Consumer medicine information

APO-Letrozole Tablets

Letrozole

BRAND INFORMATION

Brand name

APO-Letrozole Tablets

Active ingredient

Letrozole

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using APO-Letrozole Tablets.

What is in this leaflet

Read this leaflet carefully before taking your medicine.

This leaflet answers some common questions about letrozole. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

The information in this leaflet was last updated on the date listed on the last page. More recent information on this medicine may be available.

Ask your doctor or pharmacist:

  • if there is anything you do not understand in this leaflet,
  • if you are worried about taking your medicine, or
  • to obtain the most up-to-date information.

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

Pharmaceutical companies cannot give you medical advice or an individual diagnosis.

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

What this medicine is used for

The name of your medicine is APO-Letrozole. It contains the active ingredient letrozole.

It 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.

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

This medicine is available only with a doctor's prescription.

How it works

Letrozole 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 they growth of certain types of breast cancer. These cancers are called "oestrogen-dependant." Reducing the production of oestrogen may help 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.

There is no evidence that this medicine is addictive.

Use in children

This medicine should not be used in children.

Before you take this medicine

When you must not take it

Do not take this medicine if:

  • You are pregnant.
    Letrozole may affect your developing baby if you take it during pregnancy.
  • You are breast-feeding.
    Letrozole may pass into human breast milk.
  • The expiry date (EXP) printed on the pack has passed.
  • The packaging is torn, shows signs of tampering or it does not look quite right.
  • You have had an allergic reaction to Letrozole or any of the ingredients listed at the end of this leaflet.
    Symptoms of an allergic reaction may include cough, shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue, throat or other parts of the body; rash, itching or hives on the skin; fainting or hayfever-like symptoms.
  • If you think you are having an allergic reaction do not take any more of the medicine and contact your doctor immediately or go to the Accident and Emergency department at the nearest hospital.
  • Do not take letrozole 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.

Before you start to take it

Before you start taking this medicine, tell your doctor if:

  1. You have allergies to:
    - any other medicines
    - any other substances, such as foods, preservatives or dyes.
  2. You have or have had any medical conditions, especially the following:
    - kidney disease
    - liver disease
    Your doctor may want to take special precautions while you are taking this medicine.
  3. You are currently pregnant or you plan to become pregnant.
    Do not take this medicine whilst pregnant until you and your doctor have discussed the risks and benefits involved.
  4. You are currently breast-feeding or you plan to breastfeed.
    Do not take this medicine whilst breast-feeding until you and your doctor have discussed the risks and benefits involved.
  5. You are planning to have surgery or an anaesthetic.
  6. You are currently receiving or are planning to receive dental treatment.
  7. You are taking or are planning to take any other medicines.
    This includes vitamins and supplements that are available from your pharmacy, supermarket or health food shop.

Some medicines may interact with letrozole. These include:

  • Medicines dependant on cytochrome P450 2A6 and 2C19 isoenzymes.

If you are taking any of these you may need a different dose or you may need to take different medicines.

Other medicines not listed above may also interact with letrozole.

How to take this medicine

Follow carefully all directions given to you by your doctor or pharmacist. Their instructions may be different to the information in this leaflet.

How much to take

Your doctor or pharmacist will tell you how much of this medicine you should take. This will depend on your condition and whether you are taking any other medicines.

Do not stop taking your medicine or change your dosage without first checking with your doctor.

How to take it

The recommended dose of letrozole is one tablet daily.

When to take it

Take this medicine at the same time each day. Taking it at the same time each day will have the best effect and will also help you remember when to take it.

It does not matter if you take it before, with or after food.

How long to take it for

Continue taking your medicine for as long as your doctor tells you.

Make sure you have enough to last over weekends and holidays.

If you forget to take it

If it is almost time to take your next dose, skip the missed dose and take your next dose at the usual time. Otherwise, take it as soon as you remember and then go back to taking your medicine as you would normally.

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

This may increase the chance of you experiencing side effects.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints to help you remember.

If you take too much (overdose)

If you think that you or anyone else may have taken too much of this medicine, immediately telephone your doctor or the Poisons Information Centre (Tel: 13 11 26 in Australia) for advice. Alternatively, go to the Accident and Emergency department at your nearest hospital.

Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are taking this medicine

Things you must do

Tell your doctor that you are taking this medicine if:

  • you are about to be started on any new medicine
  • you are pregnant or are planning to become pregnant
  • you are breastfeeding or are planning to breast-feed
  • you are about to have any blood tests
  • you are going to have surgery or an anaesthetic or are going into hospital.

Your doctor may occasionally do tests to make sure the medicine is working and to prevent side effects. Go to your doctor regularly for a check-up.

Tell any other doctors, dentists and pharmacists who are treating you that you take this medicine.

Things you must not do

Do not:

  • Give this medicine to anyone else, even if their symptoms seem similar to yours.
  • Take your medicine to treat any other condition unless your doctor or pharmacist tells you to.
  • Stop taking your medicine, or change the dosage, without first checking with your doctor.

Things to be careful of

Be careful when driving or operating machinery until you know how this medicine affects you.

Letrozole may cause dizziness or tiredness in some people. If you have any of these symptoms, do not drive or do anything else that could be dangerous.

Possible side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking letrozole or if you have any questions or concerns.

Do not be alarmed by the following lists of side effects. You may not experience any of them. All medicines can have side effects. Sometimes they are serious but most of the time they are not.

Tell your doctor or pharmacist if you notice any of the following and they worry you.

This list includes the more common side effects. Mostly, these are mild:

  • Headache
  • Dizziness
  • Nausea
  • Vomiting
  • Constipation
  • Diarrhoea
  • Fatigue
  • Indigestion
  • Cough
  • Mood changes such as depression, anxiety, irritability, drowsiness
  • High blood cholesterol
  • Hair loss
  • Muscle and bone pain
  • Osteoporosis
  • Bone fractures
  • Constant "flu-like" symptoms
  • Increased sweating
  • Hot flushes
  • Vaginal discharge or bleeding
  • Anorexia
  • Appetite increase
  • Weight increase or loss
  • Abdominal pain
  • Needing to urinate more often
  • Urinary tract infection
  • Breast pain
  • Tumour pain (in metastatic setting only)
  • Low white cell count
  • General swelling
  • Unpleasant or abnormal sense of touch e.g. pins and needles, numbness, burning sensation
  • Taste disturbance
  • Insomnia
  • Memory impairment
  • Cataract
  • Eye irritation
  • Blurred vision
  • Fast or irregular heartbeat
  • High blood pressure
  • Shortness of breath
  • Increased liver enzymes
  • Mucosal dryness
  • Inflamed sore mouth
  • Dry mouth
  • Thirst
  • Dry skin
  • Itchiness
  • Hives or rash
  • Joint pain
  • Arthritis

If you experience any of the following, stop taking your medicine and contact your doctor immediately or go to the Accident and Emergency department at your nearest hospital.

These are very serious side effects and are usually very rare. You may need urgent medical attention or hospitalisation.

  • Severe allergic reaction
  • Yellow skin and eyes, nausea, loss of appetite, dark coloured urine (signs of hepatitis)
  • Swelling of the feet, ankles or other parts of the body due to fluid build-up
  • Rash, red skin, blistering of the lips, eyes or mouth, skin peeling, fever (signs of skin disorder)
  • Signs a blood clot 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, rapid heartbeat, bluish skin discolouration, fainting.
  • Crushing chest pain or sudden arm or leg (foot) pain (signs of a heart attack)

Other side effects not listed above may occur in some patients.

Allergic reactions

If you think you are having an allergic reaction to letrozole, do not take any more of this medicine and tell your doctor immediately or go to the Accident and Emergency department at your nearest hospital.

Symptoms of an allergic reaction may include some or all of the following:

  • cough, shortness of breath, wheezing or difficulty breathing
  • swelling of the face, lips, tongue, throat or other parts of the body
  • rash, itching or hives on the skin
  • fainting
  • hay fever-like symptoms.

Storage and disposal

Storage

Keep your medicine in its original packaging until it is time to take it.

If you take your medicine out of its original packaging it may not keep well.

Keep your medicine in a cool dry place where the temperature will stay below 25°C.

Do not store your medicine, or any other medicine, in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep this medicine 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.

Disposal

If your doctor or pharmacist tells you to stop taking this medicine or it has passed its expiry date, your pharmacist can dispose of the remaining medicine safely.

Product description

What APO-Letrozole tablets look like

  • 2.5mg Tablet:
    Dark yellow, round, biconvex, film-coated tablets. Engraved "APO" on one side, "LET" over "2.5" on the other side.

They are available in blister packs of 10 or 30 tablets and bottles of 30, 100 or 500 tablets.

* Not all strengths, pack types and/or pack sizes may be available.

Ingredients

Each tablet contains 2.5mg of letrozole as the active ingredient.

It also contains the following inactive ingredients:

  • lactose monohydrate
  • cellulose microcrystalline
  • sodium starch glycolate
  • magnesium stearate
  • hypromellose
  • hydroxypropylcellulose
  • macrogol 8000
  • titanium dioxide
  • iron oxide yellow

This medicine is gluten-free, sucrose-free, tartrazine-free and free of other azo dyes.

Australian Registration Numbers

  • APO-Letrozole 2.5mg tablets (blister pack):
    AUST R 163826
  • APO-Letrozole 2.5mg tablets (bottle):
    AUST R 163830

Sponsor

Apotex Pty Ltd
16 Giffnock Avenue
Macquarie Park NSW 2113
Australia

APO and APOTEX are registered trade marks of Apotex Inc.

This leaflet was last updated in:
April 2014

BRAND INFORMATION

Brand name

APO-Letrozole Tablets

Active ingredient

Letrozole

Schedule

S4

 

1 Name of Medicine

Letrozole.

6.7 Physicochemical Properties

Chemical Name: 4,4′-[(1H-1,2,4-triazol-1-yl)-methylene]bis-benzonitrile. Molecular Formula: C17H11N5. Molecular Weight: 285.3.

Chemical structure.


CAS number.

112809-51-5.

2 Qualitative and Quantitative Composition

Letrozole is a white to yellowish powder, practically odourless, freely soluble in dichloromethane, slightly soluble in ethanol, practically insoluble in water and a melting range of 184°C to 185°C. The partition coefficient log P is 2.5 and the pKa1 (monoprotonated form) is calculated to be approximately 1.6. According to the Biopharmaceutics Classification Scheme (BCS), letrozole is a BCS class I (high solubility, high permeability) drug. The highest dose strength (2.5 mg) solubility volume is less than 250 mL over a pH range 1 to 7.5.
Each tablet contains 2.5 mg of letrozole, as the active ingredient.
In addition, each tablet contains the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, sodium starch glycolate type A, magnesium stearate, hypromellose, hyprolose, macrogol 8000, titanium dioxide and iron oxide yellow.

3 Pharmaceutical Form

2.5 mg film coated tablets: Dark yellow, round, biconvex, film coated tablets. Engraved “APO” on one side, “LET” over “2.5” on the other side.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Pharmacotherapeutic group.

Letrozole is a nonsteroidal aromatase inhibitor (inhibitor of oestrogen biosynthesis); antineoplastic agent.

Pharmacodynamics.

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 0.1, 0.5 and 2.5 mg letrozole suppressed serum oestrone and oestradiol by 75-78% and 78% from baseline, respectively. Maximum suppression was achieved in 48-78 h.
In postmenopausal patients with advanced breast cancer, daily doses of 0.1 to 5 mg letrozole suppressed plasma concentrations of oestradiol, oestrone, and oestrone sulphate by 75-95% from baseline in all patients treated. With doses of 0.5 mg and higher, many values of oestrone and oestrone sulphate were below the limit of detection in the assays, indicating that higher oestrogen suppression is achieved with these doses. Oestrogen suppression was maintained throughout treatment in all 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-hydroxy-progesterone, ACTH or in plasma renin activity among postmenopausal patients treated with a daily dose of 0.1 to 5 mg letrozole. The ACTH stimulation test performed after 6 and 12 weeks of treatment with daily doses of 0.1, 0.25, 0.5, 1, 2.5 and 5 mg letrozole 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 LH and FSH were not affected by letrozole in patients, nor was thyroid function as evaluated by TSH, 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 8000 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 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.
Data in Table 2 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 of monotherapy vs sequencing of endocrine treatments will be conducted when the necessary number of events has been achieved.
Patients were followed for a median of 26 months, 76% of the patients for more than 2 years, and 16% (1252 patients) for 5 years or longer.
The primary endpoint of the trial was disease free survival (DFS) which was assessed as the time from randomisation to the earliest event of locoregional or distant recurrence (metastases) of the primary disease, development of invasive contralateral breast cancer, appearance of a second nonbreast primary tumour or death from any cause. Letrozole reduced the risk of recurrence by 19% compared with tamoxifen (hazard ratio 0.81; P = 0.003), corresponding to a reduction of the absolute risk by 2.6% at 5 years. The 5 year DFS rates were 84.0% for letrozole and 81.4% for tamoxifen. The improvement in DFS with letrozole was seen as early as 12 months and is maintained beyond 5 years. Letrozole also significantly reduced the risk of recurrence compared with tamoxifen whether prior adjuvant chemotherapy was given (hazard ratio 0.72; P = 0.018) or not (hazard ratio 0.84; P = 0.044). For the secondary endpoint overall survival a total of 358 deaths were reported (166 on letrozole and 192 on tamoxifen).
There was no significant difference between treatments in overall survival (hazard ratio 0.86; P = 0.15). Letrozole significantly reduced the overall risk of distant recurrence (distant metastases) (hazard ratio 0.73; P = 0.001). Patients receiving letrozole, compared to tamoxifen, had fewer second malignancies (1.9% vs. 2.4%). Particularly the incidence of endometrial cancer was lower with letrozole compared to tamoxifen (0.2% vs. 0.4%), but this difference was not statistically significant.
Tables 2 and 3 summarise the results.

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

In 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%).

Extended adjuvant treatment of early breast cancer.

A reported multicentre, double blind, randomised, placebo controlled study (CFEM345G MA-17) was conducted in over 5100 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 5 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.
In the original analysis, for the secondary endpoint overall survival (OS) a total 113 deaths were reported (51 letrozole, 62 placebo). Overall, there was no significant difference between treatments in OS (hazard ratio 0.82; P = 0.29). In node positive disease, letrozole significantly reduced the risk of all cause 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. Tables 4 and 5 summarise the results.
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 than with patients who elected not to switch to letrozole after the study was unblinded (n = 1026): hot flushes (60.9% vs. 51.4%), arthralgia/ arthritis (41.5% vs. 27.2%), sweating (34.8% vs. 29.7%), hypercholesterolemia (23.6% vs. 15.3%) and myalgia (17.7% vs. 9.4%). The majority 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, 0.7%); cardiac events (letrozole 2.1% versus placebo, 1.0%) (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 enrollment experienced more bone fractures and more (new) osteoporosis than younger women.
Updated results (median duration of follow-up was 61 months) from the substudy demonstrated that at 2 years, compared to baseline, patients receiving letrozole had a median decrease of 3.8% in hip 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 bone mineral density (BMD) at any time.
Updated results (median follow-up was approximately 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 (Table 7).
Study design allowed patients to crossover 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 crossover to the opposite treatment arm, median survival was 35 months with letrozole (n = 219, 95% CI 29 to 43 months) vs. 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 15-18 months) than for tamoxifen (median 9.3 months, 95% CI 8 to 12 months) (logrank 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 (0.50-0.94), P = 0.0208).

Second line treatment of advanced breast cancer.

In a reported 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 ER positive or unknown status. Data were collected up to 9 months after the last patient was enrolled in the core trial. This was the cutoff 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 6 months (extension trial). The end of the extension trial was the cutoff 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 with a mean absolute bioavailability of 99.9%. There is a slight decrease in the rate of absorption if taken with food (median tmax: 1 hour fasted versus 2 hours fed, and 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 of food on the absorption rate is not considered to be of clinical relevance and, therefore, letrozole may be taken without regard to mealtimes. Letrozole is not known to be a substrate of biological efflux pumps, such as P-glycoprotein, which suggests a good absorption or permeability of letrozole. The theoretical predictions are consistent with an almost complete absorption (≥ 99.9% absolute oral bioavailability) of letrozole determined by in vivo studies. Therefore, letrozole is a highly permeable drug.

Distribution.

Approximately 60% of letrozole will bind to plasma protein, mainly to albumin (55%). The concentration of letrozole in erythrocytes is about 80% of that in plasma. It has been shown that after administration of 2.5 mg 14C-labelled letrozole, approximately 82% of the radioactivity in plasma was unchanged compound. This indicates that the systemic exposure to metabolites 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.

Letrozole's major elimination pathway is the metabolic clearance of the pharmacologically inactive carbinol metabolite (CLm = 2.1 L/h) but this is relatively slow when compared to hepatic blood flow (about 90 L/h). Letrozole is converted to this metabolite by the cytochrome P450 isoenzymes 3A4 and 2A6. Formation of minor unidentified metabolites and direct renal and faecal excretion play only a minor role in the overall elimination of letrozole. It has been shown that within 2 weeks after administration of 2.5 mg 14C-labelled letrozole to healthy postmenopausal volunteers, 88.2 ± 7.6% of the radioactivity was recovered in urine and 3.8 ± 0.9% in faeces. The glucuronide of the carbinol metabolite accounts for at least 75% of the radioactivity recovered in urine up to 216 hours (84.7 ± 7.8% of the dose), about 9% to two unidentified metabolites and 6% to unchanged letrozole.
The apparent terminal elimination half-life in plasma is about 2 days. Steady-state levels are reached within 2 to 6 weeks after daily administration of 2.5 mg letrozole. Steady-state plasma concentrations are approximately 7 times higher than concentrations measured after a single dose of 2.5 mg and they are 1.5 to 2 times higher than the steady-state values which are predicted from the concentrations measured after a single dose, indicating the pharmacokinetics is slightly nonlinearity for letrozole upon daily administration of 2.5 mg. As 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: 20-50 mL/min) or hepatic dysfunction was found on the letrozole concentration.

5.3 Preclinical Safety Data

Repeat dose toxicity studies of up to 12 months duration conducted on rats and dogs have reported no effect levels for letrozole, but changes were 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.

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment of postmenopausal women with hormone receptor positive early 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.

4.3 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.

Use in 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).

Use in renal impairment.

Letrozole has not been investigated in patients with creatinine clearance < 10 mL/min, nor in a sufficient number of patients with a creatinine clearance of less than 30 mL/min. Careful consideration of the potential risk/ benefit to such patients should be carried out prior to administration of letrozole. It is believed that letrozole can be removed from circulation by dialysis due to its' weak bound to plasma proteins (see Section 5.2 Pharmacokinetic Properties). Similar caution should be exercised in patients with severe hepatic insufficiency.

Menopausal status.

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

Interactions.

Coadministration of letrozole with tamoxifen, other antiestrogens or estrogen containing therapies should be avoided as these substances may diminish the pharmacological action of letrozole. The mechanism of this interaction is unknown.

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)).

Use in the elderly.

No data available.

Paediatric use.

Letrozole is not recommended for use in children and adolescents. The safety and efficacy of letrozole in children and adolescents aged up to 18 years have not been established.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

At present, there is only minimal data on the interaction between letrozole and other drugs.
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; NSAIDs such as diclofenac sodium and ibuprofen; paracetamol; frusemide; omeprazole).
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.

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 medications that strongly inhibit these enzymes (strong CYP3A4 inhibitors: including but not limited to ketoconazole, itraconazole, voriconazole, ritonavir, clarithromycin, and telithromycin; CYP2A6 (e.g. methoxsalen) may increase exposure to letrozole. Therefore caution is recommended in patients for whom strong CYP3A4 and CYP2A6 inhibitors are indicated.

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 indicated. No drug inducer is known for CYP2A6.
Coadministration of letrozole (2.5 mg) and tamoxifen 20 mg daily resulted in a reduction of letrozole plasma levels by 38% on average. The mechanism of this interaction is unknown.

Anticancer agents.

There is limited clinical experience to date on the use of letrozole in combination with anticancer agents other than tamoxifen.

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. Caution is therefore indicated when giving letrozole concomitantly with medicinal products whose elimination is mainly dependent on CYP2C19 and whose therapeutic index is narrow (e.g. phenytoin, clopidogrel). No substrate with a narrow therapeutic index is known for CYP2A6.
Clinical interaction studies with cimetidine (a known nonspecific inhibitor of CYP2C19 and CYP3A4 and warfarin (sensitive substrate for CYP2C9 with a narrow therapeutic window and commonly used as comedication in the target population of letrozole) indicated that the coadministration of letrozole with these drugs does not result in clinically significant drug interactions.

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).
Clinical studies indicated stromal hyperplasia of the ovaries and uterine atrophy in rats administered oral doses equal to or greater than 0.3 mg/kg/day (approximately equivalent to human exposure at 25 mg/day, based on AUC). In chronic studies of female dogs, ovarian follicular atrophy and uterine atrophy were observed when the dogs were 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.
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. Increased FSH levels in turn stimulate follicular growth, and can induce ovulation.
(Category D)
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 foetal 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 foetuses 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 peri/ postnatal studies have been conducted in animals. Letrozole is contraindicated during pregnancy (see Section 4.3 Contraindications). Isolated cases of birth defects (labial fusion, ambiguous genitalia) have been reported in pregnant women exposed to letrozole.
Category D - definition: Drugs which have caused are suspected to have caused or may be expected to cause, an increased incidence of human foetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects. There is a theoretical risk of abortion or foetal abnormality if GnRH agonists are used during pregnancy.

Women of childbearing potential and contraceptive measures, if applicable.

There have been postmarketing reports of spontaneous abortions and congenital anomalies in infants of mothers who have taken letrozole. 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).

4.8 Adverse Effects (Undesirable Effects)

Letrozole is 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, 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 reactions. Generally, the observed adverse reactions are mainly mild or moderate in nature, and most are associated with oestrogen deprivation.
The most frequently reported adverse reactions in the clinical studies were hot flushes, arthralgia, nausea and fatigue. Many adverse reactions can be attributed to either the normal pharmacological consequences of oestrogen deprivation (e.g. hot flushes, alopecia and vaginal bleeding).
The following adverse events, not reported in the advanced or 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 reactions, listed in Table 1, were reported from clinical studies and from postmarketing experience with letrozole.
Adverse reactions are ranked under headings of frequency, the most frequent first, using the following convention: very common ≥ 10%; common ≥ 1% to < 10%; uncommon ≥ 0.1% to < 1%; rare ≥ 0.01% to < 0.1%; very rare < 0.01%; not known (cannot be estimated from the available data).

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 http://www.tga.gov.au/reporting-problems or contact Apotex Medical Information enquiries/Adverse Drug Reaction Reporting on 1800 195 055.

4.2 Dose and Method of Administration

Adults.

The recommended dose of letrozole is one 2.5 mg tablet daily.
Adjuvant treatment should continue for 5 years or until tumour relapse occurs, whichever comes first.
In extended adjuvant treatment, the optimal duration of treatment with letrozole is not known as data from studies planned for 5 years. However, at the time of reported analysis, of 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 5 years. The median duration of follow up was 28 months. Treatment should however, be discontinued if tumour relapse occurs.
In the adjuvant setting the median duration of treatment was 25 months, 73% of the patients were treated for more than 2 years, 22% of the patients for more than 4 years. The median duration of follow up was 30 months (the efficacy data mentioned in Clinical trials 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.

Letrozole dosage does not need to be adjusted for patients with mild renal impairment (creatinine clearance ≥ 30 mL/min). Insufficient data is available to justify a dose advice for patients with renal insufficiency that have creatinine clearance of less than 30 mL/min 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 and Section 4.4 Special Warnings and Precautions for Use).

Children.

Letrozole is not recommended for use in children and adolescents. The safety and efficacy of letrozole in children and adolescents aged up to 18 years have not been established. Limited data are available and no recommendation on a posology can be made.

Method of administration.

Letrozole should be taken orally. A 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 over the 2.5 mg recommended dose, overproportionality in systemic exposure was observed.

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.

4.9 Overdose

Only isolated cases of overdosage with letrozole have been reported. No specific treatment for overdosage is known. Treatment should be symptomatic and supportive.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

See Section 2 Qualitative and Quantitative Composition.

6.2 Incompatibilities

See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

6.3 Shelf Life

Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

Bottle (white, round HDPE bottle with child-resistant cap) of 30, 100 and 500 tablets (AUST R 163830).
Blister pack (clear PVC/Aluminium silver foil) of 10 and 30 tablets (AUST R 163826).
Not all pack sizes and/or pack types may be available.

6.6 Special Precautions for Disposal

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

Summary Table of Changes