Consumer medicine information

Letrozole AN tablets

Letrozole

BRAND INFORMATION

Brand name

Letrozole AN

Active ingredient

Letrozole

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Letrozole AN tablets.

What is in this leaflet

This leaflet answers some common questions about Letrozole AN.

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 Letrozole AN 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 Letrozole AN is used for

Letrozole AN is used for the treatment of breast cancer in post-menopausal women i.e. women who no longer have periods, either because of their natural age or following surgery or chemotherapy

Letrozole belongs to a family of medicines called aromatase inhibitors (also referred to as antioestrogens). They function by decreasing the amount of the hormone oestrogen that is produced in your body.

The growth of certain types of breast cancer is promoted by oestrogen.

These cancers are known as “oestrogen-dependent”. Decreasing the production of oestrogen may aid to prevent the cancer from growing.

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

If you have any questions about why Letrozole AN has been prescribed for you, ask your doctor.

You may have been prescribed Letrozole AN by your doctor for another reason.

Letrozole AN is only obtainable with a doctor’s prescription.

Letrozole AN is not addictive.

Before You Take Letrozole AN

When you must not take it

Do not take Letrozole AN if you are allergic to:

  • Letrozole, the active ingredient in this medicine
  • Any of the other ingredients of this medicine listed at the end of this leaflet.

If you get an allergic reaction, symptoms may include:

  • Rash, itching or hives on the skin
  • Swelling of the face, lips, tongue or other parts of the body
  • Shortness of breath, wheezing or troubled breathing

Do not take Letrozole AN if you have not yet experienced menopause. This medicine is intended only to be used in post-menopausal women (ie women who no longer have their periods.

Women of child bearing age who have recently become postmenopausal or perimenopausal are advised to use a proven method of birth control to avoid pregnancy until postmenopausal status is fully determined.

Do not use Letrozole AN if you are pregnant or breastfeeding as it may affect your baby.

Do not use Letrozole AN after the expiry date printed on the pack. It may have no effect at all, or worse, have an entirely unexpected effect if you take it after the expiry date.

Do not use Letrozole AN if the packaging is torn or shows signs of tampering. In such case, please return it to your doctor or pharmacist.

Do not use it to treat any other complaints unless your doctor says it’s safe.

Do not give this medicine to anyone else. for disposal

Before you start to take it

You must tell your doctor if you have severe kidney or liver disease. Your doctor might take special precautions while you are taking this medication.

Tell your doctor if you have a history of osteoporosis or bone fractures. Your level of hormones may be checked by your doctor before you take letrozole, to ensure you have gone through the menopause (cessation of periods).

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

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

Females of child-bearing potential and male patients

If you still until recently had menstrual periods, you should discuss with your doctor about the necessity of effective contraception as you might have the potential to become pregnant. Ask your doctor about options of effective birth control. Letrozole may reduce fertility in male patients.

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.

Other medicines may be affected by letrozole or they may affect how well it works.

Your doctor or pharmacist can tell you what to do when taking letrozole with other medicines. This includes in particular:

  • tamoxifen
  • other anti-estrogens or estrogen containing therapies
  • medicines used to treat infections, such as ketoconazole, itraconazole, voriconazole, ritonavir and clarithromycin, rifampicin
  • medicines used to treat epilepsy, such as phenytoin, carbamazepine, phenobarbital
  • St. John’s Wort (a herbal supplement)

These medicines may increase or diminish the action of Letrozole AN.

How to take Letrozole AN

When taking Letrozole AN, follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions on the box, you must ask your doctor or pharmacist for help.

How much to take

The usual dose is one Letrozole AN tablet taken per day.

How to take it

Letrozole AN tablets should be swallowed whole with a glass of water or other liquid.

If you get an upset stomach after taking the tablets, take it with a meal or a snack.

How long to take it

Continue taking Letrozole AN for as long as your doctor or pharmacist tells you.

Your progress will be checked by your doctor to ensure this medicine is working. Your doctor will make a decision on how long your treatment should continue.

Talk to your doctor if you are unsure.

If you forget to take it

If it is almost time for your next dose (eg within 2-3 hours), then 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.

If you take too much (overdose)

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

While you are taking Letrozole AN

Things you must do

Tell your doctor immediately, if you become pregnant while taking Letrozole AN. This medicine should not be taken while you are pregnant.

Your doctor's instructions should be followed carefully. If you do not, your treatment may not be helpful or you may have unwanted side effects.

Make sure you go to all of your doctor's appointments so that your progress can be checked. Your doctor may ask you to have blood tests from time to time to check on your progress and pick up any unwanted side effects. Furthermore, your doctor may decide to assess the health of your bones as this medicine may cause thinning or wasting of your bones (osteoporosis).

Tell your doctor, dentist or pharmacist that you are on Letrozole AN if you are about to start taking any other new medicine.

Tell any other doctor, dentist or pharmacist who treats you that you are using Letrozole AN.

Things you must not do

Do not use Letrozole AN to treat any other complaints unless your doctor says it’s safe.

Do not give this medicine to anyone else, even if they have the same symptoms as you.

Things to be careful of

Be careful driving or operating machinery or doing other jobs which require you to be alert until you know how Letrozole AN affects you.

This medicine may cause tiredness, dizziness or lightheadedness in some people. If any of these occur, do not drive, operate machinery 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 Letrozole AN.

Letrozole helps most people, but it may have unwanted side effects in some people. All medicines have side effects. Sometimes they are serious but most of the time they are not. You may require medical treatment if you get some of the side effects.

Do not be worried by the list of possible side effects. You may not even experience any of them.

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

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

  • signs that blood clots could 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 thighs or calves, chest pain, difficulty in breathing, coughing blood.
  • continuous "flu-like" symptoms such as chills, fever, sore throat, sores in mouth, swollen glands, tiredness or lack of energy, which could be signs of blood problems
  • swelling mainly of the face and throat (signs of allergic reaction)
  • weakness or paralysis of limbs or face, difficulty speaking (signs of stroke)
  • crushing chest pain or sudden arm or leg (foot) pain (signs of a heart attack)
  • swelling and redness along a vein which is extremely tender, possibly painful to touch (signs of thrombophlebitis)

The above are all serious side effects. You may need urgent medical attention or hospitalisation.

Tell your doctor straight away if you experience any of the following:

  • yellow skin and eyes, nausea, loss of appetite, dark coloured urine (signs of hepatitis)
  • rash, red skin, blistering of the lips, eyes or mouth, skin peeling, fever (signs of skin disorder)
  • blurred vision (sign of cataract)
  • swelling of the feet, ankles or other parts of the body due to fluid build-up (signs of oedema)

Tell your doctor if you have any of the following side effects and they worry you:

  • skin rash, itching or dry skin
  • pain in the muscles, joints or bones; joint stiffness, arthritis
  • high level of cholesterol
  • vaginal spotting or bleeding
  • whitish, thick vaginal discharge, vaginal dryness
  • headache
  • fever
  • tiredness, sleepiness, weakness or dizziness, vertigo
  • falls
  • chest pain (mild)
  • 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
  • upset stomach, nausea (feeling sick) or vomiting, indigestion, abdomen pain
  • constipation
  • diarrhoea
  • dry mouth, sore mouth, mouth ulcers and cold sores
  • increased thirst
  • dry mucous membranes of the mouth, nose, vagina
  • 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
  • pain or burning sensation in the hands or wrist (carpal tunnel syndrome)
  • fast or irregular heartbeats, palpitations, high blood pressure (hypertension)
  • thinning of bones (osteoporosis), leading to bone fractures in some cases
  • cough
  • trigger figure, a condition in which your finger or thumb catches in a bent position.
  • dark coloured urine
  • yellowish eyes and/or skin (jaundice)

Tell your doctor if you have anything else that is making you feel unwell. Other side effects listed above may not occur in some people. Some of these can be found only through laboratory testing.

After taking Letrozole AN

Storage

Keep your tablets in the blister pack until it is time to take them. If you take the tablets out of the blister pack they may not keep well.

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

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

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

Keep Letrozole AN 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 tells you to stop taking Letrozole AN, 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

LETROZOLE AN 2.5 mg tablets (AUST R 159227) are yellow, round, biconvex, film coated tablets plain on both sides. They are presented in a PVC/PVDC/Al pack size of 30 tablets.

Ingredients

Active Ingredient:

Letrozole.

Each tablet contains 2.5 mg of Letrozole.

Other Ingredients:

  • microcrystalline cellulose
  • hypromellose
  • lactose monohydrate
  • magnesium stearate
  • colloidal anhydrous silica
  • sodium starch glycollate type A
  • maize starch
  • OPADRY complete film coating system 03B82927 YELLOW

Name and Address of the Sponsor

Juno Pharmaceuticals Pty Ltd
Level 2, 6 Bond Street,
South Yarra,
VIC – 3141

Date of Preparation

March 2019

Published by MIMS May 2019

BRAND INFORMATION

Brand name

Letrozole AN

Active ingredient

Letrozole

Schedule

S4

 

1 Name of Medicine

Letrozole.

6.7 Physicochemical Properties

Letrozole is a white to off-white, crystalline powder. It is practically insoluble in water, freely soluble in methylene chloride and sparingly insoluble in methanol.
Chemical name: 4, 4'-(1H-1, 2, 4-triazol-1-ylmethylene)di- benzonitrile. Molecular formula: C17H11N5. Molecular weight: 285.3.

Chemical structure.


CAS number.

112809-51-5.

2 Qualitative and Quantitative Composition

Each Letrozole AN tablet contains letrozole 2.5 mg.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Letrozole AN is presented as yellow, round, biconvex, film-coated tablets, plain on both sides.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group of letrozole: nonsteroidal aromatase inhibitor (inhibitor of oestrogen biosynthesis); antineoplastic agent.

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 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-hydroxyprogesterone, 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.

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 tablets 2.5 mg for 5 years;
C. Tamoxifen for 2 years followed by letrozole tablets 2.5 mg for 3 years;
D. Letrozole tablets 2.5 mg for 2 years followed by tamoxifen for 3 years.
Data in Table 2 reflect results 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 have been 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 tablets 2.5 mg 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 tablets 2.5 mg and 81.4% for tamoxifen. The improvement in DFS with letrozole tablets 2.5 mg is seen as early as 12 months and is maintained beyond 5 years. Letrozole tablets 2.5 mg 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 tablets 2.5 mg and 192 on tamoxifen). There was no significant difference between treatments in overall survival (hazard ratio 0.86; P = 0.15). Letrozole tablets 2.5 mg significantly reduced the overall risk of distant recurrence (distant metastases) (hazard ratio 0.73; P = 0.001). Patients receiving letrozole tablets 2.5 mg, compared to tamoxifen, had fewer second malignancies (1.9% vs 2.4%). Particularly the incidence of endometrial cancer was lower with letrozole tablets 2.5 mg compared to tamoxifen (0.2% vs 0.4%), but this difference was not statistically significant. Tables 2 and 3 summarise the results.

Extended adjuvant treatment of early breast cancer.

A multicentre, double blind, randomised, placebo controlled study 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 tablets 2.5 mg 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 tablets 2.5 mg 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 tablets 2.5 mg 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 tablets 2.5 mg was observed regardless of nodal status: node negative, hazard ratio 0.48, P = 0.002; node positive, hazard ratio 0.61, P = 0.002.
For the secondary endpoint overall survival (OS) a total 113 deaths were reported (51 letrozole tablets 2.5 mg, 62 placebo). Overall, there was no significant difference between treatments in OS (hazard ratio 0.82; P = 0.29). In node positive disease, letrozole tablets 2.5 mg 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. Tables 4 and 5 summarise the results.
There was no difference in safety and efficacy between patients aged < 65 versus ≥ 65 years.
Updated analyses were conducted at a median follow-up of 49 months. In the letrozole tablets 2.5 mg arm at least 30% of the patients had completed 5 years and 59% had completed at least 4 years of follow-up. After the unblinding of the study, 56% of the patients in the placebo arm opted to switch to letrozole tablets 2.5 mg (i.e. late extended adjuvant population).
In this analysis of DFS, letrozole tablets 2.5 mg significantly reduced the risk of breast cancer recurrence compared with placebo (HR 0.68; 95% CI 0.55, 0.83; P = 0.0001). Letrozole tablets 2.5 mg also significantly reduced the odds of a new invasive contralateral cancer by 41% compared with placebo (OR 0.59; 95% CI 0.36, 0.96; P = 0.03). There was no significant difference in distant disease free survival or overall survival.
The clinical interpretation of these updated analyses should take into account that, after the study unblinding, over half of the patients in the placebo arm eligible to switch opted to switch to letrozole tablets 2.5 mg (i.e. late extended adjuvant population). Patients who switched to letrozole tablets 2.5 mg from placebo had been off adjuvant tamoxifen for a median 31 months (range 14 to 79 months). In placebo patients who were disease free and had follow-up information after the date of unblinding, 23 recurrences were reported in 1448 patients, who opted to switch to letrozole tablets 2.5 mg, and 47 in 851 patients who opted not to switch.
The following adverse events irrespective of causality were reported significantly more often with letrozole tablets 2.5 mg than with placebo: hot flushes (60.3% vs 52.6%), arthralgia/ arthritis (37.9% vs 26.8%) and myalgia (15.8% vs 8.9%). The majority of these adverse events were observed during the first year of treatment. In the patients in the placebo arm who switched to letrozole tablets 2.5 mg, a similar pattern of general adverse events was observed. The incidence of self reported osteoporosis, any time after randomisation, was higher in patients who received letrozole tablets 2.5 mg than for placebo (12.3% vs. 7.4%). The incidence of clinical fractures, any time after randomisation, was higher in patients who received letrozole tablets 2.5 mg than for placebo (10.9% vs 7.2%). In patients who switched to letrozole tablets 2.5 mg, newly diagnosed osteoporosis, any time after switching, was reported in 3.6% of patients while fractures were reported in 5.1% of patients any time after switching.
Updated results (median duration of follow-up was 40 months) from the bone mineral density (BMD) substudy demonstrated that at 2 years, compared to baseline, patients receiving letrozole tablets 2.5 mg had a median decrease of 3.8% in hip BMD compared to 2.0% in the placebo group (P = 0.018). There was no significant difference in terms of changes in lumbar spine BMD at any time. Updated results (median follow-up was approximately 50 months) from the lipid substudy showed no significant difference between the letrozole tablets 2.5 mg and placebo groups at any time. In the core study the incidence of cardiovascular ischemic events for letrozole tablets 2.5 mg versus placebo until switch was (11.1% vs 8.6%).

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 medicines. 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 tablets 2.5 mg to tamoxifen) and 13 months (tamoxifen to letrozole tablets 2.5 mg). Letrozole tablets 2.5 mg 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 tablets 2.5 mg and 30 months for tamoxifen. A significantly greater number of patients were alive on letrozole tablets 2.5 mg versus tamoxifen throughout the first 24 months of the study (repeated logrank test), see Table 8.
In patients who did not crossover to the opposite treatment arm, median survival was 35 months with letrozole tablets 2.5 mg (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 tablets 2.5 mg (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 tablets 2.5 mg (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 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 tablets 0.5 mg, letrozole tablets 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 tablets 2.5 mg (23.6%) compared to patients treated with megestrol acetate (16.4%) and letrozole tablets 0.5 mg (12.8%). Comparison of the response rates showed a statistically significant dose effect in favour of letrozole tablets 2.5 mg (P = 0.004) with letrozole tablets 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 tablets 0.5 mg and for megestrol acetate but was not reached for letrozole tablets 2.5 mg. The duration of response was statistically significantly longer with letrozole tablets 2.5 mg than with megestrol acetate (P = 0.01). The median time to treatment failure was longest for patients on letrozole tablets 2.5 mg (155 days) compared to patients on megestrol acetate (118 days) and letrozole tablets 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 tablets 0.5 mg (51.6%), letrozole tablets 2.5 mg (58.1%), megestrol acetate (50.3%)). Letrozole tablets 2.5 mg gave significantly fewer severe and life threatening side effects, in particular decreased cardiovascular experiences and pulmonary emboli, than megestrol acetate. Other reported medicine 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 tablets 2.5 mg 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, 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 on the absorption rate is not considered to be of clinical relevance and, therefore, letrozole may be taken without regard to mealtimes.

Distribution.

Plasma protein binding of letrozole is approximately 60%, mainly to albumin (55%). The concentration of letrozole in erythrocytes is about 80% of that in plasma. After administration of 2.5 mg 14C-labelled letrozole, 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 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. 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.
After daily administration of 2.5 mg letrozole, steady-state levels are reached within 2 to 6 weeks. Plasma concentrations at steady-state are approximately 7 times higher than concentrations measured after a single dose of 2.5 mg, while they are 1.5 to 2 times higher than 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.
In an open label, balanced, randomized, two treatment, two period, two sequence, single dose, two way crossover comparative oral bioavailability study of two formulations of letrozole 2.5 mg tablets in healthy, postmenopausal human female subjects under fasting conditions conducted by the sponsor, the mean terminal half-life found was 71.280 hours for the reference (Femara 2.5 mg) and 68.331 hours for the test product (letrozole tablets 2.5 mg).

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 medicine effects 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 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. In a study using another aromatase inhibitor (anastrozole) plasma levels of anastrozole at these doses in rats and dogs were similar to those expected in human 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.

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

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.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.
Premenopausal endocrine status; pregnancy, lactation (see Section 4.6 Fertility, Pregnancy and Lactation).

4.4 Special Warnings and Precautions for Use

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)).

Menopausal status.

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

Use with caution in the following circumstances.

Renal impairment.

Letrozole tablets 2.5 mg has not been investigated in patients with creatinine clearance < 10 mL/min nor in a sufficient number of patients with a creatinine clearance less than 30 mL/min.
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).

Use in the elderly.

No data available.

Paediatric use.

No data available.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

To date, there are minimal data on the interaction between letrozole and other medicines.
Additionally, in a large clinical trial there was no evidence of clinically relevant interaction in patients receiving other commonly prescribed medicines (e.g. benzodiazepines, barbiturates, NSAIDs such as diclofenac sodium and ibuprofen, paracetamol, frusemide, omeprazole).
Letrozole is mainly metabolised 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.
Co-administration of letrozole with tamoxifen, other anti-oestrogens or oestrogen-containing therapies should be avoided as these substances may diminish the pharmacological action of letrozole. Co-administration 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.
There is limited clinical experience to date on the use of letrozole in combination with anti-cancer 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 non-specific inhibitor of CYP2C19 and CYP3A4 and warfarin (sensitive substrate for CYP2C9 with a narrow therapeutic window and commonly used as co-medication 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).
Chronic 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 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).
The pharmacological action of letrozole is to reduce estrogen production by aromatase inhibition. In premenopausal women, the inhibition of oestrogen synthesis leads to feedback increases in gonadotropin (LH, FSH) levels. Increased FSH levels in turn stimulate follicular growth, and can induce ovulation.
(Category D).

Australian categorisation definition of 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 medicine of this class. No peri/ postnatal studies have been conducted in animals.
Letrozole tablets 2.5 mg are 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.

Women of childbearing potential.

There have been post-marketing 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 AN 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 tablets were 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 tablets 2.5 mg in the metastatic setting, approximately 70-75% of the patients in the adjuvant setting (both letrozole tablets 2.5 mg and tamoxifen arms), and approximately 40% of the patients in the extended adjuvant setting (both letrozole tablets 2.5 mg and placebo arms) can be expected to experience adverse effects. Generally, the observed adverse effects 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 events, 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 medicine effects, listed in Table 1, were reported from clinical studies and from postmarketing experience with letrozole tablets 2.5 mg.
Adverse effects 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%, including isolated report.

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.

4.2 Dose and Method of Administration

Adults.

The recommended dose of Letrozole AN is one tablet daily.
In the adjuvant setting, treatment should continue for 5 years or until tumour relapse occurs, whichever comes first.
In the extended adjuvant setting, the optimal treatment duration with Letrozole AN is not known, the planned duration of treatment in the pivotal study was 5 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 5 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 2 years, 22% of the patients for more than 4 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 AN 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/min). Insufficient data are available to justify a dose advice in cases of renal insufficiency with creatinine clearance 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; Section 4.4 Special Warnings and Precautions for Use).

Children.

Not applicable.

4.7 Effects on Ability to Drive and Use Machines

Since fatigue and dizziness have been observed with the use of letrozole tablets 2.5 mg and somnolence has been reported uncommonly, caution is advised when driving or using machines.

4.9 Overdose

Isolated cases of overdosage with letrozole tablets 2.5 mg 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 Poisons Information Centre on 13 11 26 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Lactose monohydrate, maize starch, hypromellose, microcrystalline cellulose, sodium starch glycollate (type A), colloidal anhydrous silica, magnesium stearate, Opadry complete film coating system 03B82927 Yellow.

6.2 Incompatibilities

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

6.3 Shelf Life

In 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. Protect from moisture.

6.5 Nature and Contents of Container

Letrozole AN 2.5 mg tablets are available in a PVC/PVDC/Al blister pack. Each pack contains 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.

Summary Table of Changes