Consumer medicine information

FERA

Letrozole

BRAND INFORMATION

Brand name

Fera

Active ingredient

Letrozole

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using FERA.

What is in this leaflet

This leaflet answers some common questions about FERA.

It does not contain all of the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have benefits and risks. Your doctor has weighed the risks of you taking FERA against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, talk to your doctor or pharmacist.

Keep this leaflet with your medicine. You may need to read it again.

What FERA is used for

FERA is used to treat breast cancer in women who are post-menopausal - that is, women who no longer have periods, either naturally due to their age or after surgery or chemotherapy.

FERA belongs to a family of medicines called aromatase inhibitors. They are also called "antioestrogens" because they act by reducing the production of oestrogen in your body.

Oestrogen stimulates the growth of certain types of breast cancer. These cancers are called "oestrogen-dependent." Reducing the production of oestrogen may help to keep the cancer from growing.

This may be the first time you are taking an "antioestrogen" or you may have taken another "antioestrogen" such as tamoxifen in the past.

Your doctor may have prescribed FERA for another reason. Ask your doctor if you have any questions about why FERA has been prescribed for you.

FERA is available only with a doctor's prescription.

Before you take FERA

When you must not take it

Do not take FERA if you are allergic to medicines containing letrozole or any of the ingredients listed at the end of this leaflet. Some of the symptoms of an allergic reaction may include skin rash, itching or hives, swelling of the face, lips or tongue which may cause difficulty in swallowing or breathing, wheezing or shortness of breath.

Do not take FERA if you are still having periods. This medicine is only used in women who are no longer having periods.

Women of child-bearing age who recently became postmenopausal or perimenopausal should use a proven method of birth control to avoid pregnancy, until your postmenopausal status is fully established.

Do not take FERA if you are pregnant or breastfeeding. FERA may affect your baby if you take it while pregnant or breastfeeding.

Do not take FERA if the expiry date (Exp.) printed on the pack has passed.

Do not take FERA if the packaging is torn or shows signs of tampering.

Before you start to take it

Tell your doctor if you are allergic to any other medicines, foods, dyes or preservatives.

Tell your doctor if you have severe kidney or liver disease. Your doctor may want to take special precautions while you are taking this medicine.

If you have not told your doctor about any of the above, tell them before you start taking FERA.

Taking other medicines

Tell your doctor if you are taking any other medicines, including any that you buy without a prescription from a pharmacy, supermarket or health food shop. Some medicines may be affected by FERA, or may affect how well it works.

Your doctor can tell you what to do when taking FERA with other medicines.

How to take FERA

How much to take

The usual dose is one FERA tablet daily.

Follow all directions given to you by your doctor and pharmacist carefully.

How to take FERA

Swallow the tablets with a glass of water or other liquid.

If your stomach is upset after taking the tablets, take it with a meal or after a snack.

If you forget to take FERA

If it is almost time for your next dose (e.e. within 2 to 3 hours), skip the dose you missed and take your next dose when you are meant to.

Otherwise, take the missed dose as soon as you remember, and then go back to taking your tablets as you would normally.

Do not take a double dose to make up for the dose you missed.

If you are not sure what to do, ask your doctor or pharmacist.

How long to take FERA for

Your doctor will check your progress to make sure the medicine is working and will decide how long your treatment should continue.

If you are unsure, talk to your doctor.

If you take too much FERA (overdose)

Immediately telephone your doctor, or the Poisons Information Centre (telephone 13 11 26), or go to Accident and Emergency at the nearest hospital, if you think you or anyone else may have taken too much FERA. Do this even if there are no signs of discomfort or poisoning.

While you are taking FERA

Things you must do

Before starting any new medicine, tell your doctor or pharmacist that you are taking FERA.

Tell all the doctors, dentists and pharmacists who are treating you that you are taking FERA.

If you become pregnant while taking FERA, tell your doctor immediately.

Follow your doctor's instructions carefully. If you do not follow your doctor's instructions, your treatment may not help or you may have unwanted side effects.

Be sure to keep all of your doctor's appointments so that your progress can be checked. Your doctor may want you to have blood tests from time to time to check on your progress and detect any unwanted side effects. Your doctor may also decide to monitor your bone health as this medicine may cause thinning or wasting of your bones (osteoporosis).

Things you must not do

Do not use FERA to treat any other conditions unless your doctor tells you to.

Do not give FERA to anyone else, even if they have the same condition as you.

Things to be careful of

Be careful driving, operating machinery or doing anything that requires alertness until you know how FERA affects you. FERA may cause dizziness or tiredness in some people. If this occurs, do not drive or do anything else that could be dangerous.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking FERA. Like all other medicines, FERA may have unwanted side effects in some people. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor if you notice any of the following and they worry you:

  • swelling of the feet, ankles or other parts of the body due to fluid build up
  • skin rash, itching or dry skin
  • pain in the muscles, joints or bones; joint stiffness, arthritis
  • vaginal spotting or bleeding
  • whitish, thick vaginal discharge, vaginal dryness
  • headache
  • fever
  • tiredness, sleepiness, weakness or dizziness
  • difficulty sleeping
  • numbness or tingling in hands or feet
  • mood changes such as anxiety, nervousness, irritability and depression (sad mood)
  • forgetfulness
  • change in sense of taste
  • blurred vision or eye irritation
  • stomach upset, nausea (feeling sick) or vomiting, pain in the abdomen
  • constipation
  • diarrhoea
  • dry mouth, sore mouth, mouth ulcers and cold sores
  • increased thirst
  • breast pain
  • hot flushes
  • increased sweating
  • appetite or weight changes
  • hair thinning
  • urgent need to urinate (pass water)
  • pain or burning sensation when urinating, which may be a sign of an infection
  • fast or irregular heartbeat
  • thinning of bones (osteoporosis; which can only be identified by laboratory testing), bone fractures.

Tell your doctor immediately or go to Accident and Emergency at the nearest hospital if you notice any of the following:

  • signs that blood clots may have formed, such as sudden severe headache, sudden loss of coordination, blurred vision or sudden loss of vision, slurred speech, numbness or tingling in an arm or leg, painful swelling in the calves or thighs, chest pain, difficulty breathing, coughing blood
  • constant "flu-like" symptoms (chills, fever, sore throat, sores in mouth, swollen glands, tiredness or lack of energy) that could be a sign of blood problems.

These side effects can be serious. You may need urgent medical attention or hospitalisation.

Other side effects not listed above may also occur in some patients. Tell your doctor if you notice anything that is making you feel unwell.

After using FERA

Storage

Keep FERA where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Keep your tablets in a cool dry place where the temperature stays below 25°C.

Do not store FERA or any other medicine in the bathroom or near a sink.

Do not leave FERA in the car or on window sills. Heat and dampness can destroy some medicines.

Disposal

If your doctor tells you to stop taking FERA, or your tablets have passed their expiry date, ask your pharmacist what to do with any that are left over.

Product description

What it looks like

FERA is a round yellow tablet.

Each pack contains 30 tablets.

Ingredients

The active ingredient in FERA is letrozole. Each FERA tablet contains 2.5 mg of letrozole.

The tablets also contain:

  • lactose
  • sodium starch glycollate
  • microcrystalline cellulose
  • hypromellose
  • colloidal anhydrous silica
  • magnesium stearate
  • Opadry Yellow 03B52094 (ARTG No. 106949).

The tablets do not contain gluten, sucrose, tartrazine or any other azo dyes.

Supplier

Aspen Pharma Pty Ltd
34-36 Chandos St
St Leonards NSW 2065
Australia

Australian registration numbers: FERA - AUST R 175100

Date of preparation: September 2011.

Published by MIMS August 2014

BRAND INFORMATION

Brand name

Fera

Active ingredient

Letrozole

Schedule

S4

 

1 Name of Medicine

Letrozole.

2 Qualitative and Quantitative Composition

Fera tablets contain 2.5 mg of letrozole. The tablets also contain lactose, sodium starch glycollate, cellulose - microcrystalline, hypromellose, silica - colloidal anhydrous, magnesium stearate and Opadry Yellow 03B52094 (ID No. 106949). The tablets are gluten free.
For full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Yellow, round, biconvex tablet.

4 Clinical Particulars

4.1 Therapeutic Indications

For the treatment of postmenopausal women with hormone receptor positive breast cancer (see Section 5.1 Pharmacodynamic Properties, Clinical trials). The safety and efficacy of neoadjuvant use of letrozole has not been established. Letrozole is not indicated in hormone receptor negative disease.

4.2 Dose and Method of Administration

Adults.

The recommended dose of letrozole is one tablet daily.
In the adjuvant setting, treatment should continue for five years or until tumour relapse occurs, whichever comes first.
In the extended adjuvant setting, the optimal treatment duration with letrozole is not known. The planned duration of treatment in the pivotal study was five years. However, at the time of the analysis, the median duration of treatment was 24 months, 25% of patients were treated for at least three years and less than 1% of patients were treated for the planned five years. The median duration of follow-up was 28 months. Treatment should be discontinued at tumour relapse.
In the adjuvant setting the median duration of treatment was 25 months, 73% of the patients were treated for more than two years, 22% of the patients for more than four years. The median duration of follow-up was 30 months (the efficacy data mentioned (see Section 5.1 Pharmacodynamic Properties, Clinical trials) are based on the primary core analysis with a median duration of follow-up of 26 months).
In patients with metastatic disease, treatment with letrozole should continue until tumour progression is evident.

Elderly patients.

No dose adjustment is required.

Patients with hepatic/ renal impairment.

No dosage adjustment is required for patients with mild renal impairment (creatinine clearance ≥ 30 mL/minute). Insufficient data are available to justify a dose advice in cases of renal insufficiency with creatinine clearance less than 30 mL/minute or in patients with severe hepatic insufficiency. Patients with severe hepatic impairment (Child-Pugh score C) should be kept under close supervision (see Section 5.2 Pharmacokinetic Properties; Section 4.4 Special Warnings and Precautions for Use).

Children.

Not applicable.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.
Premenopausal endocrine status; pregnancy, lactation (see Section 4.4 Special Warnings and Precautions for Use).

4.4 Special Warnings and Precautions for Use

Use with caution in the following circumstances.

Renal impairment.

Letrozole has not been investigated in patients with creatinine clearance < 10 mL/minute nor in a sufficient number of patients with a creatinine clearance less than 30 mL/minute. The potential risk/ benefit to such patients should be carefully considered before administration of letrozole. As letrozole is weakly bound to plasma proteins (see Section 5.2 Pharmacokinetic Properties), it is anticipated that it could be removed from circulation by dialysis. Similar caution should be exercised in patients with severe hepatic insufficiency.

Hepatic impairment.

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

Bone effects.

Osteoporosis and/or bone fractures have been reported with the use of letrozole. Therefore, monitoring of overall bone health is recommended during treatment (see Section 4.8 Adverse Effects (Undesirable Effects); Section 5.1 Pharmacodynamic Properties, Clinical trials).

4.5 Interactions with Other Medicines and Other Forms of Interactions

To date, there are minimal data on the interaction between letrozole and other drugs.
Clinical interaction studies with cimetidine and warfarin indicated that the coadministration of letrozole with these drugs does not result in clinically significant drug interactions.
Additionally, in a large clinical trial there was no evidence of clinically relevant interaction in patients receiving other commonly prescribed drugs (e.g. benzodiazepines, barbiturates, nonsteroidal anti-inflammatory drugs (NSAIDs) such as diclofenac sodium and ibuprofen, paracetamol, frusemide, omeprazole).
There is no clinical experience to date on the use of letrozole in combination with other anticancer agents.
In vitro studies indicate that letrozole is an inhibitor of cytochrome P450 2A6 and 2C19 isoenzymes. Thus, caution should be used in the concomitant administration of drugs whose disposition is mainly dependent on these isoenzymes and whose therapeutic index is narrow.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

In rats treated with letrozole beginning on day 7 postpartum for 9 weeks, mating and fertility were decreased at all doses (0.003-0.3 mg/kg/day; below and similar to the human exposure at 2.5 mg/day). The treated rats also displayed delayed sexual maturation, prolonged diestrus and histological changes of reproductive organs (see Section 5.3 Preclinical Safety Data).
Chronic studies indicated stromal hyperplasia of the ovaries and uterine atrophy in rats administered oral dosages equal to or greater than 0.3 mg/kg/day (approximately equivalent to human exposure at 2.5 mg/day, based on AUC). In addition, ovarian follicular atrophy and uterine atrophy were observed in chronic studies of female dogs administered doses equal to or greater than 0.03 and 0.3 mg/kg/day respectively (less than and approximately equivalent to human exposure at 2.5 mg/day).
(Category D)
Drugs which have caused, are suspected to have caused or may be expected to cause, an increased incidence of human fetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects. Accompanying texts should be consulted for further details.
Treatment of pregnant rats with letrozole at oral doses of 0.03 mg/kg/day during organogenesis was associated with a slight increase in the incidence of fetal malformation among the animals treated. It was not possible to show whether this was an indirect consequence of the pharmacological properties (inhibition of oestrogen biosynthesis) or a direct effect of letrozole in its own right. At doses of 0.003 mg/kg and above, higher incidences of resorptions and dead fetuses were also reported. These effects are consistent with the disruption of oestrogen dependent events during pregnancy and are not unexpected with a drug of this class. No perinatal/ postnatal studies have been conducted in animals. Letrozole is contraindicated during pregnancy (see Section 4.3 Contraindications).

Women of childbearing potential.

The physician needs to discuss the necessity of adequate contraception with women who have the potential to become pregnant, including women who are perimenopausal or who recently became postmenopausal, until their postmenopausal status is fully established.
 Letrozole is contraindicated during lactation. It is not known if letrozole is excreted in human or animal milk (see Section 4.3 Contraindications).

4.7 Effects on Ability to Drive and Use Machines

Since fatigue and dizziness have been observed with the use of letrozole and somnolence has been reported uncommonly, caution is advised when driving or using machines.

4.8 Adverse Effects (Undesirable Effects)

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 of early breast cancer in women who have received prior standard tamoxifen therapy.
Approximately one-third of the patients treated with letrozole in the metastatic setting, and 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 for letrozole) can be expected to experience adverse effects. Generally, the observed adverse reactions are mainly mild or moderate in nature and most are associated with oestrogen deprivation.
The most frequently reported adverse effects in the clinical studies were hot flushes, arthralgia, nausea and fatigue. Many adverse effects can be attributed to either the normal pharmacological consequences of oestrogen deprivation (e.g. hot flushes, alopecia and vaginal bleeding).
The following adverse effects, not reported in the advanced or metastatic clinical trials, were noted in the extended adjuvant setting: arthralgia/ arthritis, osteoporosis and bone fractures (see Section 5.1 Pharmacodynamic Properties, Clinical trials, Extended adjuvant treatment of early breast cancer).
The following adverse drug effects were reported from clinical studies and from postmarketing experience with letrozole. See Table 1.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

Isolated cases of overdosage with letrozole have been reported. No specific treatment for overdosage is known. Treatment should be symptomatic and supportive.
Contact the Poisons Information Centre (Australia) on 131126 for advice on the management of an overdose.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

The elimination of oestrogen mediated stimulatory effects is a prerequisite for tumour response in cases where the growth of tumour tissue depends on the presence of oestrogens. In postmenopausal women, oestrogens are mainly derived from the action of the aromatase enzyme, which converts adrenal androgens (primarily androstenedione and testosterone) to oestrone (E1) and oestradiol (E2). The suppression of oestrogen biosynthesis in peripheral tissues and the cancer tissue itself can, therefore, be achieved by specifically inhibiting the aromatase enzyme.
Letrozole is a nonsteroidal aromatase inhibitor. Data suggest it inhibits the aromatase enzyme by competitively binding to the haem of the cytochrome P450 subunit of the enzyme, resulting in a reduction of oestrogen biosynthesis in all tissues.
In healthy postmenopausal women, single doses of letrozole 0.1, 0.5 and 2.5 mg suppressed serum oestrone and oestradiol by 75 to 78% and 78% from baseline, respectively. Maximum suppression was achieved in 48 to 78 hours.
In postmenopausal patients with advanced breast cancer, daily doses of 0.1 to 5 mg letrozole suppressed plasma concentrations of oestradiol, oestrone and oestrone sulfate by 75 to 95% from baseline in all patients treated. With doses of 0.5 mg and higher, many values of oestrone and oestrone sulfate were below the limit of detection in the assays, indicating that higher oestrogen suppression is achieved with these doses. Oestrogen suppression was maintained throughout treatment in all patients.
Letrozole is highly specific in inhibiting aromatase activity. Impairment of adrenal steroidogenesis has not been observed. No clinically relevant changes were found in the plasma concentrations of cortisol, aldosterone, 11-deoxycortisol, 17-hydroxyprogesterone, adrenocorticotrophic hormone (ACTH) or in plasma renin activity among postmenopausal patients treated with a daily dose of letrozole 0.1 to 5 mg. The ACTH stimulation test performed after 6 and 12 weeks of treatment with daily doses of letrozole 0.1, 0.25, 0.5, 1, 2.5 and 5 mg did not indicate any attenuation of aldosterone or cortisol production. Thus, glucocorticoid and mineralocorticoid supplementation is not necessary.
No changes were noted in plasma concentrations of androgens (androstenedione and testosterone) among healthy postmenopausal women after 0.1, 0.5 and 2.5 mg single doses of letrozole or in plasma concentrations of androstenedione among postmenopausal patients treated with daily doses of 0.1 to 5 mg, indicating that the blockade of oestrogen biosynthesis does not lead to accumulation of androgenic precursors. Plasma levels of luteinising hormone (LH) and follicle stimulating hormone (FSH) were not affected by letrozole in patients, nor was thyroid function as evaluated by thyroid stimulating hormone, T4 and T3 uptake.

Clinical trials.

Adjuvant treatment of early breast cancer.

Study BIG 1-98. BIG 1-98, a multicentre, double blind, randomised study was conducted in over 8,000 postmenopausal women with resected receptor positive early breast cancer. In this study, patients were randomly assigned to one of the following arms: A. tamoxifen for five years; B. letrozole for five years; C. tamoxifen for two years followed by letrozole for three years; or D. letrozole for two years followed by tamoxifen for three years.
This study was designed to investigate two primary questions: whether letrozole for 5 years was superior to tamoxifen for 5 years (primary core analysis and monotherapy arms analysis) and whether switching endocrine treatments at 2 years was superior to continuing the same agent for a total of 5 years (sequential treatments analysis).
The protocol specified efficacy endpoints were disease free survival (DFS), overall survival (OS) and systemic disease free survival (SDFS). The protocol specified primary efficacy endpoint of DFS was defined as the interval between date of randomisation and earliest confirmed invasive locoregional recurrence, distant metastasis, invasive contralateral breast cancer, second invasive (nonbreast) primary cancer, or death from any cause without a prior cancer event. The protocol specified secondary efficacy endpoint of OS was defined as the interval from randomisation to death from any cause. The protocol specified secondary efficacy endpoint of SDFS was defined as the interval from randomisation to systemic relapse, distant metastasis, appearance of a second (nonbreast) primary cancer, or death from any cause, whichever occurred first (i.e. excluding locoregional recurrences in the ipsilateral or contralateral breast). In addition, secondary efficacy endpoints specified in the statistical analysis plan prior to the end of enrolment and prior to an interim analysis included time to distance metastases and time to invasive contralateral breast cancer.

Efficacy results at a median follow-up of 26 months.

Data in Table 2 reflect results of the primary core analysis (PCA) including data from nonswitching arms (arms A and B) together with data truncated 30 days after the switch in the two switching arms (arms C and D). The analysis was conducted at a median treatment duration of 24 months and a median follow-up of 26 months. Letrozole for 5 years was superior to tamoxifen for efficacy endpoints of disease free survival (protocol specified), time to distant metastases, and systemic disease free survival, but not for the efficacy endpoints of overall survival and invasive contralateral breast cancer.

MAA efficacy results at a median follow-up of 73 months.

The monotherapy arms analysis (MAA) which includes data for the monotherapy arms only provides the clinically appropriate long-term update of the efficacy of letrozole monotherapy compared to tamoxifen monotherapy (Table 3). In 2005, based on the PCA data presented in Table 3 and on recommendations by the independent data monitoring committee, the tamoxifen monotherapy arms were unblinded and patients were allowed to cross over to letrozole. 26% of patients randomised to tamoxifen elected to cross over to letrozole including a very small number of patients who crossed over to other aromatase inhibitors. To explore the impact of this selective crossover, analyses censoring DFS and OS follow-up times at the date of the selective crossover (in the tamoxifen arm) were conducted, and these analyses as well as the ITT analyses for selective endpoints disregarding selective crossover from tamoxifen to letrozole are summarised for the MAA (Table 3).
At a median follow-up of 73 months and a median treatment duration of 60 months, the risk of a DFS event was significantly reduced with letrozole compared with tamoxifen (MAA ITT analysis: HR 0.88; 95% CI 0.78, 0.99; p = 0.03; confirming the 2005 PCA results. Analysis of DFS taking account of the selective crossover shows similar benefit (HR 0.085; 95% CI 0.75, 0.96). Similarly, the updated analysis confirmed the superiority of letrozole in reducing the risk of distant disease free survival events (HR 0.87, 0.76, 1.00) as well as the risk of reducing distant metastases (HR 0.85; 95% CI 0.72, 1.00). Additionally, overall survival trended towards significance in the ITT analysis. Analysis of overall survival taking account of the selective crossover shows a significantly greater benefit (HR 0.82, 0.70, 0.96) in favour of letrozole.

Sequential treatments analyses.

The sequential treatments analysis (STA) addresses the second primary question of the study. The primary analysis for the STA was from switch (or equivalent time point in monotherapy groups) + 30 days (STA-S) with a two sided test applied to each pair wise comparison at the 2.5% level. These analyses were conducted at a median follow-up of 43 months after switch. Additional, exploratory analyses were conducted from randomisation (STA-R) at a median follow-up of 67 months, with the results for each comparison summarised by hazard ratios and 99% confidence intervals.
At a median follow-up of 43 months after switch, there were no significant differences in any endpoint from switch in the sequential treatments analysis with respect to either monotherapy (e.g. tamoxifen 2 years followed by letrozole 3 years versus tamoxifen beyond 2 years, DFS HR 0.86; 97.5% CI 0.67, 1.09; and letrozole 2 years followed by tamoxifen 3 years versus letrozole beyond 2 years, DFS HR 0.92; 97.5% CI 0.72, 1.17). At a median follow-up of 67 months from randomisation, there were no significant differences in any endpoint from randomisation in the sequential treatments analysis (e.g. tamoxifen 2 years followed by letrozole 3 years versus letrozole 5 years, DFS HR 0.96; 99% CI 0.76, 1.21). There was no evidence that a sequence of letrozole and tamoxifen was superior to letrozole alone given for 5 years.

Safety data at a median treatment duration of 60 months derived from MAA.

In a study BIG-98 at median treatment duration of 60 months, the side effects seen were consistent with the safety profile of the drug. Certain adverse reactions were prospectively specified for analysis, based on the known pharmacologic properties and side effect profiles of the two drugs.
Adverse events were analysed irrespective of drug relationship. Most adverse events reported (approximately 75% of patients reporting 1 or more AE) were grade 1 and grade 2 applying the CTC criteria version 2.0/ CTCAE, version 3.0. When considering all grades during study treatment, a statistically significantly higher incidence of events was seen for letrozole compared to tamoxifen regarding hypercholesterolemia (52% vs. 29%), fractures (10.1% vs. 7.1%), myocardial infarctions (1.0% vs. 0.5%), osteoporosis (5.1% vs. 2.7%) and arthralgia (25.2% vs. 20.4%), vulvovaginal dryness (3.6% vs. 1.7%).
A statistically significantly higher incidence was seen for tamoxifen compared to letrozole regarding hot flushes (38% vs. 33%), night sweating (17% vs. 15%), vaginal bleeding (13% vs. 5.2%), constipation (2.9% vs. 2.0%), thromboembolic events (3.6% vs. 2.1%), endometrial hyperplasia/ cancer (2.3% vs. 0.2%), and endometrial proliferation disorders (3.5% vs. 0.6%).

Adjuvant therapy in early breast cancer.

Study D2407.

Study D2407 is a phase III, open label, randomised, multicentre 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. A total of 262 postmenopausal women with hormone sensitive resected primary breast cancer were randomly assigned to either letrozole 2.5 mg daily for 5 years or tamoxifen 20 mg daily for 2 years followed 3 years of letrozole 2.5 mg 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.
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%). At 2 years, overall the median difference in lumbar spine BMD change between letrozole and tamoxifen was statistically significant in favour of tamoxifen (p < 0.0001). The current data indicates that no patient with a normal BMD at baseline became osteoporotic at year 2 and only 1 patient with osteopenia at baseline (T score of -1.9) developed osteoporosis during the treatment period (assessment by central review).
The results for total hip BMD were similar to those for lumbar spine BMD. The differences, however, were less pronounced. At 2 years, a significant difference in favour of tamoxifen was observed in the overall BMD safety population and all stratification categories (p < 0.0001). During the 2 year period, fractures were reported by 20 patients (15%) in the letrozole arm, and 22 patients (17%) in the tamoxifen arm.
In the tamoxifen arm, the median total cholesterol levels decreased by 16% after 6 months compared to baseline; a similar decrease was also observed at subsequent visits up to 24 months. In the letrozole arm, the median total cholesterol levels were relatively stable over time, with no significant increase at a single visit. The differences between the 2 arms were statistically significant in favour of tamoxifen at each time point (p < 0.0001).

Extended adjuvant treatment of early breast cancer.

A multicentre, double blind, randomised, placebo controlled study (CFEM345G- MA-17) was conducted in over 5,100 postmenopausal patients with receptor positive or unknown primary breast cancer. In this study, patients who had remained disease free after completion of adjuvant treatment with tamoxifen (4.5 to 6 years) were randomly assigned either letrozole or placebo.
The planned duration of treatment for patients in the study was five years but the trial was unblinded early because of an interim analysis showing a favourable letrozole effect. At the time of unblinding, women had been followed for a median of 28 months (25% of the patients had been followed up for up to 38 months). The primary analysis showed that letrozole reduced the risk of recurrence by 42% compared with placebo (hazard ratio 0.58; p = 0.00003). The statistically significant benefit in disease free survival (DFS) in favour of letrozole was observed regardless of nodal status (node negative, hazard ratio 0.48, p = 0.002; node positive, hazard ratio 0.61, p = 0.002).
The independent data and safety monitoring committee (DMSC) recommended that women who were disease free in the placebo arm be allowed to switch to letrozole for up to 5 years, when the study was unblinded in 2003. The study protocol was duly amended, implementing the DSMC recommendation: 60% of the eligible patients in the placebo arm opted to switch to letrozole, while the remaining patients opted to have no further treatment but agreed to continue to be monitored. The selective switch to letrozole severely compromised further comparative analyses of efficacy and safety in the final, close out analysis after median treatment duration of 5 years for letrozole, 64% of the randomised placebo arm total follow-up patient years was actually accrued under letrozole, not placebo.
In the updated, final analysis conducted in the 2008, 1,551 women opted to switch from placebo to letrozole, at a median 31 months after completion of adjuvant tamoxifen therapy. Median duration of letrozole after switch was 40 months.
All significance levels in the 2008 analysis are provided for information purposed only, not for inference. No adjustment has been made for multiple updates or for multiple endpoints. Analyses of efficacy endpoints "ignoring the switch" compare the randomised letrozole arm with a control arm in which follow-up was approximately one third placebo, two thirds letrozole. Median treatment duration for letrozole was 60 months; in the placebo arm, median duration of placebo until switch (if a switch occurred) was 37 months.
The updated final analysis, conducted at a median follow-up of 62 months confirmed the significant reduction in the risk of breast cancer recurrence with letrozole compared with placebo, despite 60% of women in the placebo arm switching to letrozole after the study was unblinded. The protocol specified 4 year DFS rate was identical in the letrozole arm for both the 2004 and 2008 analyses, confirming the stability of the data and robust effectiveness of letrozole long term. In the placebo arm, the impact of the selective switch to letrozole is seen in the increase in 4 years DFS rate and in the apparent dilution in treatment difference.
In the original analysis, for the secondary endpoint overall survival (OS) a total of 113 deaths were reported (51 letrozole, 62 placebo). Overall, there was no significant difference between treatments in OS (hazard ratio 0.82; p = 0.29). In node positive disease, letrozole significantly reduced the risk of mortality by approximately 40% (hazard ratio 0.61; p = 0.035), whereas no significant difference was seen in node negative patients (hazard ratio 1.36; p = 0.385), in patients with prior chemotherapy and in patients with no prior chemotherapy (see Tables 4 and 5).
In the updated analysis, as shown in Table 4, there was a significant reduction in the odds of an invasive contralateral breast cancer with letrozole compared with placebo, despite 60% of the patients in the placebo arm having switched to letrozole. There was no significant difference in overall survival.
There was no difference in safety and efficacy between patients aged < 65 versus ≥ 65 years.
The updated safety profile of letrozole did not reveal any new adverse event and was entirely consistent with the profile reported in 2004.
The following adverse events irrespective of causality were reported statistically significantly more often with letrozole (n = 2,567) than with patients who elected not to switch to letrozole after the study was unblinded (n = 1,026): hot flushes (letrozole, 60.9% versus placebo, 51.4%) arthralgia/ arthritis (41.5% versus 27.2%), sweating (34.8% versus 29.7%), hypercholesterolemia (23.6% versus 15.3%) and myalgia (17.7% versus 9.4%). Most of these adverse events were observed during the first year of treatment.
For patients who elected to switch to letrozole after the study was unblinded, the pattern of general adverse events reported was similar to the pattern during the first two years of treatment in the double blind study.
Cardiovascular, skeletal and endometrial events were collected with dates of onset and it is possible to report according to the treatment received.
With respect to cardiovascular events, statistically significantly more patients reported overall cardiovascular events with letrozole (9.8%) than with placebo (7.0%). Overall cardiovascular events were reported for 6.2% of the patients who elected to switch to letrozole. Significantly more patients reported stroke/ TIA with letrozole (1.5%) than with placebo (0.8%) (letrozole after switch, 1.4%); and thromboembolic events (letrozole, 0.9% versus placebo, 0.3%) (letrozole after switch, 0.6%).
Fractures were reported significantly more often with letrozole (10.4%) than with placebo (5.8%) (letrozole after switch, 7.7%) as was new osteoporosis (letrozole, 12.2% versus placebo, 6.4%) (letrozole after switch, 5.4%). Irrespective of treatment, patients aged 65 years or older at enrolment experienced more bone fractures and more (new) osteoporosis than younger women.
Updated results (median duration of follow-up was 61 months) from the bone substudy demonstrated that at 2 years, compared to baseline, patients receiving letrozole had a median decrease of 3.8% in hip bone mineral density (BMD) compared to 2.0% in the placebo group (p = 0.02). There was no significant difference between treatments in terms of changes in lumbar spine BMD at any time. Updated results (median follow-up was 62 months) from the lipid substudy showed no significant difference between the letrozole and placebo groups at any time in total cholesterol or in any lipid fraction. In the updated analysis the incidence of cardiovascular events (including cerebrovascular and thromboembolic events) during treatment with letrozole versus placebo until switch was 9.8% vs 7.0%, a statistically significant difference.

First line treatment of advanced breast cancer.

One well controlled double blind trial (study 025) was conducted comparing letrozole 2.5 mg (n = 453) to tamoxifen 20 mg daily (n = 454) as first line therapy in postmenopausal women with locally advanced or metastatic breast cancer. The percentage of patients with hormone receptor positive tumours was 64% in the letrozole group and 67% in the tamoxifen group. Letrozole was superior to tamoxifen in time to progression (primary endpoint) and in overall objective tumour response and time to treatment failure. Time to response and duration of response were the same for both drugs. Specific results are presented in Table 6.
Both time to progression and objective response rate were significantly longer/ higher for letrozole than for tamoxifen irrespective of receptor status (see Table 7).
Study design allowed patients to cross over upon progression to the other therapy or discontinue from the study. Approximately 50% of patients crossed over to the opposite treatment arm and crossover was virtually completed by 36 months. The median time to crossover was 17 months (letrozole to tamoxifen) and 13 months (tamoxifen to letrozole). Letrozole treatment in the first line therapy of advanced breast cancer patients is associated with an early survival advantage over tamoxifen. The median survival was 34 months for letrozole and 30 months for tamoxifen. A significantly greater number of patients were alive on letrozole versus tamoxifen throughout the first 24 months of the study (repeated log rank test) (see Table 8).
In patients who did not cross over to the opposite treatment arm, median survival was 35 months with letrozole (n = 219, 95% CI 29 to 43 months) versus 20 months with tamoxifen (n = 229, 95% CI 16 to 26 months).
The total duration of endocrine therapy (time to chemotherapy) was significantly longer for letrozole (median 16.3 months, 95% CI 15 to 18 months) than for tamoxifen (median 9.3 months, 95% CI 8 to 12 months) (log rank p = 0.0047).
Worsening of Karnofsky Performance Score (KPS) by 20 points or more occurred in significantly fewer patients on letrozole (19%) than tamoxifen first line (25%) (odds ratio 0.69 (0.50 to 0.94), p = 0.0208).

Second line treatment of advanced breast cancer.

In a well controlled double blind clinical trial (study AR/BC2), 551 postmenopausal women with advanced breast cancer who had relapse or disease progression following antioestrogen (e.g. tamoxifen) therapy were randomised to receive oral daily doses of either letrozole 0.5 mg, letrozole 2.5 mg or megestrol acetate 160 mg. Some of the patients had also received previous cytotoxic treatment. Patients were either oestrogen receptor positive or unknown status. Data were collected up to nine months after the last patient was enrolled in the core trial. This was the cut off date for the primary analysis of response, time to progression, time to failure and safety. For all patients who were still alive at the end of the core trial, whether still on treatment or not, extension data were collected over an additional six months (extension trial). The end of the extension trial was the cut off date for the primary analysis of survival.
At the end of the core trial, the overall objective tumour response (complete and partial response) rate was greatest in patients treated with letrozole 2.5 mg (23.6%) compared to patients treated with megestrol acetate (16.4%) and letrozole 0.5 mg (12.8%). Comparison of the response rates showed a statistically significant dose effect in favour of letrozole 2.5 mg (p = 0.004) with letrozole 2.5 mg also statistically superior to megestrol acetate (p = 0.04). The median duration of complete and partial response was 18 months for letrozole 0.5 mg and for megestrol acetate but was not reached for letrozole 2.5 mg. The duration of response was statistically significantly longer with letrozole 2.5 mg than with megestrol acetate (p = 0.01). The median time to treatment failure was longest for patients on letrozole 2.5 mg (155 days) compared to patients on megestrol acetate (118 days) and letrozole 0.5 mg (98 days) (p = 0.007). The median times to progression were not significantly different. The median times to death (unadjusted analysis) were also not significantly different among the treatment groups in the Kaplan-Meier survival curves with many patients still alive at the last analysis (patients still alive: letrozole 0.5 mg (51.6%), letrozole 2.5 mg (58.1%), megestrol acetate (50.3%)). Letrozole gave significantly fewer severe and life threatening side effects, in particular decreased cardiovascular experiences and pulmonary emboli, than megestrol acetate. Other reported drug related adverse events included headache, hot flushes, allergic rash, nausea, hair thinning and oedema (see Section 4.8 Adverse Effects (Undesirable Effects)).

Neoadjuvant treatment of breast cancer.

The safety and efficacy of letrozole has not been demonstrated in the neoadjuvant treatment of breast cancer.

5.2 Pharmacokinetic Properties

Absorption.

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

Distribution.

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

Metabolism and elimination.

Metabolic clearance to a pharmacologically inactive carbinol metabolite is the major elimination pathway of letrozole (CLm = 2.1 L/h) but is relatively slow when compared to hepatic blood flow (about 90 L/h). The cytochrome P450 isoenzymes 3A4 and 2A6 were found to be capable of converting letrozole to this metabolite. Formation of minor unidentified metabolites and direct renal and faecal excretion play only a minor role in the overall elimination of letrozole. Within 2 weeks after administration of 14C-labelled letrozole 2.5 mg to healthy postmenopausal volunteers, 88.2 ± 7.6% of the radioactivity was recovered in urine and 3.8 ± 0.9% in faeces. At least 75% of the radioactivity recovered in urine up to 216 hours (84.7 ± 7.8% of the dose) was attributed to the glucuronide of the carbinol metabolite, about 9% to two unidentified metabolites and 6% to unchanged letrozole.
The apparent terminal elimination half-life in plasma is about two days. After daily administration of letrozole 2.5 mg, steady-state levels are reached within two to six weeks. Plasma concentrations at steady state are approximately seven times higher than concentrations measured after a single dose of 2.5 mg, while they are 1.5 to 2 times higher than the steady-state values predicted from the concentrations measured after a single dose, indicating a slight nonlinearity 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.

Effect of age or impaired renal/ hepatic function on pharmacokinetics.

In the study populations (adults ranging in age from 35 to > 80 years), no change in pharmacokinetic parameters was observed with increasing age. In a study involving volunteers with varying degrees of renal function (24 hour creatinine clearance 9-116 mL/min) no effect on the pharmacokinetics of letrozole was found after a single dose of 2.5 mg. In a similar study involving subjects with varying degrees of hepatic function, the mean AUC values of the volunteers with moderate hepatic impairment (Child-Pugh score B) was 37% higher than in normal subjects, but still within the range seen in subjects without impaired function. In a study comparing the pharmacokinetics of letrozole after a single oral dose in eight subjects with liver cirrhosis and severe hepatic cirrhosis (Child-Pugh score C) to those in healthy subjects (n = 8), AUC and t1/2 increased on average by 95 and 187%, respectively, although uncertainty exists about the exact figures because of the wide confidence intervals in the study. Breast cancer patients with this type of severe hepatic impairment are thus expected to be exposed to higher levels of letrozole than patients without severe hepatic dysfunction. The available data do not allow any conclusions to be drawn about patients with predominant hepatocellular damage, for example, those with hepatitis C. If the opinion of the treating doctor is that the risk is acceptable, a patient with severe hepatic impairment may be treated without dose reduction, but close monitoring of possible adverse drug reactions is recommended. In addition, in two well controlled studies involving 359 patients with advanced breast cancer, no effect of renal impairment (calculated creatinine clearance: 20 to 50 mL/min) or hepatic dysfunction was found on the letrozole concentration.
In a study comparing Letrozole 2.5 mg tablets with the reference (Femara 2.5 mg) tablets, the two products were shown to be bioequivalent. The geometric mean ratio and 90% confidence intervals for Letrozole AUC0-∞ were found to be 98.26%, and (0.958 ,1.0007), respectively, while those for Cmax were 94.33%, and (0.887, 1.006), respectively.

5.3 Preclinical Safety Data

Repeat dose toxicity studies of up to 12 months duration were conducted in rats and dogs. No effect levels were not established for letrozole, but changes observed at the lowest doses used (0.03 mg/kg/day) were related directly to the pharmacological properties of letrozole. Plasma levels of letrozole at the lowest dose in rats and dogs were similar to those expected in postmenopausal women during treatment with letrozole.
At higher doses of letrozole, associated with plasma letrozole concentrations 3 to 100 times greater than those expected in humans, changes were observed in the liver (probably related to the enzyme inducing properties of letrozole), the pituitary gland, skin, salivary gland, thyroid gland, haematopoietic system, kidneys, adrenal cortex and skeletal system (increased bone fragility). Additional lesions observed at similar doses in studies of longer duration were ocular and cardiac lesions in mice.
In juvenile rats, letrozole treatment beginning on day 7 postpartum for 6-12 weeks resulted in skeletal, neuroendocrine and reproductive changes at all doses 0.003-0.3 mg/kg/day; below and similar to the human exposure. Bone growth was decreased in males and increased in females. Bone mineral density (BMD) was decreased in females. Decreased fertility was accompanied by hypertrophy of the hypophysis, testicular changes which included a degeneration of the seminiferous tubular epithelium and atrophy of the female reproductive tract and ovarian cysts. With the exception of bone size and morphological changes in the testes, all effects were at least partially reversible.

Genotoxicity.

Letrozole did not show evidence of genotoxicity in in vitro assays for gene mutations and in vitro and in vivo assays for chromosomal damage.

Carcinogenicity.

A 104 week carcinogenicity study with oral doses of letrozole at 0.1, 1 or 10 mg/kg/day in rats showed an increased development of ovarian benign gonadal stromal tumours at the highest dose (approximately 400 times human exposure at the maximum recommended clinical dose, based on AUC). Female rats showed a reduced incidence of benign and malignant mammary tumours at all dose levels of letrozole. Female mice treated with oral doses of letrozole at 0.6, 6 or 60 mg/kg/day in a lifetime carcinogenicity study showed an increased incidence of ovarian benign granulosa theca cell tumours at all dose levels.

6 Pharmaceutical Particulars

6.1 List of Excipients

See Section 2 Qualitative and Quantitative Composition.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

36 months.

6.4 Special Precautions for Storage

Store below 25°C.
Protect from moisture. Protect from light.

6.5 Nature and Contents of Container

Blister (PVC/PE/PVDC/Al ) packs of 30 tablets.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

The chemical name for letrozole is 4,4'-[(1H-1,2,4-triazol-1-yl)-methylene]bis-benzonitrile. C17H11N5. Molecular weight: 285.3. Letrozole is a white to yellowish crystalline powder which is practically insoluble in water, freely soluble in dichloromethane and slightly soluble in alcohol.

Chemical structure.

Its structural formula is:

CAS number.

112809-51-5.

7 Medicine Schedule (Poisons Standard)

S4.

Summary Table of Changes