorption rate is not considered to be of clinical relevance, and therefore Letrozole Taj Pharma may be taken without regard to mealtimes.

Distribution

Plasma protein binding of Letrozole Taj Pharma is approximately 60%, mainly to albumin (55%). The concentration of Letrozole Taj Pharma in erythrocytes is about 80% of that in plasma. After administration of 2.5mg 14C-labelled Letrozole Taj Pharma, approximately 82% of the radioactivity in plasma was unchanged compound. Systemic exposure to metabolites is therefore low. Letrozole Taj Pharma is rapidly and extensively distributed to tissues. Its apparent volume of distribution at steady state is about 1.87 ± 0.47 L/kg.

Biotransformation

Metabolic clearance to a pharmacologically inactive carbinol metabolite is the major elimination pathway of Letrozole Taj Pharma (CLm= 2.1 L/h) but is relatively slow when compared to hepatic blood flow (about 90 L/h). The cytochrome P450 isoenzymes 3A4 and 2A6 were found to be capable of converting Letrozole Taj Pharma to this metabolite. in vitro, but their individual contributions to Letrozole Taj Pharma clearance in vivo have not been established. In an interaction study co-administration with cimetidine, which is known to inhibit only the 3A4 isoenzyme, did not result in a decrease in Letrozole Taj Pharma clearance suggesting that in vivo the 2A6 isoenzyme plays an important part in total clearance. In this study a slight decrease in AUC and increase in Cmax were observed.

Formation of minor unidentified metabolites and direct renal and faecal excretion play only a minor role in the overall elimination of Letrozole Taj Pharma. Within 2 weeks after administration of 2.5mg 14C-labelled Letrozole Taj Pharma to healthy postmenopausal volunteers, 88.2 ± 7.6% of the radioactivity was recovered in urine and 3.8 ± 0.9% in faeces. At least 75% of the radioactivity recovered in urine up to 216 hours (84.7 ± 7.8% of the dose) was attributed to the glucuronide of the carbinol metabolite, about 9% to two unidentified metabolites, and 6% to unchanged Letrozole Taj Pharma.

Elimination

The apparent terminal elimination half-life in plasma is about 2 to 4 days. After daily administration of 2.5mg steady-state levels are reached within 2 to 6 weeks. Plasma concentrations at steady state are approximately 7 times higher than concentrations measured after a single dose of 2.5mg, while they are 1.5 to 2 times higher than the steady-state values predicted from the concentrations measured after a single dose, indicating a slight non-linearity in the pharmacokinetics of Letrozole Taj Pharma upon daily administration of 2.5mg. Since steady-state levels are maintained over time, it can be concluded that no continuous accumulation of Letrozole Taj Pharma occurs.

Linearity/non-linearity

The pharmacokinetics of Letrozole Taj Pharma were dose proportional after single oral doses up to 10mg (dose range: 0.01 to 30mg) and after daily doses up to 1.0mg (dose range: 0.1 to 5mg). After a 30mg single oral dose there was a slightly dose over-proportional increase in AUC value. The dose over-proportionality is likely to be the result of a saturation of metabolic elimination processes. Steady levels were reached after 1 to 2 months at all dosage regimens tested (0.1-5.0mg daily).

Special populations

Elderly

Age had no effect on the pharmacokinetics of Letrozole Taj Pharma.

Special populations

Renal impairment

In a study involving 19 volunteers with varying degrees of renal function (24 hour creatinine clearance 9-116 ml/min) no effect on the pharmacokinetics of Letrozole Taj Pharma or the urinary excretion of the glucoronide of its carbinol metabolite was found after a single dose of 2.5mg. In addition to the above study assessing the influence of renal impairment on Letrozole Taj Pharma, a covariate analysis was performed on the data of two pivotal studies (Study AR/BC2 and Study AR/BC3). Calculated creatinine clearance (CLcr) [Study AR/BC2 range: 19 to 187 mL/min; Study AR/BC3 range: 10 to 180 mL/min] showed no statistically significant association between Letrozole Taj Pharma plasma trough levels at steady-state (Cmin). Futhermore, data of Study AR/BC2 and Study AR/BC3 in secondline metastatic breast cancer showed no evidence of an adverse effect of Letrozole Taj Pharma on CLcr or an impairment of renal function.

Therefore, no dose adjustment is required for patients with renal impairment (CLcr ≥10 mL/min). Little information is available in patients with severe impairment of renal function (CLcr <10 mL/min).

Hepatic impairment

The Cmax, AUC and half-life of the metabolite have not been determined. In a similar study involving subjects with varying degrees of hepatic function, the mean AUC values of the volunteers with moderate hepatic impairment (Child-Pugh B) was 37% higher than in normal subjects, but still within the range seen in subjects without impaired function. In a study comparing the pharmacokinetics of Letrozole Taj Pharma after a single oral dose in eight male subjects with liver cirrhosis and severe hepatic impairment (Child-Pugh C) to those in healthy volunteers (N=8), AUC and t½ increased by 95 and 187%, respectively. Thus, Letrozole Taj Pharma should be administered with caution to patients with severe hepatic impairment and after consideration of the risk/benefit in the individual patient.

Preclinical safety data

In a variety of preclinical safety studies conducted in standard animal species, there was no evidence of systemic or target organ toxicity.

Letrozole Taj Pharma showed a low degree of acute toxicity in rodents exposed up to 2000mg/kg. In dogs, Letrozole Taj Pharma caused signs of moderate toxicity at 100mg/kg.

In repeated-dose toxicity studies in rats and dogs up to 12 months, the main findings observed can be attributed to the pharmacological action of the compound. The no-adverse-effect level was 0.3mg/kg in both species.

Oral administration of Letrozole Taj Pharma to female rats resulted in decreases in mating and pregnancy ratios and increases in pre-implantation loss

Both in vitro and in vivo investigations of Letrozole Taj Pharma’s mutagenic potential revealed no indications of any genotoxicity.

Effects on the liver (increased weight, hepatocellular hypertrophy, fatty changes) were observed, mainly at high dose levels. Increased incidences of hepatic vacuolation (both sexes, high dose) and necrosis (intermediate and high dose females) were also noted in rats treated for 104 weeks in a carcinogenicity study. They may have been associated with the endocrine effects and hepatic enzyme-inducing properties of Letrozole Taj Pharma. However, a direct drug effect cannot be ruled out.

In a 104-week mouse carcinogenicity study, dermal and systemic inflammation occurred, particularly at the highest dose of 60mg/kg, leading to increased mortality at this dose level. Again it is not known whether these findings were an indirect consequence of the pharmacological activity of Letrozole Taj Pharma (i.e. linked to long-term oestrogen deprivation) or a direct drug effect.

The pharmacological effects of Letrozole Taj Pharma resulted in skeletal, neuroendocrine and reproductive findings in a juvenile rat study at doses between 0.003mg/kg/day and 0.3mg/kg/day. Bone growth and maturation were decreased from the lowest dose (0.003mg/kg/day) in males and increased from the lowest dose (0.003mg/kg) in females. In addition, bone mineral density (BMD) was decreased at that dose in females. In the same study, decreased fertility at all doses was accompanied by hypertrophy of the hypophysis, testicular changes which included a degeneration of the seminiferous tubular epithelium, ovarian cysts and atrophy of the female reproductive tract. Effects on bone size in females at 0.3mg/kg/day and males at 0.03mg/kg/day and morphological changes in the testes were not reversible. All other effects were at least partially reversible at 0.003 and 0.03mg/kg/day. Both in vitro and in vivo investigations on Letrozole Taj Pharma’s mutagenic potential revealed no indication of any genotoxicity.

In the carcinogenicity studies no treatment-related tumours were noted in male animals. In female animals, treatment-related changes in genital tract tumours (a reduced incidence of benign and malignant mammary tumours in rats, an increased incidence of benign ovarian stromal tumours in mice) were secondary to the pharmacological effect of the compound.

Letrozole Taj Pharma was embryotoxic and foetotoxic in pregnant rats and rabbits following oral administration at clinically relevant doses. In rats that had live foetuses, there was an increase in the incidence of foetal malformations including domed head and cervical/centrum vertebral fusion. An increased incidence of foetal malformations was not seen in the rabbit. It is not known whether this was an indirect consequence of the pharmacological properties (inhibition of oestrogen biosynthesis) or a direct drug effect (see sections 4.3 and 4.6).

Preclinical observations were confined to those associated with the recognised pharmacological action, which is the only safety concern for human use derived from animal studies.

  1. Pharmaceutical particulars

List of excipients

Tablet core:

Lactose monohydrate, Sodium starch glycolate, Microcrystalline cellulose, Hypromellose 6 cP, Colloidal anhydrous silica, Magnesium stearate

Film coat (Opadry 04F52158 Yellow):

Hypromellose 15 cP, PEG 6000, Titanium dioxide, Iron oxide yellow, Iron oxide red, FD&C yellow #5 Aluminium lake,

Incompatibilities

None known.

Shelf life

2 years

Special precautions for storage

Store in in the original package

Nature and contents of container

PVC/PE/PVDC Aliminium blister packs

Pack Size:
14, 28, 56, 100, 200, 300 or 500 film coated tablets.

Not all pack size may be marketed.

  • Special precautions for disposal and other handling

No specific instructions for use/handling.

Manufactured in India by:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com

Letrozole Tablet USP 2.5mg Taj Pharma

Package leaflet: Information for the user

(letrozole)

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

  • Keep this leaflet. You may need to read it again.
  • If you have any further questions, ask your doctor or pharmacist.
  • This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
  • If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

  1. What Letrozole Taj Pharma tablets are and what they are used for
  2. What you need to know before you take Letrozole Taj Pharma tablets
  3. How to take Letrozole Taj Pharma tablets
  4. Possible side effects
  5. How to store Letrozole Taj Pharma tablets
  6. Contents of the pack and other information

1. What letrozole tablets are and what they are used for

What Letrozole Taj Pharma tablets are and how they work

Letrozole Taj Pharma, the active ingredient in Letrozole Taj Pharma tablets. It belongs to a group of medicines called aromatase inhibitors. It is a hormonal (or “endocrine”) breast cancer treatment. Growth of breast cancer is frequently stimulated by oestrogens which are female sex hormones. Letrozole Taj Pharma reduces the amount of oestrogen by blocking an enzyme (“aromatase”) involved in the production of oestrogens and therefore may block the growth of breast cancer that needs oestrogens to grow. As a consequence tumour cells slow or stop growing and/or spreading to other parts of the body.

What Letrozole Taj Pharma tablets are used for

Letrozole Taj Pharma tablets are used to treat breast cancer in post-menopausal women. They can be used either before surgery to reduce the size of the tumour, or after surgery to help prevent the tumour from returning.

They can also be used in patients with advanced breast cancer to help stop the tumour spreading to other parts of the body.

  1. What you need to know before you take letrozole Tablets

Follow all the doctor’s instructions carefully. They may differ from the general information in this leaflet.

Do not take Letrozole Taj Pharma tablets

  • If you are allergic to letrozole or any of the other ingredients of the medicine (listed in section 6),
  • If you still have periods, i.e. if you have not yet gone through the menopause,
  • if you are pregnant or if there is a possibility that you might be pregnant.
  • if you are breast-feeding.

If any of these conditions apply to you, do not take this medicine and talk to your doctor.

Warnings and Precautions

Talk to your doctor or pharmacist before taking Letrozole Taj Pharma tablets

  • if you suffer from any serious kidney disease.
  • If you have severe liver disease
  • if you have a history of osteoporosis (thinning or wasting of bones) or bone fractures. (see also “Follow-up during letrozole treatment” in section 3).

If any of these conditions apply to you, tell your doctor. Your doctor will take this into account during your treatment with letrozole.

Your doctor may want to measure your bone density before and during your treatment. Drugs like

Letrozole Taj Pharma Tablets reduce the levels of female hormones. This can lead to a loss of minerals in bones and cause osteoporosis (decrease in bone density and strength). Letrozole Taj Pharma may cause inflammation in tendons or tendon injury (see section 4). At any sign of tendon pain or swelling – rest the painful area and contact your doctor.

Men

Letrozole Taj Pharma is not to be used by men.

Children and adolescents (below 18 years)

Letrozole Taj Pharma is not to be used by children or adolescents.

Older people (age 65 years and over)

Letrozole Taj Pharma tablets can be used by people aged 65 years and over at the same dose as for other adults.

Other medicines and Letrozole Taj Pharma tablets

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including medicines obtained without a prescription.

Letrozole Taj Pharma tablets and food and drink

Taking food and drink has no influence on your treatment with Letrozole Taj Pharma tablets.

Pregnancy, breast-feeding and fertility

  • You should only take Letrozole Taj Pharma tablets when you have gone through the menopause. However, your doctor should discuss with you the use of effective contraception, as you may still have the potential to become pregnant during treatment with Letrozole Taj Pharma tablets.
  • You must not take Letrozole Taj Pharma tablets if you are pregnant or breast feeding as it may harm your baby.

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

Driving and using machines

Do not drive or work with machinery if you feel dizzy, tired or drowsy when you start to take Letrozole Taj Pharma Tablets.

Letrozole Taj Pharma Tablets contain lactose and sodium

If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.

Sodium

This medicine contains less than 1 mmol sodium (23mg) per tablet, that is to say essentially ‘sodiumfree’.

  1. How to take letrozole tablets

Always take this medicine exactly as your doctor or pharmacist has told you. You should check with your doctor or pharmacist if you are not sure.

The usual dose is one tablet of letrozole to be taken once a day. Taking letrozole tablets at the same time each day will help you remember when to take your tablet. You will probably continue to take Letrozole Taj Pharma tablets for a number of years.

The tablet can be taken with or without food and should be swallowed whole with a glass of water or another liquid.

Follow-up during Letrozole Taj Pharma treatment

You should only take this medicine under strict medical supervision. Your doctor will regularly monitor your condition to check whether the treatment is having the right effect.

Letrozole Taj Pharma may cause thinning or wasting of your bones (osteoporosis) due to the reduction of oestrogens in your body. Your doctor may decide to measure your bone density (a way of monitoring for osteoporosis) before, during and after treatment.

If you take more Letrozole Taj Pharma Tablets than you should

If you accidentally take too many Letrozole Taj Pharma tablets than you have been told to take, tell your doctor at once or contact your nearest hospital casualty department. Take your medicine with you.

If you forget to take Letrozole Taj Pharma Tablets

  • If it is almost time for your next dose (e.g. within 2 or 3 hours), skip the dose you missed and take your next dose when you are meant to
  • Otherwise, take the dose as soon as your remember, and then take the next tablet as you would normally
  • Do not take a double dose to make up for the one that you missed.

Do not stop taking your tablets, even if you are feeling well, unless your doctor tells you.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

  1. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Most of the side effects are mild or moderate and will generally disappear after a few days to few weeks of treatment.

Some side effects can be serious, such as hot flushes, hair loss or vaginal bleeding, may be due to the lack of oestrogens in your body. Severe allergic reactions, angina, heart attack, thrombosis, pulmonary embolism or stroke have occasionally been reported as side effects.

If any of the above occurs, tell your doctor straight away.

You should also inform the doctor straight away if you experience any of the following symptoms during treatment with letrozole:

  • Swelling mainly of the face and throat (signs of allergic reaction).
  • Yellow skin and eyes, nausea, loss of appetite, dark-coloured urine (signs of hepatitis).
  • Rash, red skin, blistering of the lips, eyes or mouth, skin peeling, fever (signs of skin disorder).

Stop taking the tablets and tell your doctor or go to the emergency department at your nearest hospital IMMEDIATELY if you get any of the following symptoms:

  • Heavy or tight chest or pain in the chest, spreading to your arms or shoulders, neck, teeth or jaw, abdomen or back
  • Coughing blood
  • Unusual pains or swelling of your arms or legs
  • Sudden shortness of breath, difficulty in speaking or breathing
  • Fainting
  • Numbness or weakness in your arm or leg or any part of your body
  • Loss of co-ordination
  • Vision changes
  • Sudden severe headache
  • Severe rash or redness, which might include blistering and peeling and be accompanied by fever
  • Itching, swollen throat, face, eyelids or lips, difficulty breathing.

Cases of hepatitis (inflammation of the liver) have been reported.

If any of these affects you seriously, tell your doctor.

Very common (may affect more than 1 in 10 people):

  • Hot flushes
  • Increased level of cholesterol (hypercholesterolaemia)
  • Fatigue
  • Increased sweating
  • Pains in the joints (arthralgia)

Common (may affect up to 1 in 10 people):

  • Loss of appetite or increased appetite
  • Gastrointestinal disorders such as nausea, vomiting, indigestion, constipation, diarrhea
  • Malaise (generally feeling unwell)
  • Weight gain
  • Raised blood pressure (hypertension)
  • Abdominal pain
  • Dry Skin
  • Depression
  • Headache
  • Dizziness
  • Hair loss
  • Skin rash
  • Muscle pain
  • Bone problems (pain, bone thinning or wasting of your bones (osteoporosis), leading to bone fractures in some cases (see also “Follow-up during letrozole treatment” in section 3)
  • Feeling tired
  • Swelling of arms, hands, feet, ankles (oedema) due to fluid retention
  • Vaginal bleeding
  • Palpitations, rapid heart rate
  • Joint stiffness (arthritis)
  • Joint stiffness (arthritis)
  • Chest pain.

Uncommon (may affect up to 1 in 100 people):

  • Urinary tract infections, urinating more often
  • Pain in the breast including in the tumour or in the stomach
  • General swelling due to fluid retention
  • Decreased white blood cells which can lead to infections (leucopenia)
  • Mental problems (anxiety, nervousness, irritability, loss of memory, drowsiness)
  • Sleep problems (sleepiness or difficulty in sleeping)
  • Changes in sensation, including touch sensation (pins and needles), taste changes
  • Eye problems such as cataract (loss of transparency of the lens of the eye), eye irritation, blurred

vision, dry eyes

  • Heart problems such as irregular heart beat (arrhythmia), angina and heart attack (ischemic cardiovascular disease)
  • Inflamed blood vessels
  • Breathlessness
  • Dry mouth or mouth ulcers
  • Liver problems
  • Itchy skin or raised wheals
  • Vaginal discharge, vaginal dryness
  • Fever
  • Thirst
  • Weight loss
  • Cough
  • Pain or burning sensation in the hands or wrist (carpal tunnel syndrome).
  • Increased level of enzymes
  • Yellowing of the skin and eyes,
  • High blood levels of bilirubin (a breakdown product of red blood cells)
  • Inflammation of a tendon or tendonitis (connective tissues that connect muscles to bones)

Rare (may affect up to 1 in 1,000 people):

  • Thrombosis (clotting in the blood vessels e.g. legs)
  • Pulmonary embolism (a blood clot in the lungs)
  • Rupture of a tendon (connective tissues that connect muscles to bones)

Not known: frequency cannot be estimated from the available data:

  • Trigger finger, a condition in which your finger or thumb catches in a bent position.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.

By reporting side effects you can help provide more information on the safety of this medicine.

  1. How to store letrozole tablets
    • Store in the original package.
    • Keep this medicine out of the sight and reach of children.
    • Do not take Letrozole Taj Pharma tablets after the expiry date which is stated on the carton after EXP. The expiry date refers to the last day of that month.
    • Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.
  2. Contents of the pack and other information

What Letrozole Taj Pharma tablets contains

  • The active substance is letrozole. Each film-coated tablets contains 2.5mg letrozole.
  • The other ingredients are lactose monohydrate, sodium starch glycollate, microcrystalline cellulose, hypromellose 6 cP, colloidal anhydrous silica, magnesium stearate.
  • The film coat contains hypromellose 15 cP, macrogol 6000, titanium dioxide, iron oxide yellow, iron oxide red and tartrazine.

What Letrozole Taj Pharma tablets looks like and contents of the pack

Letrozole Taj Pharma 2.5mg film-coated tablets are yellow, circular, biconvex film coated tablets plain on both sides.
Letrozole Taj Pharma 2.5mg film-coated tablets are available in blister packs.

Pack Size:
14, 28, 56, 100, 200, 300 or 500 film coated tablets.

Not all pack size may be marketed.

Manufactured in India by:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com