Consumer medicine information

Letrozole RBX Tablets

Letrozole

BRAND INFORMATION

Brand name

Letrozole RBX Tablets

Active ingredient

Letrozole

Schedule

S4

 

Consumer medicine information (CMI) leaflet

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

What is in this leaflet

This leaflet answers some common questions about LETROZOLE RBX tablets.

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.

This leaflet was last updated on the date at the end of this leaflet. More recent information may be available. The latest Consumer Medicine Information is available from https://www.ebs.tga.gov.au/ and may contain important information about the medicine and its use of which you should be aware.

All medicines have risks and benefits. Your doctor has weighed the risks of your taking LETROZOLE RBX against the benefits it is expected to 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 LETROZOLE RBX is used for

LETROZOLE RBX 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.

LETROZOLE RBX contains the active ingredient letrozole. Letrozole tablets are used to treat breast cancer in postmenopausal women, that is, women who no longer have periods, either naturally due to their age or after surgery or chemotherapy.

Letrozole belongs to a class of medicines known as aromatase inhibitors. They are also called “anti-oestrogens” because they block production of the hormone, oestrogen.

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 “anti-oestrogen” such as letrozole or you may have taken another “anti-estrogen” such as tamoxifen in the past.

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

Your doctor may have prescribed LETROZOLE RBX for another reason.

LETROZOLE RBX is available only with a doctor’s prescription.

Before you take LETROZOLE RBX

When you must not use it

Do not take LETROZOLE RBX if you are allergic to letrozole or any of the other ingredients of LETROZOLE RBX 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 difficulty in breathing.

Do not take LETROZOLE RBX 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 the postmenopausal status is fully established.

Do not take LETROZOLE RBX if you are pregnant or breast-feeding.

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

If you are not sure whether you should start taking LETROZOLE RBX, talk to your doctor or pharmacist.

Do not take LETROZOLE RBX after the use-by (expiry) date printed on the pack, or if the packaging is torn or shows signs of tampering.

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

If it has expired or is damaged, return it to your pharmacist for disposal.

Before you start to take it

Tell your doctor if you have liver disease (yellowing of skin and whites of eyes with decreased appetite, abdominal pain) or kidney disease.

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

You must also tell your doctor if you:

  • suffer from a disease of the bone that leads to loss of bone protein and minerals (osteoporosis) resulting in an increased risk of fracture and/or you have had a history of recurrent fractures
  • have not yet gone through menopause.

Your level of hormones may be checked by your doctor before you take LETROZOLE RBX 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.

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

If you have not told your doctor or pharmacist about any of the above, please do so before you take LETROZOLE RBX.

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 LETROZOLE RBX or they may affect how well it works.

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

  • tamoxifen
  • other anti-estrogens or estrogen-containing therapies

These substances may diminish the action of LETROZOLE RBX.

Women of child-bearing potential

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.

HOW to take LETROZOLE RBX

Follow all directions given to you by your doctor or 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 LETROZOLE RBX tablet daily.

How to take it

Swallow the tablet whole 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

Your doctor will advise you on how long you should continue to take your tablets. You will need to see your doctor from time to time to review your treatment and assess your symptoms.

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 your dose as soon as you remember, and then go back to taking your medicine as you would normally.

Do not take a double dose to make up for the dose you missed. This may increase the chance of you getting an unwanted side effect.

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

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

If you have taken too much (Overdose)

If you have taken too much, immediately telephone your doctor or the Poisons Information Centre (Tel. No. 13 11 26) for advice, or go to Accident & Emergency at your nearest hospital.

Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention. Keep these numbers handy in case of an emergency.

While you are taking LETROZOLE RBX

Things you must do

If you become pregnant while taking LETROZOLE RBX, 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 how well the medicine works and to 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 start on any new medicine, remind your doctor and pharmacist that you are taking LETROZOLE RBX.

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

This medicine contains lactose. If you have been told by your doctor that you have intolerance to some sugars, contact your doctor before taking LETROZOLE RBX.

Things you must not do

  • Do not use LETROZOLE RBX to treat any other complaints unless your doctor tells you to.
  • 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 LETROZOLE RBX 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 LETROZOLE RBX.

Letrozole may have unwanted side effects in some people in addition to its beneficial effects. All medicines can 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 up 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).

These 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 (signs of oedema).

Tell your doctor as soon as possible 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 (feeling sad)
  • 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 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 feel unwell.

Other side effects not listed above may also occur in some people.

Some of these can only be found by laboratory testing.

After using LETROZOLE RBX

Storage

Keep your tablets in the container until it is time to take them.

Store the tablets in cool dry place below 25 degrees Celcius. Do not store LETROZOLE RBX 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. LETROZOLE RBX will keep well if it is in cool and dry place.

Keep LETROZOLE RBX where children cannot reach it.

A locked cupboard at least one and a half metres (1.5 m) above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking LETROZOLE RBX 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 LETROZOLE RBX looks like

LETROZOLE RBX 2.5 mg tablets are yellow, round, biconvex, film-coated tablets with ‘LET1’ on one side and plain on the other side; available in blister packs of 30 tablets.

Ingredients

Active ingredient:
2.5 mg of letrozole

Inactive ingredients:

  • Lactose,
  • maize starch,
  • hypromellose,
  • microcrystalline cellulose,
  • sodium starch glycollate,
  • colloidal anhydrous silica,
  • magnesium stearate,
  • macrogol 6000,
  • titanium dioxide,
  • purified talc and
  • iron oxide yellow CI77492.

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

Sponsor

LETROZOLE RBX is supplied in Australia by:
Ranbaxy Australia Pty Ltd.
9-13 Waterloo Road
Macquarie Park NSW 2113
AUSTRALIA

Australian Registration Number
AUST R 167832

This leaflet was prepared in September 2013.

BRAND INFORMATION

Brand name

Letrozole RBX Tablets

Active ingredient

Letrozole

Schedule

S4

 

Name of the medicine

Letrozole.

Excipients.

Lactose, maize starch, hypromellose, microcrystalline cellulose, sodium starch glycollate, anhydrous colloidal silica, magnesium stearate, macrogol 6000, titanium dioxide, purified talc and iron oxide yellow CI77492.

Description

Chemical name: 4,4'-[(1H-1, 2, 4-triazol-1-yl)- methylene]bis- benzonitrile. Molecular formula: C17H11N5. MW: 285.303. CAS: 112809-51-5. Letrozole is a white or yellowish crystalline powder. It is practically insoluble in water, freely soluble in methylene chloride and sparingly soluble in methanol.

Pharmacology

Pharmacodynamics.

The elimination of oestrogen mediated stimulatory effects is a prerequisite for tumour response in cases where the growth of tumour tissue depends on the presence of oestrogens.
In postmenopausal women, oestrogens are mainly derived from the action of the aromatase enzyme, which converts adrenal androgens (primarily androstenedione and testosterone) to oestrone (E1) and oestradiol (E2). The suppression of oestrogen biosynthesis in peripheral tissues and the cancer tissue itself can, therefore, be achieved by specifically inhibiting the aromatase enzyme.
Letrozole is a nonsteroidal aromatase inhibitor. Data suggest it inhibits the aromatase enzyme by competitively binding to the haem of the cytochrome P450 subunit of the enzyme, resulting in a reduction of oestrogen biosynthesis in all tissues.
In healthy postmenopausal women, single doses of 0.1, 0.5 and 2.5 mg letrozole suppressed serum oestrone and oestradiol by 75-78% and 78% from baseline, respectively. Maximum suppression was achieved in 48-78 h.
In postmenopausal patients with advanced breast cancer, daily doses of 0.1 to 5 mg letrozole suppressed plasma concentrations of oestradiol, oestrone and oestrone sulphate by 75-95% from baseline in all patients treated. With doses of 0.5 mg and higher, many values of oestrone and oestrone sulphate were below the limit of detection in the assays, indicating that higher oestrogen suppression is achieved with these doses. Oestrogen suppression was maintained throughout treatment in all patients.
Letrozole is highly specific in inhibiting aromatase activity. Impairment of adrenal steroidogenesis has not been observed. No clinically relevant changes were found in the plasma concentrations of cortisol, aldosterone, 11-deoxycortisol, 17-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 meal times.

Distribution.

Plasma protein binding of letrozole is approximately 60%, mainly to albumin (55%). The concentration of letrozole in erythrocytes is about 80% of that in plasma. After administration of 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 excretion.

The major elimination pathway of letrozole is metabolic clearance to a pharmacologically inactive carbinol metabolite (CLm = 2.1 L/h). Elimination 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 two 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.
The apparent terminal elimination half-life in plasma is about 2 days. 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.

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

No change in pharmacokinetic parameters was observed with increasing age in clinical studies in adults ranging in age from 35 to > 80 years.
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. This was 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. Available data do not allow any conclusions to be drawn about patients with predominant hepatocellular damage, e.g. those with hepatitis C. If the opinion of the treating doctor is that the risk is acceptable, a patient with severe hepatic impairment may be treated without dose reduction, but close monitoring of possible adverse drug reactions is recommended. In addition, in two well controlled studies involving 359 patients with advanced breast cancer, no effect of renal impairment (calculated creatinine clearance: 20-50 mL/min) or hepatic dysfunction was found on the letrozole concentration.

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 for 5 years;
C. Tamoxifen for 2 years followed by letrozole for 3 years;
D. Letrozole for 2 years followed by tamoxifen for 3 years.
Data in Table 1 reflects 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), assessed as time from randomisation to the earliest event of locoregional or distant recurrence (metastases) of the primary disease), development of invasive contralateral breast cancer, and appearance of a second nonbreast primary tumour or death from any cause. Letrozole reduced the risk of recurrence by 19% compared with tamoxifen (hazard ratio 0.81; p = 0.003), corresponding to a reduction of the absolute risk by 2.6% at 5 years. The 5 year DFS rates were 84.0% for letrozole and 81.4% for tamoxifen. The improvement in DFS with letrozole was seen as early as 12 months and was maintained beyond 5 years. Letrozole also significantly reduced the risk of recurrence compared with tamoxifen whether prior adjuvant chemotherapy was given (hazard ratio 0.72; p = 0.018) or not (hazard ratio 0.84; p = 0.044). For the secondary endpoint overall survival a total of 358 deaths were reported (166 on letrozole and 192 on tamoxifen). There was no significant difference between treatments in overall survival (hazard ratio 0.86; p = 0.15). Letrozole significantly reduced the overall risk of distant recurrence (distant metastases) (hazard ratio 0.73; p= 0.001). Patients receiving letrozole had fewer second malignancies (1.9% vs 2.4%) compared to tamoxifen. Particularly the incidence of endometrial cancer was lower with letrozole compared to tamoxifen (0.2% vs 0.4%), but this difference was not statistically significant.
Results are summarised in Tables 1 and 2.

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 (4.5-6 years) were randomly assigned either letrozole or placebo.
The planned treatment duration was 5 years. The trial, however, was unblinded early because of an interim analysis showing a favourable letrozole effect. At the time of unblinding, women had been followed for a median of 28 months (25% of the patients had been followed up for up to 38 months). Primary analysis showed that letrozole reduced the risk of recurrence by 42% compared with placebo (hazard ratio 0.58; p = 0.00003).
Statistically significant benefit in disease free survival (DFS) in favour of letrozole was observed regardless of nodal status (node negative, hazard ratio 0.48, p = 0.002; node positive, hazard ratio 0.61, p = 0.002).
For the secondary endpoint overall survival (OS), a total 113 deaths were reported (51 letrozole, 62 placebo). Overall, there was no significant difference between treatments in OS (hazard ratio 0.82; p = 0.29). In node positive disease, letrozole significantly reduced the risk of 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. Results are summmarised in Tables 3 and 4.
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 arm, at least 30% of the patients had completed 5 years and 59% had completed a minimum of 4 years of follow-up. After unblinding of the study, 56% of the patients in the placebo arm opted to switch to letrozole (i.e. late extended adjuvant population).
In this analysis of DFS, letrozole significantly reduced the risk of breast cancer recurrence compared with placebo (HR 0.68; 95% CI 0.55, 0.83; p = 0.0001). It 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.
Clinical interpretation of these updated analyses should take into account that, after study unblinding, > 50% of the patients in the placebo arm who were eligible to switch opted to switch to letrozole (i.e. late extended adjuvant population). These patients 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, and 47 in 851 patients who opted not to switch.
The following adverse events irrespective of causality were reported significantly more often with letrozole 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 patients in the placebo arm who switched to letrozole, 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 than for placebo (12.3% vs. 7.4%). The incidence of clinical fractures, any time after randomisation, was higher in patients who received letrozole than for placebo (10.9% vs 7.2%). In patients who switched to letrozole, 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 40 months of follow-up) from the bone mineral density (BMD) substudy demonstrated that at 2 years, compared to baseline, patients receiving letrozole had a median decrease of 3.8% in hip BMD compared to 2.0% in the placebo group (p = 0.018). 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 a lipid substudy showed no significant difference between the letrozole and placebo groups at any time. In the core study the incidence of cardiovascular ischemic events for letrozole versus placebo until switch was (11.1% vs 8.6%).

First line treatment of advanced breast cancer.

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

Second line treatment of advanced breast cancer.

In a controlled double blind clinical trial, 551 postmenopausal women with advanced breast cancer who had relapse or disease progression following antioestrogen (e.g. tamoxifen) therapy were randomised to receive oral daily doses of either letrozole 0.5 mg, letrozole 2.5 mg or megestrol acetate 160 mg. Some of the patients had also received previous cytotoxic treatment. Patients were either ER positive or of 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 2.5 mg (23.6%) compared to patients treated with megestrol acetate (16.4%) and letrozole 0.5 mg (12.8%). Comparison of the response rates showed a statistically significant dose effect in favour of letrozole 2.5 mg (p = 0.004) with letrozole 2.5 mg also statistically superior to megestrol acetate (p = 0.04). The median duration of complete and partial response was 18 months for letrozole 0.5 mg and for megestrol acetate but was not reached for letrozole 2.5 mg. The duration of response was statistically significantly longer with letrozole 2.5 mg than with megestrol acetate (p = 0.01).
The median time to treatment failure was longest for patients on letrozole 2.5 mg (155 days) compared to patients on megestrol acetate (118 days) and letrozole 0.5 mg (98 days) (p = 0.007). The median times to progression were not significantly different. The median times to death (unadjusted analysis) were also not significantly different among the treatment groups in the Kaplan-Meier survival curves with many patients still alive at the last analysis (patients still alive: letrozole 0.5 mg (51.6%), letrozole 2.5 mg (58.1%), megestrol acetate (50.3%)). Letrozole gave significantly fewer severe and life threatening side effects, in particular decreased cardiovascular experiences and pulmonary emboli, than megestrol acetate. Other reported drug related adverse events included headache, hot flushes, allergic rash, nausea, hair thinning and oedema (refer to Adverse Effects).

Neoadjuvant treatment of breast cancer.

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

Indications

Letrozole RBX is indicated 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

Letrozole RBX is contraindicated in hypersensitivity to letrozole or to any of the ingredients; premenopausal endocrine status; pregnancy, lactation (see Precautions).

Precautions

Use with caution in the following circumstances.

Renal impairment.

Letrozole has not been investigated in patients with creatinine clearance < 10 mL/min nor in a sufficient number of patients with a creatinine clearance < 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 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 Pharmacokinetics).

Effects on ability to drive and use machines.

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

Menopausal status.

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

Interactions.

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

Preclinical safety data.

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

Effects on fertility.

Studies to investigate the effect of letrozole on fertility have not been conducted. Chronic studies indicated stromal hyperplasia of the ovaries and uterine atrophy in rats administered oral doses ≥ 0.3 mg/kg/day (approximately equivalent to human exposure at the maximum recommended clinical dose, based on AUC). In addition, ovarian follicular atrophy and uterine atrophy were observed in chronic studies of female dogs administered doses ≥ 0.03 and 0.3 mg/kg/day respectively (less than and approximately equivalent to human exposure at the maximum recommended clinical dose, based on AUC). It is not known whether these effects on the reproductive organs of animals are associated with impaired fertility in humans.
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 foetal malformations 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. At doses of ≥ 0.003 mg/kg, higher incidences of resorptions and dead foetuses were also reported. These effects are consistent with the disruption of oestrogen dependent events during pregnancy and are not unexpected with a drug of this class. No perinatal/ postnatal studies have been conducted in animals. Letrozole is contraindicated during pregnancy (see Contraindications).
Isolated cases of birth defects (labial fusion, ambiguous genitalia) have been reported in pregnant women exposed to letrozole.

Women of childbearing potential and contraceptive measures, if applicable.

There have been postmarketing reports of spontaneous abortions and congenital anomalies in infants of mothers who have taken letrozole. The physician needs to discuss the necessity of adequate contraception with women who have the potential to become pregnant, including women who are perimenopausal or who recently became postmenopausal, until their postmenopausal status is fully established.

Use in lactation.

Letrozole 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 and Clinical Trials).

Lactose.

Letrozole RBX (letrozole tablets) contain lactose as an excipient. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, glucose-galactose malabsorption should not take this medicine.

Interactions

To date, there are minimal data on the interaction between letrozole and other drugs.
Additionally, in a large clinical trial there was no evidence of clinically relevant interaction in patients in a large clinical trial receiving other commonly prescribed drugs (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 increase plasma concentrations of letrozole. The concomitant administration of medications that induce CYP3A4 (e.g. phenytoin, rifampicin, carbamazepine, phenobarbital, and St. John's wort) may reduce exposure to letrozole. Therefore caution is recommended in patients for whom strong CYP3A4 inducers are indicated. No drug inducer is known for CYP2A6.
Coadministration of letrozole (2.5 mg) and tamoxifen 20 mg daily resulted in a reduction of letrozole plasma levels by 38% on average. The mechanism of this interaction is unknown.
There is limited clinical experience to date on the use of letrozole in combination with anticancer agents other than tamoxifen.

Drugs that may have their systemic serum concentrations altered by letrozole.

In vitro, letrozole inhibits the cytochrome P450 isoenzymes CY2A6 and, moderately, CYP2C19, but the clinical relevance is unknown. Caution is therefore indicated when giving letrozole concomitantly with medicinal products whose elimination is mainly dependent on CYP2C19 and whose therapeutic index is narrow (e.g. phenytoin, clopidogrel). No substrate with a narrow therapeutic index is known for CYP2A6.
Clinical interaction studies with cimetidine (a known nonspecific inhibitor of CYP2C19 and CYP3A4) and warfarin (sensitive substrate for CYP2C9 with a narrow therapeutic window and commonly used as comedication in the target population of letrozole) indicated that the coadministration of letrozole with these drugs does not result in clinically significant drug interactions.

Adverse Effects

Letrozole was generally well tolerated across all studies as first line and second line treatment for advanced breast cancer, as adjuvant treatment of early breast cancer and as extended adjuvant treatment of early breast cancer in women who have received prior standard tamoxifen therapy.
Approximately one-third of the patients treated with letrozole in the metastatic setting, and approximately 70-75% of the patients in the adjuvant setting (both letrozole and tamoxifen arms), and approximately 40% of the patients in the extended adjuvant setting (both letrozole and placebo arms) can be expected to experience adverse reactions. Generally, the observed adverse reactions are mainly mild or moderate in nature and most are associated with oestrogen deprivation.
The most frequently reported adverse reactions in the clinical studies were hot flushes, arthralgia, nausea and fatigue. Many adverse reactions can be attributed to either the normal pharmacological consequences of oestrogen deprivation (e.g. hot flushes, alopecia and vaginal bleeding).
The following adverse events, not reported in the advanced or metastatic 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 drug reactions were reported from clinical studies and from postmarketing experience with letrozole.
Adverse reactions are ranked under headings of frequency, the most frequent first, using the following convention: very common ≥ 10%, common ≥ 1% to < 10%; uncommon ≥ 0.1% to < 1%; rare ≥ 0.01% to < 0.1%; very rare < 0.01%, not known (cannot be estimated from the available data.

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 events2,3 (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.

Hepatobiliary 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, erythema 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.
Including: 1Adverse drug reactions reported only in metastatic settings.
2In the adjuvant setting, irrespective of causality, the following adverse events occurred in the letrozole and tamoxifen groups respectively: thromboembolic events (1.2% vs. 3.0%), angina pectoris (0.8% vs. 0.8%), myocardial infarction (0.5% vs. 0.4%) and cardiac failure (0.8% vs. 0.3%).
3In the extended adjuvant setting, at a median treatment duration of 60 months for letrozole and 37 months for placebo, the following AEs were repored for letrozole and placebo (excluding all switches to letrozole) 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 Letrozole RBX 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 is not known. Treatment in the pivotal study was planned for 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 letrozole should continue until tumour progression is evident.

Elderly patients.

No dose adjustment is required.

Patients with hepatic/ renal impairment.

No dosage adjustment of letrozole 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 < 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 Pharmacokinetics and Precautions).

Children.

Not applicable.

Overdosage

Isolated cases of overdosage with letrozole have been reported. No specific treatment for overdosage is known. Treatment should be symptomatic and supportive. For information on the management of overdose, contact the Poisons Information Centre on 131 126 (Australia).

Presentation

Tablets, 2.5 mg (yellow, round, biconvex, film coated, marked LET1 on one side, plain on reverse): 30's (PVC/ PE/ PVdC/ Al blister pack).

Storage

Store below 25°C.

Poison Schedule

S4.