MINT-LETROZOLE TABLET

Canada - English - Health Canada

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Active ingredient:
LETROZOLE
Available from:
MINT PHARMACEUTICALS INC
ATC code:
L02BG04
INN (International Name):
LETROZOLE
Dosage:
2.5MG
Pharmaceutical form:
TABLET
Composition:
LETROZOLE 2.5MG
Administration route:
ORAL
Units in package:
100
Prescription type:
Prescription
Therapeutic area:
ANTINEOPLASTIC AGENTS
Product summary:
Active ingredient group (AIG) number: 0132937001; AHFS: 10:00.00
Authorization status:
APPROVED
Authorization number:
02508109
Authorization date:
2020-11-20

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PRODUCT MONOGRAPH

Pr

MINT-LETROZOLE

(letrozole tablets USP)

2.5 mg

Non-steroidal aromatase inhibitor;

inhibitor of estrogen biosynthesis;

anti-tumour agent

Mint Pharmaceuticals Inc.

6575 Davand Drive

Mississauga, ON, L5T 2M3

Canada

Date of Preparation:

November 17, 2020

Submission Control No

239927

MINT-LETROZOLE Product Monograph

Page 2 of 60

Table of Contents

PART I: HEALTH PROFESSIONAL INFORMATION ....................................................... 3

SUMMARY PRODUCT INFORMATION ............................................................................. 3

INDICATIONS AND CLINICAL USE ................................................................................... 3

CONTRAINDICATIONS ........................................................................................................ 4

WARNINGS AND PRECAUTIONS ....................................................................................... 4

ADVERSE REACTIONS ......................................................................................................... 9

DRUG INTERACTIONS ....................................................................................................... 24

DOSAGE AND ADMINISTRATION ................................................................................... 25

OVERDOSAGE ..................................................................................................................... 26

ACTION AND CLINICAL PHARMACOLOGY ................................................................. 27

STORAGE AND STABILITY ............................................................................................... 29

DOSAGE FORMS, COMPOSITION AND PACKAGING .................................................. 29

PART II: SCIENTIFIC INFORMATION ............................................................................. 30

PHARMACEUTICAL INFORMATION ............................................................................... 30

CLINICAL TRIALS ............................................................................................................... 31

DETAILED PHARMACOLOGY .......................................................................................... 45

TOXICOLOGY ...................................................................................................................... 51

REFERENCES ....................................................................................................................... 55

PART III: CONSUMER INFORMATION............................................................................ 57

MINT-LETROZOLE Product Monograph

Page 3 of 60

Pr

MINT-LETROZOLE

(letrozole tablets USP)

PART I: HEALTH PROFESSIONAL INFORMATION

SUMMARY PRODUCT INFORMATION

Route of

Administration

Pharmaceutical

Form/ Strength

Clinically Relevant Nonmedicinal

Ingredients

Oral

Tablets, 2.5 mg

Lactose Monohydrate

For a complete listing see DOSAGE FORMS,

COMPOSITION AND PACKAGING section.

INDICATIONS AND CLINICAL USE

MINT-LETROZOLE (letrozole) tablets are indicated for:

The adjuvant treatment of postmenopausal women with hormone receptor-positive invasive early

breast cancer.

Clinical effectiveness is based on superior Disease-Free Survival (DFS) compared to

tamoxifen. Overall, survival was not significantly different between the two treatments (see

CLINICAL TRIALS section).

The extended adjuvant treatment of hormone receptor-positive invasive early breast cancer in

postmenopausal women who have received approximately 5 years of prior standard adjuvant

tamoxifen therapy.

Clinical effectiveness is based on superior Disease-Free Survival (DFS) compared to placebo

in the overall study population, at a median follow-up of 28 months. However, overall survival

was not significantly different between the two treatments for the overall population and an

increase in deaths was seen in node-negative patients in the letrozole arm versus the placebo

arm (see WARNINGS AND PRECAUTIONS and CLINICAL TRIALS sections).

First-line therapy in postmenopausal women with advanced breast cancer.

The hormonal treatment of advanced/metastatic breast cancer after relapse or disease progression,

women

with

natural

artificially-induced

postmenopausal

endocrine

status,

have

previously been treated with anti-estrogens.

MINT-LETROZOLE tablets are not indicated in hormone-receptor negative disease

MINT-LETROZOLE Product Monograph

Page 4 of 60

Men

letrozole

with

breast

cancer

been

studied

(see

WARNINGS

PRECAUTIONS section, Sexual Function/Reproduction).

CONTRAINDICATIONS

Patients who are hypersensitive to letrozole, other aromatase inhibitors, or to any ingredient in

the formulation or component of the container. For a complete listing, see the DOSAGE

FORMS, COMPOSITION AND PACKAGING section.

Premenopausal women (see WARNINGS AND PRECAUTIONS section).

Pregnant women (see WARNINGS AND PRECAUTIONS section).

Breast-feeding women (see WARNINGS AND PRECAUTIONS section).

In the absence of clinical experience with the use of letrozole in children or adolescents (under

18 years of age), MINT-LETROZOLE should not be used in these patients.

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

MINT-LETROZOLE (letrozole) should be prescribed and managed by a qualified physician

who is experienced in the use of anti-cancer agents.

MINT-LETROZOLE increases the risk of osteoporosis and bone fractures.

General

No studies on the effects of letrozole on the ability to drive and use machines have been performed.

However, since fatigue, dizziness, and uncommonly somnolence have been observed with the use of

letrozole, caution is advised when driving or operating machinery while such symptoms persist.

Co-administration

MINT-LETROZOLE

with

tamoxifen,

other

anti-estrogens

estrogen-

containing therapies should be avoided as these substances may diminish the efficacy of letrozole. (see

INTERACTIONS section).

The benefit risk assessment should be carefully considered prior to prescribing MINT-LETROZOLE

as extended adjuvant treatment for early breast cancer patients with low risk of recurrence. The risk of

death in the node-negative subgroup was increased by ~35% in patients treated with letrozole

compared to patients receiving placebo at median follow-up of 28 months (HR: 1.36; 95% CI: 0.68,

MINT-LETROZOLE Product Monograph

Page 5 of 60

1.81) and 62 months (HR 1.34; 95% CI: 0.99, 1.81) in the MA-17 study (see CLINICAL TRIALS

section).

Cardiovascular Disease

The use of aromatase inhibitors, including letrozole, may increase the risk of cardiovascular events

(see ADVERSE REACTIONS section).

The overall incidence of cardiovascular events in the BIG 1-98 study at a median treatment duration

of 25 months for letrozole and tamoxifen was 10.1% vs. 11.4%, respectively. A significantly higher

incidence of events was seen for letrozole vs. tamoxifen in cardiac failure (0.8% vs. 0.3%), and a

significantly lower incidence in thromboembolic events (1.2% vs. 3.0%). Numerically (but not

significantly) more cases of myocardial infarction were seen with letrozole (20, 0.5%) than with

tamoxifen (15, 0.4%), as well as hypertension (151, 3.8% vs. 137, 3.4%, respectively), ischemic

cardiovascular events (60, 1.5% vs. 55, 1.4%, respectively), and cerebrovascular events (55, 1.4% vs.

50, 1.3%, respectively); and, reported any time after randomization (irrespective of treatment and

irrespective of a cancer event) at a median follow up of 30 months, fatal cardiac events (18, 0.4% vs.

7, 0.2% respectively) and fatal stroke (7, 0.2% vs. 5, 0.2% respectively).

The overall incidence of cardiovascular events (including cerebrovascular and thromboembolic

events) in the BIG 1-98 study for letrozole and tamoxifen at a median treatment duration of 60 months

and a median follow up of 96 months was 15.3% vs. 16.3%, respectively (a non-significant difference).

During treatment, or within 30 days of stopping treatment, a significantly higher risk of myocardial

infarction was observed for letrozole (1.0%) than for tamoxifen (0.5%) (Risk Ratio, RR: 2.00; 95% CI

1.00, 3.99) while a significantly lower risk of thromboembolic events was seen for letrozole (2.1%)

than for tamoxifen (3.6%) (RR: 0.57; 95% CI 0.41, 0.80). Numerically (but not significantly) more

cases of cardiac failure were seen with letrozole (1.1%) than with tamoxifen (0.6%) (RR 1.80; 95% CI

0.96, 3.37).

In the extended adjuvant setting, in the updated analysis of MA-17, the overall incidence of

cardiovascular events (including cerebrovascular and thromboembolic events) during treatment or

within 30 days of stopping treatment (median duration of treatment of 60 months) was significantly

higher for letrozole (9.8%) than for placebo (7.0%) (RR: 1.39; 95% CI 1.16, 1.67). There was a higher

risk of stroke/transient ischemic attack with letrozole (1.5%) than with placebo (0.8%) (RR 1.86; 95%

CI 1.10, 3.16) and of thromboembolic events with letrozole (0.9%) than with placebo (0.3%) (RR 2.57;

95% CI 1.19, 5.53) (see ADVERSE REACTIONS section).

At a median treatment period of 60 months, the number of deaths during treatment or within 30 days

of stopping treatment was slightly higher in the placebo arm [82 / 2577 (3.2%)] than in the letrozole

arm [77 / 2567 (3.0%)], but the difference was not statistically significant. Of the 19 deaths attributed

to a cardiovascular cause in the placebo arm, 12 occurred in the group of 1026 patients who did not

switch to letrozole after study unblinding, and 7 occurred in the group of 1551 patients who switched

to letrozole. A total of 7 patients died from a stroke – 6 in the letrozole arm and 1 after switching from

placebo to letrozole after study unblinding.

MINT-LETROZOLE Product Monograph

Page 6 of 60

Endocrine and Metabolism

Hyperlipidemia: The use of aromatase inhibitors, including letrozole, may increase lipid levels. In

adjuvant

therapy

trial

(BIG

1-98),

median

treatment

duration

months,

hypercholesterolemia was reported in 52.3% of patients treated with letrozole compared to 28.6% of

patients treated with tamoxifen. In a smaller study (D2407) comparing 2 years of adjuvant treatment

with letrozole or tamoxifen, significant differences were observed between treatments at all time-

points in total cholesterol, LDL cholesterol and the HDL: LDL ratio in favour of tamoxifen. Clinically

relevant changes in total cholesterol at 2 years occurred significantly more often for patients treated

with letrozole (17%) than with tamoxifen (5%). Monitoring of serum cholesterol is advised for patients

treated with MINT-LETROZOLE (see also ADVERSE REACTIONS, ACTION AND CLINICAL

PHARMACOLOGY, CLINICAL TRIALS and DETAILED PHARMACOLOGY sections).

Musculoskeletal

Bone Mineral Density: The use of estrogen lowering agents, including letrozole, may cause a

reduction in bone mineral density (BMD) with a possible consequent increased risk of osteoporosis

and fracture.

During study treatment or within 30 days of stopping treatment in study BIG 1-98 (median treatment

duration of 60 months and a median follow up of 96 months), there was a significantly higher incidence

of osteoporosis in patients treated with letrozole (5.1%) than with tamoxifen (2.7%). Similarly,

significantly more patients receiving letrozole experienced bone fractures (10.2%) than those receiving

tamoxifen (7.2%). During treatment or within 30 days of stopping treatment (median duration of

treatment of 60 months) in study MA-17, there was a significantly higher incidence of osteoporosis in

patients treated with letrozole (12.2%) than with placebo (6.4%). Similarly, significantly more patients

receiving

letrozole

experienced

bone

fractures

(10.4%)

than

those

receiving

placebo

(5.8%).

Therefore,

monitoring

overall

bone

health

recommended

during

treatment

with

MINT-

LETROZOLE. Women should have their osteoporosis risk assessed and managed according to local

clinical

practice

guidelines

(see

also

Special

Populations

Geriatrics,

ADVERSE

REACTIONS, ACTION AND CLINICAL PHARMACOLOGY, CLINICAL TRIALS and

DETAILED PHARMACOLOGY sections).

Arthralgia/arthritis: In the adjuvant setting, a significantly increased risk of arthralgia/arthritis was

reported with letrozole (25.4%) compared to tamoxifen (20.6%) at a median treatment duration of 60

months. In a smaller study (D2407) which reported two years adjuvant treatment, arthralgia/arthritis

was reported in 26% of patients who received letrozole compared with 15% who received tamoxifen

(significant difference).

In the extended adjuvant setting, in the original analysis of the double-blind study, significantly more

patients treated with letrozole (28%) than with placebo (22%) experienced arthralgia/arthritis (median

duration of treatment 24 months).

Myalgia: In the adjuvant setting, the risk of myalgia was not significantly higher for letrozole (9.0%)

than for tamoxifen (8.7%) (study BIG 1-98). In a smaller study (D2407) after two years of adjuvant

therapy, myalgia was reported for 3.8% of patients with letrozole and for 0.8% of patients with

tamoxifen (difference not statistically significant).

MINT-LETROZOLE Product Monograph

Page 7 of 60

In the extended adjuvant setting, myalgia was reported significantly more often for letrozole, (9.5%)

than for placebo (6.7%) (median duration of treatment 24 months).

Sexual Function/Reproduction

Reproductive Toxicology: Letrozole was evaluated for maternal toxicity as well as embryotoxic,

fetotoxic and teratogenic potential in female rats and rabbits. Oral administration of letrozole to

pregnant Sprague-Dawley rats resulted in teratogenicity and maternal toxicity at 0.03 mg / kg (about

1 / 10 the daily maximum recommended human dose (MRHD)), and embryotoxicity and fetotoxicity

at doses ≥0.003 mg / kg (about 1 / 100 the daily MRHD). Teratogenic effects included fetal domed

head and cervical/centrum vertebral fusion. Embryotoxic and fetotoxic effects included intrauterine

mortality, increased resorption, increased postimplantation loss, decreased numbers of live fetuses and

fetal anomalies including absence and shortening of renal papilla, dilation of ureter, edema and

incomplete ossification of frontal skull and metatarsals. In New Zealand White rabbits, letrozole was

embryotoxic at doses ≥ 0.002 mg / kg, and fetotoxic when administered at 0.02 mg / kg (about 1 /

100,000 and 1 / 10,000 the daily MRHD). Fetal anomalies included incomplete ossification of the

skull, sternebrae, and forelegs and hind legs. It is not known whether these effects are an indirect

consequence of the pharmacological activity of letrozole (inhibition of estrogen biosynthesis) or a

direct drug effect.

Fertility: The pharmacological action of letrozole is to reduce estrogen production by aromatase

inhibition. In premenopausal women, the inhibition of estrogen synthesis leads to feedback increases

in gonadotropin (LH, FSH) levels, stimulation of follicular growth, and ovulation induction (see

Monitoring and Laboratory Tests section). In premenopausal women, these feedback mechanisms

increase the risk of inducing ovarian hyperstimulation syndrome. In addition, spontaneous abortions

and congenital anomalies have been reported in infants born to women exposed to letrozole while

pregnant. Letrozole is contraindicated in premenopausal women (see CONTRAINDICATIONS

section).

Based on animal studies, letrozole may impair fertility in males of reproductive potential (See

Reproductive and Developmental Toxicity).

Special Populations

Hepatic Impairment: In a single dose trial with 2.5 mg letrozole in volunteers with impairment of

hepatic function, mean AUC values of the volunteers with moderate hepatic impairment (Child-Pugh

score B) was 37% higher than in normal volunteers, but still within the range seen in volunteers with

normal hepatic function. In a study comparing the pharmacokinetics of letrozole after a single oral

dose of 2.5 mg in eight volunteers with liver cirrhosis and severe non-metastatic hepatic impairment

(Child-Pugh score C) to those in healthy volunteers (N=8), AUC and t

increased by 95% and 187%,

respectively. Breast cancer patients with severe hepatic impairment are thus expected to be exposed to

higher levels of letrozole than patients without severe hepatic dysfunction. Long term effects of this

increased exposure have not been studied.

These results indicate that no dosage adjustment is necessary for breast cancer patients with mild to

moderate hepatic dysfunction. However, since letrozole elimination depends mainly on intrinsic

MINT-LETROZOLE Product Monograph

Page 8 of 60

metabolic clearance, caution is recommended. Insufficient data are available to recommend a dose

adjustment in breast cancer patients with severe non-metastatic hepatic impairment. Therefore, such

patients should be kept under close supervision for adverse events.

Renal Impairment: Pharmacokinetics of a single 2.5 mg letrozole dose were unchanged in a study in

postmenopausal women with varying degrees of renal function (24-hour creatinine clearance = 9-116

mL / min.). In a study in 364 patients with advanced breast cancer there was no significant association

between letrozole plasma levels and calculated CL

(range 22.9 - 211.9 mL / min). No dosage

adjustment is required in patients with CL

10 mL / min. No data are available for patients with CL

≤ 9 mL / min. The potential risks and benefits to such patients should be considered carefully before

prescribing letrozole.

Pregnant Women: Letrozole must not be given to pregnant women (see CONTRAINDICATIONS

section). Isolated cases of birth defects (labial fusion, ambiguous genitalia) have been reported in

infants

born

women

exposed

letrozole

during

pregnancy

(see

also

Sexual

Function/Reproduction - Reproductive Toxicology section).

Women of Child-Bearing Potential: There are no clinical trials conducted in pregnant women with

letrozole.

However,

there

arepost-marketing

reports

spontaneous

abortions

congenital

anomalies in infants of mothers who took letrozole during pregnancy. Letrozole should not be given

to women with premenopausal endocrine status (see CONTRAINDICATIONS section). Women

who are not premenopausal but have the potential to become pregnant, including women who are

perimenopausal or who recently became postmenopausal, should use appropriate contraception

(methods that result in less than 1% pregnancy rates) while being treated with letrozole and for 20 days

after stopping treatment with letrozole (see also Sexual Function/Reproduction-Reproductive

Toxicology section).

Nursing

Women:

Letrozole

must

administered

nursing

mothers

(see

CONTRAINDICATIONS section). It is not known if letrozole is excreted in human milk. There are

no data on the effects of letrozole on the breastfed child or the effects of letrozole on milk production,

however, exposure of letrozole in lactating rats led to impaired fertility of male offspring (See

Reproductive and Developmental Toxicity).

Women of Unclear Menopausal status: Women treated with letrozole whose menopausal status has

not been confirmed are at an increased risk of becoming pregnant and experiencing spontaneous

abortions or congenital anomalies in their infants (see also Sexual Function/Reproduction -

Reproductive Toxicology section). In patients whose menopausal status is unclear or who become

amenorrheic after chemotherapy, luteinising hormone (LH), follicle-stimulating hormone (FSH)

and/or estradiol levels should be measured before initiating treatment with MINT-LETROZOLE and

regularly during the first 6 months of treatment. Appropriate contraception should be used to avoid

pregnancy. Only women of confirmed postmenopausal endocrine status should receive MINT-

LETROZOLE.

Geriatrics

(

65

years

of

age):

There

have

been

age-related

effects

observed

pharmacokinetics of letrozole. No major difference in general safety was observed in patients aged <

65 years versus ≥ 65 years; however, patients ≥ 65 years experienced more bone fractures and more

osteoporosis, irrespective of treatment.

MINT-LETROZOLE Product Monograph

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In the adjuvant setting, more than 8000 postmenopausal women were enrolled in the clinical study

(see CLINICAL TRIALS section). In total, 36% of patients were aged 65 years or older at enrolment,

while 12% were 75 or older. Although more adverse events were generally reported in elderly patients

irrespective of study treatment allocation, the differences between the two treatment groups were

similar to those of younger patients.

In the extended adjuvant study, more than 5000 postmenopausal women were enrolled in the study;

41% of the patients were aged 65 years or older at enrolment, while 12% were 75 or older.

In the extended adjuvant study, after a median follow-up of 28 months, fracture rates recorded any

time after randomization in patients 65 years and older at study enrolment were 7.1% (77 / 1090) in

the letrozole arm compared to 7.5 % (77 / 1033) in the placebo arm; the difference is not statistically

significant (P= 0.74). These results were obtained prior to study unblinding.

In the extended adjuvant study, after a median treatment of 60 months for letrozole, fracture rates

reported during treatment or within 30 days of stopping treatment in patients aged 65 years or older at

enrollment were 11.4% (124 / 1091) for letrozole compared to 7.7% (79 / 1032) for placebo until

switch, and 11.2% (59 / 528) for patients switching from placebo to letrozole. After a median follow-

up of 62 months for letrozole, fracture rates reported any time after randomization in patients aged 65

years or older at enrollment were 15.7% (171 / 1091) for letrozole compared to 11.5% (119 / 1032)

for placebo, and 11.9% (63 / 528) for letrozole after switch.

Monitoring and Laboratory Tests

Plasma Lipids: Women should have their cholesterol levels assessed and managed according to

current clinical practice and guidelines (see Hyperlipidemia section above).

Bone Mineral Density: Monitoring of overall bone health is recommended during treatment with

MINT-LETROZOLE (see Musculoskeletal section above). In patients whose menopausal status is

unclear

become

amenorrheic

after

chemotherapy,

luteinising

hormone

(LH),

follicle-

stimulating hormone (FSH) and/or estradiol levels should be measured before initiating treatment with

MINT-LETROZOLE and regularly during the first 6 months of treatment.

ADVERSE REACTIONS

Adverse Drug Reactions Overview

Letrozole 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 and as extended adjuvant

treatment

women

completed

prior

standard

adjuvant

therapy

with

tamoxifen.

Approximately

third

patients

treated

with

letrozole

metastatic

setting,

approximately 80% of the patients in the adjuvant setting (both letrozole and tamoxifen arms, at a

median treatment duration of 60 months), and extended adjuvant setting (both letrozole and placebo

arms, at a median treatment duration of 60 months) experienced adverse reactions

. The observed

adverse reactions are mainly mild or moderate in nature, and many are associated with estrogen

“Adverse reactions” defined as adverse events (AEs) suspected of being related to study treatment (including AEs with

missing relationship).

MINT-LETROZOLE Product Monograph

Page 10 of 60

deprivation. The updated safety profile of letrozole in both the adjuvant (96 months median follow-

up, median treatment duration 60 months) and the extended adjuvant (62 months median follow-up,

median treatment duration 60 months) settings did not reveal any new adverse reaction and was

consistent with the profile reported at earlier analyses.

Adverse Events in Adjuvant Study BIG 1-98

After reviewing the results of the Primary Core Analysis, at a median treatment duration of 25 months,

the independent Data and Safety Monitoring Committee, observed a difference in incidence in grade

5 myocardial infarctions (9 vs. 2 in the letrozole and tamoxifen arms, respectively) and recommended

that cardiac events and certain other safety data be reviewed. Consequently, a blinded medical review

of more than 2000 patients with pre-specified adverse events (Common Toxicity Criteria, CTC grade

3-5 cardiovascular events, fractures, arthritis/arthralgia, myalgia, any adverse event leading to

discontinuation) or death without a prior cancer event was conducted. This medical review resulted in

a change in the cause of death for 25 patients, 19 of which were reclassified from a cardiac cause to

either “sudden death, cause unknown” (9 cases in letrozole arm, 7 cases in tamoxifen arm) or to “other”

(3 cases in letrozole arm). Some adverse events (such as arthritis/arthralgia and edema) reported in the

primary analysis did not meet the definition of a treatment-emergent adverse event as they were present

at baseline and did not worsen in severity during treatment. Patients in the BIG 1-98 study continued

to be monitored by blinded medical review for cardiovascular, skeletal and endometrial events,

survival status and breast cancer status as well as for events leading to discontinuation of trial

treatment, throughout the trial for median treatment duration of 60 months and a median follow-up of

96 months.

Patients with other non-malignant systemic diseases (cardiovascular, renal, hepatic, lung embolism,

etc.) which would prevent prolonged follow-up were ineligible for enrolment in the BIG 1-98 trial.

Patients with previous DVT (deep vein thrombosis) were only included if medically suitable.

Letrozole was generally well tolerated as adjuvant treatment of early breast cancer. At the primary

analysis (25 months median treatment) approximately 92% vs. 87% of the patients allocated letrozole

or tamoxifen, respectively, experienced adverse events, irrespective of suspected relationship to study

drug. The most frequently reported adverse events in the adjuvant setting were hot flushes (letrozole:

34%, tamoxifen: 38%), arthralgia/arthritis (letrozole: 21%, tamoxifen 13%), night sweats (letrozole:

14%, tamoxifen: 16%) and weight increased (letrozole: 11%, tamoxifen: 13%). Most adverse events

reported (81%) were grade 1 and grade 2 applying the Common Toxicity Criteria Version 2.0.

At a median treatment duration of 60 months and a median follow-up of 96 months, more than 90%

of the patients in each treatment arm experienced adverse events, irrespective of suspected relationship

to study drug. The observed adverse events were mainly mild or moderate in nature (a quarter of the

patients in each treatment arm reported CTC grade 3 or 4 adverse events), and many events were

associated with estrogen deprivation (see Clinical Trial Adverse Drug Reactions section, Table 1).

At a median treatment duration of 60 months, there was a significantly lower risk of endometrial

hyperplasia or cancer with letrozole (0.2%) than with tamoxifen (2.3%) (RR 0.11; 95% CI 0.05, 0.24).

At a median follow up of 96 months, there remained a significantly lower risk of endometrial

hyperplasia or cancer with letrozole (0.4%) than with tamoxifen (2.9%) (RR 0.15; 95% CI 0.08, 0.29).

Apart from the occurrence of endometrial cancer, no major differences in the frequency of second non-

breast primary malignancies were observed (see CLINICAL TRIALS section).

MINT-LETROZOLE Product Monograph

Page 11 of 60

Adverse Events in Extended Adjuvant Study MA-17

Adverse events discussed below were analyzed irrespective of relationship to study treatment.

Letrozole was generally well tolerated as extended adjuvant treatment in women who had received

prior standard adjuvant tamoxifen treatment. After a median treatment duration of 24 months for

letrozole, 87% vs. 84% of the patients on letrozole vs. placebo experienced adverse events.

The most frequent adverse events (CTC grades 1-4), irrespective of suspected relationship to study

treatment, reported during treatment by at least 2% of the patients in any treatment arm are presented

in Table 2. The initial safety results, reported after a median treatment duration of 24 months, were:

hot flushes (letrozole 50% vs. placebo 43%), fatigue (lethargy, asthenia, malaise) (letrozole 34% vs.

placebo 32%), arthralgia/arthritis (letrozole 28% vs. placebo 22%), and sweating (diaphoresis)

(letrozole 24% vs. placebo 22%). Most adverse events reported were grade 1 or grade 2 based on the

Common Toxicity Criteria version 2.0. At a median treatment duration of 60 months for letrozole,

adverse events were reported for more than 90% of the patients in each treatment arm.

When the study was unblinded (at a median follow-up of 28 months), patients randomized placebo

were offered to switch to letrozole. The placebo results beyond 28 months median follow-up are

confounded by the fact that 60% of patients in the placebo arm opted to switch to letrozole, resulting

in different median exposure to treatment (60 months for letrozole, 28 months for placebo generally

and 40 months for letrozole after switch); cardiovascular and skeletal events had a median exposure

of 37 months to placebo/standard care. Dates of onset were recorded for targeted adverse events of

fracture, osteoporosis and cardiovascular events (including cerebrovascular and thromboembolic

events). Many general adverse events were collected by check-lists without dates of onset. In most

cases it cannot be determined if the adverse events in the placebo group occurred before switch to

letrozole or after switch to letrozole. General adverse event data after unblinding of the study should

be interpreted with caution. The majority of these general adverse events, however, were observed

during the first year of treatment (see ADVERSE REACTIONS, Clinical Trial Adverse Drug

Reactions section, Table 2, updated results).

In the updated results, hot flashes were reported significantly more often with letrozole (61%) than

with placebo (58%). Arthralgia/arthritis and myalgia tended to be reported more often with letrozole

(including in patients who switched to letrozole) than with placebo (see also WARNINGS AND

PRECAUTIONS section).

The risk of osteoporosis during treatment or within 30 days of stopping treatment was significantly

higher for letrozole (12.2%) than for placebo until switch (6.4%) (RR 1.90; 95% CI 1.59, 2.27).

Clinical fractures were reported more often for letrozole (10.4%) than for placebo until switch (5.8%)

(RR 1.79; 95% CI 1.48, 2.17). In patients who switched to letrozole, osteoporosis was reported in 5.4%

of patients and fractures in 7.7% of patients.

Irrespective of treatment, patients ≥ 65 years at study entry experienced more bone fractures and more

osteoporosis.

Updated results (median follow-up of 61 months) from the bone mineral density (BMD) substudy

conducted in a subset of 219 patients (117 on letrozole and 102 on placebo, including 77 who switched

from placebo to letrozole) showed that, at 2 years, patients receiving letrozole had a median decrease

of 3.8% compared to baseline in hip BMD compared to 2.0% for patients receiving placebo until

MINT-LETROZOLE Product Monograph

Page 12 of 60

switch (P=0.02). There was no significant difference between treatments in changes in lumbar spine

BMD (see Table 14). All patients should have received vitamin D and calcium supplementation.

Vitamin D was not recorded. Calcium supplementation was reported for 44-66% of patients.

Bisphosphonates were received by approximately a third of the patients treated with letrozole,

compared with a quarter or fewer patients in the placebo arm.

Updated results (median follow-up of 62 months) from the lipid substudy showed no significant

differences between treatments in changes in total cholesterol or in any lipid fraction. The lipid

substudy included 309 patients: 168 allocated letrozole and 141 allocated placebo. In total, 94 (67%)

of the patients in the placebo arm switched to letrozole after the study was unblinded. None of the

patients received lipid-lowering agents at enrolment to the substudy. Lipid-lowering agents were

introduced during treatment for 22% (37 / 168 patients) of the patients in the randomized letrozole

arm, 21% (29 / 141 patients) of the patients in the placebo until switch group, and 15% (14 / 94 patients)

of patients after switching to letrozole (see Table 16).

In the updated analysis of cardiovascular events (including cerebrovascular and thromboembolic

events) the overall incidence of events during treatment or within 30 days of stopping treatment was

significantly higher for letrozole (9.8%) than for placebo until switch (7.8%). The reported frequency

of thromboembolic events was significantly higher for letrozole (0.9%) than for placebo until switch

(0.3%). The reported frequency of stroke/transient ischemic attack was also significantly higher for

letrozole (1.5%) than for placebo until switch (0.8%).

Adverse Events in First-Line and Second-Line Treatment of Advanced Breast Cancer

Letrozole was generally well tolerated across all studies as first-line and second-line treatment for

advanced breast cancer. Approximately one third of patients treated with letrozole in the metastatic

setting experienced adverse reactions

. The most frequently reported adverse reactions in the clinical

trials were hot flushes, nausea and fatigue. The adverse drug reactions reported from clinical trials are

summarized in Tables 4 and 5 for first-line and second-line treatment with letrozole.

Clinical Trial Adverse Drug Reactions

Adverse Events in Adjuvant Treatment of Early Breast Cancer in Postmenopausal Women,

Median Treatment Duration 25 Months

At a median duration of treatment of 25 months, serious adverse events (SAEs) suspected to be related

to study treatment were significantly less frequent with letrozole (204 / 3975 patients, 5.1%) than with

tamoxifen (319 / 3988 patients, 8.0%). Table 1 summarizes adverse events during study treatment

(median duration of treatment 25 months; median follow-up 28 months). The most frequent SAEs

were thromboembolic event (letrozole 0.6%, tamoxifen 1.7%); fracture (letrozole 1.2%, tamoxifen

0.9%); transient ischemic attack (letrozole 0.6%, tamoxifen 0.8%); uterine polyp (letrozole <0.1%,

tamoxifen 0.8%); vaginal hemorrhage (letrozole 0.1%, tamoxifen 0.7%); myocardial infarction

(letrozole 0.3%, tamoxifen 0.3%); endometrial hyperplasia (letrozole 0%, tamoxifen 0.6%) and angina

pectoris (letrozole 0.3%, tamoxifen 0.3%).

Hypercholesterolemia determined from non-fasting laboratory evaluations was defined as an increase

in total serum cholesterol in patients who had baseline values of total serum cholesterol within the

“Adverse reactions” defined as adverse events (AEs) suspected of being related to study treatment (including AEs with

missing relationship).

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Page 13 of 60

normal range, and then subsequently, had an increase in total serum cholesterol of ≥ 1.5* ULN at least

once. The incidence of laboratory evaluated hypercholesterolemia was more frequent in patients

treated with letrozole (5.6%) compared to tamoxifen (1.1%) (see Table 1).

Letrozole treatment was associated with a significantly higher risk of osteoporosis (2.2 vs. 1.2% with

tamoxifen). Bone fractures were significantly higher in the letrozole arm than the tamoxifen arm (6.3

vs. 4.7%, respectively) (see Table 1).

Adverse Events in Adjuvant Treatment of Early Breast Cancer in Postmenopausal Women,

Median Treatment Duration 60 Months

In study BIG 1-98, at a median treatment duration of 60 months and a median follow-up of 96 months

for reporting cardiovascular, skeletal and urogenital/endometrial events for patients receiving letrozole

and tamoxifen, the side effects seen were consistent with the safety profile of the drug.

Certain adverse events were prospectively specified for analysis, based on the known pharmacologic

properties and side effect profiles of the two drugs.

Most adverse events reported (75%) were grade 1 and grade 2 applying the Common Toxicity Criteria

(CTC) Version 2.0 / Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. Table

1 summarizes adverse events during study treatment (median duration of treatment 60 months; median

follow-up 96 months).

At a median duration of follow-up of 96 months, the following adverse events were reported for

letrozole and tamoxifen, respectively: bone fracture (14.7% vs 11.4%), osteoporosis (5.1% vs 2.7%),

thromboembolic

events

(3.2%

4.6%),

myocardial

infarction

(1.7%

1.1%),

endometrial

hyperplasia/endometrial cancer (0.4% vs 2.9%).

At a median duration of follow up of 96 months, serious adverse events suspected of being related to

study treatment were significantly less frequent with letrozole (199 / 2448 patients, 8.1%) than with

tamoxifen (270 / 2447 patients, 11%). The most frequent SAEs were fracture (letrozole 2.2%,

tamoxifen group (1.6%); thromboembolic event (letrozole 0.8%, tamoxifen 1.6%); transient ischemic

attack (letrozole 1.0%, tamoxifen 1.0%); uterine polyp (letrozole <0.1%, tamoxifen 1.2%); myocardial

infarction (letrozole 0.6%, tamoxifen 0.4%); angina pectoris (letrozole 0.5%, tamoxifen 0.4%);

endometrial hyperplasia (letrozole 0%, tamoxifen 0.9%); vaginal hemorrhage

(letrozole 0.2%,

tamoxifen 0.9%); cataract (letrozole 0.4%, tamoxifen 0.3%); ovarian cyst (letrozole 0.1%, tamoxifen

0.4%) and endometrial hypertrophy (letrozole 0%, tamoxifen 0.3%).

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Table 1

Adverse events, irrespective of relationship to study treatment, reported in the adjuvant study, BIG

1-98, in 2% or more patients in any treatment arm (Safety population)

Median duration of treatment

Preferred term

25 months (PCA)

1

26 months (PCA)

60 months (MAA)

96 months (MAA)

Letrozole

N=3975

n (%)

Tamoxifen

N=3988

n (%)

Letrozole

N=2448

n (%)

Tamoxifen

N=2447

n (%)

No. of patients with ≥ 1 AE gr

3659 (92.1)

3463 (86.8)

2311 (94.4)

2215 (90.5)

No. of patients with ≥ 1 AE gr

3657 (92.0)

3460 (86.8)

2309 (94.3)

2212 (90.4)

No. of patients with ≥ 1 AE gr

752 (18.9)

754 (18.9)

636 (26.0)

606 (24.8)

Vascular disorders

Hot flashes *

1367 (34.4)

1534 (38.5)

819 (33.5)

929 (38.0)

Hypertension*

131 (3.3)

121 (3.0)

138 (5.6)

139 (5.7)

Hypertension*

151 (3.8)

137 (3.4)

160 (6.5)

175 (7.2)

Thromboembolic event *

48 (1.2)

119 (3.0)

51 (2.1)

89 (3.6)

Thromboembolic event *

58 (1.5)

128 (3.2)

79 (3.2)

113 (4.6)

General disorders

Fatigue

(lethargy,

malaise,

asthenia) *

348 (8.8)

352 (8.8)

235 (9.6)

250 (10.2)

Edema *

236 (5.9)

231 (5.8)

164 (6.7)

160 (6.5)

Investigations

Weight increased

447 (11.2)

537 (13.5)

317 (12.9)

378 (15.4)

Weight decreased

185 (4.7)

169 (4.2)

140 (5.7)

129 (5.3)

Musculoskeletal and connective

tissue disorders

Arthralgia/arthritis *

804 (20.2)

519(13.0)

621 (25.4)

504 (20.6)

Myalgia *

265 (6.7)

236 (5.9)

221 (9.0)

212 (8.7)

Back pain

137 (3.4)

149 (3.7)

125 (5.1)

136 (5.6)

Bone pain

166 (4.2)

127 (3.2)

123 (5.0)

109 (4.5)

Pain in extremity

150 (3.8)

116 (2.9)

103 (4.2)

79 (3.2)

Osteopenia

41 (1.0)

27 (0.7)

87 (3.6)

76 (3.1)

Osteoporosis *

86 (2.2)

46 (1.2)

126 (5.1)

67 (2.7)

Skin

&

subcutaneous

tissue

disorders

Night sweats *

578 (14.5)

664 (16.6)

356 (14.5)

426 (17.4)

Alopecia

121 (3.0)

113 (2.8)

83 (3.4)

84 (3.4)

Nervous system disorders

Headache *

148 (3.7)

139 (3.5)

105 (4.3)

94 (3.8)

Dizziness/light-headedness *

101 (2.5)

118 (3.0)

84 (3.4)

84 (3.4)

Cerebrovascular accident/

transient ischemic attack *

48 (1.2)

49 (1.2)

51 (2.1)

47 (1.9)

Cerebrovascular accident/

transient ischemic attack *

54 (1.4)

55 (1.4)

74 (3.4)

68 (2.8)

Metabolism

&

nutritional

disorders

Hypercholesterolemia *

1824 (45.9)

795 (19.9)

1280 (52.3)

700 (28.6)

Total cholesterol > 1.5*ULN

174 / 3109

36 / 3131

155 / 1843

71 / 1840

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Median duration of treatment

Preferred term

25 months (PCA)

1

26 months (PCA)

60 months (MAA)

96 months (MAA)

Letrozole

N=3975

n (%)

Tamoxifen

N=3988

n (%)

Letrozole

N=2448

n (%)

Tamoxifen

N=2447

n (%)

(5.6)

(1.1)

(8.4)

(3.9)

Gastrointestinal disorders

Nausea *

394 (9.9)

424 (10.6)

284 (11.6)

277 (11.3)

Constipation *

62 (1.6)

103 (2.6)

49 (2.0)

71 (2.9)

Diarrhea NOS

84 (2.1)

55 (1.4)

64 (2.6)

40 (1.6)

Vomiting *

110 ( 2.8)

107 (2.7)

80 (3.3)

80 (3.3)

Abdominal pain upper

61 (1.5)

50 (1.3)

59 (2.4)

43 (1.8)

Respiratory, thoracic &

mediastinal disorders

Dyspnea

89 (2.2)

90 (2.3)

68 (2.8)

77 (3.1)

Cough

64 (1.6)

82 (2.1)

48 (2.0)

62 (2.5)

Endometrial

hyperplasia/cancer

10 / 3090 (0.3)

62 / 3157 (2.0)

6 / 1909 (0.3)

57 / 1943 (2.9)

Endometrial

hyperplasia/cancer

12 / 3090 (0.4)

69 / 3157 (2.2)

11 / 1909 (0.6)

70 / 1943 (3.6)

Psychiatric disorders

Insomnia

72 (1.8)

60 (1.5)

55 (2.2)

47 (1.9)

Depression

154 (3.9)

163 (4.1)

119 (4.9)

114 (4.7)

Reproductive system & breast

disorders

Endometrial proliferative disorders

14 (0.6)

86 (3.5)

Vaginal haemorrhage *

190 (4.8)

433 (10.9)

129 (5.3)

320 (13.1)

Vaginal irritation

145 (3.6)

124 (3.1)

112 (4.6)

77 (3.1)

Vulvovaginal dryness

111 ( 2.8)

73 (1.8)

88 (3.6)

41 (1.7)

Eye disorders

Cataract

46 (1.2)

38 (1.0)

49 (2.0)

54 (2.2)

Injury, poisoning & procedural

complications

Bone fracture *

252 (6.3)

187 (4.7)

249 (10.2)

175 (7.2)

Bone fracture *

282 ( 7.1)

227 ( 5.7)

361 (14.7)

280 (11.4)

Neoplasms benign, malignant &

unspecified (including cysts &

polyps)

Second malignancies *

54 (2.2)

79 (3.2)

Second malignancies *

3, 6

76 / 4003 ( 1.9)

96 / 4007 ( 2.4)

129 (5.3)

150 ( 6.1)

PCA = Primary Core Analysis; MAA = Monotherapy Arms Analysis NOS = Not otherwise specified; ULN = Upper

limit of normal

AEs marked * are specific target events consisting of multiple MedDRA terms

Note: Cardiovascular, skeletal, endometrial events and second malignancies were collected life-long.

Based on PCA 120-day safety update

During study treatment + 30 days. Median duration of treatment for PCA 120-day safety update 25 months; for MAA

median is 60 months

Any time after randomization. Median follow-up 28 months for PCA 120-day safety update; median 96 months for

Excluding women who had undergone hysterectomy prior to study enrollment

Denominator is patients who had baseline total cholesterol ≤1.5*ULN

Second malignancies included as DFS events – based on original PCA analysis, median duration of follow-up 26

months; no breakdown of DFS events conducted in 120-day safety update analysis

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Deaths during study treatment or within 30 days of stopping treatment due to any cause were reported

for 2.2% patients in each treatment arm. Deaths due to cardiac cause were infrequent in both treatment

arms (9 patients in the letrozole arm versus 7 patients in the tamoxifen arm). Myocardial infarction

was reported as cause of death for 4 patients (0.2%) treated with letrozole compared to 1 patient

(<0.1%) in the tamoxifen arm. Death from cardiac failure was reported for 3 patients treated with

letrozole and for 3 patients treated with tamoxifen. Deaths related to stroke/CVA were observed in 9

patients

letrozole,

tamoxifen).

There

were

major

differences

regarding

fatal

thromboembolic events and deaths related to second non-breast malignancy.

In the adjuvant setting, total cholesterol levels remained relatively stable over 6 years (median 0 to

5.5% decrease) in the letrozole arm whereas there was an expected decrease (median 10-14% decrease)

over 5 years observed in the tamoxifen arm. Hypercholesterolemia recorded at least once as a check-

listed adverse event was more frequent in patients treated with letrozole (52%) compared with

tamoxifen (29%). Hypercholesterolemia determined from non-fasting laboratory evaluations was

defined as an increase in total serum cholesterol in patients who had baseline values of total serum

cholesterol within the normal range, and then subsequently, had an increase in total serum cholesterol

of ≥ 1.5* ULN at least once. The incidence of laboratory evaluated hypercholesterolemia was more

frequent in patients treated with letrozole (8.4%) than with tamoxifen (3.9%) (see Table 1).

See Adverse Events in Extended Adjuvant Treatment below for data with respect to placebo.

Adverse Events in Extended Adjuvant Treatment of Early Breast Cancer in Postmenopausal

Women, Median Treatment Duration 24 Months

At a median follow-up of 28 months, the incidence of cardiovascular events from the MA-17 core

study was not significantly different between patients who received letrozole 6.8% (175) and those

who received placebo 6.5% (167). The most frequent cardiovascular events were: new or worsening

angina (1.4% in the letrozole arm vs. 1.0% in the placebo arm), myocardial infarction (0.6% in the

letrozole arm vs. 0.7% in the placebo arm), and stroke/transient ischemic attack (0.9% in the letrozole

arm vs. 0.9% in the placebo arm). These results were obtained prior to unblinding the study.

At a median follow-up of 28 months, the incidence of osteoporosis any time after randomization was

higher in patients who received letrozole (6.9%) than in patients who received placebo (5.5%)

(P=0.04). The incidence of clinical fractures any time after randomization was slightly (non-

significantly) higher in patients who received letrozole than in those who received placebo (5.9% vs.

5.5% respectively). Fracture rates any time after randomization in patients with a history of

osteoporosis were 10.6% in the letrozole arm compared to 7.3% in the placebo arm; the difference is

not statistically significant. In patients with a previous history of fractures, fracture rates were 12.2%

in the letrozole arm compared to 8.7% in the placebo arm; the difference is not statistically significant.

These results were obtained prior to study unblinding.

Adverse Events in Extended Adjuvant Treatment of Early Breast Cancer in Postmenopausal

Women, Median Treatment Duration 60 Months

Table 2 summarizes general adverse events reported in at least 2% of the patients in either treatment

arm (collected during treatment) (median treatment duration 24 months for letrozole and placebo and

60 months for letrozole); table 3 summarizes cardiovascular and skeletal events collected life-long

MINT-LETROZOLE Product Monograph

Page 17 of 60

(including after discontinuation or completion of study treatment) in the study of letrozole versus

placebo as extended adjuvant therapy.

The median duration of extended adjuvant treatment was 60 months for patients receiving letrozole

and 28 months for placebo. The median duration of letrozole treatment was 60 months (median follow-

up 62 months) and the median duration of placebo/standard care until switch was 37 months (same

median follow-up). The median duration of letrozole treatment after switch was 40 months (median

follow-up 42 months). Most adverse events reported were grade 1 or grade 2 based on the Common

Toxicity Criteria Version 2.0.

Table 2

Adverse events, irrespective of relationship to study treatment, reported at a frequency of 2% or

greater in any treatment arm in study MA-17 (Safety population)

Median treatment duration

Preferred term

24 months

1

60 months

Letrozole

N=2567

2

n (%)

Letrozole

N=2563

n (%)

Placebo

N=2573

n (%)

No. of patients with ≥ 1 grade 1-5 AE

2234 (87.2)

2174 (84.5)

2431 (93.7)

No. of patients with ≥ 1 grade 1-4 AE

2229 (87.0)

2170 (84.3)

2429 (94.6)

No. of patients with ≥1 grade 3-4 AE

419 (16.3)

389 (15.1)

672 (26.2)

Vascular disorders

Hot flashes *

1273 (49.7)

1114 (43.3)

1564 (60.9)

Hypertension NOS

122 (4.8)

110 (4.3)

205 (8.0)

General disorders

Fatigue (lethargy, malaise, asthenia) *

867 (33.8)

832 (32.3)

1202 (46.8)

Edema *

535 (20.9)

487 (18.9)

715 (27.9)

Chest pain

59 (2.3)

69 (2.7)

87 (3.4)

Investigations

Weight decreased

52 (2.0)

38 (1.5)

85 (3.3)

Weight increased

55 (2.1)

51 (2.0)

75 (2.9)

Musculoskeletal and connective tissue disorders

Arthralgia/arthritis *

709 (27.7)

570 (22.2)

1065 (41.5)

Myalgia *

243 (9.5)

173 (6.7)

455 (17.7)

Bone pain

70 (2.7)

81 (3.1)

198 (7.7)

Back pain

129 (5.0)

112 (4.4)

170 (6.6)

Pain in extremity

70 (2.7)

62 (2.4)

93 (3.6)

Osteopenia

14 (0.5)

9 (0.3)

55 (2.1)

Skin & subcutaneous tissue disorders

Sweating (diaphoresis) *

624 (24.3)

578 (22.5)

890 (34.7)

Alopecia

112 (4.4)

83 (3.2)

161 (6.3)

Dermatitis exfoliative NOS

34 (1.3)

43 (1.7)

60 (2.3)

Rash NOS

41 (1.6)

53 (2.1)

58 (2.3)

Dry skin

42 (1.6)

49 (1.9)

62 (2.4)

Nervous system disorders

Headache *

525 (20.5)

512 (19.9)

810 (31.6)

Dizziness/light-headedness *

365 (14.2)

344 (13.4)

568 (22.1)

Memory impairment

35 (1.4)

34 (1.3)

56 (2.2)

Metabolism and nutrition disorders

Hypercholesterolemia *

401 (15.6)

399 (15.5)

598 (23.3)

Hypergylcemia NOS

48 (1.9)

40 (1.6)

84 (3.3)

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Median treatment duration

Preferred term

24 months

1

60 months

Letrozole

N=2567

2

n (%)

Letrozole

N=2563

n (%)

Placebo

N=2573

n (%)

Gastrointestinal disorders

Nausea *

275 (10.7)

278 (10.8)

465 (18.1)

Constipation *

290 (11.3)

304 (11.8)

449 (17.5)

Diarrhea NOS

128 (5.0)

143 (5.3)

208 (8.1)

Anorexia *

119 (4.6)

96 (3.7)

195 (7.6)

Dyspepsia

72 (2.8)

82 (3.2)

136 (5.3)

Vomiting *

75 (2.9)

83 (3.2)

126 (4.9)

Abdominal pain NOS

74 (2.9)

86 (3.3)

116 (4.5)

Flatulence

47 (1.8)

49 (1.9)

57 (2.2)

Respiratory, thoracic and mediastinal disorders

Dyspnea

140 (5.5)

137 (5.3)

228 (8.9)

Cough

96 (3.7)

94 (3.7)

156 (6.1)

Psychiatric disorders

Insomnia

149 (5.8)

120 (4.7)

232 (9.0)

Depression

115 (4.5)

104 (4.0)

174 (6.8)

Anxiety

78 (3.0)

73 (2.8)

111 (4.3)

Reproductive system and breast disorders

Vaginal haemorrhage *

145 (5.7)

204 (7.9)

195 (7.6)

Vulvovaginal dryness

137 (5.3)

127 (4.9)

200 (7.8)

Renal and urinary disorders

Pollakiuria

47 (1.8)

38 (1.5)

69 (2.7)

Incontinence NOS

45 (1.8)

32 (1.2)

61 (2.4)

Infections and infestations

Infection NOS

41 (1.6)

32 (1.2)

61 (2.4)

AEs after the first month of treatment

Additional patients documented as having taken treatment for at least 1 day

NOS = Not otherwise specified

*Specific events that may include multiple MedDRA preferred terms

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Table 3

Cardiovascular and skeletal events in the extended adjuvant study, MA-17 (Safety population)

Reporting period / event

Initial analysis

Update

Letrozole

N=2567

1

n (%)

Letrozole

N=2563

n (%)

Placebo

N=2573

n (%)

During treatment or within 30 days of stopping treatment

Median duration of treatment

24 months

24 months

60 months

Cardiovascular events

143 (5.6)

139 (5.4)

251 (9.8)

Myocardial infarction

11 (0.4)

14 (0.5)

25 (1.0)

New or worsening angina

30 (1.2)

23 (0.9)

37 (1.4)

Angina requiring surgery

6 (0.2)

14 (0.5)

21 (0.8)

Thromboembolic event

10 (0.4)

6 (0.2)

23 (0.9)

Stroke/transient ischemic attack

18 (0.7)

15 (0.6)

39 (1.5)

Other

94 (3.7)

83 (3.2)

156 (6.1)

CNS/Cerebrovascular

3 (0.1)

2 (0.1)

8 (0.3)

Cardiac

24 (0.9)

20 (0.8)

53 (2.1)

Arrhythmia

40 (1.6)

48 (1.9)

70 (2.7)

Vascular

13 (0.5)

6 (0.2)

22 (0.9)

Valvular

5 (0.2)

2 (0.1)

7 (0.3)

Other

15 (0.6)

10 (0.4)

8 (0.3)

Skeletal events

Fracture (clinical)

134 (5.2)

117 (4.5)

266 (10.4)

Patients with 1 fracture

115 (4.5)

103 (4.0)

222 (8.6)

Patients with > 1 fracture

19 (0.7)

14 (0.5)

44 (1.7)

Osteoporosis

164 (6.4)

126 (4.9)

314 (12.2)

Any time after randomization

Median duration of follow-up

28 months

28 months

62 months

Cardiovascular events

175 (6.8)

167 (6.5)

369 (14.4)

Myocardial infarction

15 (0.6)

17 (0.7)

44 (1.7)

New or worsening angina

37 (1.4)

25 (1.0)

51 (2.0)

Angina requiring surgery

14 (0.5)

18 (0.7)

32 (1.2)

Thromboembolic event

12 (0.5)

11 (0.4)

34 (1.3)

Stroke/transient ischemic attack

23 (0.9)

22 (0.9)

68 (2.6)

Other

110 (4.3)

105 (4.1)

227 (8.8)

CNS/Cerebrovascular

3 (0.1)

3 (0.1)

10 (0.4)

Cardiac

31 (1.2)

27 (1.0)

76 (3.0)

Arrhythmia

50 (2.0)

58 (2.3)

104 (4.1)

Vascular

14 (0.5)

8 (0.3)

31 (1.2)

Valvular

5 (0.2)

2 (0.1)

11 (0.4)

Other

16 (0.6)

13 (0.5)

20 (0.8)

Skeletal events

Fracture (clinical)

152 (5.9)

142 (5.5)

341 (13.3)

Patients with 1 fracture

129 (5.0)

121 (4.7)

276 (10.8)

Patients with > 1 fracture

23 (0.9)

21 (0.8)

65 (2.5)

Osteoporosis

176 (6.9)

141 (5.5)

373 (14.5)

Additional patients documented as having taken study treatment

Note: Patients are counted once in each row but may have multiple events, so that numbers are not additive

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The most frequent adverse events irrespective of drug relationship (cut-off frequency of at least 2%)

reported in the 1251 / 2567 (49%) patients randomized letrozole who completed 5 years of treatment

were: hot flashes (823, 66%), asthenia (610, 49%), arthralgia (514, 41%), increased sweating (490,

39%), headache (425, 34%), hypercholesterolemia (367, 29%), edema NOS (337, 27%), dizziness

(294, 23%) and myalgia (236, 19%).

The incidence of reported osteoporosis in the extended adjuvant study was significantly higher in

patients who received letrozole (during treatment: 12.2%; any time after randomization: 14.5%) than

in those who received placebo/no treatment (during treatment: 6.4%; any time after randomization:

7.8%). Amongst women who switched from placebo to letrozole, osteoporosis was reported by 5.4%

during treatment (median duration of treatment after switching was 40 months) and 5.9% any time

after randomization. During treatment, the incidence of clinical fractures was 10.4% for letrozole

compared to 5.8% for placebo. Any time after randomization, the incidence increased to 13.3% for

patients in the letrozole arm and to 7.8% for patients in the placebo arm. Amongst patients who

switched from placebo to letrozole, clinical fractures were reported for 7.7% during treatment (median

duration of letrozole after switching was 40 months), rising to 8.3% if the post treatment follow-up

was included.

Irrespective of treatment, patients with a history of osteoporosis reported fractures at a higher rate than

patients without such a history, as did patients with a history of bone fractures – e.g. during treatment

or within 30 days of stopping treatment, fractures were reported for letrozole in 16% of patients with

a history of osteoporosis and 17% with a history of previous fractures compared with 9.5% (history of

osteoporosis) and 9.9% (history of fractures) for placebo; letrozole 9.6%, placebo 5.3% (no history of

osteoporosis); letrozole 9.5%, placebo 5.2% (no previous fractures). Amongst patients who switched

from placebo to letrozole, fractures were reported by 10% of patients with a history of osteoporosis,

7.4% for patients with no such history, and by 14.7% of patients who had previously experienced bone

fractures compared with 6.8% for those without a history of fractures.

Results (median duration of letrozole treatment was 60 months) from the MA-17 bone sub-study

demonstrated that, at 2 years, compared to baseline, patients receiving letrozole had a median decrease

(versus baseline) of 3.8% versus 2.0% (P=0.022) for placebo in total hip bone mineral density.

Although there was a similar reduction in lumbar spine (L2-L4) bone mineral density at 2 years

(letrozole median 3.8% decrease versus 2.0% for placebo), this difference was not statistically

significant.

During study treatment or within 30 days of stopping treatment (median duration of treatment 60

months for letrozole and 28 months for placebo), the incidence of cardiovascular events overall in

study MA-17 was significantly higher for letrozole (9.8%) than for placebo (7.0%). Most of the

difference

accounted

cerebrovascular

events

(letrozole

1.5%

placebo

0.8%),

thromboembolic events (letrozole 0.9% vs. placebo 0.3%) and “other” cardiovascular events (letrozole

6.1% vs. placebo 4.2%). At any time after randomization (i.e. including the post-treatment follow-up

period, median duration of follow-up 62 months for letrozole, 37 months for placebo), the overall

incidence of cardiovascular events was higher in the letrozole arm (14.4%) than in the placebo arm

(9.8%). In the letrozole arm, there was a significantly higher reported incidence of myocardial

infarction (letrozole 1.7% vs. placebo 1.0%), thromboembolic events (letrozole 1.3% vs. placebo

0.7%), stroke/transient ischemic attack (letrozole 8.8% vs. placebo 6.3%) (see Table 3).

MINT-LETROZOLE Product Monograph

Page 21 of 60

There was no significant difference between treatments in the overall number of patients dying during

treatment or within 30 days of stopping treatment (letrozole 3.0% vs. placebo 3.2%; placebo not

switching 4.5%; letrozole after switching 2.3%). There were, however, differences in cause of death:

approximately twice as many patients who had received placebo died of the underlying breast cancer

(placebo not switching 1.3% vs. letrozole 0.7% and letrozole after switching 0.6%); fatal strokes

occurred in 6 cases (0.2%) in the letrozole randomized arm and in 1 case (0.1%) after switching to

letrozole (0 cases for placebo).

During treatment or within 30 days of stopping treatment (median duration of treatment 60 months),

in the randomized letrozole arm, 1.7% of patients experienced more than one fracture, compared with

1.3% in the placebo until switch group and 2.3% in the letrozole after switch from placebo group. Of

the 120 / 1551 patients who experienced a fracture after switching to letrozole from placebo, 76

patients had previously experienced a fracture on placebo (and 7 of these patients had experienced

more than one fracture on placebo).

In the 77 patients who switched from placebo to letrozole, BMD in the hip and lumbar spine showed

a median decrease from baseline of approximately 1-3% at each of the first, second, third and fourth

annual visits after switching to letrozole. The median treatment duration in each group was 60 months

for letrozole, 22 months for placebo until switch and 43 months for letrozole after switch from placebo

respectively.

Results from the MA-17 lipid sub-study (median duration of letrozole was 60 months) did not show

significant differences between the letrozole and placebo groups. Patients in the sub-study had no prior

history of hyperlipidemia. As per normal clinical practice and guidelines for postmenopausal women,

physicians should continue their routine monitoring of lipid levels on a regular basis.

Adverse Events in First-Line Treatment

Overall, 455 postmenopausal women with locally advanced or metastatic breast cancer were treated

with letrozole in a well-controlled clinical trial and the median time of exposure was 11 months. The

incidence of adverse events was similar for letrozole and tamoxifen. The most frequently reported

adverse

events

were

bone

pain,

flushes,

back

pain,

nausea,

arthralgia

dyspnea.

Discontinuations for adverse events other than progression of tumour occurred in 10/455 (2%) of

patients on letrozole and in 15 / 455 (3%) of patients on tamoxifen.

Table 4 below shows the frequency of adverse reactions considered possibly related to trial drug that

have been reported with an incidence of more than 2.0% (whether for letrozole or for tamoxifen) in a

well-controlled clinical study with letrozole (2.5 mg daily) and tamoxifen (20 mg daily).

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Table 4

Adverse Reaction

System Organ Class / Preferred term

Letrozole

N= 455

(%)

Tamoxifen

N=455

(%)

Gastrointestinal Disorders

Nausea

Constipation

Vomiting

General Disorders and Administration Site Conditions

Fatigue

Metabolism and Nutrition Disorders

Decreased Appetite

Increased Appetite

Nervous System Disorders

Headache

Skin and Subcutaneous Tissue Disorders

Alopecia

Hyperhidrosis

Vascular Disorders

Hot Flush

16.7

14.3

Thromboembolic Events

Adverse Events in Second-Line Treatment

Table 5 below shows in decreasing order of frequency the adverse reactions – considered possibly

related to trial drug according to the investigator - that have been reported with an incidence of more

than 1.0% for letrozole in a controlled clinical trial with letrozole (2.5 mg daily) and megestrol acetate

(160 mg daily) for up to 33 months.

Table 5

Adverse Reaction

Letrozole

% (N=174)

Megestrol Acetate

% (N=189)

Headache

Nausea

Peripheral edema

Fatigue

Hot flush

Hair thinning

Rash

Vomiting

Dyspepsia

Weight increase

Musculoskeletal pain

Anorexia

Vaginal haemorrhage

Leukorrhea

Constipation

Dizziness

MINT-LETROZOLE Product Monograph

Page 23 of 60

Increased appetite

Hyperhidrosis

Including: erythematous rash, maculopapular rash.

Including: arm pain, back pain, leg pain, skeletal pain.

There were no differences in the incidence and severity of adverse reactions in patients <55 years, 55-

69 years and ≥70 years.

Post-Market Adverse Drug Reactions

Other adverse drug reactions are presented below (Table 6); some of them are reported spontaneously.

Because spontaneous events are reported voluntarily from a population of uncertain size, it is not

always possible to reliably estimate their frequency or clearly establish a causal relationship to

letrozole exposure.

Table 6 Other adverse drug reactions reported in patients receiving letrozole

Blood and lymphatic system

disorders

Leukopenia

Cardiac disorders

Palpitations, tachycardia, ischemic cardiac events (including

new or worsening angina, angina requiring surgery, myocardial

infarction and myocardial ischemia), atrial fibrillation, atrial

flutter, cardiac failure

Eye disorders

Cataract, eye irritation, blurred vision

Gastrointestinal disorders

Dyspepsia, abdominal pain, stomatitis, dry mouth

General disorders and administration

site conditions

Pyrexia, mucosal dryness, thirst

Hepato-biliary disorders

Increased

hepatic

enzymes,

hyperbilirubinaemia,

jaundice,

hepatitis

Immune system disorders

Anaphylactic reaction

Infections and infestations

Injury, poisoning and procedural

complications

Urinary tract infection

Fall

Investigations

Weight

increased,

weight

decreased,

increase

aminotransferases

Musculoskeletal and connective

tissue disorders

Myalgia, osteoporosis, bone fractures, trigger finger

Neoplasms benign, malignant

and unspecified (incl. cysts and

polyps)

Tumour pain

Nervous system disorders

Somnolence, memory impairment, dysaesthesia (including

paresthesia,

hypoesthesia),

dysgeusia,

cerebrovascular

accident, carpal tunnel syndrome

Psychiatric disorders

Anxiety (including nervousness), irritability

Renal and urinary disorders

Pollakiuria

Reproductive system and breast

disorders

Vaginal discharge, breast pain

Respiratory, thoracic and mediastinal

disorders

Cough

MINT-LETROZOLE Product Monograph

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Skin and subcutaneous tissue

disorders

Rash (including erythematous, maculopapular, psoriaform and

vesicular

rash),

pruritis,

skin,

urticaria,

angioedema,

erythema multiforme, toxic epidermal necrolysis

Vascular disorders

Thrombophlebitis

(including

superficial

deep

vein

thrombophlebitis), hypertension, pulmonary embolism, arterial

thrombosis, cerebral infarction

In some post-marketing cases, fall was reported as a consequence of other adverse events such as dizziness and vertigo

Tumour pain was reported only in the metastatic setting

DRUG INTERACTIONS

Drug-Drug Interactions

Drugs that may alter letrozole serum concentrations: Letrozole is mainly metabolized in the liver

and the cytochrome P450 enzymes CYP3A4 and CYP2A6 mediate the metabolic clearance of

letrozole. Therefore, the systemic elimination of letrozole may be influenced by drugs known to affect

the CYP3A4 and CYP2A6 (see ACTION AND CLINICAL PHARMACOLOGY section).

A clinical interaction study with cimetidine (a non-specific inhibitor of CYP2C19 and CYP3A4)

indicated that co-administration with letrozole does not result in a clinically significant drug

interaction.

Drugs that may increase letrozole serum concentrations

Inhibitors of CYP3A4 and CYP2A6 activities could decrease the metabolism of letrozole and thereby

increase plasma concentrations of letrozole. The concomitant administration of strong CYP3A4

inhibitors (e.g. ketoconazole, itraconazole, voriconazole, ritonavir, clarithromycin, and telithromycin)

or strong CYP2A6 inhibitors (e.g. methoxsalen) may increase exposure to letrozole. Therefore, caution

is recommended for patients administered strong CYP3A4 and CYP2A6 inhibitors.

Drugs that may decrease letrozole serum concentrations

Inducers of CYP3A4 activity could increase the metabolism of letrozole and thereby decrease plasma

concentrations of letrozole. The concomitant administration of medications that induce CYP3A4 (e.g.

phenytoin, rifampicin, carbamazepine, phenobarbital, and St. John’s Wort) may reduce exposure to

letrozole. Therefore caution is recommended in patients for whom strong CYP3A4 inducers are

administered. No drug inducer is known for CYP2A6.

Co-administration of letrozole and tamoxifen 20 mg daily resulted in a mean reduction of letrozole

plasma levels of 37.6%. The mechanism of this interaction is unknown. (see Use with Other

Anticancer Agents section).

Drugs that may have their systemic serum concentrations altered by letrozole: In vitro, letrozole

inhibits the cytochrome P450 isoenzymes CYP2A6 and, moderately, CYP2C19, but the clinical

relevance is unknown. Medicinal products with a narrow therapeutic index that are substrates for

CYP2C19 (e.g. phenytoin, clopidogrel) should be used with caution when administered concomitantly

with letrozole. No substrate with a narrow therapeutic index is known for CYP2A6.

A clinical interaction study with warfarin (a CYP2C9 substrate) indicated that co-administration with

letrozole does not result in a clinically significant drug interaction.

MINT-LETROZOLE Product Monograph

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A review of the clinical trial database indicated no evidence of other clinically relevant interactions

with other commonly prescribed drugs.

Use with Other Anticancer Agents: Co-administration of letrozole and tamoxifen 20 mg daily

resulted in a reduction of letrozole plasma levels by 38% on average. The clinical significance of this

finding has not been explored in prospective clinical trials.

There is no clinical experience to date on the use of letrozole in combination with other anti-cancer

agents.

Drug-Food Interactions

Food slightly decreases the rate of absorption (median t

1 hour fasted vs. 2 hours fed and mean C

129±20.3 nmol / L fasted vs. 98.7±18.6 nmol / L fed), but the extent of absorption (area under the

curve (AUC)) remains unchanged. This minor effect on absorption rate is not considered to be of

clinical relevance and therefore letrozole may be taken with or without food.

Drug-Laboratory Interactions

No clinically significant changes in the results of clinical laboratory tests have been observed.

DOSAGE AND ADMINISTRATION

Dosing Considerations

Insufficient data available to recommend dose adjustment in patients with severe hepatic impairment

(see Hepatic impairment section).

Recommended Dose and Dosage Adjustment

Adults: The recommended dose is one 2.5 mg tablet once daily.

In the adjuvant setting, the intended duration of treatment is 5 years.

In the extended adjuvant setting, treatment with MINT-LETROZOLE (letrozole) are intended for 5

years and should be initiated within 3 months of completion of approximately 5 years of prior standard

adjuvant tamoxifen therapy.

In the first- and second-line advanced breast cancer settings, MINT-LETROZOLE treatment should

continue until further tumour progression is evident.

MINT-LETROZOLE Product Monograph

Page 26 of 60

Special populations

Hepatic impairment: No dose adjustment of MINT-LETROZOLE is required for patients with mild

to moderate hepatic impairment (Child-Pugh score A or B). Insufficient data are available to

recommend a dose adjustment in breast cancer patients with severe hepatic impairment (Child-Pugh

C). Therefore, patients with severe hepatic impairment should be kept under close supervision for

adverse events (see WARNINGS AND PRECAUTIONS section).

Renal impairment: No dosage adjustment is required for patients with renal impairment with a

creatinine clearance (CLcr) ≥10 mL / min. Insufficient data are available in cases of renal impairment

with CLcr <10 mL / min. (see WARNINGS AND PRECAUTIONS section).

Pediatrics (< 18 years of age): MINT-LETROZOLE is contraindicated in children and adolescents.

The safety and efficacy of letrozole in children and adolescents (under 18 years of age) have not been

established.

Geriatrics (

65 years of age):: No dose adjustment is required for elderly patients.

Missed Dose

The missed dose should be taken as soon as the patient remembers. However, if it is almost time for

the next dose, 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 at 2.5 mg or above, over-

proportionality

systemic

exposure

observed

(see

ACTION

CLINICAL

PHARMACOLOGY section).

Administration

MINT-LETROZOLE should be taken orally and can be taken with or without food (see Drug-Food

Interactions section)

OVERDOSAGE

For management of a suspected drug overdose, contact your regional Poison Control Centre

immediately.

Isolated cases of letrozole overdose have been reported. In these instances, the highest single dose

ingested was 125 mg or 50 tablets. While no serious adverse events were reported in these cases,

because of the limited data available, no firm recommendations for treatment can be made. In single

dose studies the highest dose used was 30 mg, which was well tolerated; in multiple dose trials, the

largest dose of 10 mg was well tolerated.

In general, treatment of overdose with letrozole should be supportive and symptomatic. Vital signs

should be monitored in all patients. Complete blood count (CBC) and liver function tests should be

monitored in symptomatic patients. Fluid and electrolyte status should be monitored in patients with

significant vomiting and/or diarrhea. Administration of activated charcoal may be appropriate in some

cases.

MINT-LETROZOLE Product Monograph

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ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

MINT-LETROZOLE tablets (letrozole) are a potent and highly specific non-steroidal aromatase

inhibitor. It inhibits the aromatase enzyme by competitively binding to the heme of the cytochrome

P450 subunit of the enzyme, resulting in a reduction of estrogen biosynthesis in all tissues.

Pharmacodynamics

Letrozole exerts its anti-tumour effect by depriving estrogen-dependent breast cancer cells of one of

their growth stimuli. In postmenopausal women, estrogens are derived mainly from the action of the

aromatase enzyme, which converts adrenal androgens - primarily androstenedione and testosterone -

to estrone (E1) and estradiol (E2). The suppression of estrogen biosynthesis in peripheral tissues and

the malignant tissue can be achieved by specifically inhibiting the aromatase enzyme.

In healthy postmenopausal women, single oral doses of 0.1, 0.5 and 2.5 mg letrozole suppressed serum

estrone by 75-78% and estradiol by 78% from baseline. Maximum suppression is achieved in 48-78

hours.

In postmenopausal women with advanced breast cancer, daily letrozole doses of 0.1 to 5 mg suppress

estradiol, estrone and estrone sulphate plasma levels by 75-95% from baseline in all patients treated.

With 0.5 mg doses and higher, many plasma levels of estrone and estrone sulphate are below the limit

of detection of the assays, indicating that higher estrogen suppression is achieved with these doses.

Estrogen suppression was maintained throughout treatment in all patients.

Letrozole is highly specific in inhibiting aromatase activity. Impairment of adrenal steroidogenesis has

not been observed. No clinically relevant changes in the plasma levels of cortisol, aldosterone, 11-

deoxycortisol, 17-hydroxy-progesterone, ACTH (adrenocorticotropic hormone) or in plasma renin

activity were found in postmenopausal patients treated with 0.1 to 5 mg letrozole daily. The ACTH

stimulation test performed after 6 and 12 weeks of treatment with daily doses of 0.1 to 5 mg letrozole

did not indicate any attenuation of aldosterone or cortisol production. Thus, glucocorticoid or

mineralocorticoid supplementation is not required.

Letrozole had no effect on plasma androgen concentrations (androstenedione and testosterone) among

healthy

postmenopausal

women

after

single

doses

0.1,

plasma

androstenedione concentrations among postmenopausal patients treated with daily doses of 0.1 to 5

mg. These results indicate that accumulation of androgenic precursors does not occur. Plasma levels

of LH and FSH are not affected by letrozole in patients, nor is thyroid function as evaluated by TSH,

and T

uptake.

The effect of aromatase inhibitors, including letrozole, on estrogen suppression may consequently

decrease bone mineral density (BMD) and increase the rate of bone fractures and of osteoporosis. In

both the adjuvant setting and extended adjuvant setting, at a median treatment duration of 60 months,

a significantly higher risk of osteoporosis as well as of clinical bone fractures was seen with letrozole

compared with tamoxifen (adjuvant treatment) or placebo (extended adjuvant treatment) (see also

DETAILED PHARMACOLOGY, Human Pharmacodynamics section).

MINT-LETROZOLE Product Monograph

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In a bone substudy (median follow-up of 61 months) in the extended adjuvant setting, a significantly

greater decrease in median total hip BMD change from baseline was seen at 2 years for letrozole

compared with placebo, but no significant changes were observed in lumbar spine BMD (see also

DETAILED PHARMACOLOGY, Human Pharmacodynamics section).

In a study comparing 2 years of adjuvant treatment with letrozole or tamoxifen (D2407), significant

differences in favour of tamoxifen were observed over the 2 years in BMD changes from baseline (see

also CLINICAL TRIALS and DETAILED PHARMACOLOGY, Human Pharmacodynamics

sections).

In a lipid substudy (median follow-up of 62 months) in the extended adjuvant setting, no significant

differences between letrozole and placebo were observed in total cholesterol or in any lipid fraction

(see

also

CLINICAL

TRIALS

and

DETAILED

PHARMACOLOGY,

Human

Pharmacodynamics sections).

In the adjuvant setting study comparing 2 years of treatment with letrozole or tamoxifen, median levels

of total cholesterol and LDL cholesterol remained stable with letrozole, but decreased with tamoxifen.

Consequently, total cholesterol, LDL cholesterol and the HDL:LDL ratio differed significantly

between treatments in favour of tamoxifen (see also DETAILED PHARMACOLOGY, Human

Pharmacodynamics section).

Pharmacokinetics

Absorption: Letrozole is rapidly and completely absorbed from the gastrointestinal tract (absolute

bioavailability = 99.9%). Food slightly decreases the rate of absorption (median t

1 hour fasted vs.

2 hours fed and mean C

129±20.3 nmol / L fasted vs. 98.7±18.6 nmol / L fed), but the extent of

absorption (area under the curve (AUC)) remains unchanged. This minor effect on absorption rate is

not considered to be of clinical relevance and therefore letrozole may be taken with or without food.

Distribution: Letrozole is rapidly and extensively distributed into tissues (Vd

= 1.87 ± 0.47 L / kg).

Plasma protein binding is approximately 60%, mainly to albumin. The letrozole concentration in

erythrocytes is about 80% of that in plasma. After administration of 2.5 mg

C-labelled letrozole,

approximately 82% of the radioactivity in plasma was unchanged compound. Systemic exposure to

metabolites is therefore low.

Metabolism:

Metabolic

clearance

pharmacologically

inactive

carbinol

metabolite,

44645, is the major elimination pathway of letrozole (Cl

= 2.1 L / h), but it 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. With CYP3A4, the metabolism of

letrozole was not saturable up to concentrations of 100 mcmol / L, while with CYP 2A6 apparent

saturation was observed at concentrations above 12.5 mcmol / L. Formation of minor unidentified

metabolites and direct renal and fecal excretion play only a minor role in the overall elimination of

letrozole.

Within

weeks

after

administration

C-labelled

letrozole

healthy

postmenopausal volunteers, 88.2 ± 7.6% of the radioactivity was recovered in urine and 3.8 ± 0.9% in

feces. 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.

MINT-LETROZOLE Product Monograph

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Excretion: The apparent mean terminal elimination half-life in plasma ranges from approximately 2

to 5 days. After daily administration of 2.5 mg 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 2.5 mg, while they are 1.5 to 2 times higher than 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 2.5 mg. Since steady state levels are

maintained over time, it can be concluded that no continuous accumulation of letrozole occurs.

Linearity/non-linearity

The pharmacokinetics of letrozole were dose proportional after single oral doses up to 10 mg (dose

range: 0.01 to 30 mg) and after daily doses up to 1.0 mg (dose range: 0.1 to 5 mg). After a 30 mg single

oral dose there was up to a 7.5-fold dose over-proportional increase in AUC value. With daily doses

of 2.5 and 5 mg the AUC values increased about 3.8 and 12 fold instead of 2.5 and 5 fold, respectively,

when compared to the 1.0 mg/day dose. The recommended dose of 2.5 mg/day may thus be a

borderline dose at which an onset of over-proportionality becomes apparent, whereas at 5 mg/day the

over-proportionality is more pronounced. The dose over-proportionality may be the result of a

saturation of metabolic elimination processes.

STORAGE AND STABILITY

Protect from heat (store at room temperature 15°C

to 30°C). Protect from moisture.

Keep out of reach and sight of children and pets.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Each yellow, round, biconvex, film coated tablets marked with “LT” on one side and plain on other

side, contains: the medicinal ingredient letrozole (2.5 mg) and nonmedicinal ingredients cellulose

compounds (microcrystalline cellulose and hypromellose), maize starch, iron oxide yellow, lactose

monohydrate, magnesium stearate, polyethylene glycol, sodium starch glycolate, colloidal anhydrous

silica, talc and titanium dioxide.

Available in blister packages containing 30 tablets.

MINT-LETROZOLE Product Monograph

Page 30 of 60

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name:

Letrozole

Chemical name:

4,4'-[(1

H-

1,2,4-triazol-1-yl) methylene] bis-benzonitrile

Molecular formula: C

Molecular mass:

285.3 g/mol

Structural formula:

Solubility:

Solvent

Temp.

Solubility

Water

25°C

0.144 mmol/L

Water

37°C

0.235 mmol/L

0,1 N HCl

25°C

0.26 mmol/L

0,1 N HCl

37°C

0.428 mmol/L

0,067 M phosphate buffer

25°C

0.123 mmol/L

Simulated intestinal fluid

37°C

0.218 mmol/L

Dichloromethane

25°C

410-440 mmol/L

96% Ethanol

25°C

21-23 mmol/L

Methanol

25°C

40-50 mmol/L

Toluene

25°C

6-7 mmol/L

Melting range:

184-185°C

pK value:

0.7 ± 0.2 in water at 22°C (triazole)

MINT-LETROZOLE Product Monograph

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CLINICAL TRIALS

COMPARATIVE BIOAVAILABILITY STUDIES

Summary of studies establishing bioequivalence of MINT-LETROZOLE to Femara

®

tablets

(Reference Listed Drug)

A single dose crossover comparative bioavailability study of MINT-LETROZOLE and FEMARA

(Novartis Pharmaceuticals Canada Inc.) tablets following a single dose of 2.5 mg letrozole in 26 healthy

female adult volunteers between the ages of 45-65 under fasting conditions was conducted. The results

indicate that MINT-LETROZOLE 2.5 mg tablets are bioequivalent to FEMARA

letrozole 2.5 mg

tablets. The summary of results is presented in the following table.

SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

Letrozole

(1 X 2.5 mg tablets)

From measured data

Geometric Mean

Arithmetic Mean (CV %)

Parameter

Test*

Reference+

% Ratio of

Geometric

Means

Confidence

Interval

0-72

(ng.h/mL)

1194.199, 1209.443 (16.5)

1153.253, 1166.652 (15.9)

103.2

101.25-105.15%

(ng.h/mL)

2094.331, 2146.307 (22.8)

2034.377, 2092.934 (23.6)

102.1

98.16-106.12%

(ng/mL)

41.040, 41.701 (18.1)

37.422, 38.045 (18.5)

109.3

102.70-116.39%

1.500 (0.750– 4.000)

2.000 (0.500– 4.000)

61.848 (26.0)

63.860 (27.1)

* MINT-LETROZOLE 2.5 mg tablets (Mint Pharmaceuticals Inc.)

+

Femara (Letrozole) 2.5 mg tablets (Novartis Pharmaceuticals Canada Inc., Quebec, Canada)

Expressed as the median (range) only

Expressed as the arithmetic mean (CV%) only

MINT-LETROZOLE Product Monograph

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Adjuvant Treatment of Early Breast Cancer in Postmenopausal Women, Study BIG 1-98

In a multi-centre, double-blind study (BIG 1-98) in the adjuvant setting, enrolling over 8,000

postmenopausal women with resected, receptor-positive early breast cancer, patients were randomly

allocated 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

The primary endpoint of this trial was disease-free survival (DFS) (i.e. interval between randomization

and earliest occurrence of a local, regional, or distant recurrence, or invasive contralateral breast

cancer, second primary cancer, or death from any cause). The secondary endpoints were overall

survival (OS), systemic disease-free survival (SDFS), invasive contralateral breast cancer, distant

disease-free survival (DDFS), time to breast cancer recurrence (TBR) and time to distant metastasis

(TDM).

The Primary Core Analysis (PCA) included patients in all treatment arms, but follow-up in the two

sequencing arms was truncated to 30 days after the switch in treatments. The original PCA analysis

was conducted at a median treatment duration of 24 months and a median follow-up of 26 months

(Table 8 and Figures 1 and 2). In 2005, based on the original PCA data showing a significant advantage

in DFS with letrozole compared with tamoxifen (HR 0.81; 95% CI 0.70, 0.93; P=0.003) (Table 8) and

on the recommendations of the independent Data Monitoring Committee, the protocol was amended,

the tamoxifen arms were unblinded and patients were allowed to cross over to letrozole to complete

their adjuvant therapy if tamoxifen had been given for 2 to 4.5 years, or to start extended adjuvant

therapy if tamoxifen had been given for at least 4.5 years. In total, 632 (26%) patients opted to cross

to letrozole, 448 patients to complete adjuvant therapy and 184 to start extended adjuvant therapy.

(These 184 patients include 12 women who crossed to another aromatase inhibitor.)

The design of the PCA is not optimal to evaluate the effect of letrozole after a longer time because

follow-up was truncated in two arms at around 25 months. The Monotherapy Arms Analysis (MAA),

despite the confounding of the tamoxifen reference arm by a selective crossover to letrozole*,

provides the comparison of 5 years of letrozole* monotherapy compared to tamoxifen monotherapy

(Table 9). Approximately 7% of the total patient-years follow-up time in the tamoxifen-alone arms

was affected by the selective crossover in the MAA.

Selected baseline characteristics for the study population are shown in Table 7.

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Table 7

Selected Study Population Demographics for Adjuvant Study (ITT population)

Characteristic

Primary Core Analysis

(PCA)

Monotherapy Arms Analysis

(MAA)

Letrozole

N=4003

(%)

Tamoxifen

N=4007

(%)

Letrozole

N=2463

(%)

Tamoxifen

N=2459

(%)

Age (median, years)

Age range (years)

38-89

39-90

38-88

39-90

Hormone receptor status (%)

ER+ and/or PgR+

99.7

99.7

99.7

99.7

Both unknown

Nodal status (%)

Node negative

Node positive

Nodal status unknown

Prior adjuvant chemotherapy

Race

White / Caucasian

97.4

97.6

97.6

98.2

Black

<0.1

Asian

Other / Missing

PCA Efficacy Results

Data in Table 8 and Figures 1 and 2 reflect results of the Primary Core Analysis (PCA) including data

from non-switching arms (arms A and B) together with data truncated 30 days after the switch in the

two switching arms (arms C and D). Data in Table 8 report results of the PCA at both 26 months and

60 months median follow-up, respectively.

In the initial analysis, conducted after a median follow-up of 26 months, the estimated 5-year DFS

rates were 84.0% for letrozole* and 81.4% for tamoxifen.

Table 8

Disease-free and overall survival (PCA ITT population) at a median follow-up of 26 months and of 60

months

Endpoint

Original PCA

Median follow-up 26 months

Median treatment 24 months

Hazard ratio (95% CI); P

Updated PCA

Median follow-up 60 months*

Median treatment 32 months

Hazard ratio (95% CI); P

0.81 (0.70, 0.93); P=0.003

0.86 (0.77, 0.96); P=0.008

DFS excluding second primaries

0.79 (0.68, 0.92); P=0.002

0.85 (0.76, 0.96); P=0.008

Time to distant metastases

0.73 (0.60, 0.88)

0.79 (0.68, 0.92)

DDFS

0.82 (0.70, 0.97)

0.84 (0.74, 0.95)

SDFS

0.83 (0.72, 0.97)

0.87 (0.77, 0.98)

Contralateral breast cancer

(invasive)

0.61 (0.35, 1.08)

0.76 (0.50, 1.15)

0.86 (0.70, 1.06)

0.87 (0.75, 1.01)

DFS events: Loco-regional recurrence, distant metastasis, invasive contralateral breast cancer, second non-breast primary

cancer or death without prior cancer event, from any cause

Risk of distant metastases only.

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Distant disease-free survival events: Earlier event of either distant metastasis or death from any cause

Systemic disease-free survival events: Same as protocol definition, but excluding all breast events

*Note: At original analysis, median duration of treatment was 24 months. In the updated analysis, the two sequencing

treatment arms were truncated 30 days after the switch (at approximately 2 years), while in the monotherapy arms, median

treatment duration was 60 months. Overall, the truncation in two arms brought the median duration of treatment to

approximately 32 months.

Figure 1: Forest plot for DFS by subgroup (median follow-up of 26 months)

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Figure 2: Forest plot for time to distant metastasis by subgroup (median follow-up of 26

months)

MAA Efficacy Results

The Monotherapy Arms Analysis (MAA) comparing the efficacy of letrozole monotherapy to

tamoxifen monotherapy at a median duration of treatment of 5 years and a median follow-up of 96

months is presented in Table 9.

Table 9

Key efficacy results at a median duration of 60 months and a median follow- up

of 96 months (MAA ITT population)

Letrozole*

N=2463

Tamoxifen

N=2459

Hazard ratio

(95% CI)

P value

1

Disease-free survival (primary)

Events (protocol definition)

0.87

(0.78, 0.97)

0.01

5-year DFS rate (%)

85.5

82.5

Events (excluding second non-

breast primary malignancies)

0.87

(0.77, 0.97)

0.01

5-year DFS rate (%)

87.4

84.7

Overall survival (secondary)

Number of deaths

0.89

(0.77, 1.02)

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Letrozole*

N=2463

Tamoxifen

N=2459

Hazard ratio

(95% CI)

P value

1

Distant metastasis (secondary)

0.86

(0.74, 1.01)

Distant disease-free survival

(secondary)

0.89

(0.78, 1.01)

Systemic disease-free survival

(secondary)

Protocol definition

0.89

(0.80, 1.00)

Excluding second non-breast

primary malignancies

0.89

(0.79, 1.01)

Contralateral breast cancer

(invasive) (secondary)

0.62

(0.43, 0.90)

Logrank test, stratified by randomization option and use of chemotherapy (yes/no)

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

Adjuvant Treatment of Early Breast Cancer in Postmenopausal Women, Study D2407 (see

also DETAILED PHARMACOLOGY section)

Study D2407 was a phase III, open-label, randomized, multi-centre study designed to compare

the effects of adjuvant treatment with letrozole to tamoxifen on bone mineral density (BMD),

bone markers and fasting serum lipid profiles. In total, 263 postmenopausal women with

hormone sensitive resected primary breast cancer were randomly assigned either letrozole 2.5

mg daily for 5 years or tamoxifen 20 mg daily for 2 years followed by 3 years of letrozole daily.

The primary objective was to compare the effects on lumbar spine (L2-L4) BMD of letrozole

versus tamoxifen, evaluated as percent change from baseline lumbar spine BMD at 2 years

(assessment by central review, based on dual X-ray absorptiometry, DXA).

At 24 months, the lumbar spine (L2-L4) BMD showed a median decrease of 4.1% in the letrozole

arm compared to a median increase of 0.3% in the tamoxifen arm (difference = 4.4%) a

statistically significant difference in favour of tamoxifen (

P

<0.0001). Significant differences in

favour of tamoxifen were noted irrespective of category of initial T-score.

At 24 months, total hip BMD showed a median decrease of 3.0% from baseline with letrozole

compared to a median increase of 1.2% for tamoxifen (difference = 4.2%, a significant

difference). Significant differences in favour of tamoxifen were noted irrespective of category of

initial T-score.

Significantly more patients receiving letrozole than tamoxifen were found by central review to

have had a decrease of 8% or greater from baseline over 2 years in lumbar spine BMD (letrozole,

15.5%; tamoxifen, 1.0%) or in total hip BMD (letrozole, 7.8%; tamoxifen, 3.1%).

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During the 2 year period, fractures were reported (central review, treatment-blinded) for 20

patients (15%) in the letrozole arm, and 22 patients (17%) in the tamoxifen arm. Of these, 7

patients (5%) in each treatment arm had clinical fractures. There was no significant difference

between treatments in fracture rate. All patients should have received vitamin D and calcium

supplementation. Post baseline bisphosphonates were given in 14% of patients treated with

letrozole, 5% of those treated with tamoxifen.

At 5 years, in the letrozole arm, there was a median decrease of 5.66% from baseline in the

lumbar spine BMD (n=56) and a median decrease of 5.77% in total hip (n=62). There was a

general shift downwards in T-score over the 5 years. Amongst patients whose DXA readings

were centrally evaluated and who had received bisphosphonate therapy, for lumbar spine and

total hip normal T-scores (> 1.0), there were 51 patients each at baseline and 39 and 47,

respectively, at 5 years. For lumbar spine and total hip osteopenic T-scores (≤ -1.0 and > -2.5),

there were 5 and 11 patients, respectively, at baseline and 17 and 15, respectively, at 5 years.

No patient with a normal BMD (normal T score) at baseline became osteoporotic during 5 years

as evaluated by central review. One patient evaluated as having osteopenia at baseline (T score

of -1.9) was diagnosed with osteoporosis during the treatment period by central review, despite

unevaluable T-scores in L2-L4 (due to severe degenerative disk disease) and hip T-scores that

remained higher than -2.5 at all times. Over the 5-year study, 37% of patients treated with

letrozole received bisphosphate therapy, including 18% of patients who started bisphosphonate

therapy after initiating treatment with letrozole.

Tamoxifen is known to decrease total cholesterol and particularly, LDL cholesterol. Over the

first 2 years of the study, median LDL cholesterol levels remained stable for letrozole, but

decreased by up to 28% for tamoxifen. Median HDL cholesterol levels remained relatively

stable over the 2 years in both treatment arms, giving rise to significant differences in favour of

tamoxifen in the HDL:LDL ratio. No significant treatment differences were observed in

triglyceride

levels.

Clinically

relevant

changes

total

cholesterol

years

occurred

significantly more often for patients treated with letrozole (17%) than with tamoxifen (5%).

Significantly more patients receiving letrozole received lipid lowering agents (20%) than

receiving tamoxifen (8%). Dietary measures for reducing lipids were reported for 4% of patients

in each treatment arm. At 5 years, on the letrozole arm, 23% of patients experienced clinically

relevant changes in total cholesterol.

At 2 years, significantly more patients treated with letrozole received lipid-lowering drugs

(20%) than patients treated with tamoxifen (8%). Dietary control of lipids occurred equally

often in both treatment arms (4%). Lipid-lowering agents were generally introduced when total

cholesterol values rose above 6 mmol / L. At 5 years, on the letrozole arm, 32% of patients

received lipid lowering drugs.

Extended Adjuvant Treatment of Early Breast Cancer in Postmenopausal Women

The MA-17 (CFEM345G MA-17) trial was a multi-centre, double-blind, randomized,

placebo-controlled phase III trial, performed in over 5100 postmenopausal women with

receptor-positive (or unknown) primary breast cancer. Patients who had remained disease-free

after completion of adjuvant treatment with tamoxifen (4.5-6 years) were randomly assigned

either letrozole 2.5 mg daily or placebo for 5 years.

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Disease-free survival (DFS) was the primary endpoint, defined according to the study protocol

as the time from randomization to the earliest event of time to recurrence of the primary disease

(i.e. loco-regional recurrence or distant metastasis) or development of contralateral breast cancer

(i.e. breast cancer recurrence). (The protocol definition excluded deaths.) Secondary endpoints

included: overall survival (OS), time to distant metastasis, contralateral breast cancer, and other

clinical and laboratory safety parameters.

Following review of the results of the first planned interim analysis, conducted after a median

follow-up of 28 months and a median treatment duration of 24 months, in light of the statistically

significant benefit in DFS in favour of letrozole, the study was unblinded and women who were

disease-free in the placebo arm were allowed to switch to letrozole for up to 5 years. MA-17

transformed into an open-label, observational, non-randomized study, with a substantial impact

on the subsequent safety and efficacy results.

Updated analyses were conducted at a median overall follow-up of 62 months and median

duration of treatment in the randomized letrozole arm of 60 months. 48.7% of the patients in the

original randomized letrozole arm have completed 5 years of extended adjuvant treatment with

letrozole. Following study unblinding, 1551 women (60% of those eligible to switch) switched

from placebo to letrozole at a median 31 months after completion of adjuvant tamoxifen therapy

(range 12-106 months). Subsequent patient-years of follow-up under letrozole after switch

account for 64% of the total years of follow-up in the randomized placebo arm. Median duration

of follow-up in the letrozole after switch group was 42 months and median duration of letrozole

treatment after switch was 40 months. Following study unblinding, open-label letrozole was

continued in the randomized letrozole arm and was given to those women who opted to switch

from placebo to letrozole. In patients who opted not to switch, placebo was no longer dispensed

– these women received standard care (i.e. observation). Median duration of placebo/standard

care (up until any switch to letrozole that may have occurred) was 37 months.

Selected baseline characteristics for the study population are shown in Table 10.

Table 10 Selected study population demographics (ITT population

)

Baseline status

Letrozole

N=2583

Placebo

N=2587

Age: Median (years) at enrolment

Minimum-maximum (years)

32-90

34-94

< 65 years at enrolment (%)

≥ 65 years at enrolment (%)

Race (%)

Caucasian

Black

Oriental

Other

Hormone receptor status (%)

Node negative

Node positive

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Nodal status unknown

Chemotherapy (%)

Note: Prior treatment with tamoxifen in both arms ranged from 4.5 to 6 years, with a median duration of 5 years

Figure 3 Time to breast cancer recurrence (MA-17 protocol definition of DFS event)

in updated analysis

Note: Switches in the placebo arm to letrozole are ignored.

Tables 11 and 12 show disease-free and overall survival with subset analysis by receptor status,

nodal status and previous chemotherapy at median follow-up of 28 months and 62 months.

In the primary analysis (conducted at a median follow-up of 28 months), letrozole was shown to

reduce the risk of breast cancer recurrence (protocol definition of DFS) by 42% compared with

placebo (hazard ratio 0.58; 95% CI 0.45, 0.76; P=0.00003). Subgroup sensitivity analysis

confirmed the robustness of the data. The statistically significant benefit in DFS in favour of

letrozole was observed regardless of nodal status (node negative, hazard ratio 0.48; 95% CI 0.30,

0.78; P=0.002; node positive, hazard ratio 0.61; 95% CI 0.44, 0.83; P=0.002).

The risk of distant metastases was significantly lower with letrozole than with placebo (hazard

ratio 0.61; 95% CI 0.44, 0.83; P=0.003).

The risk of developing contralateral breast cancer was also substantially reduced with letrozole

compared with placebo (40% reduction in the risk) although the difference between treatments

was not statistically significant (P=0.12).

Overall survival did not show significant differences between treatments; relatively few deaths

had occurred at the time of the analysis. Subgroup analysis indicated a more pronounced benefit

in node positive patients (hazard ratio 0. 61, 95% CI 0.38, 0.97). In node-negative patients, there

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was an increase in the number of deaths in the letrozole arm (19/1298 patients, 1.5%) compared

with the placebo arm (14/1301 patients, 1.1%) (hazard ratio 1.36; 95% CI 0.68, 2.71).

The updated final analysis, conducted at a median follow-up of 62 months, confirmed the

significant reduction in the risk of recurrence of the primary disease with letrozole compared

with placebo. For time to distant metastases and overall survival, however, there was no

significant difference between treatments. In addition, in the subgroup of patients with node

negative disease, an increase in the number of deaths was observed in the letrozole arm (90 /

1298 patients, 6.9%) compared with the placebo arm (79 / 1301 patients, 6.1%) (hazard ratio

1.34; 95% CI 0.99, 1.81). There was no difference between treatments in the risk of death in

patients with node-positive disease (letrozole 128 / 1184 patients, 10.8%; placebo 145 / 1187

patients, 12.2%; hazard ratio 0.96; 95% CI 0.75, 1.29). Figures 4 and 5 show Kaplan-Meier

curves for the overall population for the node-negative and node-positive subgroups. All updated

analyses were affected by the confounding effects of around 60% of the patients in the placebo

arm switching to letrozole when the study was unblinded.

Table 11

Disease-free survival, time to distant metastases, contralateral breast cancer and overall

survival (Modified ITT population)

2004 primary analysis – median

follow-up 28 months

2008 updated analysis

1

– median

follow-up 62 months

Letrozole

N=2582

Placebo

N=2586

HR (95% CI)

2

P value

Letrozole

N=2582

Placebo

N=2586

HR (95% CI)

2

P value

Disease-free survival (protocol definition)

3

Events

(3.6%)

(6.0%)

0.58

(0.45, 0.76)

0.00003

(8.1%)

(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

(4.7%)

(7.5%)

0.62

(0.49, 0.78)

0.00003

(13.3%)

(15.5%)

0.89

(0.77, 1.03)

0.120

5-year DFS rate

90.5%

80.8%

88.8%

86.7%

Time to distant metastases

Events

57 (2.2%)

93 (3.6%)

0.61

(0.44, 0.84)

(5.5%)

(6.5%)

0.88

(0.70, 1.10)

Overall survival

Deaths

51 (2.0%)

62 (2.4%)

0.82

(0.56, 1.19)

(9.1%)

(9.0%)

1.13

(0.95, 1.36)

Contralateral breast cancer

Invasive

15 (0.6%)

25 (1.0%)

0.60

(0.31, 1.14)

33 (1.3%)

51 (2.0%)

0.644

(0.41, 1.00)

HR = Hazards ratio; CI = Confidence Interval

1

When the study was unblinded in 2003, 1551 patients in the randomized placebo arm (60% of those eligible to

switch – i.e. who were disease-free) switched to letrozole at a median 31 months after randomization. The analyses

presented here ignore the switching under the ITT principle.

2

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

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3

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

breast cancer.

4

Odds ratio and 95% CI for the odds ratio.

Table 12

Disease-free

and

overall

survival

by

receptor

status,

nodal

status

and

previous

chemotherapy (Modified ITT population)

2004 analysis – median follow-

up 28 months

2008 analysis – median follow-

up 62 months

1

HR (95% CI)

2

P value

HR (95% CI)

2

P value

Disease-free survival (protocol definition)

Receptor status positive

0.57 (0.44,

0.75)

0.00003

0.74 (0.62,

0.89)

0.001

Nodal status

Negative

0.48 (0.30,

0.78)

0.002

0.67 (0.49,

0.93)

0.015

Positive

0.61 (0.44,

0.83)

0.002

0.78 (0.62,

0.97)

0.027

Chemotherapy

None

0.58 (0.40,

0.84)

0.003

0.71 (0.54,

0.92)

0.010

Received

0.59 (0.41,

0.84)

0.003

0.79 (0.62,

1.01)

0.055

Overall survival

Nodal status

Negative

1.36 (0.68,

2.71)

1.34 (0.99,

1.81)

Positive

0.61 (0.38,

0.97)

0.96 (0.75,

1.21)

HR = Hazards ratio; CI = Confidence Interval

1

Including 60% of eligible patients who switched from placebo to letrozole after the study was unblinded in 2003

2

From Cox regression models

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Figure 4

Overall survival (Time to death) - Randomised treatment group regardless

of switch (Modified ITT population)

Figure 5

Overall survival (Time to death) by nodal status - Randomised treatment

group regardless of switch (Modified ITT population)

Health related quality of life was also assessed in the MA-17 study using the SF-36 Health Survey

Questionnaire as well as the MENQOL, a quality of life scale specifically addressing menopausal

symptoms. The SF-36 instrument has 36 questions, which yield two summary scores: physical

and mental health summary measures. In the initial analysis, no significant differences were

observed in global physical or mental summary scores. Treatment differences in favour of

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placebo were observed in assessments by patients particularly in the measures of physical

functioning, bodily pain, vitality, sexual and vasomotor items.

In the updated analysis of quality of life, restricting the analysis to women who had received

letrozole or placebo/no treatment for at least 3 years, there were no significant differences

between treatments in physical component summary score or mental component summary score,

or in any domain score (physical health; role function-physical; bodily pain; general health;

vitality; social function; role function-emotional; or mental health – all SF-36 scale). There was

no significant difference from baseline between treatments in any domain on the specific

menopausal symptoms scale (MENQOL) (vasomotor; psychological; physical or sexual).

Considering all women in the sub-study and looking at the individual symptoms of the MENQOL

scale, significantly more women who received letrozole than who received placebo/no treatment

were most bothered (generally in the first year of treatment) by those symptoms deriving from

estrogen deprivation – hot flashes and vaginal dryness. The symptom that bothered most patients

in both arms (but significantly more in the letrozole arm than in the placebo arm) was aching

muscles.

First-Line Treatment

large,

randomized,

well-controlled,

multinational,

double-blind

Phase

trial

conducted in 907 postmenopausal patients with locally advanced or metastatic breast cancer.

Patients were randomized to letrozole 2.5 mg daily or tamoxifen 20 mg daily.

Time to progression (TTP) was the primary endpoint of the trial. In 907 women, letrozole was

superior to tamoxifen in TTP (P<0.0001). Median TTP was 9.4 months for letrozole versus 6.0

months for tamoxifen. Letrozole was also superior to tamoxifen in secondary

endpoints

consisting of overall objective tumour response [Complete Response (CR) + Partial Response

(PR)],

time

treatment

failure

(TTF)

clinical

benefit

(CR+PR+NC

weeks).

Objective response rate (ORR) was statistically significant (P=0.0002) for letrozole as compared

to tamoxifen: 32% of patients in the letrozole arm achieved a confirmed response (CR, 9%; PR,

23%; 95% CI for ORR 28 to 36 %), compared with 21% (CR, 3%; PR, 18%; CI for ORR 17 to

25%) in the tamoxifen arm. Median duration of objective tumour response was 25 months for

letrozole (95% CI 21 to 36 months) compared with a median 23 months for tamoxifen (95% CI

20 to 26 months). Although the difference was not statistically significant (P=0.0578), the

difference favoured letrozole. The hazard ratio comparing the subsequent risk of progression in

responding patients treated with letrozole to the risk in responding patients treated with tamoxifen

was 0.74 (95% CI 0.54 to 1.01), P=0.0578. In addition to a significantly higher response rate

with letrozole, where response occurred, the subsequent risk of progression was reduced by 26%

with letrozole compared to the risk with tamoxifen (hazard ratio 0.74; 95% CI for the hazard

ratio: 46% reduction in the subsequent risk of progression with letrozole to 1% increase in the

subsequent risk of progression with letrozole compared with tamoxifen in responding patients).

TTF was statistically significant for letrozole as compared to tamoxifen (P<0.0001). Median TTF

was 9.0 months for letrozole versus 5.7 months for tamoxifen. Clinical benefit was statistically

significant for letrozole when compared to tamoxifen (50% vs. 38%, P=0.0004).

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Data from this trial were further analyzed to determine the impact of prior adjuvant tamoxifen

therapy on TTP. The superiority of letrozole was observed in the sub-group of patients who

received no prior adjuvant tamoxifen therapy. Patients treated with letrozole had a median TTP

of 9.5 months (n=369) vs. 6.0 months for tamoxifen-treated patients (n=371), P=0.0003. Similar

results were seen in those patients who had received prior adjuvant tamoxifen. The median TTP

for letrozole-treated patients was significantly longer at 8.9 months (n=84), vs. the tamoxifen-

treated group at 5.9 months (n=83), P=0.0033. Treatment with letrozole lead to a significantly

longer TTP compared with tamoxifen, irrespective of whether patients had received prior

adjuvant therapy.

Sub-group analysis was also performed on the Objective Response Rate (CR+PR). Patients who

received no prior adjuvant tamoxifen had an objective response rate of 33% in the letrozole arm

(n=369) vs. 24% in the tamoxifen arm (n=371), P=0.0039. In patients who had received prior

adjuvant tamoxifen, significantly more patients achieved an objective response rate with

letrozole (26%) vs. tamoxifen (8%), P=0.0038. These data demonstrate that the Objective

Response Rate with letrozole is superior to tamoxifen regardless of whether prior adjuvant

therapy was initiated.

Letrozole treatment in first-line therapy of advanced breast cancer patients is associated with an

early survival advantage over tamoxifen. The median overall survival was 34 months for

letrozole and 30 months for tamoxifen. Although this difference in overall survival was not

statistically significant (logrank P=0.53), there was a statistically significant early survival

advantage for patients in the randomized letrozole arm compared to the randomized tamoxifen

arm over the first 2 years, as shown in the primary analysis (Kolmogorov-Smirnov-type test,

P=0.005). Supportive analyses (repeated logrank tests) confirmed the early survival advantage

(see Figure 6). The total duration of endocrine therapy (time to chemotherapy) was significantly

longer for letrozole (median 16 months, 95% CI 15 to 18 months) than for tamoxifen [(median 9

months, 95% CI 8 to 12 months) (logrank P=0.0047)].

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Figure 6

Second-Line Treatment

In a controlled double-blind clinical trial, the overall objective tumour response rate (complete

and partial response) was 23.6% in letrozole -treated patients compared to 16.4% in patients on

160 mg megestrol acetate. Treatment comparison of the response rate showed a statistically

significant difference in favour of 2.5 mg letrozole (p=0.04).

In an open-label, randomized clinical trial, survival at 2 years was 55.1% for patients treated with

letrozole compared to 38.8% for patients treated with 500 mg aminoglutethimide. Treatment

comparison

showed

statistically

significantly

prolonged

overall

survival

with

letrozole

(adjusted Cox regression hazard ratio 0.68, 95% CI 0.52-0.87, p=0.003).

DETAILED PHARMACOLOGY

Animal Pharmacology

Pharmacodynamics

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Letrozole is a more potent and selective aromatase inhibitor than aminoglutethimide (AG). In

vitro studies in human placental microsomal preparations showed that letrozole is about 150-250

times more potent than AG in its aromatase inhibition. This selectivity was documented by

studying inhibition of estradiol and progesterone synthesis in hamster ovarian slices in vitro, and

inhibition of adrenal steroidogenesis in rat adrenal fragments in vitro (see Table 13).

Table

13

Inhibition of steroid production in vitro

Letrozole

Anastrozole

Formestane

nM (Rel. Potency)*

1900 (1)

11.5 (165)

15 (127)

62 (31)

nM (Rel. Potency)

530 (1)

2.1 (250)

-

20 (26.5)

* Concentration required to inhibit steroid production by 50%.

The results show that, when compared with the IC

for estradiol production, letrozole does not

inhibit corticosterone production at concentrations 17,000 times higher and inhibits aldosterone

production at concentrations 10,000 times higher than those required for inhibiting estrogen

production. In contrast, AG inhibits estradiol, corticosterone and aldosterone at concentrations

which are within one order of magnitude of each other.

Letrozole is >650 times more potent than AG in inhibiting estradiol production, whereas

formestane is about 30 times more potent, and anastrozole, about 127 times more potent.

Further, whereas AG inhibited adrenal steroidogenesis (corticosterone and aldosterone), letrozole

did not, even at concentrations 3 orders of magnitude higher than those required for inhibition of

estradiol production.

To complement the in vitro studies in rat adrenal fragments, inhibition of adrenal steroidogenesis

was investigated in ACTH-stimulated male rats in vivo. At 4 mg / kg p.o., letrozole showed no

significant effect on plasma concentrations of either corticosterone or aldosterone in ACTH-

stimulated male rats. This dose is about 500 times higher than the dose which was maximally

effective in inhibiting aromatase in vivo and 4 times higher than the dose which was as effective

as ovariectomy in reducing uterine weight in adult female rats. Under the same experimental

conditions, AG at a dose of 100 mg / kg p.o. significantly suppressed plasma concentrations of

both corticosterone and aldosterone.

Aromatase-mediated uterine hypertrophy was antagonized by letrozole with an ED

of 1-3 μg /

kg and a minimum effective dose of 0.3 μg / kg when administered orally to pre-pubertal rats

treated with androstenedione. AG, under the same conditions, antagonized this androstenedione-

induced uterotrophic effect with an ED

of 30 mg / kg. Thus, in this assay, letrozole is over

10,000 times as potent as AG.

In adult female rats treated for 14 days with 0.03, 0.1, and 1 mg / kg letrozole p.o., there was a

dose-dependent increase in body weight and LH, in addition to a highly pronounced, significant,

dose-dependent effect on the disruption of ovarian cyclicity (all rats in continuous diestrus at 1

mg / kg) and reduction of relative uterine weight. At 1 mg / kg, letrozole was as effective as

ovariectomy in causing these estrogen-related changes.

MINT-LETROZOLE Product Monograph

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In a study comparing the effects of a 14-day treatment with letrozole and anastrozole on the

uterus in adult cyclic rats, 1 mg / kg letrozole was again shown to be equivalent to ovariectomy

in reducing uterine weight. Anastrozole, in contrast, at doses of 1 and 10 mg / kg, did not

significantly affect uterine weight when compared to a group of untreated control animals. Thus,

letrozole is more than 10 times as potent as anastrozole in reducing uterine weight.

In estrogen-dependent DMBA- and NMU-induced mammary carcinomas in adult female rats,

oral daily treatment with letrozole for 6 weeks resulted in a dose-dependent effect on mean

tumour volume with an estimated ED50 of 0.03 mg / kg. Maximal efficacy was seen in both

models at 0.3 mg / kg. At this dose, letrozole suppressed appearance of new tumours.

In a direct comparison between letrozole (0.1-1 mg / kg) and anastrozole (1-10 mg / kg) in rats

bearing DMBA-induced mammary carcinomas, 0.1 mg / kg letrozole was more effective in

reducing mean tumour volume than was anastrozole at a dose of 10 mg / kg. Thus in this DMA

model, the anti-tumour efficacy of letrozole is more than 100-fold higher than that of anastrozole.

In a 104-week carcinogenicity study in rats there was a dose-dependent decrease in the incidence

of benign and malignant spontaneous mammary tumours in females at all doses (0-10 mg / kg)

compared to controls. At the highest dose, appearance of spontaneous benign or malignant

tumours was completely suppressed.

Pharmacokinetics

Peroral absorption of single doses of letrozole was almost complete in all species studied (mice,

rats, dogs). Peroral bioavailability was high in all three species, indicative of low first-pass

metabolism.

In mice, rats and dogs, unchanged letrozole was the predominant drug-related substance in the

plasma. In all three species, systemic exposure to letrozole metabolites was at most very low,

thus, following administration of

C-letrozole the concentrations of total radioactivity in plasma

approximate those of unchanged letrozole.

Clearance of the parent drug from plasma decreased in the order: mouse > male rat > female rat

> dog. After single doses, the apparent terminal plasma elimination half-life was approximately

4-5 hours in mice, 7-10 hours in male rats, 20-50 hours in female rats and 60-90 hours in dogs.

Dose- and time-dependent kinetics were observed in rats.

Radioactivity from

letrozole was distributed rapidly and extensively throughout the whole

body of mice, rats and dogs. Particularly high levels were seen in the adrenals and liver. In

pigmented rats, letrozole showed a marked but reversible affinity for melanin-containing

structures of the eye and fur. Radioactivity declined substantially in the 14 days after dosing

followed by a very slow terminal decline of low residual radioactivity levels.

Similar metabolic profiles between species (including humans) and genders suggest that the

same pathways are involved, but that differences in the quantity of enzymes and in the renal

clearance of letrozole affect the rate and extent of metabolism. Metabolic clearance, mainly

MINT-LETROZOLE Product Monograph

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formation of the carbinol metabolite, CGP 44645, followed by glucuronidation, is the major

clearance pathway in rats and man. In mice, renal excretion of unchanged letrozole is the major

elimination pathway.

Human Pharmacodynamics

Adjuvant and extended adjuvant setting

Updated results from the extended adjuvant study bone substudy (median follow-up of 61

months) indicated a significantly greater decrease in BMD from baseline for hip BMD at 24

months (Table 14).

Table 14

Percentage change from baseline in bone mineral density (BMD) of total hip and

lumbar spine in extended adjuvant bone substudy (Per protocol bone substudy

population)

MA-17 bone substudy

Lumbar spine (L2-L4)

1

Total hip

2

Month

Statistic

Letrozole

Placebo

3

Letrozole

Placebo

3

Median

-2.4

-2.4

-2.2

-2.3

Median

-3.7

-2.0

-3.8

-2.0

Median

-2.9

-0.4

-3.7

-1.7

Median

-2.8

-4.0

-4.2

-5.0

Median

-3.0

-5.3

-3.6

-6.7

1

Primary endpoint in bone substudy

2

Secondary endpoint

3

Placebo until switch (if a switch occurred)

4

Statistically significant difference from placebo on Wilcoxon signed rank test (adjusted for bisphosphonate use)

Note: All patients should have received vitamin D and calcium supplementation. Vitamin D was not recorded.

Calcium supplementation was reported for 44-66% of patients. Bisphosphonates were received by approximately a

third of the patients treated with letrozole, compared with a quarter or fewer patients in the placebo arm.

Table 15 summarizes clinically relevant changes in study D2407 after adjuvant treatment with

letrozole or tamoxifen for 2 years.

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Table 15

Clinically relevant changes in lumbar spine and total hip BMD in adjuvant study after 2

years treatment (Per protocol population)

D2407 study

Clinically relevant change

from baseline

Lumbar spine (L2-L4)

Total hip

Letrozole

N=103

n (%)

Tamoxifen

N=97

n (%)

Letrozole

N=103

n (%)

Tamoxifen

N=97

n (%)

No. of pts with ≥ 1 change

34 (33.0)

22 (22.7)

25 (24.3)

25 (25.8)

6% reduction in 1 year

21 (20.4)

2 ( 2.1)

9 ( 8.7)

4 ( 4.1)

8% cumulative reduction

16 (15.5)

1 ( 1.0)

8 ( 7.8)

3 ( 3.1)

T-score -2.5 or lower

1 ( 1.0)

Clinical fracture

4 ( 3.9)

6 ( 6.2)

4 ( 3.9)

6 ( 6.2)

Impending fracture

11 (10.7)

15 (15.5)

11 (10.7)

15 (15.5)

There was no significant difference between treatments in the number of patients who had 1 or more clinically

relevant change in BMD over 2 years (odds ratio).

Note: All patients should have received vitamin D and calcium supplementation. Post baseline bisphosphonates

were given in 14% of patients treated with letrozole, 5% of those treated with tamoxifen.

Table 16 summarizes clinically relevant changes in study D2407 after adjuvant treatment with

letrozole at 5 years.

Table 16

Clinically relevant changes in lumbar spine (L2-L4) and total hip BMD at 5

years by central assessment (Safety population)

Letrozole

Lumbar spine

N=133

n (%)

Total hip

N=130

n (%)

Number

patients

with

more

following

changes:

68 (51.1)

60 (45.1)

6% reduction over a year

32 (24.1)

14 (10.5)

8% reduction at any time up to 5 years

33 (24.8)

26 (19.5)

T-score ≤ -2.5 at any time up to 5 years

9 (6.8)

Fracture at or before 5 years

17 (12.8)

Impending fracture at or before 5 years

19 (14.3)

Based on DXA readings centrally assessed, all 9 patients had either a lumbar spine or a total hip T-score below

-2.5 at baseline.

Clinical fractures evaluated centrally on DXA scans and/or on X-ray. Clinical fractures include fractures at

any site.

Impending fractures evaluated centrally only, seen on X-ray.

Table 17 summarizes updated results from the extended adjuvant lipid substudy (median follow-

up of 62 months). There were no significant differences between letrozole and placebo in changes

from baseline in total cholesterol or any lipid fraction.

MINT-LETROZOLE Product Monograph

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Table 17

Percentage change in total cholesterol and LDL cholesterol in the extended adjuvant lipid

substudy (Per protocol lipid population)

MA-17 lipid substudy

Total cholesterol

LDL cholesterol

Month

Statistic

Letrozole

Placebo

1

Letrozole

Placebo

1

140

115

140

114

Median

13.70

11.79

21.31

21.28

12

137

114

136

113

Median

16.81

11.71

28.14

23.13

84

128

84

Median

14.40

12.18

22.11

24.94

120

120

49

Median

9.69

11.06

19.18

21.60

12

19

102

19

Median

6.16

7.92

13.02

12.21

60

85

8

85

8

Median

9.29

11.40

15.74

9.93

Placebo until switch (if switch occurred)

In the adjuvant study, D2407, although total cholesterol and LDL cholesterol values remained

stable over 2 years in the letrozole arm, a median decrease of around 16% in total cholesterol and

around 20% in LDL cholesterol was observed at 6 months in the tamoxifen arm, with subsequent

values remaining around the same decreased levels, leading to significant differences between

treatments at all time-points in total cholesterol, LDL cholesterol and the HDL:LDL ratio. No

significant treatment differences were observed over the 2 years in triglyceride levels.

In the large adjuvant study BIG 1-98, total cholesterol levels (generally measured under non-

fasting conditions) remained stable over 5 years of treatment in the letrozole arm. In the

tamoxifen arm, there was an immediate decrease of around 14% observed at 6 months with

subsequent median decreases of 10-14% over 5 years of treatment, returning to baseline levels 1

year after treatment completion (Figure 7).

MINT-LETROZOLE Product Monograph

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Figure 7

Total cholesterol values over time in adjuvant study, BIG 1-98 (Safety

population)

Overall, in the large adjuvant study BIG 1-98, there was a significantly higher risk of

hypercholesterolemia for letrozole relative to tamoxifen (RR 1.83; 95% CI 1.70, 1.97), albeit at

low CTC grades (0.4% of patients receiving letrozole had CTC grade 3-4 hypercholesterolemia).

Lipid-lowering agents were given post baseline in approximately 25 % of patients treated with

letrozole, compared with approximately 16% treated with tamoxifen.

TOXICOLOGY

In a variety of preclinical safety studies conducted in standard animal species, there was no

evidence of systemic or target organ toxicity.

Letrozole showed a low degree of acute toxicity in rodents exposed up to 2000 mg / kg. In dogs,

letrozole caused signs of moderate toxicity at 100 mg / kg (see Table 18).

In repeated dose toxicity studies of up to 12 months duration in rats treated with 0.3, 3 and 30

mg/kg and dogs treated with 0.03, 0.3 and 3 mg / kg, the main findings can be attributed to the

pharmacological action of the compound. Effects on the liver (increased weight, hepatocellular

hypertrophy, fatty changes) were observed, mainly at the high dose level. The no-adverse effect

level was 0.3 mg / kg in both species (see Table 19). 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.

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The pharmacological effects of letrozole resulted in skeletal, neuroendocrine and reproductive

findings in a juvenile rat study at doses between 0.003 mg / kg / day and 0.3 mg / kg / day. Bone

growth and maturation were decreased from the lowest dose (0.003 mg / kg / day) in males and

increased from the lowest dose (0.003 mg / kg) in females. Bone mineral density (BMD) was

also decreased at that dose in females. In the same study, decreased fertility at all doses was

accompanied

hypertrophy

hypophysis,

testicular

changes

which

included

degeneration of the seminiferous tubular epithelium, ovarian edema, ovarian cysts and atrophy

of the female reproductive tract. Effects on bone size in females at 0.3 mg / kg / day and males

at 0.03 mg / kg / day and morphological changes in the testes were not reversible. All other effects

were at least partially reversible at 0.003 mg / kg / day and 0.03 mg / kg / day.

Table 18 - Acute Toxicity

Species

Dose mg/kg

Route

Findings

Mouse

200, 2000

p.o.

: >2000 mg/kg

2000

p.o.

>2000 mg/kg

100, 200

p.o.

100 mg/kg: signs of general toxicity; 12 days

after dosing: asymptomatic.

200 mg/kg: death within 48 hours

50, 500

i.p.

: >500 mg/kg

Table 19 - Long-Term Toxicity

Duration of dosing

Species

Dose (mg/kg)

/Route

Main findings

13 weeks

Mouse

0.6, 6, 60 /p.o.

Pharmacological effects on reproductive tract.

60 mg/kg: ↑ Liver weight

28 days (pilot)

0.5, 5, 50 /p.o.

Pharmacological effects on reproductive tract.

50 mg/kg: ↑ Liver weight

3 months

0.3, 3, 30 /p.o.

Pharmacological effects on reproductive tract.

3 and 30 mg/kg: ↑ Liver weight

30 mg/kg: Signs of thyroid activation.

No-adverse effect level: 0.3 mg/kg.

6 / 12 months

0.3, 3, 30 /p.o.

Pharmacological effects on reproductive tract.

30 mg/kg: Fractures of long bones (5/40 f); liver

weight ↑ (m).

No-adverse effect level: 0.3 mg/kg.

12 weeks (from day

7 post partum) + 6

weeks recovery

0.003, 0.03 and

0.3 mg/kg/day.

Oral gavage

Bone growth and maturation ↓ from 0.003 in males

and ↑ from 0.003 in females BMD ↓ 0.003 in

females

From

0.003,

fertility,

hypertrophy

hypophysis, testicular changes which included a

degeneration of the seminiferous tubular epithelium

and ovarian edema

From 0.03, ovarian cysts and atrophy of the female

reproductive tract

28 days (pilot)

5 /p.o.

Pharmacological effects on reproductive tract.

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3 months

0.03, 0.3, 3.0

/p.o.

Pharmacological effects on reproductive tract.

Hypertrophy Leydig cells, impaired

spermatogenesis at 0.03 mg/kg.

6/12 months

0.03, 0.3, 3.0

/p.o.

Pharmacological effects on reproductive tract.

3 mg/kg: Centrilobular hypertrophy of liver cells

(f);

No-adverse effect level: 0.3 mg/kg

Two 104-week carcinogenicity studies have been conducted. In one study, rats were treated with

letrozole, administered orally, in doses of 0.1, 1.0 and 10 mg / kg / day; in the second study, mice

were treated with letrozole orally at doses of 0.6, 6 and 60 mg / kg / day. 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 at all doses in rats and

an increased incidence of benign ovarian granulosa theca cell tumours at all doses in mice) were

secondary to the pharmacological effect of the compound. In the mouse carcinogenicity study,

dermal and systemic inflammations were also noted, particularly in the high dose group, leading

to increased mortality at this dose level. It is not known whether these findings were an indirect

consequence of the pharmacological activity of letrozole (i.e. linked to long-term estrogen

deprivation) or a direct drug effect.

Table 20 - Mutagenicity Studies

Study

Test System(s)

Strain(s)/

Target cells

Concentration /

Dose

Observations

in vitro

Ames

Salmonella

typhimurium

TA 98, 100,

1535, 1537

313-5000 mcg/plate*

No evidence of

mutagenicity

gene mutation

Chinese Hamster

cells

V 79 cells

60-1800 mcg/mL*

No evidence of

mutagenicity

chromosome

aberration

Chinese Hamster

cells

Ovary cell line

CCL 61

Chromosome study:

50/800 mcg/mL*

Cytogenetic test:

145-1160 mcg/mL*

No mutagenic or

clastogenic effects

in vivo

Micronucleus

40, 80, 160 mg/kg / p.o.

No clastogenic or

aneugenic effects

* With or without metabolic activation by a fraction of rat liver microsomes (S-9 mix)

MINT-LETROZOLE Product Monograph

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Reproductive and Development Toxicology:

Letrozole was evaluated for maternal toxicity as well as embryotoxic, fetotoxic and teratogenic

potential in female rats and rabbits. Oral administration of letrozole to pregnant Sprague-

Dawley rats resulted in teratogenicity and maternal toxicity at 0.03 mg/kg (about 1/10 the daily

maximum recommended human dose (MRHD)), and embryotoxicity and fetotoxicity at doses

≥0.003 mg/kg (about 1/100 the daily MRHD). Teratogenic effects included fetal domed head

and cervical/centrum vertebral fusion. Embryotoxic and fetotoxic effects included intrauterine

mortality, increased resorption, increased postimplantation loss, decreased numbers of live

fetuses and fetal anomalies including absence and shortening of renal papilla, dilation of ureter,

edema and incomplete ossification of frontal skull and metatarsals. In New Zealand White

rabbits, letrozole was embryotoxic at doses ≥ 0.002 mg/kg, and fetotoxic when administered at

0.02 mg/kg (about 1/100,000 and 1/10,000 the daily MRHD). Fetal anomalies included

incomplete ossification of the skull, sternebrae, and forelegs and hind legs. It is not known

whether these effects are an indirect consequence of the pharmacological activity of letrozole

(inhibition of estrogen biosynthesis) or a direct drug effect.

Oral administration of letrozole to female rats resulted in a decrease in mating ratio at 0.03

mg/kg. No animals mated at 0.3 mg/kg. Decreases in pregnancy ratios were noted at doses as

low as 0.003 mg/kg and increases in pre-implantation loss at doses of 0.003 and 0.03 mg/kg.

Oral administration of letrozole to male rats at doses of 0, 0.03, 0.3 or 3 mg/kg/day resulted in

adverse effects on male fertility at all doses, and included alterations in sperm parameters

(decreased counts and motility) as well as testicular changes (decreased weights, pallor, tubular

atrophy). Secondary to these effects, severe reductions in the number of sperm-positive and

pregnant females were evident in all treatment groups.

Exposure

lactating

rats

letrozole

associated

with

impaired

reproductive

performance of the male offspring at a letrozole dose as low as 0.003 mg/kg/day. There were

no effects on the reproductive performance of female offspring.

MINT-LETROZOLE Product Monograph

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REFERENCES

BHATNAGAR AS, NADJAFI C, and STEINER R. Aromatase inhibitors in cancer treatment.

IN: Stoll BA (ed). Endocrine management of cancer. Karger Verlag, Basel 1988; 2: 30-42.

BHATNAGAR AS, HÄUSLER A, SCHIEWECK K, LANG M, and BOWMAN R. Highly

selective inhibition of estrogen biosynthesis by CGS 20267, a new non-steroidal aromatase

inhibitor. J Steroid Biochem Molec Biol 1990; 37: 1021-1027.

BHATNAGAR AS, BATZL C, HÄUSLER A, and NOGUES V. The role of estrogen in the

feedback regulation of follicle-stimulating hormone secretion in the female rat. J Steroid

Biochem Molec Biol 1993; 47: 161-166.

BIG 1-98 COLLABORATIVE GROUP. A comparison of Letrozole and Tamoxifen in

Postmenopausal Women with Early Breast Cancer. NEJM 2005; 353: 2747-2757.

Dombernowsky P, Smith I, Falkson G, et al. Letrozole, a new oral aromatase inhibitor

foradvanced breast cancer: Double-blind randomized trial showing a dose effect and improved

efficacy and tolerability compared with megestrol acetate. J Clin Oncol; 1998 Feb; 16 (2):453-

461.

GERSHANOVICH M, CHAUDRI HA, CAMPOS D et al. Letrozole, a new oral aromatase

inhibitor: Randomised trial comparing 2.5 mg daily, 0.5 mg daily and aminoglutethimide in

postmenopausal women with advanced breast cancer. Annals of Oncology 1998:9;639-645.

GOSS

INGLE

MARTINO

randomized

trial

letrozole

postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N

Engl J Med. 2003; 349(19): 1793-1802.

GRODIN JM, SIITERI PK, and MacDONALD PC. Source of estrogen production in the

postmenopausal woman. J Clin Endocrinol Metab 1973; 36: 207-214.

HÄUSLER

MONNET

BORER

BHATNAGAR

Evidence

that

corticosterone is not an obligatory intermediate in aldosterone biosynthesis in the rat adrenal.

J Steroid Biochem 1989; 34: 567-570.

IVESON TJ, SMITH IE, AHERN J, SMITHERS DA, TRUNET PF, and DOWSETT M.

Phase

study

oral

nonsteroidal

aromatase

inhibitor

20267

healthy

postmenopausal women. J Clin Endocrinol Metab 1993; 77: 324-331.

IVESON TJ, SMITH IE, AHERN J, SMITHERS DA, TRUNET PF, and DOWSETT M.

Phase I study of the oral nonsteroidal aromatase inhibitor CGS 20267 in postmenopausal

patients with advanced breast cancer. Cancer Res 1993; 53: 266-270.

JENSEN EV, GREENE GL, CLOSS LE, DeSOMBRE ER, and NADJI M. Receptors

reconsidered - A 20-year perspective. Recent Prog Horm Res 1982; 38: 1-34.

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KNUDSEN JF, and MAHESH VB. Initiation of precocious sexual maturation in the

immature rat treated with dehydroepiandrosterone. Endocrinology 1975; 97: 458-468.

KRAULIS I, TRAIKOV H, SHARPE M, RUF KB, and NAFTOLIN F. Steroid induction of

gonadotropin surges in the immature rat. I. Priming effects of androgens. Endocrinology

1978; 103: 1822-1828.

McGUIRE WL. Steroid hormone receptors in breast cancer treatment strategy. Recent Prog

Horm Res 1980; 36: 135-146.

SCHIEWECK K, BHATNAGAR AS, and MATTER A. CGS 16949A, a new nonsteroidal

aromatase inhibitor: Effects on hormone-dependent and --independent tumors in vivo.

Cancer Res 1988; 48: 834-838.

WINER EP, HUDIS C, BURSTEIN HJ, et al. American Society of Clinical Oncology

Technology

Assessment

aromatase

inhibitors

adjuvant

therapy

postmenopausal women with hormone receptor-positive breast cancer: Status Report 2004.

JCO 2005; 23(3): 1-11.

FEMARA

(letrozole) 2.5 mg tablets, Control No

203017 Product Monograph. Novartis

Pharmaceuticals Canada Inc. July 20, 2017.

IMPORTANT: PLEASE READ

MINT-LETROZOLE Product Monograph

Page 57 of 60

PART III: CONSUMER INFORMATION

Pr

MINT-LETROZOLE

(letrozole tablets USP)

This

leaflet

is

part

III

of

a

three-part

“Product

Monograph”

published

when

MINT-LETROZOLE

tablets were approved for sale in Canada and is designed

specifically for Consumers. This leaflet is a summary

and

will

not

tell

you

everything

about

MINT-

LETROZOLE. Contact your doctor or pharmacist if

you have any questions about the drug.

ABOUT THIS MEDICATION

What MINT-LETROZOLE tablets are used for:

The adjuvant treatment of postmenopausal women with

hormone receptor-positive invasive early breast cancer;

The extended adjuvant treatment of hormone receptor

positive invasive early breast cancer in postmenopausal

women who have received approximately 5 years of

prior standard adjuvant tamoxifen therapy;

The first-line therapy in postmenopausal women with

advanced breast cancer; and

The hormonal treatment of advanced metastatic breast

cancer

after relapse or disease progression in women

with

natural

artificially-induced

postmenopausal

endocrine status, who have previously been treated with

antiestrogens.

What do MINT-LETROZOLE tablets do:

Estrogen is a normally occurring female sex hormone that

stimulates normal breast tissue and the growth of some

types

breast

cancer.

MINT-LETROZOLE

aromatase inhibitor which acts by binding to aromatase, a

substance

needed

make

estrogen.

result,

production of estrogen and the growth of breast cancer are

reduced.

What is adjuvant therapy:

Adjuvant

therapy

breast

cancer

refers

treatment

following breast surgery (the primary or initial treatment)

in order to reduce the risk of recurrence. The purpose of

adjuvant therapy with MINT-LETROZOLE is to treat

hormone

receptor-positive

early

breast

cancer,

after

surgery, in postmenopausal women to reduce the risk of

recurrence.

What is extended adjuvant therapy:

The purpose of extended adjuvant therapy with MINT-

LETROZOLE is to treat hormone receptor-positive early

breast cancer in postmenopausal women who have received

approximately 5 years of prior standard adjuvant tamoxifen

therapy in order to prevent recurrence. Treating breast

cancer with MINT-LETROZOLE beyond the standard 5

years of hormone therapy is called "extended adjuvant

therapy".

When it should not be used:

MINT-LETROZOLE should not be used in children and

adolescents under 18 years of age.

MINT-LETROZOLE

should

used

hormone-

receptor negative disease

Do not take MINT-LETROZOLE if you:

have

ever

unusual

allergic

reaction

letrozole

other

ingredient

MINT-

LETROZOLE ;

still have menstrual periods;

are pregnant or breast-feeding, as MINT-LETROZOLE

may harm your baby.

What the medicinal ingredient is:

Letrozole

What the nonmedicinal ingredients are:

MINT-LETROZOLE

also

contains

following

nonmedicinal

ingredients

needed

make

tablets:

cellulose

compounds

(microcrystalline

cellulose

hypromellose), maize starch, iron oxide yellow, lactose

monohydrate,

magnesium

stearate,

polyethylene

glycol,

sodium starch glycolate, colloidal anhydrous silica, talc and

titanium dioxide

What dosage forms it comes in:

MINT-LETROZOLE (letrozole) 2.5 mg tablets

MINT-LETROZOLE is supplied as film-coated tablets. The

film-coated tablets are yellow, round, biconvex, film coated

tablets marked with “LT” on one side and plain on other

side.

MINT-LETROZOLE is supplied in blister packs containing

30 tablets.

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

MINT-LETROZOLE

should

used

under

supervision of a doctor experienced in the use of anti-

cancer drugs.

MINT-LETROZOLE reduces blood estrogen levels

which may cause a reduction in bone mineral density

and a potential increase in bone loss (osteoporosis)

and/or bone fractures.

aromatase

inhibitors,

including

MINT-

LETROZOLE, may increase the risk of cardiovascular

events compared to tamoxifen, such as heart attacks and

stroke. Women at risk of heart disease should be carefully

monitored by their doctor.

should

not

MINT-LETROZOLE

become pregnant, or are pregnant. There is a potential risk

harm

fetus.

There

reports

spontaneous abortions and abnormalities in babies born to

mothers who

IMPORTANT: PLEASE READ

MINT-LETROZOLE Product Monograph

Page 58 of 60

took letrozole during pregnancy. If you have the potential

become

pregnant

(this

includes

women

perimenopausal or who recently became postmenopausal),

you should discuss with your doctor about the need for

effective contraception.

Use effective birth control during

treatment and for at least 20 days after stopping MINT-

LETROZOLE.

your

doctor

about

options

effective birth control.

should

MINT-LETROZOLE

breastfeeding. There is a potential risk of harm to breastfed

babies.

MINT-LETROZOLE may reduce fertility in males.

there

exposure

MINT-LETROZOLE

during

pregnancy, you should contact your doctor immediately to

discuss the potential of harm to your fetus and potential risk

for loss of the pregnancy.

MINT-LETROZOLE should not be used in children and

adolescents under 18 years of age.

Before you take MINT-LETROZOLE:

Tell your doctor if you:

have a serious kidney or serious liver disease

are taking hormone replacement therapy;

are taking other medication to treat your cancer;

have a personal or family history of osteoporosis or

have ever been diagnosed with low bone density or

have a recent history of fractures (in order for your

doctor to assess your bone health on a regular basis);

have

personal

family

history

high

blood

cholesterol or lipid levels. MINT-LETROZOLE may

increase lipid levels;

have

have

cardiovascular

heart

disease

including any of the following: heart attack, stroke or

uncontrolled

blood

pressure.

MINT-LETROZOLE

increase

risk

cardiovascular

heart

diseases;

have an intolerance to milk sugar (lactose);

have pain in bones, or joints or muscles.

Your level of hormones may be checked by your doctor

before you take MINT-LETROZOLE and regularly during

the first 6 months of treatment to confirm your menopausal

status (cessation of periods).

Driving a vehicle or using machinery:

MINT-LETROZOLE is unlikely to affect your ability to

drive a car or to use machinery. However, some patients

may occasionally feel tired, dizzy, sleepy or experience

visual disorders. If this happens, you should not drive or

operate any tools or machinery until you feel normal again.

INTERACTIONS WITH THIS MEDICATION

Please tell your doctor or pharmacist if you are taking or

have recently taken any other prescription or over-the-

counter

medicines,

vitamins

natural

health

products

during your treatment with MINT-LETROZOLE.

This includes in particular:

Tamoxifen.

Other anti-estrogens or estrogen-containing therapies.

These

substances

diminish

action

MINT-

LETROZOLE.

PROPER USE OF THIS MEDICATION

Usual dose:

The usual dosage is one tablet of MINT-LETROZOLE to

be taken once daily. The tablet should be swallowed whole

with

small

glass

water.

take

MINT-

LETROZOLE with or without food. It is best to take MINT-

LETROZOLE at about the same time every day.

Overdose:

If overdosage is known or suspected, contact your doctor or

the nearest poison control centre for advice immediately.

Show

pack

tablets.

Medical

treatment

necessary.

Missed Dose:

If you forget to take a dose of MINT-LETROZOLE, don't

worry, take the missed dose as soon as you remember.

However, if it is almost time for the next dose (e.g. within 2

or 3 hours), skip the missed dose and go back to your regular

dosage schedule. Do not take a double dose to make up for

the one that you missed.

As with all medicines, patients taking MINT-LETROZOLE

may experience side effects. Most side effects that have

been observed were mild to moderate and will generally

disappear after a few days to a few weeks of treatment.

Check with your doctor if the unwanted effects do not go

away during treatment or become bothersome.

Some side effects, such as hot flushes, hair loss or vaginal

bleeding may be due to the lack of estrogen in your body.

Very common side effects (they affect more than 10 in

every 100 patients)

increased level of cholesterol (hypercholesterolemia)

hot flushes

increased sweating

night sweats

fatigue (including weakness and malaise (generally

feeling unwell))

pain in bones and joints (arthralgia).

Common side effects (they affect between 1 to 10 in every

100 patients)

SIDE EFFECTS AND WHAT TO DO ABOUT

THEM

IMPORTANT: PLEASE READ

MINT-LETROZOLE Product Monograph

Page 59 of 60

headache

rash

dizziness, vertigo

gastrointestinal disorders (such as, nausea,

vomiting, indigestion, constipation, diarrhea)

increase in or loss of appetite

increased blood sugar (hyperglycaemia)

urinary incontinence

pain in muscles

bone loss (osteoporosis)

bone fractures

depression

weight increase

anxiety

insomnia

hair loss

vaginal bleeding

dry skin

raised blood pressure (hypertension)

abdominal pain.

back pain

fall

palpitations (rapid heart rate)

joint stiffness (arthritis)

chest pain

Uncommon side effects (they affect between 1 to 10 in

every 1000 patients)

nervous

disorders

(such

nervousness,

irritability,

drowsiness)

pain or burning sensation in the hands or wrists (carpal

tunnel syndrome)

reduced sense of touch (dysaesthesia)

eye irritation

itchy rash (urticaria), rapid swelling of face, lips, tongue,

throat (angioedema)

severe allergic reaction (anaphylactic reaction)

vaginal disorders (such as discharge or dryness)

breast pain

fever

thirst, taste disorder, dry mouth

dryness of mucous membranes

weight decrease

urinary tract infection, increased frequency of urination

cough

abnormal liver function test results (blood test

disorders).

Increased bilirubin level (dark coloured urine)

Jaundice (yellowish eyes and/or skin).

Side effects with frequency not known

trigger finger, a condition in which your finger or thumb

catches in a bent position.

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

If you notice any other side effects not listed in this leaflet,

please tell your doctor or pharmacist.

SERIOUS SIDE EFFECTS, HOW OFTEN THEY

HAPPEN AND WHAT TO DO ABOUT THEM

Symptom/ effect

Talk with

your doctor

or

pharmacist

Stop taking

drug and

call your

doctor or

pharmacist

Only if

severe

In all

cases

Common

- Pain in the muscles, bones

and joints;

- Joint stiffness;

- Persistent sad mood (i.e.

depression)

Uncommon

- Tightness or feeling of

heaviness in the chest or pain

radiating from your chest to

your arms or shoulders, neck,

teeth or jaw, abdomen or

back (signs of angina pectoris

or heart attack);

- Numbness or weakness in

arm or leg or any part of the

body, loss of coordination,

vision changes, sudden

headache, nausea, loss of

coordination, difficulty in

speaking or breathing (signs

of brain disease e.g. stroke)

-Swelling and redness along a

vein which is extremely

tender and possibly painful

when touched (signs of

inflammation of a vein due to

a blood clot, e.g.

thrombophlebitis);

- Difficulty breathing, chest

pain, fainting rapid heart rate,

bluish skin discoloration

(signs of blood clot

formation in the lung such as

pulmonary embolism);

- Swelling of arms, hands,

feet, ankles or other parts of

the body (signs of oedema);

- Swelling mainly of the face

and throat (signs of allergic

reaction);

Severe

fever,

chills

mouth

ulcers

infections (signs of low level

of white blood cells);

- Blurred vision (sign of

cataract).

- Yellow skin and eyes,

IMPORTANT: PLEASE READ

MINT-LETROZOLE Product Monograph

Page 60 of 60

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).

This

is

not

a

complete

list

of

side

effects.

For

any

unexpected

effects

while

taking

MINT-LETROZOLE,

contact your doctor or pharmacist.

HOW TO STORE IT

Store your tablets in a dry place at room temperature 15°C

to 30°C. Avoid places where the temperature may rise

above 30°C. Protect from moisture.

Keep this medicine out of the reach and sight of children and

pets.

Expiry date:

Do not take MINT-LETROZOLE after the expiry date

which is stated on the carton after EXP. The expiry date

refers to the last day of the month. Remember to take any

unused medication back to your pharmacist.

REPORTING SIDE EFFECTS

You can report any suspected side effects associated

with the use of health products to Health Canada by:

Visiting the Web page on Adverse Reaction

Reporting (https://www.canada.ca/en/health-

canada/services/drugs-health-products/medeffect-

canada/adverse-reaction-reporting.html) for

information on how to report online, by mail or by

fax; or

Calling toll-free at 1-866-234-2345.

NOTE: Contact your health professional if you need

information about how to manage your side effects.

The

Canada

Vigilance

Program

does

not

provide

medical advice.

MORE INFORMATION

If

you

want

more

information

about

MINT-

LETROZOLE:

Talk to your healthcare professional

Find the full product monograph that is prepared

for healthcare professionals and includes this Part

III: Consumer Information by visiting the Health

Canada website (https://health-

products.canada.ca/dpd-bdpp/index-eng.jsp); or

by calling the sponsor Mint Pharmaceuticals Inc.

at 1-877-398-9696.

This leaflet was prepared by:

Mint Pharmaceuticals Inc.

6575 Davand Drive

Mississauga, ON, L5T 2M3

Canada

Manufactured by:

Intas Pharmaceuticals Limited,

Ahmedabad, India

Date prepared: November 17, 2020

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