Letrozole 2.5mg Tablets Taj Pharma-SmPC by QC TAJ PHARMA

Letrozole Ta blets USP 2. 5mg Taj P harma : Uses -P ostme nopausal wome n with hor mone-depe nde nt advance d breast cancer , Side Effects -Hair los s, Interacti ons, Pi ctures, Warnings , Letroz ole Dosage & Rx I nfo | Letroz ole Use s, Side Effect s â&#x20AC;&#x201C;Hair loss, Letroz ole : Indications, Side Effe cts- Nausea, diarrhea, vomiting, diz zines s, Warning s, Letrozole - Drug Infor mation - Taj Phar ma, Letrozole dose Taj pharma ceutical s Letrozole intera ctions, Taj Pharma ceuti cal Letrozole contraindications, Letrozole pri ce, Letrozole Taj P harma Letroz ole 2.5 mg, SMPC- Taj Phar ma Stay conne cted to all updated on Letrozole Taj P harmaceuticals Taj pharma ce uticals. Patient I nformation Lea flets, SMPC.

Letrozole Tablets USP 2.5mg Taj Pharma 1. NAME OF THE MEDICINAL PRODUCT Letrozole Tablets USP 2.5mg Taj Pharma 2. 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

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. 4.2 Posology and method of administration

Excipient with known effect

Posology

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

Adult and elderly patients

For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Film-coated tablet, Yellow Oxide of Iron, Titanium Dioxide USP, Red oxide of Iron and Tartarazine 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Adjuvant treatment of postmenopausal women with hormone receptor positive invasive early breast cancer. Extended adjuvant treatment of hormonedependent early invasive breast cancer in postmenopausal women who have received prior standard adjuvant tamoxifen therapy for 5 years.

The recommended dose of Letrozole Taj Pharma tablet is 2.5mg once daily. In patients with advanced or metastatic breast cancer, treatment with letrozole 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 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 tablets should be discontinued and surgery scheduled and/or further treatment options discussed with the patient. Following standard adjuvant tamoxifen therapy, treatment with letrozole tablets should continue

Letrozole Ta blets USP 2. 5mg Taj P harma : Uses -P ostme nopausal wome n with hor mone-depe nde nt advance d breast cancer , Side Effects -Hair los s, Interacti ons, Pi ctures, Warnings , Letroz ole Dosage & Rx I nfo | Letroz ole Use s, Side Effect s –Hair loss, Letroz ole : Indications, Side Effe cts- Nausea, diarrhea, vomiting, diz zines s, Warning s, Letrozole - Drug Infor mation - Taj Phar ma, Letrozole dose Taj pharma ceutical s Letrozole intera ctions, Taj Pharma ceuti cal Letrozole contraindications, Letrozole pri ce, Letrozole Taj P harma Letroz ole 2.5 mg, SMPC- Taj Phar ma Stay conne cted to all updated on Letrozole Taj P harmaceuticals Taj pharma ce uticals. Patient I nformation Lea flets, SMPC.

for 5 years or until tumour relapse occurs, whichever comes first. In patients with metastatic disease, treatment with letrozole 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 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 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 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, overproportionality in systemic exposure was observed (see section 5.2). 4.3 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). 4.4 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. Only women of postmenopausal endocrine status should receive letrozole. 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 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.

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. In the adjuvant setting a sequential treatment schedule (letrozole 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 is a potent oestrogen lowering agent, reductions in bone mineral density can be anticipated. 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. Treatment or prophylaxis for osteoporosis should be initiated as appropriate and patients treated with letrozole 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 with tamoxifen, other anti-oestrogens or oestrogen-containing therapies should be avoided as these substances may diminish the pharmacological action of letrozole (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'. 4.5 Interaction with other medicinal products and other forms of interaction Metabolism of letrozole is partly mediated via CYP2A6 and CYP3A4. Clinical interaction studies with cimetidine and warfarin indicated that the co-administration of letrozole 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 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 in combination with oestrogens or other anticancer agents, other than tamoxifen. Tamoxifen, other anti-oestrogens or oestrogencontaining therapies may diminish the

pharmacological action of letrozole. In addition, co-administration of tamoxifen with letrozole has been shown to substantially decrease plasma concentrations of letrozole. Co-administration of letrozole with tamoxifen, other anti-oestrogens or oestrogens should be avoided.

administered during pregnancy. Studies in animals have shown reproductive toxicity (see section 5.3).

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 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).

Breast-feeding

4.6 Fertility, pregnancy and lactation Women of perimenopausal status or childbearing 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 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 may cause congenital malformations when

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

It is unknown whether letrozole 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 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. 4.7 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 and somnolence has been reported uncommonly, caution is advised when driving or using machines. 4.8 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

Letrozole Ta blets USP 2. 5mg Taj P harma : Uses -P ostme nopausal wome n with hor mone-depe nde nt advance d breast cancer , Side Effects -Hair los s, Interacti ons, Pi ctures, Warnings , Letroz ole Dosage & Rx I nfo | Letroz ole Use s, Side Effect s –Hair loss, Letroz ole : Indications, Side Effe cts- Nausea, diarrhea, vomiting, diz zines s, Warning s, Letrozole - Drug Infor mation - Taj Phar ma, Letrozole dose Taj pharma ceutical s Letrozole intera ctions, Taj Pharma ceuti cal Letrozole contraindications, Letrozole pri ce, Letrozole Taj P harma Letroz ole 2.5 mg, SMPC- Taj Phar ma Stay conne cted to all updated on Letrozole Taj P harmaceuticals Taj pharma ce uticals. Patient I nformation Lea flets, SMPC.

with letrozole in the metastatic and neoadjuvant settings, and approximately 80% of the patients in the adjuvant setting (both letrozole and tamoxifen arms, at a median treatment duration of 60 months), and approximately 80% of the patients treated following standard adjuvant tamoxifen (both letrozole 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.

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). Frequ Very ency Commo n Orga (≥1/10) n Syste m

Com Uncom Rare Ver mon mon y (≥1/1 rare (≥1/ (≥1/1,0 0,00 100 00 to 0 to (<1/ to <1/100 <1/1, 10,0 <1/1 ) 000) 00), 0)

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 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 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 tablets. Table 1 Adverse reactions are ranked under headings of frequency, the most frequent first, using the

Infecti ons and infest ations

Urinary tract infectio n

Neopl asms benig n, malig nant and unspe cified (inclu ding cysts and polyp s)

Tumou r pain6

Blood

Leucop

Not kno wn (can not be esti mate d from the avail able data )

and lymph atic syste m disord ers

enia

Immu ne syste m disord ers

syndro me

Eye disord ers

Catarac t, eye irritatio n, blurred vision

Cardi ac disord ers

Tachyc ardia, ischae mic cardiac events (includi ng new or worsen ing Palpi angina, tatio angina ns6 requiri ng surgery , myocar dial infarcti on and myocar dial ischae mia)

Ana Angi phyl oede actic ma react ions

Metab Anor olism exia, and Hyperch Genera appe nutriti olesterol l tite on aemia oedema incre disord ase, ers Psych iatric disord ers

Anxiet Depr 1 y, essio irritabil n ity

Nervo us syste m disord ers

Somnol ence, insomn ia, memor y impair ment, dysaest hesia2, taste disturb ance, cerebro vascula r acciden t, carpal tunnel

Head ache, dizzi ness

Vascu lar Hot disord flushes ers

Throm bophle bitis3, Hyp ischemi erten c sion cardiac events7, 8

Pulm onar y embo lism, arteri al thro mbos is, cereb rovas

cular infar ction Respir atory, thorac ic and media stinal disord ers

Dyspno ea, cough

Gastr ointes tinal disord ers

Naus ea, dysp epsia 6 , const ipati Dry on, mouth, abdo stomati mina tis6 l pain, diarr hoea, vomi ting

Hepat obiliar y disord ers

Skin and Increase subcut d aneou sweating s tissue

Alop ecia, rash4 , dry skin

disord ers

olysi s, eryth ema multi form e

Myal gia, Musc bone uloske pain6 letal , and osteo Arthralgi Tendon conne poro a itis ctive sis, tissue bone disord fract ers ures, arthr itis. Renal and urinar y disord ers

Increas ed urinary frequen cy Vagina l Vagi dischar nal ge, blee vaginal ding dryness , breast pain

Increas ed hepatic enzyme s, hyperbi lirubine mia, jaundic e.

Hepa titis

Repro ductiv e syste m and breast disord ers

Pruritu s, urticari a

Toxi c epid erma l necr

Gener Genera al Perip l disord heral oedema ers Fatigue5, oede , and hot pyrexia admin flushes ma, , chest istrati pain. mucosa on l site dryness condit

Tend on ruptu re

Trig ger finge r

ions Invest igatio ns

, thirst Wei ght Weight incre loss ase

treatment duration of 60 months. The reporting period includes 30 days after cessation of trial therapy. Table 2: CTC grades 1-4

Including: (1) nervousness, irritability (2) paraesthesia, hypoaesthesia

Prespecified event

(3) superficial and deep thrombophlebitis

Letrozol Tamoxi Letroz e Taj fen ole Pharma Taj N - 2447 Phar N = 2448 ma

(4) erythematous, maculopapular, psoriaform and vesicular rash n

(6) in metastatic/neoadjuvant setting only

(8) After standard adjuvant tamoxifen, at a median treatment duration of 60 months for letrozole and 37 months for placebo, the following AEs were reported for letrozole and placebo (excluding all switches to letrozole) 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 or tamoxifen monotherapy, at a median

Tamo xifen N= 2447

N= 2448

(5) aesthenia and malaise

(7) in the adjuvant setting, irrespective of causality, the following adverse events occurred in the letrozole 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).

CTC grades 3-4

(% n )

(% n (% n (% ) ) )

Hypercholest 1280 (52 700 (28 11 (0. 6 (0. erolaemia .3) .6) 4) 2) Hot flashes / 821 (33 929 (38 0 hot flushes .5) .0)

0 -

Arthralgia / 617 (25 500 (20 84 (3. 49 (2. arthritis .2) .4) 4) 0) Night sweats 357 (14 426 (17 0 .6) .4)

0 -

Nausea

283 (11 277 (11 6 (0. 9 (0. .6) .3) 2) 4)

Bone fractures

245 (10 170 (6. 83 (3. 43 (1. .0) 9) 4) 8)

Fatigue (lethargy, malaise, asthenia)

235 (9. 250 (10 6 (0. 7 (0. 6) .2) 2) 3)

Myalgia

217 (8. 212 (8. 18 (0. 14 (0. 9) 7) 7) 6)

Letrozole Ta blets USP 2. 5mg Taj P harma : Uses -P ostme nopausal wome n with hor mone-depe nde nt advance d breast cancer , Side Effects -Hair los s, Interacti ons, Pi ctures, Warnings , Letroz ole Dosage & Rx I nfo | Letroz ole Use s, Side Effect s –Hair loss, Letroz ole : Indications, Side Effe cts- Nausea, diarrhea, vomiting, diz zines s, Warning s, Letrozole - Drug Infor mation - Taj Phar ma, Letrozole dose Taj pharma ceutical s Letrozole intera ctions, Taj Pharma ceuti cal Letrozole contraindications, Letrozole pri ce, Letrozole Taj P harma Letroz ole 2.5 mg, SMPC- Taj Phar ma Stay conne cted to all updated on Letrozole Taj P harmaceuticals Taj pharma ce uticals. Patient I nformation Lea flets, SMPC.

Vaginal bleeding

128 (5. 320 (13 1 (<0 8 (0. 2) .2) .1) 3)

Cataract

(2. 54 0)

(2. 16 (0. 17 (0. 2) 7) 7)

Oedema

164 (6. 160 (6. 3 (0. 1 (<0 7) 5) 1) .1)

Breast pain

(1. 43 5)

(1. 1 (<0 0 8) .1)

Headache

105 (4. 94 3)

(3. 9 (0. 5 (0. 8) 4) 2)

Endometrial 6/19 (0. 57/1 (2. hyperplasia 09 3) 943 3) or cancer4

Osteoporosis 124 (5. 66 1)

(2. 10 (0. 5 (0. 7) 4) 2)

Vaginal irritation

(3. 2 (<0 2 (<0 1) .1) .1)

111 (4. 77 5)

Anorexia

(0. 20 8)

(0. 1 (<0 1 (<0 8) .1) .1)

(1. 24 1)

(1. 0)

Osteopaenia 87

(3. 74 6)

(3. 0 0)

Dizziness / lightheadedness

(3. 84 4)

(3. 1 (<0 6 (0. 4) .1) 2)

Angina 26 pectoris (new worsening, or requiring surgical intervention)

Vomiting

(3. 80 3)

(3. 3 (0. 5 (0. 3) 1) 2)

Cardiac failure 2

(1. 24 2)

(1. 0)

Myocardial infarction2

(1. 12 0)

(0. 5)

Ovarian cyst 11

(0. 18 4)

(0. 4 (0. 4 (0. 7) 2) 2)

Total serum 151/ (8. 57/1 (3. cholesterol> 1843 2) 840 1) 1.5*ULN1

2 (<0 .1)

Thromboem 51 bolic event2

(2. 89 1)

(3. 6)

Constipation 49

(2. 71 0)

(2. 3 (0. 1 (<0 9) 1) .1)

Cerebrovasc 52 ular accident/ Transient ischaemic attack2, 3

(2. 46 1)

(1. 9)

Endometrial 14 proliferation disorders

(0. 86 6)

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. 0 5)

14 (0. 6)

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

Denominator is number of patients not having

Letrozole Ta blets USP 2. 5mg Taj P harma : Uses -P ostme nopausal wome n with hor mone-depe nde nt advance d breast cancer , Side Effects -Hair los s, Interacti ons, Pi ctures, Warnings , Letroz ole Dosage & Rx I nfo | Letroz ole Use s, Side Effect s –Hair loss, Letroz ole : Indications, Side Effe cts- Nausea, diarrhea, vomiting, diz zines s, Warning s, Letrozole - Drug Infor mation - Taj Phar ma, Letrozole dose Taj pharma ceutical s Letrozole intera ctions, Taj Pharma ceuti cal Letrozole contraindications, Letrozole pri ce, Letrozole Taj P harma Letroz ole 2.5 mg, SMPC- Taj Phar ma Stay conne cted to all updated on Letrozole Taj P harmaceuticals Taj pharma ce uticals. Patient I nformation Lea flets, SMPC.

undergone hysterectomy at baseline After standard adjuvant tamoxifen, the following adverse events irrespective of causality were reported significantly more often with letrozole than with placebo – hot flushes (letrozole, 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 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 than for placebo (12.2% versus 6.4%). The incidence of clinical fractures during treatment was significantly higher for letrozole than for placebo patients (10.4% versus 5.8%). In patients who switched to letrozole, newly diagnosed osteoporosis during treatment with letrozole 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 versus tamoxifen monotherapy and in the letrozole-tamoxifen sequential treatment therapy: Table 3 Adjuvant letrozole monotherapy versus tamoxifen monotherapy – adverse events with significant differences Letrozole Taj

Tamoxifen,

Pharma, incidence rate incidence rate N=2448

N=2447

Duri ng treat ment (Med ian 5y)

Any time after randomi zation (Median 8y)

Duri ng treat ment (Med ian 5y)

14.7%

7.2% 11.4%

Bone fracture 10.2 %

Any time after randomi zation (Median 8y)

Osteoporosis 5.1% 5.1%

2.7% 2.7%

Thromboemb 2.1% 3.2% olic events

3.6% 4.6%

Myocardial infarction

1.0% 1.7%

0.5% 1.1%

Endometrial 0.2% 0.4% hyperplasia/en dometrial cancer

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 monotherapy – adverse events with significant differences Letrozole Taj Pharma monother apy

Letrozol e Taj Pharma >tamoxi fen

Tamoxif en>Letroz ole Taj Pharma

N=1535

N=1527 N=1541

5 years

2 yrs-> 2 yrs-> 3y 3y

Bone fractures

10.0%

7.7%*

Endometrial proliferative disorders

0.7%

3.4%** 1.7%*

9.7%

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

Hypercholesterol 52.5% aemia

44.2%* 40.8%*

Hot flushes

41.7%** 43.9%**

37.6%

Vaginal bleeding 6.3%

9.6%** 12.7%**

* Significantly less than with letrozole monotherapy ** Significantly more than with letrozole monotherapy

For skeletal safety data from the adjuvant setting, please refer to Table 2. In the extended adjuvant setting, significantly more patients treated with letrozole 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, compared with 3 years for placebo. Reporting of suspected adverse reactions

Description of selected 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.

Cardiac adverse reactions

4.9 Overdose

In the adjuvant setting, in addition to the data presented in Table 2, the following adverse events were reported for letrozole 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%).

There is no clinical experience of overdosage only isolated cases of overdose with letrozole have been reported. In animal studies, letrozole 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 resulting in lifethreatening symptoms.

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

In the extended adjuvant setting for letrozole (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.

There is no specific antidote to letrozole. In general, supportive care, symptomatic treatment

and frequent monitoring of vital signs are appropriate. 5. PHARMACOLOGICAL PROPERTIES 5.1 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 suppress serum oestrone and oestradiol by 75%, 78% and 78% from baseline respectively. Maximum suppression is achieved in 48-78 hours.

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 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 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 in patients, nor is thyroid function as evaluated by TSH, T4 and T3 uptake test. Adjuvant treatment

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

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 for 5 years; C. tamoxifen for 2 years followed by letrozole for 3 years; D, letrozole for 2 years followed by tamoxifen for 3 years. This study was designed to investigate two primary questions: whether letrozole 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 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 Median follow-up 26 months 60 months Letro zole Taj Phar ma

Tamox HR Letro 1 ifen zole Taj N=400 (95 Phar 7 % ma CI) N=40 P N=40 03 03

Tamox HR 1 ifen N=400 (95 7 % CI) P

Disease 351 -free surviva l (primar y) events (protoc ol definiti on2)

428

0.8 585 1 (0. 70, 0.9 3) 0.0 03

664

0.8 6 (0. 77, 0.9 6) 0.0 08

Overall 166 surviva l (second ary) Numbe r of deaths

192

0.8 330 6 (0. 70, 1.0 6)

374

0.8 7 (0. 75, 1.0 1)

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) longterm update of the efficacy of letrozole monotherapy compared to tamoxifen monotherapy (median duration of adjuvant treatment: 5 years) is presented in Table 6. The Monotherapy Arms Analysis (MAA) longterm update of the efficacy of letrozole 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) Letrozo Tamoxif Hazard P Val le Taj en Ratio1 (95 ue Pharm % CI) N=2459 a N=2463 Disease- 626 free survival events (primary) 2

698

Time to 301 distant metastasi s (secondar y)

342

Overall 393 survival (secondar y) deaths

436

Censored 626 analysis

649

0.87 (0.78, 0.01 0.97)

of DFS3

0.92)

Censored 393 analysis of OS3

0.89 (0.77, 0.08 1.02)

0.83 (0.74,

0.81 (0.70, 0.93)

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 Sequential Treatments Analysis (STA) The Sequential Treatments Analysis (STA) addresses the second primary question of BIG 198, namely whether sequencing of tamoxifen and letrozole 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 as initial endocrine agent (STA switch population) N

0.86 (0.74, 0.06 1.01)

419

Numb Hazar (97.5% Cox er of d confiden model 1 2 events ratio ce P-value interval)

[Letrozol 146 254 e Taj 0 Pharma â&#x2020;&#x2019;] Tamoxif en Letrozol 146 249 e Taj 4

1.03

(0.84, 1.26)

0.72

Letrozole Ta blets USP 2. 5mg Taj P harma : Uses -P ostme nopausal wome n with hor mone-depe nde nt advance d breast cancer , Side Effects -Hair los s, Interacti ons, Pi ctures, Warnings , Letroz ole Dosage & Rx I nfo | Letroz ole Use s, Side Effect s –Hair loss, Letroz ole : Indications, Side Effe cts- Nausea, diarrhea, vomiting, diz zines s, Warning s, Letrozole - Drug Infor mation - Taj Phar ma, Letrozole dose Taj pharma ceutical s Letrozole intera ctions, Taj Pharma ceuti cal Letrozole contraindications, Letrozole pri ce, Letrozole Taj P harma Letroz ole 2.5 mg, SMPC- Taj Phar ma Stay conne cted to all updated on Letrozole Taj P harmaceuticals Taj pharma ce uticals. Patient I nformation Lea flets, SMPC.

Pharma 1 Protocol definition, including second nonbreast primary malignancies, after switch / beyond two years

Table 8 Sequential Treatments Analyses from randomisation (STA-R) of disease-free survival (ITT STA-R population) Letrozole Taj Letrozole Pharma→Tamoxifen Taj Pharma

Number of patients with DFS events (protocol definition)

330

1546

319

Hazard 1.04 (0.85, 1.27) ratio1 (99% CI) Letrozole Taj Tamoxifen2 Pharma→Tamoxifen Number of patients

1540

Number of patients with DFS events (protocol definition)

330

Adjusted by chemotherapy use (yes/no)

626 (40%) patients selectively crossed to letrozole after tamoxifen arm unblinded in 2005

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

1540

2 Adjusted by chemotherapy use

Number of patients

Hazard 0.92 (0.75, 1.12) ratio1 (99% CI)

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 over tamoxifen in reducing the risk of a diseasefree 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 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 or another aromatase inhibitor (12 patients), mostly to complete adjuvant therapy.

1548

353

Table 9: Comparison of letrozole and tamoxifen monotherapy at a median followup of 26 months and of 73 months PCA (median follow-up 26 months)

MAA (median follow-up 73 months)

(PCA ITT

(MAA ITT

Letrozole Ta blets USP 2. 5mg Taj P harma : Uses -P ostme nopausal wome n with hor mone-depe nde nt advance d breast cancer , Side Effects -Hair los s, Interacti ons, Pi ctures, Warnings , Letroz ole Dosage & Rx I nfo | Letroz ole Use s, Side Effect s –Hair loss, Letroz ole : Indications, Side Effe cts- Nausea, diarrhea, vomiting, diz zines s, Warning s, Letrozole - Drug Infor mation - Taj Phar ma, Letrozole dose Taj pharma ceutical s Letrozole intera ctions, Taj Pharma ceuti cal Letrozole contraindications, Letrozole pri ce, Letrozole Taj P harma Letroz ole 2.5 mg, SMPC- Taj Phar ma Stay conne cted to all updated on Letrozole Taj P harmaceuticals Taj pharma ce uticals. Patient I nformation Lea flets, SMPC.

Eve 166 nts

population)

Letroz Tamoxi HR ole fen (95 Taj % Pharm CI) 1 a

N=40 N=400 P val N=40 N=400 P val 03 7 ue 03 7 ue

428

0.81 509

565

0.88

(0.70 , 0.93)

(0.78 , 0.99)

0.00 3

0.03

5- 84.0% 81.4% --year DFS rate

85.6% 82.6% ---

249

0.73 257

298

(0.60 , 0.88)

318

0.82 385

(0.70 , 1.06) 5- 91.1% 89.7% --year OS rate

Eve --nts

0.87 (0.75 , 1.02)

89.3% 88.1% ---

---

509

543

0.85 (0.75 , 0.96)

Censored analysis of OS5 Eve --nts

---

303

338

0.82

432

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

0.85

(0.72 , 1.00)

Distant disease-free survival (DDFS) (secondary endpoint)4 Eve 265 nts

343

(0.70 , 0.96)

Time to distant metastases (TDM) (secondary endpoint)3 Eve 184 nts

0.86 303

Censored analysis of DFS (protocol definition)5

Disease-free survival (DFS) (protocol definition)2 (primary endpoint) Eve 351 nts

192

0.87

Adjusted by stratification factors of randomisation option and use of adjuvant chemotherapy Protocol definition of DFS events: locoregional recurrence, distant metastasis, invasive contralateral breast cancer, second non-breast primary cancer, death from any cause without a prior cancer event 3

(0.70 , 0.97)

(0.76 , 1.00)

Time to distant metastasis. Note: In original analysis, this endpoint was erroneously labelled “distant disease-free survival” (DDFS) 4

Overall survival (OS) (secondary endpoint)

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

Letrozole Ta blets USP 2. 5mg Taj P harma : Uses -P ostme nopausal wome n with hor mone-depe nde nt advance d breast cancer , Side Effects -Hair los s, Interacti ons, Pi ctures, Warnings , Letroz ole Dosage & Rx I nfo | Letroz ole Use s, Side Effect s –Hair loss, Letroz ole : Indications, Side Effe cts- Nausea, diarrhea, vomiting, diz zines s, Warning s, Letrozole - Drug Infor mation - Taj Phar ma, Letrozole dose Taj pharma ceutical s Letrozole intera ctions, Taj Pharma ceuti cal Letrozole contraindications, Letrozole pri ce, Letrozole Taj P harma Letroz ole 2.5 mg, SMPC- Taj Phar ma Stay conne cted to all updated on Letrozole Taj P harmaceuticals Taj pharma ce uticals. Patient I nformation Lea flets, SMPC.

Follow-up times censored at date of selectively crossing from tamoxifen to letrozole, 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

Tamoxife Letrozo Letrozo Tamoxife n le Taj le Taj n 2 Pharma Pharma N=1460

% CI) 3 P valu 0.42 e

0.14

DFS censoring follow-up times at date of selective crossover in tamoxifen arm 2 Event --s

---

HR --(97.5 % CI) 3

160

165

0.76 (0.59, 0.97)

Overall survival (secondary endpoint) Event 72 s

HR 0.85 (0.59, 1.22) (97.5 % CI) 3

0.92 (0.66, 1.28)

OS censoring follow-up times at date of selective crossover in tamoxifen arm 2 Event --s HR --(97.5 % CI) 3

---

0.73 (0.52, 1.02)

N=1463 N=1446 N=1459 HR = Hazard ratio; CI = Confidence interval

Disease-free survival (protocol definition) (primary endpoint)

Event 160 s

178

HR 0.92 (0.72, 1.17) (97.5

160

186

0.85 (0.67, 1.09)

Median follow-up beyond switch approximately 43 months 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

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 and tamoxifen on bone mineral density (BMD) and serum lipid profiles. A total of 262 patients were assigned either letrozole for 5 years or tamoxifen for 2 years followed by letrozole 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 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 arm, 17% in the tamoxifen arm.

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 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 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 was observed regardless of nodal status or prior chemotherapy. There was no significant difference in overall survival: (letrozole 51 deaths; placebo 62; HR 0.82; 95% CI 0.56, 1.19).

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 arm, total cholesterol levels were relatively stable over time, giving a statistically significant difference in favour of tamoxifen at each time point.

The independent Data and Safety Monitoring Committee recommended that women who were disease free in the placebo arm be allowed to switch to letrozole 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 at a median 31 months after completion of adjuvant tamoxifen therapy. Median duration of letrozole after switch was 40 months.

Treatment after standard adjuvant tamoxifen, study CFEM345G MA-17

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 compared with placebo, despite 60% of eligible patients in the placebo arm switching to letrozole after the study was unblinded. In the letrozole 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 arm for both the 2004 and the 2008 analyses, confirming the stability of the data and robust effectiveness of letrozole 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. 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, 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

Updated analysis 1

Median follow-up 28 months

Median follow-up 62 months

Letro Plac HR2 (9 zole ebo 5% Taj CI) Phar ma

N = N = P value N = N = P value 2582 2586 2582 2586 n (%) n

(%)

Disease-free survival (protocol definition)3 Even 92 155 0.58 ts (3.6) (6.0) (0.45, 0.76)

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

0.0000 3 494.4% 89.8 year % DFS rate

0.001

94.4% 91.4 %

Disease-free survival including deaths from any cause Even 122 193 0.62 ts (4.7) (7.5) (0.49, 0.78)

344 402 0.89 (13.3) (15.5 (0.77, ) 1.03)

590.5% 80.8 year % DFS rate

88.8% 86.7 %

Distant metastases Even 57 93 0.61 ts (2.2) (3.6) (0.44, 0.84)

142 169 0.88 (5.5) (6.5) (0.70, 1.10)

Overall survival Deat 51 62 0.82 hs (2.0) (2.4) (0.56, 1.19)

236 232 1.13 (9.1) (9.0) (0.95, 1.36)

Deat --hs 4

236 170 0.78 (9.1) 5 (6.6) (0.64, 6 0.96)

---

Contralateral breast cancer (invasive)

n (%) n Even 15

0.60 7 ( 33

0.64 7 (

Letrozole Ta blets USP 2. 5mg Taj P harma : Uses -P ostme nopausal wome n with hor mone-depe nde nt advance d breast cancer , Side Effects -Hair los s, Interacti ons, Pi ctures, Warnings , Letroz ole Dosage & Rx I nfo | Letroz ole Use s, Side Effect s –Hair loss, Letroz ole : Indications, Side Effe cts- Nausea, diarrhea, vomiting, diz zines s, Warning s, Letrozole - Drug Infor mation - Taj Phar ma, Letrozole dose Taj pharma ceutical s Letrozole intera ctions, Taj Pharma ceuti cal Letrozole contraindications, Letrozole pri ce, Letrozole Taj P harma Letroz ole 2.5 mg, SMPC- Taj Phar ma Stay conne cted to all updated on Letrozole Taj P harmaceuticals Taj pharma ce uticals. Patient I nformation Lea flets, SMPC.

(0.6) (1.0) 0.31, 1.14)

(1.3) (2.0) 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; 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 at a median 31 months after randomisation. The analyses presented here ignore the switching under the ITT principle

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 (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 compared with placebo, despite 60% of the patients in the placebo arm having switched to letrozole. There was no significant difference in overall survival.

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

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

Exploratory analysis, censoring follow-up times at the date of switching (if a switch occurred) – see footnote 1. 5

Median follow-up 62 months

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 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

There was no difference in safety and efficacy between patients aged < 65 versus ≥ 65 years. The updated safety profile of letrozole 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 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 and placebo groups at any time. In the updated analysis, the incidence of cardiovascular events (including cerebrovascular and thromboembolic events) during treatment with letrozole 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, 1.5%; placebo until switch, 0.8%); new or worsening angina (letrozole, 1.4%; placebo until switch, 1.0%); myocardial infarction (letrozole, 1.0%; placebo until switch, 0.7%); thromboembolic events (letrozole, 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 than placebo until switch. The interpretation of safety results should consider that there was an imbalance in the median duration of treatment with letrozole (60 months) compared with placebo (37 months) due to the switch from placebo to letrozole which occurred in approximately 60% of the patients.

This finding was consistently confirmed by ultrasound (letrozole 35% vs tamoxifen 25%, P=0.04) and mammography (letrozole 34% vs tamoxifen 16%, P<0.001). In total 45% of patients in the letrozole 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 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 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 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 â&#x2030;Ľ 24 weeks). The results are summarised in Table 12: Table 12 Results at a median follow-up of 32 months Variable

Statis ic

Letrozole Tamoxifen Taj N=454 Pharma

Neoadjuvant treatment N=453 A double blind trial (P024) was conducted in 337 postmenopausal breast cancer patients randomly allocated either letrozole 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 arm versus 36% for the tamoxifen arm (P<0.001).

Time of Median progression

9.4 months 6.0 months

(95% CI (8.9, 11.6 for median) months) Hazard 0.72 ratio (HR)

(5.4, 6.3 months)

(95% CI for HR)

(0.62, 0.83)

P <0.0001 Objective CR+PR response rate (ORR)

145 (32%) 95 (21%)

(95% CI for rate)

(28, 36%) (17, 25%)

Pre-operative treatment

Odds ratio 1.78 (95% CI for oddsrate)

P=0.53, not significant). The absence of an advantage for letrozole 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.

(1.32, 2.40)

P=0.0002 Time to progression was significantly longer, and response rate significantly higher for letrozole irrespective of whether adjuvant antioestrogen therapy had been given or not. Time to progression was significantly longer for letrozole irrespective of dominant site of disease. Median time to progression was 12.1 months for letrozole and 6.4 months for tamoxifen in patients with soft tissue disease only and median 8.3 months for letrozole 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 to tamoxifen) and 13 months (tamoxifen to letrozole). 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

A double blind trial (P024) was conducted in 337 postmenopausal breast cancer patients randomly allocated either letrozole 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 breastconserving surgery. There were 55% objective responses in the letrozole 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 group who became suitable for and underwent breast-conserving therapy (45% of patients in the letrozole 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 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 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.

Letrozole Ta blets USP 2. 5mg Taj P harma : Uses -P ostme nopausal wome n with hor mone-depe nde nt advance d breast cancer , Side Effects -Hair los s, Interacti ons, Pi ctures, Warnings , Letroz ole Dosage & Rx I nfo | Letroz ole Use s, Side Effect s –Hair loss, Letroz ole : Indications, Side Effe cts- Nausea, diarrhea, vomiting, diz zines s, Warning s, Letrozole - Drug Infor mation - Taj Phar ma, Letrozole dose Taj pharma ceutical s Letrozole intera ctions, Taj Pharma ceuti cal Letrozole contraindications, Letrozole pri ce, Letrozole Taj P harma Letroz ole 2.5 mg, SMPC- Taj Phar ma Stay conne cted to all updated on Letrozole Taj P harmaceuticals Taj pharma ce uticals. Patient I nformation Lea flets, SMPC.

Time to progression was not significantly different between letrozole 2.5mg and megestrol acetate (P=0.07). Statistically significant differences were observed in favour of letrozole 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).

administration of 2.5mg 14C-labelled letrozole, 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

In the second study, the response rate was not significantly different between letrozole 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 in men with breast cancer has not been studied. 5.2 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 may be taken without regard to mealtimes. Distribution Plasma protein binding of letrozole is approximately 60%, mainly to albumin (55%). The concentration of letrozole in erythrocytes is about 80% of that in plasma. After

Metabolic clearance to a pharmacologically inactive carbinol metabolite is the major elimination pathway of letrozole (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 to this metabolite. in vitro, but their individual contributions to letrozole clearance in vivo have not been established. In an interaction study coadministration with cimetidine, which is known to inhibit only the 3A4 isoenzyme, did not result in a decrease in letrozole 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. Within 2 weeks after administration of 2.5mg 14C-labelled letrozole 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

Letrozole Ta blets USP 2. 5mg Taj P harma : Uses -P ostme nopausal wome n with hor mone-depe nde nt advance d breast cancer , Side Effects -Hair los s, Interacti ons, Pi ctures, Warnings , Letroz ole Dosage & Rx I nfo | Letroz ole Use s, Side Effect s –Hair loss, Letroz ole : Indications, Side Effe cts- Nausea, diarrhea, vomiting, diz zines s, Warning s, Letrozole - Drug Infor mation - Taj Phar ma, Letrozole dose Taj pharma ceutical s Letrozole intera ctions, Taj Pharma ceuti cal Letrozole contraindications, Letrozole pri ce, Letrozole Taj P harma Letroz ole 2.5 mg, SMPC- Taj Phar ma Stay conne cted to all updated on Letrozole Taj P harmaceuticals Taj pharma ce uticals. Patient I nformation Lea flets, SMPC.

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 upon daily administration of 2.5mg. Since steady-state levels are maintained over time, it can be concluded that no continuous accumulation of letrozole occurs.

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, 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 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 on CLcr or an impairment of renal function.

Linearity/non-linearity The pharmacokinetics of letrozole 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 (0.15.0mg daily). Special populations Elderly Age had no effect on the pharmacokinetics of letrozole. 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 or the urinary

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 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 should be administered with caution to patients with severe hepatic impairment and after consideration of the risk/benefit in the individual patient.

5.3 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 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 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'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. 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 (i.e. linked

to long-term oestrogen deprivation) or a direct drug effect. The pharmacological effects of letrozole 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's mutagenic potential revealed no indication of any genotoxicity. In the carcinogenicity studies no treatmentrelated 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. 6. PHARMACEUTICAL PARTICULARS 6.1 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, 6.2 Incompatibilities None known. 6.3 Shelf life 2 years 6.4 Special precautions for storage Store in in the original package 6.5 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.

6.6 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 & 1-800222-825) Monday through Saturday 9:00 a.m. to 7:00 p.m. EST E-mail: tajgroup@tajpharma.com