Consumer medicine information

Letroz Tablets

Letrozole

BRAND INFORMATION

Brand name

Letroz Tablets

Active ingredient

Letrozole

Schedule

What is in this leaflet

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

You should ensure that you speak to your pharmacist or doctor to obtain the most up to date information on the medicine.

Those updates may contain important information about the medicine and is use of which you should be aware.

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

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

Keep this leaflet with the medicine.

You may need to read it again.

What Letroz is used for

Letroz 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.

Letroz is available in tablets containing 2.5 mg of the active ingredient, letrozole.

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

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

Ask your doctor if you have any questions about why Letroz has been prescribed for you.

Your doctor may have prescribed Letroz for another reason.

Letroz is only available with a doctor's prescription. It is not addictive.

Before you take Letroz

When you must not use it

Do not take Letroz if you have an allergy to:

letrozole, the active ingredient in Letroz
any other ingredients of Letroz listed at the end of this leaflet.

Some of the symptoms of an allergic reaction 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 Letroz if you are still having periods.

This medicine is only used in women who are no longer having periods.

Women of child-bearing age who recently became postmenopausal or perimenopausal should use a proven method of birth control to avoid pregnancy, until your postmenopausal status is fully established. Do not take Letroz if you are pregnant or breast feeding.

It may affect your baby if you take it while you are pregnant or breast feeding.

Do not take Letroz after the use by (expiry) date printed on the pack.

If you take this medicine after the expiry date has passed, it may not work or it may make you unwell.

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

In that case, return it to your pharmacist.

Before you start to take it

Tell your doctor if you have severe kidney or liver disease.

Your doctor may want to take special precautions while you are taking this medicine.

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

Your doctor will want to know if you are prone to allergies.

If you have not told your doctor about any of these things, tell them before you take Letroz.

Taking other medicines

Tell your doctor if you are taking any other medicines, including medicines that you buy without a prescription from a pharmacy, supermarket or health food shop.

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

Your doctor or pharmacist can tell you what to do when taking Letroz with other medicines.

How to take Letroz

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

These directions may differ from the information contained in this leaflet.

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

How much to take

The usual dose is one Letroz tablet daily.

How to take it

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

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

How long to take it

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

If you are unsure, talk to your doctor.

If you forget to take it

If it is almost time for your next dose (e.g. within 2 or 3 hours), skip the dose you missed and take your next dose when you are meant to. Otherwise, take the dose as soon as you remember, and then go back to taking your tablet as you would normally.

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

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

If you take too much

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

While you are taking Letroz

Things you must do

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

You should not take this medicine while you are pregnant.

Follow your doctor's instructions carefully.

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

Be sure to keep all of your doctor's appointments so that your progress can be checked.

Your doctor may want you to have blood tests from time to time to check on your progress and detect any unwanted side effects. Your doctor may also decide to monitor your bone health as this medicine may cause thinning or wasting of your bones (osteoporosis).

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking Letroz.

Tell any other doctor, dentist or pharmacist who treats you that you are taking Letroz.

Things you must not do

Do not use Letroz to treat any other complaints unless your doctor says you can.

Do not give this medicine to anyone else, even if their symptoms seem to be similar to yours.

Things to be careful of

Be careful driving, operating machinery or doing jobs that require you to be alert while you are taking Letroz until you know how it affects you.

This medicine 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.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Letroz

It may have unwanted side effects in some people in addition to its beneficial effects. All medicines have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

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

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

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

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

Tell your doctor if you notice 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
difficulty sleeping
numbness or tingling in hands or feet
mood changes such as anxiety, nervousness, irritability and depression (sad mood)
drowsiness
forgetfulness
blurred vision or eye irritation
stomach upset, nausea (feeling sick) or vomiting, indigestion, pain in the abdomen
constipation
diarrhoea
dry mouth, sore mouth, mouth ulcers and cold sores
thirst, change in sense of taste, dry mouth
dry mucous membranes of the mouth, nose, vagina
breast pain
hot flushes
increased sweating
appetite changes
increase or decrease in weight
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), bone fractures
cough
trigger finger, a condition in which your finger or thumb catches in a bent position.

Tell your doctor if you notice anything else that is making you unwell.

Other side effects not listed above may happen in some people.

Some of these can only be found by laboratory testing.

After taking Letroz

Storage

Keep your tablets in the container until it is time to take them.
Store the tablets below 25°C. Protect from Moisture.
Do not store Letroz in the bathroom or any other place that is hot or steamy.
Do not leave the tablets in the car or on window sills.

Heat and dampness can destroy some medicines. Letroz will keep well if it is cool and dry.

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 tells you to stop taking Letroz or the tablets have passed their use by (expiry date), ask your pharmacist what to do with any that are left over.

Product description

What it looks like

Letroz is yellow, round, biconvex, film-coated tablet plain on both sides, supplied in blister pack and each pack contains 30 tablets.

Ingredients

Letroz contains 2.5mg of Letrozole as the active ingredient.

The tablets also contain:

Lactose
Maize starch
Hypromellose
Microcrystalline cellulose
Sodium starch glycollate (Type A)
Colloidal anhydrous silica
Magnesium stearate
Opadry 03B82927 yellow (Hypromellose, Titanium dioxide, Iron oxide yellow CI 77492, Macrogol 400 & Purified talc)

Letroz does not contain sucrose, gluten, tartrazine or any other azo dyes.

BRAND INFORMATION

Brand name

Letroz Tablets

Active ingredient

Letrozole

Schedule

Name of the medicine

Letrozole.

Excipients.

Lactose monohydrate, maize starch, hypromellose, microcrystalline cellulose, sodium starch glycollate (Type A), colloidal anhydrous silica, magnesium stearate and opadry 03B82927 yellow (hypromellose, titanium dioxide, iron oxide yellow CI77492, macrogol 400 and purified talc).

Description

Letrozole Film-coated Tablets 2.5 mg.
4,4'-(1H-1,2,4-Triazol-1-ylmethylene)dibenzonitrile. CAS number: 112809-51-5. Molecular formula: C₁₇H₁₁N₅. Molecular weight: 285.31.
Letrozole is a white or yellowish crystalline powder. It is practically insoluble in water, freely soluble in methylene chloride and sparingly soluble in methanol.
Letroz is yellow, round, biconvex, film-coated tablets plain on both sides containing 2.5 mg Letrozole and includes the following excipients: lactose monohydrate, maize starch, hypromellose, microcrystalline cellulose, sodium starch glycollate (Type A), colloidal anhydrous silica, magnesium stearate and opadry 03B82927 yellow (hypromellose, titanium dioxide, iron oxide yellow CI77492, macrogol 400 and purified talc.

Pharmacology

Pharmacotherapeutic group.

Non-steroidal 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 non-steroidal 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.

Pharmacokinetics.

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 (CL_m = 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 non-linearity in the pharmacokinetics of letrozole upon daily administration of 2.5 mg. Since steady-state levels are maintained over time, it can be concluded that no continuous accumulation of letrozole occurs.
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, post menopausal 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 t_1/2 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.

Clinical Trials

Adjuvant treatment of early breast cancer.

Study BIG 1-98.

BIG 1-98, a multi-centre, 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.
This study was designed to investigate two primary questions: whether Letrozole Tablets for 5 years was superior to tamoxifen for 5 years (Primary Core Analysis and Monotherapy Arms Analysis and whether switching endocrine treatments at 2 years was superior to continuing the same agent for a total of 5 years (Sequential Treatments Analysis).
The protocol specified efficacy endpoints were disease free survival (DFS), overall survival (OS) and systemic disease-free survival (SDFS). The protocol specified primary efficacy endpoint of DFS was defined as the interval between date of randomisation and earliest confirmed invasive loco-regional recurrence, distant metastasis, invasive contralateral breast cancer, second invasive (non-breast) primary cancer, or death from any cause without a prior cancer event. The protocol specified secondary efficacy endpoint of OS was defined as the interval from randomisation to death from any cause. The protocol specified secondary efficacy endpoint of SDFS was defined as the interval from randomisation to systemic relapse, distant metastasis, appearance of a second (nonbreast) primary cancer, or death from any cause, whichever occurred first (i.e. excluding loco regional recurrences in the ipsilateral or contralateral breast). In addition, secondary efficacy endpoints specified in the statistical analysis plan prior to the end of enrollment and prior to an interim analysis included time to distant metastases and time to invasive contralateral breast cancer.

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

Data in Table 1 reflect results of the Primary Core Analysis (PCA) including data from non-switching arms (arms A and B) together with data truncated 30 days after the switch in the two switching arms (arms C and D). This analysis was conducted at a median treatment duration of 24 months and a median follow-up of 26 months. Letrozole Tablets for 5 years was superior to tamoxifen for efficacy endpoints of disease free survival (protocol specified), time to distant metastases, and systemic disease free survival, but not for the efficacy endpoints of overall survival and invasive contralateral breast cancer.

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

The Monotherapy Arms Analysis (MAA) which include data for the monotherapy arms only provides the clinically appropriate long-term update of the efficacy of Letrozole Tablets monotherapy compared to tamoxifen monotherapy (Table 3). In 2005, based on the PCA data presented in Table 2 and on recommendations by the independent Data Monitoring Committee, the tamoxifen monotherapy arms were unblinded and patients were allowed to cross over to Femara. 26 % of patients randomized to tamoxifen elected to cross over to Letrozole Tablets - including a very small number of patients who crossed over to other aromatase inhibitors. To explore the impact of this selective crossover, analyses censoring DFS and OS follow-up times at the date of the selective crossover (in the tamoxifen arm) were conducted, and these analyses as well as the ITT analyses for selective endpoints disregarding selective crossover from tamoxifen to letrozole are summarised for the MAA (Table 2).
At a median follow-up of 73 months and a median treatment duration of 60 months, the risk of a DFS event was significantly reduced with Letrozole Tablets compared with tamoxifen (MAA ITT analysis: HR 0.88; 95% CI 0.78, 0.99; P = 0.03; confirming the 2005 PCA results. Analysis of DFS taking account of the selective crossover shows similar benefit (HR 0.85; 95% CI 0.75, 0.96). Similarly, the updated analysis confirmed the superiority of Letrozole Tablets in reducing the risk of distant disease free survival events (HR 0.87, 0.76, 1.00) as well as the risk of reducing distant metastases (HR 0.85; 95% CI 0.72, 1.00). Additionally, overall survival trended towards significance in the ITT analysis. Analysis of overall survival taking account of the selective crossover shows a significantly greater benefit (HR 0.82 0.70, 0.96) in favour of Letrozole Tablets.

Sequential treatments analyses.

The Sequential Treatments Analysis (STA) addresses the second primary question of the study. The primary analysis for the STA was from switch (or equivalent time-point in monotherapy groups) + 30 days (STA-S) with a two-sided test applied to each pair-wise comparison at the 2.5% level. These analyses were conducted at a median follow-up of 43 months after switch. Additional, exploratory analyses were conducted from randomisation (STA-R) at a median follow up of 67 months, with the results for each comparison summarised by hazard ratios and 99% confidence intervals.
At a median follow up of 43 months after switch, there were no significant differences in any endpoint from switch in the Sequential Treatments Analysis with respect to either monotherapy (e.g. [Tamoxifen 2 years followed by] Letrozole Tablets 3 years versus tamoxifen beyond 2 years, DFS HR 0.85; 97.5% CI 0.67, 1.09 and [Letrozole Tablets 2 years followed by] tamoxifen 3 years versus Letrozole Tablets beyond 2 years, DFS HR 0.92; 97.5% CI 0.71, 1.17). At a median follow up of 67 months from randomisation, there were no significant differences in any endpoint from randomisation in the Sequential Treatments Analysis (e.g. tamoxifen 2 years followed by Letrozole Tablets 3 years versus Letrozole Tablets 5 years, DFS HR 1.05; 99% CI 0.84, 1.32; Letrozole Tablets 2 years followed by tamoxifen 3 years versus Letrozole Tablets 5 years, DFS HR 0.96; 99% CI 0.76, 1.21). There was no evidence that a sequence of Letrozole Tablets and tamoxifen was superior to Letrozole Tablets alone given for 5 years.

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

In study BIG-98 at a 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 analyzed 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 Tablets 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 Tablets regarding hot flushes (38% vs. 33%), night sweating (17% vs. 15%), vaginal bleeding (13% vs. 5.2%), constipation (2.9% vs. 2.0%), thromboembolic events (3.6% vs. 2.1%), endometrial hyperplasia/cancer (2.3% vs. 0.2%), and endometrial proliferation disorders (3.5% vs. 0.6%).

Adjuvant therapy in early breast cancer, study D2407.

Study D2407 is a phase III, open-label, randomised, multicentre study designed to compare the effects of adjuvant treatment with letrozole to tamoxifen on bone mineral density (BMD), bone markers and fasting serum lipid profiles. A total of 262 postmenopausal women with hormone sensitive resected primary breast cancer were randomly assigned to either letrozole 2.5 mg daily for 5 years or tamoxifen 20 mg daily for 2 years followed by 3 years of letrozole 2.5 mg daily.
The primary objective was to compare the effects on lumbar spine (L2-L4) BMD of letrozole versus tamoxifen, evaluated as percent change from baseline lumbar spine BMD at 2 years.
At 24 months, the lumbar spine (L2-L4) BMD showed a median decrease of 4.1% in the letrozole arm compared to a median increase of 0.3% in the tamoxifen arm (difference = 4.4%). At 2 years, overall the median difference in lumbar spine BMD change between letrozole and tamoxifen was statistically significant in favour of tamoxifen (P < 0.0001). The current data indicates that no patient with a normal BMD at baseline became osteoporotic at year 2 and only 1 patient with osteopenia at baseline (T score of -1.9) developed osteoporosis during the treatment period (assessment by central review).
The results for total hip BMD were similar to those for lumbar spine BMD. The differences, however, were less pronounced. At 2 years, a significant difference in favour of tamoxifen was observed in the overall BMD safety population and all stratification categories (P < 0.0001). During the 2 year period, fractures were reported by 20 patients (15%) in the letrozole arm, and 22 patients (17%) in the tamoxifen arm.
In the tamoxifen arm, the median total cholesterol levels decreased by 16% after 6 months compared to baseline; a similar decrease was also observed at subsequent visits up to 24 months. In the letrozole arm, the median total cholesterol levels were relatively stable over time, with no significant increase at a single visit. The differences between the 2 arms were statistically significant in favour of tamoxifen at each time point (P < 0.0001).

Extended adjuvant treatment of early breast cancer.

A multi-centre, double-blind, randomised, placebo-controlled study (CFEM345G MA17) 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.
The independent Data and Safety Monitoring Committee (DSMC) recommended that women who were disease-free in the placebo arm be allowed to switch to Letrozole Tablets for up to 5 years, when the study was unblinded in 2003. The study protocol was duly amended, implementing the DSMC recommendation: 60% of the eligible patients in the placebo arm opted to switch to Femara, while the remaining patients opted to have no further treatment but agreed to continue to be monitored. The selective switch to Letrozole Tablets severely compromised further comparative analyses of efficacy and safety - in the final, close-out analysis after a median treatment duration of 5 years for Femara, 64% of the randomised placebo arm total follow-up patient-years was actually accrued under Femara, not placebo.
In the updated, final analysis conducted in 2008, 1551 women opted to switch from placebo to Femara, at a median 31 months after completion of adjuvant tamoxifen therapy. Median duration of Letrozole Tablets after switch was 40 months.
All significance levels in the 2008 analysis are provided for information purposes only, not for inference. No adjustment has been made for multiple updates or for multiple endpoints. Analyses of efficacy endpoints “ignoring the switch” compare the randomised Letrozole Tablets arm with a control arm in which follow-up was approximately one third placebo, two-thirds Femara. Median treatment duration for Letrozole Tablets was 60 months; in the placebo arm, median duration of placebo until switch (if a switch occurred) was 37 months.
The updated final analysis, conducted at a median follow-up of 62 months, confirmed the significant reduction in the risk of breast cancer recurrence with Letrozole Tablets compared with placebo, despite 60% of women in the placebo arm switching to Letrozole Tablets after the study was unblinded. The protocol-specified 4-year DFS rate was identical in the Letrozole Tablets arm for both the 2004 and 2008 analyses, confirming the stability of the data and robust effectiveness of Letrozole Tablets long-term. In the placebo arm, the impact of the selective switch to Letrozole Tablets is seen in the increase in 4-year DFS rate and in the apparent dilution in treatment difference.
In the original analysis, for the secondary endpoint overall survival (OS) a total 113 deaths were reported (51 Letrozole 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 3 and 4 summarise the results.

In the updated analysis, as shown in Table 3, there was a significant reduction in the odds of an invasive contralateral breast cancer with Letrozole Tablets compared with placebo, despite 60% of the patients in the placebo arm having switched to Femara. 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 Tablets 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 Tablets (n = 2567) than with patients who elected not to switch to Letrozole Tablets after the study was unblinded (n = 1026) - hot flushes (Femara, 60.9% versus placebo, 51.4%), arthralgia/arthritis (41.5% versus 27.2%), sweating (34.8% versus 29.7%), hypercholesterolemia (23.6% versus 15.3%) and myalgia (17.7% versus 9.4%). Most of these adverse events were observed during the first year of treatment.
For patients who elected to switch to Letrozole Tablets 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 Tablets (9.8%) than with placebo (7.0%). Overall cardiovascular events were reported for 6.2% of the patients who elected to switch to Femara. Significantly more patients reported stroke/TIA with Letrozole Tablets (1.5%) than with placebo (0.8%) (Letrozole Tablets after switch, 0.7%); cardiac events (Femara, 2.1% versus placebo, 1.0%) (Letrozole Tablets after switch, 1.4%); and thromboembolic events (Femara, 0.9% versus placebo, 0.3%) (Letrozole Tablets after switch, 0.6%).
Fractures were reported significantly more often with Letrozole Tablets (10.4%) than with placebo (5.8%) (Letrozole Tablets after switch, 7.7%) as was new osteoporosis (Femara, 12.2% versus placebo, 6.4%) (Letrozole Tablets 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 bone sub-study demonstrated that at 2 years, compared to baseline, patients receiving Letrozole Tablets had a median decrease of 3.8% in hip bone mineral density (BMD) compared to 2.0% in the placebo group (P = 0.02). There was no significant difference between treatments in terms of changes in lumbar spine BMD at any time.
Updated results (median follow-up was 62 months) from the lipid sub-study showed no significant difference between the Letrozole Tablets 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 Tablets 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 medicines. Specific results are presented in Table 5.

Both time to progression and objective response rate were significantly longer/higher for letrozole than for tamoxifen irrespective of receptor status (Table 6).

Study design allowed patients to cross-over upon progression to the other therapy or discontinue from the study. Approximately 50% of patients crossed-over to the opposite treatment arm and cross-over was virtually completed by 36 months. The median time to cross-over 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 log rank test), see Table 7.

In patients who did not cross-over 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 cut-off date for the primary analysis of response, time to progression, time to failure and safety. For all patients who were still alive at the end of the core trial, whether still on treatment or not, extension data were collected over an additional 6 months (extension trial). The end of the extension trial was the cut-off date for the primary analysis of survival.
At the end of the core trial, the overall objective tumour response (complete and partial response) rate was greatest in patients treated with Letrozole 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 doseeffect 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 Adverse 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.

Indications

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

Contraindications

Hypersensitivity to the active substance or to any of the excipients.
Premenopausal endocrine status; pregnancy, lactation (see Precautions).

Precautions

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 Letroz. As letrozole is weakly bound to plasma proteins (see Pharmacology, Pharmacokinetics), 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 Pharmacology, Pharmacokinetics).

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.

Menopausal status.

In patients whose menopausal status is unclear. Luteinising hormone (LH), folliclestimulating hormone (FSH) and/or estradiol levels should he measured before initiating treatment with Letrozole Tablets. Only women of postmenopausal endocrine status should receive Letrozole Tablets.

Interactions.

Preclinical safety data.

Repeat dose toxicity studies of up to 12 months duration were conducted in rats and dogs. No-effect levels were not established for letrozole, but changes observed at the lowest doses used (0.03 mg/kg/day) were related directly to the pharmacological properties of letrozole. Plasma levels of letrozole at the lowest dose in rats and dogs were similar to those expected in post-menopausal 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 post partum 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.

Effects on fertility.

In rats treated with letrozole beginning on day 7 post partum 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 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 estrogen synthesis leads to feedback increases in gonadotropin (LH, FSH) levels. Increased FSH levels in turn stimulate follicular growth, and can induce ovulation.

Use in pregnancy.

(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 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 Contraindications). Isolated cases of birth defects (labial fusion, ambiguous genitalia) have been reported in pregnant women exposed to Letrozole Tablets.
Australian Categorization 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.

Women of child-bearing potential and contraceptive measures, if applicable.

There have been post-marketing reports of spontaneous abortions and congenital anomalies in infants of mothers who have taken Letrozole Tablets. 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.

Use in lactation.

Letroz is contraindicated during lactation. It is not known if letrozole is excreted in human or animal milk (see Contraindications).

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 Adverse Effects, Pharmacology and Clinical Trials).

Interactions

Co-administration of Letrozole Tablets with tamoxifen, other anti-estrogens or estrogen containing therapies should be avoided as these substances may diminish the pharmacological action of Letrozole. The mechanism of this interaction is unknown.
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 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.
Co-administration of Letrozole Tablets 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 Tablets 2.5 mg 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, clopidrogel). 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 Femara with these drugs does not result in clinically significant drug interactions.

Adverse 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, and approximately 80% of the patients in the adjuvant setting (both Letrozole Tablets 2.5 mg and tamoxifen arms, at a median treatment duration of 60 months), and extended adjuvant setting (both Letrozole Tablets 2.5 mg and placebo arms, at a median treatment duration of 60 months for Letrozole Tablets 2.5 mg) can be expected to experience adverse effects. Generally, the observed adverse effects are mainly mild or moderate in nature, and many 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 clinical trials, were noted in the extended adjuvant setting: arthralgia/arthritis, osteoporosis and bone fractures (see Clinical Trials, Extended adjuvant treatment of early breast cancer).
The following adverse medicine effects, listed below, were reported from clinical studies and from post-marketing 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%, not known (cannot be estimated from the available data).

Infections and infestations.

Uncommon: urinary tract infection.

Neoplasms benign and malignant (including cysts and polyps).

Uncommon: tumour pain¹.

Blood and the lymphatic system disorders.

Uncommon: leucopenia.

Immune system disorders.

Very rare: anaphylactic reaction.

Metabolism and nutrition disorders.

Very common: hypercholesterolaemia. Common: anorexia, appetite increase.

Psychiatric disorders.

Common: depression. Uncommon: anxiety (including nervousness), irritability.

Nervous system disorders.

Common: headache, dizziness. Uncommon: somnolence, insomnia, memory impairment, dysaesthesia (including paraesthesia, hypoaesthesia), taste disturbance, cerebrovascular accident, carpal tunnel syndrome.

Eye disorders.

Uncommon: cataract, eye irritation, blurred vision.

Cardiac disorders.

Uncommon: palpitations¹, tachycardia, ischemic cardiac events^2,3 (including new or worsening angina, angina requiring surgery, myocardial infarction and myocardial ischemia).

Vascular disorders.

Very common: hot flushes. Common: hypertension. Uncommon: thrombophlebitis (including superficial and deep vein thrombophlebitis). Rare: pulmonary embolism, arterial thrombosis, cerebrovascular infarction.

Respiratory, thoracic and mediastinal disorders.

Uncommon: dyspnoea, cough.

Gastrointestinal disorders.

Common: nausea, vomiting, dyspepsia¹, constipation, diarrhoea, abdominal pain. Uncommon: stomatitis, dry mouth.

Hepato-biliary disorders.

Uncommon: increased hepatic enzymes. Very rare: hepatitis.

Skin and subcutaneous tissue disorders.

Very common: increased sweating. Common: alopecia, dry skin, rash (including erythematous, maculopapular, psoriaform and vesicular rash). Uncommon: pruritus, urticaria. Very rare: angioedema, toxic epidermal necrolysis, erytherma multiforme.

Musculoskeletal, connective tissue and bone disorders.

Very common: arthralgia. Common: myalgia, bone pain¹, osteoporosis, bone fractures. Uncommon: arthritis. Not Known: trigger finger.

Renal and urinary disorders.

Uncommon: increased urinary frequency.

Reproductive system and breast disorders.

Common: vaginal bleeding. Uncommon: vaginal discharge, vaginal dryness, breast pain.

General disorders and administration site conditions.

Very common: fatigue (including asthenia and malaise). Common: peripheral oedema. Uncommon: general oedema, pyrexia, mucosal dryness, thirst.

Investigations.

Common: weight increase. Uncommon: weight loss.
¹ Adverse drug reactions reported only in the metastatic setting.
² In the adjuvant setting, irrespective of causality, the following adverse events occurred in the Letrozole Tablets 2.5 mg and tamoxifen groups respectively: thromboembolic events (2.1% vs. 3.6%), angina pectoris (1.1% vs. 1.0%), myocardial infarction (1.0% vs. 0.5%) and cardiac failure (0.8% vs, 0.5%).
³ In the extended adjuvant setting, at a median treatment duration of 60 months for letrozole and 37 months for placebo, the following AEs were reported for Letrozole Tablets 2.5 mg and placebo (excluding all switches to Letrozole Tablets 2.5 mg) respectively: new or worsening angina (1.4% vs. 1.0%); angina requiring surgery (0.8% vs. 0.6%); myocardial infarction (1.0% vs. 0.7%); thromboembolic event (0.9% vs. 0.3%); stroke/TIA (1.5% vs. 0.8%).

Dosage and Administration

Adults.

The recommended dose of Letroz is one 2.5 mg 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 Letroz 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 in 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 Letroz should continue until tumour progression is evident.

Elderly patients.

No dose adjustment is required.

Patients with hepatic / renal impairment.

No dosage adjustment of Letroz is required for patients with mild renal impairment (creatinine clearance ≥ 30 mL/min). Insufficient data are available to justify dose advice in cases of renal insufficiency with creatinine clearance less than 30 mL/min. Insufficient data are available to justify dose advice in patients with severe hepatic insufficiency. Patients with severe hepatic impairment (Child-Pugh score C) should be kept under close supervision (see Pharmacology, Pharmacokinetics and Precautions).

Children.

Letroz is not recommended for use in children and adolescents. The safety and efficacy of Letrozole tablets 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.

Letroz 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.

Overdosage

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.
Contact the Poisons Information Centre (Telephone 131 126) for advice on the management of an overdose.

Presentation

Letroz (AUST R 203220).
Letroz is presented as yellow, round, biconvex, film-coated tablets plain on both sides; available in PVC/PVDC/Al blister pack and each pack contains 30 tablets.

Storage

Store below 25°C. Protect from Moisture.

Poison Schedule

S4.

Log in

Consumer medicine information

Letroz Tablets

Letrozole

Keep track of your medicines

BRAND INFORMATION

Letroz 2.5 mg Tablets

Pharmacor Letrozole 2.5 mg Tablets