Consumer medicine information

Letrozole FBM

Letrozole

BRAND INFORMATION

Brand name

Letrozole FBM

Active ingredient

Letrozole

Schedule

What is in this leaflet

This leaflet answers some common questions about LETROZOLE FBM.

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

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

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

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

What LETROZOLE FBM is used for

LETROZOLE FBM 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 FBM belongs to a group of medicines called aromatase inhibitors also called ‘antioestrogens’. These medicines work 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 LETROZOLE FBM or you may have taken another "antioestrogen" such as femara or tamoxifen in the past.

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

LETROZOLE FBM is available only with a doctor's prescription.

There is no evidence that LETROZOLE FBM is addictive.

Before you take LETROZOLE FBM

When you must not take it

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

Do not take LETROZOLE FBM 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 peri menopausal should use a proven method of birth control to avoid pregnancy, until your post menopausal status is fully established.

Do not take LETROZOLE FBM if you are pregnant. LETROZOLE FBM may affect your developing baby if you take it during pregnancy.

Do not take LETROZOLE FBM if you are breastfeeding.

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

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

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:

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 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 FBM 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.

Tell your doctor if you plan to become pregnant or breastfeed

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

Taking other medicines

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

Some medicines may be affected by LETROZOLE FBM, or may affect how well it works. This includes in particular:

tamoxifen
other anti-estrogens or estrogencontaining therapies

These substances may diminish the action of LETROZOLE FBM.

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.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking LETROZOLE FBM.

How to take LETROZOLE FBM

How much to take

The usual dose is one LETROZOLE FBM tablet.

Your doctor may advise you to take a different dose. This depends on your condition and whether or not you are taking any other medicines.

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

How to take LETROZOLE FBM

Swallow the tablets with a whole glass of water.

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

If you forget to take LETROZOLE FBM

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

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

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

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

How long to take LETROZOLE FBM for

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

If you take too much LETROZOLE FBM (overdose)

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

While you are taking LETROZOLE FBM

Things you must do

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

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

If you become pregnant while taking LETROZOLE FBM, 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.

Your doctor may want you to have blood tests from time to time to check on your progress and detect 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 LETROZOLE FBM.

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

Things you must not do

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

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

Things to be careful of

Be careful driving or operating machinery until you know how LETROZOLE FBM affects you. This medicine may cause drowsiness, dizziness or light headedness in some people. If any of these occur, do not drive, operate machinery or do anything else that could be dangerous.

Side effects

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

Like all other medicines, LETROZOLE FBM may have unwanted side effects in some people. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

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

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

Tell your doctor if you notice any of the following:

swelling of the feet, ankles or other parts of the body due to fluid build up
skin rash, itching or dry skin
pain in the muscles, joints or bones; joint stiffness, arthritis
vaginal spotting or bleeding
high level of cholesterol
whitish, thick vaginal discharge, vaginal dryness
headache
fever
tiredness, sleepiness, weakness or dizziness
difficulty sleeping
numbness or tingling in hands or feet
mood changes such as anxiety, nervousness, irritability and depression (sad mood)
forgetfulness
change in sens of taste
blurred vision or eye irritation
stomach upset, nausea (feeling sick) or vomiting, pain in the abdomen
constipation
diarrhoea
dry mouth, sore mouth, mouth ulcers and cold sores
thirst, change in sense of taste, dry mouth
dry mucous membranes of the mouth, nose, vagina
increased thirst
breast pain
hot flushes
increased sweating
appetite or weight changes
hair thinning
urgent need to urinate (pass water)
pain or burning sensation when urinating, which may be a sign of an infection
fast or irregular heartbeats
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 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 immediately or go to Accident and Emergency at the nearest hospital if you notice any of the following:

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

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

Other side effects not listed above may also occur in some patients. Some of these can only be found by laboratory testing.

After using LETROZOLE FBM

Storage

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

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

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

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

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

Disposal

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

Product description

What it looks like

LETROZOLE FBM is a yellow, round biconvex film-coated tablet with ‘LET1’ on one side and plain on the other side.

Each blister pack contains 30 tablets.

Ingredients

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

The tablets also contain:

cellulose - microcrystalline
hypromellose
lactose
magnesium stearate
opadry 03F52007 yellow
silica - colloidal anhydrous
sodium starch glycollate
starch - maize.

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

Supplier

Southern Cross Pharma Pty Ltd
56 Illabunda Drive
Malua Bay NSW 2536
ABN 47 094 447 677

Australian registration numbers:
LETROZOLE FBM - AUST R 167833

Date of preparation: November 2013.

Published by MIMS September 2017

BRAND INFORMATION

Brand name

Letrozole FBM

Active ingredient

Letrozole

Schedule

1 Name of Medicine

Letrozole.

2 Qualitative and Quantitative Composition

Letrozole FBM film coated tablets contain the active ingredient letrozole.
Each Letrozole FBM film coated tablet contains 2.5 mg of letrozole.
Letrozole is a white or yellowish crystalline powder. It is practically insoluble in water, freely soluble in methylene chloride and sparingly soluble in methanol.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Letrozole FBM 2.5 mg film coated tablets are yellow, round, biconvex, film-coated tablets plain on both sides.

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment of post-menopausal women with hormone receptor-positive breast cancer (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
The safety and efficacy of neoadjuvant use of letrozole have not been established. Letrozole is not indicated in hormone receptor negative disease.

4.2 Dose and Method of Administration

Adults.

The recommended dose for adults 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 Section 5.1 Pharmacodynamic Properties, Clinical trials are based on the Primary Core Analysis with a median duration of follow up of 26 months).
In patients with metastatic disease, treatment with letrozole should continue until tumour progression is evident.

Elderly patients.

No dose adjustment is required.

Patients with hepatic / renal impairment.

No dosage adjustment 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 Section 5.2 Pharmacokinetic Properties and Section 4.4 Special Warnings and Precautions for Use).

Children.

Not applicable.

4.3 Contraindications

Hypersensitivity to letrozole or to any of the ingredients.
Pre-menopausal endocrine status; pregnancy, lactation (see Section 4.4 Special Warnings and Precautions for Use).

4.4 Special Warnings and Precautions for Use

Use with caution in the following circumstances:

Use in hepatic impairment.

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

Use in renal impairment.

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

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.

Use in the elderly.

No data available.

Paediatric use.

No data available.

Effects on laboratory tests.

Interactions with laboratory tests have not been established.

Bone effects.

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

Lactose.

Letrozole FBM (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.

4.5 Interactions with Other Medicines and Other Forms of Interactions

To date, there are minimal data on the interaction between letrozole and other drugs.
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.
Co-administration of letrozole (2.5 mg) and tamoxifen 20 mg daily resulted in a reduction of letrozole plasma levels by 38% on average. The mechanism of this interaction is unknown.
There is limited clinical experience to date on the use of letrozole in combination with anti-cancer agents other than tamoxifen.

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

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

4.6 Fertility, Pregnancy and Lactation

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.
(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 peri/postnatal studies have been conducted in animals. Letrozole is contraindicated in pregnancy (see Section 4.3 Contraindications).
Isolated cases of birth defects (labial fusion, ambiguous genitalia) have been reported in pregnant women exposed to letrozole.

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

4.7 Effects on Ability to Drive and Use Machines

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

4.8 Adverse Effects (Undesirable Effects)

Letrozole was generally well tolerated across all studies as first-line and second-line treatment for advanced breast cancer, as adjuvant treatment of early breast cancer, and as extended adjuvant treatment of early breast cancer in women who have received prior standard tamoxifen therapy.
Approximately one-third of the patients treated with letrozole in the metastatic setting, and approximately 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 Section 5.1 Pharmacodynamic Properties, Clinical trials - Extended adjuvant treatment of early breast cancer).
The adverse drug reactions listed in Table 1, were reported from clinical studies and from post-marketing experience with letrozole.
Reporting suspected adverse reactions after registration of the medical product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at http://www.tga.gov.au/reporting-problems.

4.9 Overdose

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).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

The elimination of oestrogen-mediated stimulatory effects is a prerequisite for tumour response in cases where the growth of tumour tissue depends on the presence of oestrogens.
In postmenopausal women, oestrogens are mainly derived from the action of the aromatase enzyme, which converts adrenal androgens - primarily androstenedione and testosterone - to oestrone (E1) and oestradiol (E2). The suppression of oestrogen biosynthesis in peripheral tissues and the cancer tissue itself can, therefore, be achieved by specifically inhibiting the aromatase enzyme.
Letrozole is a non-steroidal aromatase inhibitor. Data suggest that 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 post-menopausal 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 post-menopausal patients with advanced breast cancer, daily doses of 0.1 to 5 mg letrozole suppressed plasma concentrations of oestradiol, oestrone, and oestrone sulphate by 75-95% from baseline in all patients treated. With doses of 0.5 mg and higher, many values of oestrone and oestrone sulphate were below the limit of detection in the assays, indicating that higher oestrogen suppression is achieved with these doses. Oestrogen suppression was maintained throughout treatment in all patients.
Letrozole is highly specific in inhibiting aromatase activity. Impairment of adrenal steroidogenesis has not been observed. No clinically relevant changes were found in the plasma concentrations of cortisol, aldosterone, 11-deoxycortisol, 17-hydroxy-progesterone, ACTH or in plasma renin activity among post-menopausal 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 post-menopausal women after 0.1, 0.5 and 2.5 mg single doses of letrozole or in plasma concentrations of androstenedione among postmenopausal patients treated with daily doses of 0.1 to 5 mg, indicating that the blockade of oestrogen biosynthesis does not lead to accumulation of androgenic precursors. Plasma levels of LH and FSH were not affected by letrozole in patients, nor was thyroid function as evaluated by TSH, T4 and T3 uptake.

Clinical trials.

Adjuvant treatment of early breast cancer.

A 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 for 5 years;
C. tamoxifen for 2 years followed by letrozole for 3 years;
D. letrozole for 2 years followed by tamoxifen for 3 years.
Data in Table 2 reflect results 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). 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 loco-regional or distant recurrence (metastases) of the primary disease), development of invasive contralateral breast cancer, and appearance of a second non-breast 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 2 and 3.

Extended adjuvant treatment of early breast cancer.

A multi-centre, double-blind, randomised, placebo-controlled study was conducted in over 5100 postmenopausal patients with receptor-positive or unknown primary breast cancer. In this study, patients who had remained disease-free after completion of adjuvant treatment with tamoxifen (4.5 to 6 years) were randomly assigned either letrozole 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 summarised in Tables 4 and 5.

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) sub-study 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 sub-study 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 letrozole 2.5 mg (N = 453) to tamoxifen 20 mg daily (N = 454) as first-line therapy in post-menopausal 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 6.

Both time to progression and objective response rate were significantly longer/higher for letrozole than for tamoxifen irrespective of receptor status (see Table 7).

Study design allowed patients to cross over upon progression to the other therapy or discontinue from the study. Approximately 50% of patients crossed over to the alternative treatment arm and cross-over was virtually completed by 36 months. The median time to cross over 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 8].

In patients who did not cross over to the opposite treatment arm, median survival was 35 months with letrozole (n = 219, 95% CI 29 to 43 months) vs. 20 months with tamoxifen (n = 229, 95% CI 16 to 26 months).
The total duration of endocrine therapy (time to chemotherapy) was significantly longer for letrozole (median 16.3 months, 95% CI 15 to 18 months) than for tamoxifen (median 9.3 months, 95% CI 8 to 12 months) [logrank p = 0.0047].
Worsening of Karnofsky Performance Score (KPS) by 20 points or more occurred in significantly fewer patients on letrozole (19%) than tamoxifen first-line (25%) [odds ratio 0.69 (0.50 to 0.94), p = 0.0208].

Second-line treatment of advanced breast cancer.

In a controlled double-blind clinical trial, 551 post-menopausal women with advanced breast cancer who had relapse or disease progression following antioestrogen (e.g. tamoxifen) therapy were randomised to receive daily oral 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 (see Section 4.8 Adverse Effects (Undesirable Effects)).

Neoadjuvant treatment of breast cancer.

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

5.2 Pharmacokinetic Properties

Absorption.

Letrozole is rapidly and completely absorbed from the gastrointestinal tract (mean absolute bioavailability 99.9%). Food slightly decreases the rate of absorption (median t_max: 1 hour fasted versus 2 hours fed, and mean C_max: 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.

The major elimination pathway of letrozole is metabolic clearance to a pharmacologically inactive carbinol metabolite (CL_m = 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 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.

Excretion.

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 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.

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 subject. 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 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. 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 to 50 mL/min) or hepatic dysfunction was found on the letrozole concentration.

5.3 Preclinical Safety Data

Repeat-dose toxicity studies of up to 12 months 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.
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 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.

Genotoxicity.

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

Carcinogenicity.

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

6 Pharmaceutical Particulars

6.1 List of Excipients

Letrozole 2.5 mg film coated tablets contain the following inactive ingredients: lactose, maize starch, hypromellose, microcrystalline cellulose, sodium starch glycollate (Type A), colloidal anhydrous silica, magnesium stearate and Opadry 03B82927 Yellow (hypromellose, titanium dioxide, purified talc, macrogol 400 and iron oxide yellow CI77492).

6.2 Incompatibilities

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

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Store below 25°C. Protect from moisture.

6.5 Nature and Contents of Container

Letrozole FBM 2.5 mg film coated tablets are available in PVC/ PVDC/Al blister packs of 30 tablets and starter pack of 10 tablets.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Chemical name: 4, 4'-[(1H-1, 2, 4-triazol-1-yl)-methylene]bis-benzonitrile.
Molecular formula: C₁₇H₁₁N₅.
Molecular weight: 285.303.

Chemical structure.

CAS number.

112809-51-5.

7 Medicine Schedule (Poisons Standard)

S4.

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