Consumer medicine information

Femolet

Letrozole

BRAND INFORMATION

Brand name

Femolet

Active ingredient

Letrozole

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Femolet.

SUMMARY CMI

FEMOLET®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I taking FEMOLET?

FEMOLET contains the active ingredient letrozole. FEMOLET is used to treat breast cancer in post-menopausal women.

For more information, see Section 1. Why am I taking FEMOLET? in the full CMI.

2. What should I know before I take FEMOLET?

Do not use if you have ever had an allergic reaction to letrozole or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding. Your doctor will want to check your hormone levels to ensure you are no longer having periods.

For more information, see Section 2. What should I know before I take FEMOLET? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with FEMOLET and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I take FEMOLET?

  • The usual dose is one FEMOLET tablet every day.
  • Always swallow your tablet whole with a glass of water or other liquid.

More instructions can be found in Section 4. How do I take FEMOLET? in the full CMI.

5. What should I know while taking FEMOLET?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using FEMOLET.
  • If you become pregnant while taking FEMOLET, tell your doctor immediately.
  • Be sure to keep all your appointments with your doctor so your progress can be checked.
Things you should not do
  • Do not stop using this medicine suddenly.
  • Do not use FEMOLET to treat any other conditions unless your doctor tells you to.
  • Do not give FEMOLET to anyone else.
Driving or using machines
  • FEMOLET may occasionally cause drowsiness, dizziness or other symptoms, which could affect your ability to drive or operate machinery.
Drinking alcohol
  • FEMOLET may cause drowsiness or dizziness. Alcohol may increase this effect.
Looking after your medicine
  • Keep your tablets in a cool dry place where the temperature stays below 25°C. Store in original container.

For more information, see Section 5. What should I know while taking FEMOLET? in the full CMI.

6. Are there any side effects?

Common side effects include muscle/joints/back/breast pain, raised blood pressure/cholesterol, feeling tired, sick, annoyed, anxious, nervous, dizzy; headache, vertigo, hot flush, vomiting, cough, stomach pain, diarrhoea, frequent urination, constipation, sweating, hair loss, weight change, vaginal bleeding/discharge. More serious side effects include allergic reaction i.e. wheezing, difficulty breathing, swelling of lips, tongue/face, blisters/spreading rash on eyes, lips, face; yellow eyes/skin, unable to urinate; loss of vision, balance, co-ordination; difficulty speaking, confusion, constant flu-like symptoms i.e. fever, chills, sore throat; bluish/pale skin, heart palpitations, irregular/fast heartbeat, crushing chest pain, numb/tingling limbs, swelling and redness along a vein, bone fracture, tendonitis, pain or swelling around joints, tendon tears.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

FEMOLET®

Active ingredient(s): letrozole

Consumer Medicine Information (CMI)

This leaflet provides important information about using FEMOLET. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using FEMOLET.

Where to find information in this leaflet:

1. Why am I taking FEMOLET?
2. What should I know before I take FEMOLET?
3. What if I am taking other medicines?
4. How do I take FEMOLET?
5. What should I know while taking FEMOLET?
6. Are there any side effects?
7. Product details

1. Why am I taking FEMOLET?

FEMOLET contains the active ingredient letrozole. FEMOLET is belongs to a family of medicines called aromatase inhibitors. They are also called "antioestrogens" because they act by reducing the production of oestrogen in your body.

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

FEMOLET is used to treat breast cancer in women who are post-menopausal, or in other words, women who no longer have periods, either naturally due to their age or after surgery or chemotherapy.

2. What should I know before I take FEMOLET?

Warnings

Do not take FEMOLET if:

  • you are allergic to letrozole, or any of the ingredients listed at the end of this leaflet.
  • always check the ingredients to make sure you can use this medicine.
  • you are still having periods. This medicine is only used in women who are no longer having periods.
    Women of child-bearing age who recently became postmenopausal or perimenopausal should use a proven method of birth control to avoid pregnancy, until your postmenopausal status is fully established.
    Ask your doctor about options of effective birth control.
    Your doctor may send you for a blood test to check your hormone levels and confirm you are no longer having periods.
  • you are male.
    Men are not normally treated with FEMOLET as it may reduce fertility in male patients.
  • the person you intend to give this medicine to is a child.
    FEMOLET is not recommended for use in children.

Check with your doctor if you:

  • have a kidney or liver condition.
    Your doctor may want to take special precautions while you are taking this medicine if you have any of these conditions.
  • have a history of bone fractures or brittle bones from reduced bone mass (a condition called osteoporosis).
    Your doctor may want to check on your bones during treatment using a bone density test or may send you for an X-Ray.
  • are allergic to any other medicines, foods, dyes or preservatives.
    Your doctor will want to know if you are prone to allergies.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Your doctor will discuss with you the potential risks of taking FEMOLET during pregnancy. There are reports of abnormalities in babies born to mothers who took FEMOLET during pregnancy.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

It may pass into your breast milk and harm your baby.

3. What if I am taking other medicines?

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

Some medicines may interfere with FEMOLET and affect how it works.

Medicines that may affect FEMOLET include:

  • anti-fungal medicines such as ketoconazole, itraconazole, voriconazole
  • medicines for HIV such as ritonavir
  • antibiotics such as clarithromycin, and telithromycin
  • methoxsalen which is used for some skin conditions
  • medicines for seizures (fits) such as phenytoin or phenobarbital
  • clopidogrel which you may be taking if you have had previously had a heart attack or a stroke.
  • some antibiotics like rifampicin.
  • some other breast cancer medicines such as carbamazepine or tamoxifen.
  • St. John's wort (a herbal extract) used in a variety of conditions.
  • other medicines that contain oestrogen or affect the amount of oestrogen in your body.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect FEMOLET.

4. How do I take FEMOLET?

How much to take

  • The usual dose is one FEMOLET tablet every day.
  • Follow the instructions provided and use FEMOLET until your doctor tells you to stop.
    Your doctor will check your progress to make sure the medicine is working and will decide how long your treatment should continue.

How to take FEMOLET

  • Always swallow the tablet whole with a glass of water or other liquid.
    You can take the tablet with or without food.
  • If your stomach is upset after taking the tablet, take it with a meal or after a snack.

When to take FEMOLET

  • Take FEMOLET at about the same time each day.
    Taking your tablet at about the same time each day will have the best effect. It will also help you remember when to take it.

If you forget to take FEMOLET

If you miss your dose at the usual time and it is almost time for your next dose (e.g. within 2 or 3 hours), skip the dose you missed and take your next dose when you are meant to.

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

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

If you miss more than one dose, or are not sure what to do, check with your doctor or pharmacist.

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

If you take too much FEMOLET

If you think that you have used too much FEMOLET, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (Australia telephone 13 11 26) for advice, or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while taking FEMOLET?

Things you should do

Tell your doctor immediately if you become pregnant while taking FEMOLET.

Your doctor needs to know immediately so that FEMOLET can be replaced by another medicine. You should not take this medicine while you are pregnant. Use birth control to avoid pregnancy, until your postmenopausal status is fully established.

Call your doctor straight away if you are experiencing an allergic reaction to the medicine.

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 trouble breathing.

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 your appointments with your doctor so your progress can be checked.

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

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

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

If you go into hospital, please let the medical staff know that you are taking FEMOLET.

Things you should not do

  • Do not take FEMOLET for a longer time than your doctor has prescribed.
  • Do not let yourself run out of FEMOLET over the weekend or on holidays.
  • Do not stop taking this medicine suddenly.
  • Do not use FEMOLET to treat any other conditions unless your doctor tells you to.
  • Do not give FEMOLET to anyone else, even if their symptoms seem to be similar to yours.

Driving or using machines

Be careful before you drive, use any machines or tools or do jobs that require you to be alert until you know how FEMOLET affects you.

FEMOLET may occasionally cause drowsiness, dizziness or other symptoms, which could affect your ability to drive or operate machinery. Make sure you know how you are affected by this medicine before you drive or use machinery.

Drinking alcohol

FEMOLET can make you drowsy or dizzy. Alcohol may increase the effect.

Looking after your medicine

  • Keep your tablets in the original pack until it is time to take them.
    If you take the tablets out of the pack they will not keep well.
  • Keep your tablets in a cool dry place where the temperature stays below 25°C. Store in original container.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.
  • Heat and dampness can destroy some medicines.

Keep it where young children cannot reach it.

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

When to discard your medicine

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

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date or if the packaging is torn or shows signs of tampering.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
Stomach Problems:
  • Constipation or diarrhoea
  • Indigestion or discomfort/pain
Vaginal Problems:
  • Spotting or bleeding
  • Dryness
  • Thick, whitish discharge
General Well-Being:
  • Feeling sick (nausea or vomiting)
  • High cholesterol
  • Cough, headache
  • Trouble sleeping (insomnia) or feeling sleepy (drowsy)
  • Increased sweating or thirst
  • Changes to appetite or weight
  • Hair loss
  • Feeling anxious, nervous, annoyed or sad
  • Trouble remembering things
Skin/Soft Tissue Problems:
  • Dry, itchy, red, irritated skin or eyes
  • Hot flushes
  • Dry or sore mouth, ulcers (mouth sores), cold sores
Bladder Problems:
  • Urgent need to urinate (pass water)
  • Pain or burning sensation when urinating, which may be a sign of an urinary tract infection
Muscle or Joint Problems:
  • Back/breast/muscle/joint pain
  • Pain in arms and legs, stiffness
  • Arthritis, carpal tunnel, or trigger finger (finger bend and stuck)
Balance Problems:
  • Feeling dizzy, vertigo, falls
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Heart Problems:
  • Fast or irregular heartbeat
  • Increased blood pressure
  • Crushing chest pain or sudden shooting arm or leg (foot) pain (signs of a heart attack)
Signs of an Allergic Reaction:
  • Trouble breathing, wheezing
  • Spreading rash, red skin, blistering of lips, eyes or mouth, skin peeling (signs of skin disorder)
  • Swelling of the face or throat
Liver and Kidney Problems:
  • Yellow skin or eyes (jaundice)
  • Very dark urine or unable to urinate
Vision Problems:
  • Blurry vision (cataract) or blindness
Blood or Circulation Problems:
  • Weakness or being unable to move limbs or face, difficulty speaking/slurred speech, problems balancing or moving properly (signs of stroke)
  • Swelling and redness along a vein which is extremely tender or painful to touch (signs of thrombophlebitis)
  • Numbness or painful swelling/tingling in hands or feet, limbs
  • Bluish skin, coughing up blood, fainting
  • Swelling of the feet, ankles or other parts of the body due to fluid build-up (signs of oedema)
Infections:
  • Flu-like symptoms including fever, chills, sore throat, general lack of energy or tiredness
  • Feeling constantly sick, sores in mouth
Bone and Connective Tissue Problems:
  • Thinning of bones (osteoporosis), bone fractures
  • Tendon disorders including tendonitis (inflammation of the tendon) and tenosynovitis (inflammation of the tissue surrounding the tendon): pain, swelling and tenderness near a joint
  • Tendon tears: feeling a snap or pop when the tear happened, severe pain, swelling
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

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

What FEMOLET contains

Active ingredient (main ingredient)Letrozole 2.5 mg
Other ingredients (inactive ingredients)
  • Colloidal anhydrous silica
  • Microcrystalline cellulose
  • Lactose monohydrate
  • Magnesium stearate
  • Maize Starch
  • Sodium starch glycollate
  • OPADRY II complete film coating system 40L38238 YELLOW (ARTG PI No: 107043).
Potential allergensContains lactose, sulfites and trace amounts of phenylalanine.

Do not take this medicine if you are allergic to any of these ingredients.

What FEMOLET looks like

FEMOLET is a 2.5 mg dark yellow, capsule-shaped, slightly biconvex film-coated tablet debossed with "LZ 2.5" on one side and "G" on the other side. (AUST R 166010).

FEMOLET comes in blister packs containing 30 tablets.

Who distributes FEMOLET

Alphapharm Pty Ltd trading as Viatris
Level 1, 30 The Bond
30-34 Hickson Road
Millers Point NSW 2000
www.viatris.com.au
Phone: 1800 274 276

This leaflet was prepared in July 2024.

FEMOLET® is a Viatris company trade mark

FEMOLET_cmi\Jul24/00

Published by MIMS September 2024

BRAND INFORMATION

Brand name

Femolet

Active ingredient

Letrozole

Schedule

S4

 

1 Name of Medicine

Letrozole.

2 Qualitative and Quantitative Composition

Femolet is a film-coated tablet containing 2.5 mg letrozole as the active ingredient.

Excipients with known effect.

Lactose, sulfites and trace amounts of phenylalanine.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Femolet tablets are dark yellow, capsule-shaped, slightly biconvex film-coated tablets debossed with "LZ 2.5" on one side and "G" on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

For the treatment of postmenopausal women with hormone receptor positive breast cancer (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
The safety and efficacy of neoadjuvant use of letrozole has not been established. Letrozole is not indicated in hormone receptor negative disease.

4.2 Dose and Method of Administration

Adults.

The recommended dose of Femolet 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. The planned duration of treatment in the pivotal study was 5 years. However, at the time of the analysis, the median duration of treatment was 24 months, 25% of patients were treated for at least three years and less than 1% of patients were treated for the planned 5 years. The median duration of follow-up was 28 months. Treatment should be discontinued at tumour relapse.
In the adjuvant setting the median duration of treatment was 25 months, 73% of the patients were treated for more than 2 years, 22% of the patients for more than 4 years. The median duration of follow-up was 30 months (the efficacy data mentioned, see Section 5.1 Pharmacodynamic Properties, Clinical trials, are based on the primary core analysis with a median duration of follow-up of 26 months).
In patients with metastatic disease, treatment with letrozole should continue until tumour progression is evident.

Elderly patients.

No dose adjustment is required.

Patients with hepatic/renal impairment.

No dosage adjustment is required for patients with mild renal impairment (creatinine clearance ≥ 30 mL/min). Insufficient data are available to justify a dose advice in cases of renal insufficiency with creatinine clearance less than 30 mL/min or in patients with severe hepatic insufficiency. Patients with severe hepatic impairment (Child-Pugh score C) should be kept under close supervision (see Section 5.2 Pharmacokinetic Properties; Section 4.4 Special Warnings and Precautions for Use).

Children.

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

Method of administration.

Letrozole should be taken orally. A missed dose should be taken as soon as the patient remembers. However, if it is almost time for the next dose, the missed dose should be skipped, and the patient should go back to their regular dosage schedule. Doses should not be doubled because with daily doses over the 2.5 mg recommended dose, over-proportionality in systemic exposure was observed.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.
Premenopausal endocrine status; pregnancy, lactation (see Section 4.4 Special Warnings and Precautions for Use).

4.4 Special Warnings and Precautions for Use

Use with caution in the following circumstances.

Use in hepatic impairment.

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

Use in renal impairment.

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

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.

Co-administration of letrozole with tamoxifen, other anti-oestrogens or oestrogen-containing therapies should be avoided as these substances may diminish the pharmacological action of letrozole. The mechanism of this interaction is unknown.

Bone effects.

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

Tendon disorders.

The use of third generation aromatase inhibitors, including letrozole, were found to be associated with tendonitis and tenosynovitis in randomised controlled trials. Tendon rupture was found to be a potential risk. Tendonitis and tenosynovitis were estimated to be of uncommon occurrence, and tendon rupture of rare occurrence. Monitor patients for signs and symptoms of tendon disorders during treatment with Femolet.

Use in the elderly.

No data available.

Paediatric use.

No data available.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

To date, there are minimal data on the interaction between letrozole and other drugs.
Additionally, in a large clinical trial there was no evidence of clinically relevant interaction in patients receiving other commonly prescribed drugs (e.g. benzodiazepines; barbiturates; NSAIDs such as diclofenac sodium and ibuprofen; paracetamol; furosemide; omeprazole).
Letrozole is mainly metabolised in the liver and the cytochrome P450 enzymes CYP3A4 and CYP2A6 mediate the metabolic clearance of letrozole. Therefore, the systemic elimination of letrozole may be influenced by drugs known to affect the CYP3A4 and CYP2A6.

Drugs that may increase letrozole serum concentrations.

Inhibitors of CYP3A4 and CYP2A6 activities could decrease the metabolism of letrozole and thereby increase plasma concentrations of letrozole. The concomitant administration of medications that strongly inhibit these enzymes (strong CYP3A4 inhibitors: including but not limited to ketoconazole, itraconazole, voriconazole, ritonavir, clarithromycin, and telithromycin; CYP2A6 (e.g. methoxsalen) may increase exposure to letrozole. Therefore, caution is recommended in patients for whom strong CYP3A4 and CYP2A6 inhibitors are indicated.

Drugs that may decrease letrozole serum concentrations.

Inducers of CYP3A4 activity could increase the metabolism of letrozole and thereby decrease plasma concentrations of letrozole. The concomitant administration of medications that induce CYP3A4 (e.g. phenytoin, rifampicin, carbamazepine, phenobarbital, and St John's wort) may reduce exposure to letrozole. Therefore, caution is recommended in patients for whom strong CYP3A4 inducers are indicated. No drug inducer is known for CYP2A6.
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 CYP2A6 and, moderately, CYP2C19, but the clinical relevance is unknown. Caution is therefore indicated when giving letrozole concomitantly with medicinal products whose elimination is mainly dependent on CYP2C19 and whose therapeutic index is narrow (e.g. phenytoin, clopidogrel). No substrate with a narrow therapeutic index is known for CYP2A6.
Clinical interaction studies with cimetidine (a known nonspecific inhibitor of CYP2C19 and CYP3A4 and warfarin (sensitive substrate for CYP2C9 with a narrow therapeutic window and commonly used as comedication in the target population of letrozole) indicated that the co-administration of letrozole with these drugs does not result in clinically significant drug interactions.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

In rats treated with letrozole beginning on day 7 postpartum for 9 weeks, mating and fertility were decreased at all doses (0.003-0.3 mg/kg/day; below and similar to the human exposure at 2.5 mg/day). The treated rats also displayed delayed sexual maturation, prolonged diestrus and histological changes of reproductive organs (see Section 5.3 Preclinical Safety Data).
Chronic studies indicated stromal hyperplasia of the ovaries and uterine atrophy in rats administered oral doses equal to or greater than 0.3 mg/kg/day (approximately equivalent to human exposure at 2.5 mg/day, based on AUC). In addition, ovarian follicular atrophy and uterine atrophy were observed in chronic studies of female dogs administered doses equal to or greater than 0.03 and 0.3 mg/kg/day respectively (less than and approximately equivalent to human exposure at 2.5 mg/day).
The pharmacological action of letrozole is to reduce oestrogen production by aromatase inhibition. In premenopausal women, the inhibition of oestrogen synthesis leads to feedback increases in gonadotropin (LH, FSH) levels. Increased FSH levels in turn stimulate follicular growth and can induce ovulation.
(Category D)
Treatment of pregnant rats with letrozole at oral doses of 0.03 mg/kg/day during organogenesis was associated with a slight increase in the incidence of fetal malformation among the animals treated. It was not possible to show whether this was an indirect consequence of the pharmacological properties (inhibition of oestrogen biosynthesis) or a direct effect of letrozole in its own right. At doses of 0.003 mg/kg and above, higher incidences of resorptions and dead fetuses were also reported. These effects are consistent with the disruption of oestrogen dependent events during pregnancy and are not unexpected with a drug of this class. No peri/postnatal studies have been conducted in animals.
Letrozole is contraindicated during pregnancy (see Section 4.3 Contraindications). Isolated cases of birth defects (labial fusion, ambiguous genitalia) have been reported in pregnant women exposed to letrozole.
Australian Categorisation Definition of Category D: Drugs which have caused, are suspected to have caused or may be expected to cause, an increased incidence of human fetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects. Accompanying texts should be consulted for further details.

Women of childbearing potential and contraceptive measures, if applicable.

There have been postmarketing reports of spontaneous abortions and congenital anomalies in infants of mothers who have taken letrozole. The physician needs to discuss the necessity of adequate contraception with women who have the potential to become pregnant including women who are perimenopausal or who recently became postmenopausal, until their postmenopausal status is fully established.
 Letrozole is contraindicated during lactation. It is not known if letrozole is excreted in human or animal milk (see Section 4.3 Contraindications).

4.7 Effects on Ability to Drive and Use Machines

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

4.8 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, approximately 80% of the patients in the adjuvant setting (both letrozole and tamoxifen arms, at a median treatment duration of 60 months), and extended adjuvant setting (both letrozole and placebo arms, at a median treatment duration of 60 months for letrozole) can be expected to experience adverse reactions. Generally, the observed adverse reactions are mainly mild or moderate in nature, and many 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 following adverse drug reactions listed in Table 1, were reported from clinical studies and from postmarketing experience with letrozole.
Adverse reactions are ranked under headings of frequency, the most frequent first, using the following convention: very common ≥ 10%, common ≥ 1% to < 10%; uncommon ≥ 0.1% to < 1%; rare ≥ 0.01% to < 0.1%; very rare < 0.01%, not known (cannot be estimated from the available data).

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at 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 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

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

Mechanism of action.

The elimination of oestrogen mediated stimulatory effects is a prerequisite for tumour response in cases where the growth of tumour tissue depends on the presence of oestrogens. In postmenopausal women, oestrogens are mainly derived from the action of the aromatase enzyme, which converts adrenal androgens, primarily androstenedione and testosterone, to oestrone (E1) and estradiol (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 estradiol by 75-78% and 78% from baseline, respectively. Maximum suppression was achieved in 48-78 hours.
In postmenopausal patients with advanced breast cancer, daily doses of 0.1 to 5 mg letrozole suppressed plasma concentrations of estradiol, oestrone, and oestrone sulfate by 75-95% from baseline in all patients treated. With doses of 0.5 mg and higher, many values of oestrone and oestrone sulfate were below the limit of detection in the assays, indicating that higher oestrogen suppression is achieved with these doses. Oestrogen suppression was maintained throughout treatment in all patients.
Letrozole is highly specific in inhibiting aromatase activity. Impairment of adrenal steroidogenesis has not been observed. No clinically relevant changes were found in the plasma concentrations of cortisol, aldosterone, 11-deoxycortisol, 17-hydroxyprogesterone, ACTH or in plasma renin activity among postmenopausal patients treated with a daily dose of 0.1 to 5 mg letrozole. The ACTH stimulation test performed after 6 and 12 weeks of treatment with daily doses of 0.1, 0.25, 0.5, 1, 2.5 and 5 mg letrozole did not indicate any attenuation of aldosterone or cortisol production. Thus, glucocorticoid and mineralocorticoid supplementation is not necessary.
No changes were noted in plasma concentrations of androgens (androstenedione and testosterone) among healthy postmenopausal women after 0.1, 0.5 and 2.5 mg single doses of letrozole or in plasma concentrations of androstenedione among postmenopausal patients treated with daily doses of 0.1 to 5 mg, indicating that the blockade of oestrogen biosynthesis does not lead to accumulation of androgenic precursors. Plasma levels of LH and FSH were not affected by letrozole in patients, nor was thyroid function as evaluated by TSH, T4 and T3 uptake.

Clinical trials.

Adjuvant treatment of early breast cancer.

Study BIG 1-98. A multicentre, double blind, randomised study was conducted in over 8000 postmenopausal women with resected receptor positive early breast cancer. In this study, patients were randomly assigned to one of the following arms:
A. Tamoxifen for 5 years.
B. Letrozole for 5 years.
C. Tamoxifen for 2 years followed by letrozole for 3 years.
D. Letrozole for 2 years followed by tamoxifen for 3 years.
This study was designed to investigate two primary questions: whether letrozole for 5 years was superior to tamoxifen for 5 years (primary core analysis and monotherapy arms analysis and whether switching endocrine treatment at 2 years was superior to continuing the same agent for a total of 5 years (sequential treatments analysis).
The protocol specified efficacy endpoints were disease free survival (DFS), overall survival (OS) and systemic disease free survival (SDFS). The protocol specified primary efficacy endpoint of DFS was defined as the interval between date of randomisation and earliest confirmed invasive locoregional recurrence, distant metastasis, invasive contralateral breast cancer, second invasive (nonbreast) primary cancer, or death from any cause without a prior cancer event. The protocol specified secondary efficacy endpoint of OS was defined as the interval from randomisation to death from any cause. The protocol specified secondary efficacy endpoint of SDFS was defined as the interval from randomisation to systemic relapse, distant metastasis, appearance of a second (nonbreast) primary cancer, or death from any cause, whichever occurred first (i.e. excluding loco regional recurrences in the ipsilateral or contralateral breast). In addition, secondary efficacy endpoints specified in the statistical analysis plan prior to the end of enrolment and prior to an interim analysis included time to distant metastases and time to invasive contralateral breast cancer.

Efficacy results at a median follow up of 26 months.

Data in Table 2 reflect results of the primary core analysis (PCA) including data 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). This analysis was conducted at a median treatment duration of 24 months and a median follow up of 26 months. Letrozole for 5 years was superior to tamoxifen for efficacy endpoints of disease free survival (protocol specified), time to distant metastases, and systemic disease free survival, but not for the efficacy endpoints of overall survival and invasive contralateral breast cancer.

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

The monotherapy arms analysis (MAA) which include data for the monotherapy arms only provides the clinically appropriate long-term update of the efficacy of letrozole monotherapy compared to tamoxifen monotherapy (Table 4). In 2005, based on the PCA data presented in Table 3 and on recommendations by the independent data monitoring committee, the tamoxifen monotherapy arms were unblinded and patients were allowed to cross over to letrozole. 26% of patients randomised to tamoxifen elected to cross over to letrozole, including a very small number of patients who crossed over to other aromatase inhibitors. To explore the impact of this selective crossover, analyses censoring DFS and OS follow up times at the date of the selective crossover (in the tamoxifen arm) were conducted, and these analyses as well as the ITT analyses for selective endpoints disregarding selective crossover from tamoxifen to letrozole are summarised for the MAA (Table 3).
At a median follow up of 73 months and a median treatment duration of 60 months, the risk of a DFS event was significantly reduced with letrozole compared with tamoxifen (MAA ITT analysis: HR 0.88; 95% CI 0.78, 0.99; P = 0.03; confirming the 2005 PCA results. Analysis of DFS taking account of the selective crossover shows similar benefit (HR 0.85; 95% CI 0.75, 0.96). Similarly, the updated analysis confirmed the superiority of letrozole in reducing the risk of distant disease free survival events (HR 0.87, 0.76, 1.00) as well as the risk of reducing distant metastases (HR 0.85; 95% CI 0.72, 1.00). Additionally, overall survival trended towards significance in the ITT analysis. Analysis of overall survival taking account of the selective crossover shows a significantly greater benefit (HR 0.82 0.70, 0.96) in favour of letrozole.

Sequential treatments analyses.

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

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

In study BIG-98 at a median treatment duration of 60 months, the side effects seen were consistent with the safety profile of the drug. Certain adverse reactions were prospectively specified for analysis, based on the known pharmacologic properties and side effect profiles of the two drugs. Adverse events were analysed irrespective of drug relationship. Most adverse events reported (approximately 75% of patients reporting 1 or more AE) were grade 1 and grade 2 applying the CTC criteria version 2.0/CTCAE, version 3.0. When considering all grades during study treatment, a statistically significantly higher incidence of events was seen for letrozole compared to tamoxifen regarding hypercholesterolemia (52% vs. 29%), fractures (10.1% vs. 7.1%), myocardial infarctions (1.0% vs. 0.5%), osteoporosis (5.1% vs. 2.7%) and arthralgia (25.2% vs. 20.4%), vulvovaginal dryness (3.6% vs. 1.7%).
A statistically significantly higher incidence was seen for tamoxifen compared to letrozole regarding hot flushes (38% vs. 33%), night sweating (17% vs. 15%), vaginal bleeding (13% vs. 5.2%), constipation (2.9% vs. 2.0%), thromboembolic events (3.6% vs. 2.1%), endometrial hyperplasia/cancer (2.3% vs. 0.2%), and endometrial proliferation disorders (3.5% vs. 0.6%).
Adjuvant therapy in early breast cancer, study D2407. Study D2407 is a phase III, open label, randomised, multicentre study designed to compare the effects of adjuvant treatment with letrozole to tamoxifen on bone mineral density (BMD), bone markers and fasting serum lipid profiles. A total of 262 postmenopausal women with hormone sensitive resected primary breast cancer were randomly assigned to either letrozole 2.5 mg daily for 5 years or tamoxifen 20 mg daily for 2 years followed by 3 years of letrozole 2.5 mg daily.
The primary objective was to compare the effects on lumbar spine (L2-L4) BMD of letrozole versus tamoxifen, evaluated as percent change from baseline lumbar spine BMD at 2 years.
At 24 months, the lumbar spine (L2-L4) BMD showed a median decrease of 4.1% in the letrozole arm compared to a median increase of 0.3% in the tamoxifen arm (difference = 4.4%). At 2 years, overall the median difference in lumbar spine BMD change between letrozole and tamoxifen was statistically significant in favour of tamoxifen (P < 0.0001). The current data indicates that no patient with a normal BMD at baseline became osteoporotic at year 2 and only 1 patient with osteopenia at baseline (T score of -1.9) developed osteoporosis during the treatment period (assessment by central review).
The results for total hip BMD were similar to those for lumbar spine BMD. The differences, however, were less pronounced. At 2 years, a significant difference in favour of tamoxifen was observed in the overall BMD safety population and all stratification categories (P < 0.0001). During the 2 year period, fractures were reported by 20 patients (15%) in the letrozole arm, and 22 patients (17%) in the tamoxifen arm.
In the tamoxifen arm, the median total cholesterol levels decreased by 16% after 6 months compared to baseline; a similar decrease was also observed at subsequent visits up to 24 months. In the letrozole arm, the median total cholesterol levels were relatively stable over time, with no significant increase at a single visit. The differences between the 2 arms were statistically significant in favour of tamoxifen at each time point (P < 0.0001).

Extended adjuvant treatment of early breast cancer.

A multicentre, double blind, randomised, placebo controlled study (CFEM345G MA-17) was conducted in over 5100 postmenopausal patients with receptor positive or unknown primary breast cancer. In this study, patients who had remained disease free after completion of adjuvant treatment with tamoxifen (4.5 to 6 years) were randomly assigned either letrozole or placebo.
The planned duration of treatment for patients in the study was 5 years but the trial was unblinded early because of an interim analysis showing a favourable letrozole effect. At the time of unblinding, women had been followed for a median of 28 months (25% of the patients had been followed up for up to 38 months). The primary analysis showed that letrozole significantly reduced the risk of recurrence by 42% compared with placebo (hazard ratio 0.58; P = 0.00003). The statistically significant benefit in disease free survival (DFS) in favour of letrozole was observed regardless of nodal status: node negative, hazard ratio 0.48, P = 0.002; node positive, hazard ratio 0.61, P = 0.002.
The independent data and safety monitoring committee (DSMC) recommended that women who were disease free in the placebo arm be allowed to switch to letrozole for up to 5 years, when the study was unblinded in 2003. The study protocol was duly amended, implementing the DSMC recommendation: 60% of the eligible patients in the placebo arm opted to switch to letrozole, while the remaining patients opted to have no further treatment but agreed to continue to be monitored. The selective switch to letrozole severely compromised further comparative analyses of efficacy and safety; in the final, close out analysis after a median treatment duration of 5 years for letrozole, 64% of the randomised placebo arm total follow up patient years was actually accrued under letrozole, not placebo.
In the updated, final analysis conducted in 2008, 1551 women opted to switch from placebo to letrozole, at a median 31 months after completion of adjuvant tamoxifen therapy. Median duration of letrozole after switch was 40 months.
All significance levels in the 2008 analysis are provided for information purposes only, not for inference. No adjustment has been made for multiple updates or for multiple endpoints. Analyses of efficacy endpoints "ignoring the switch" compare the randomised letrozole arm with a control arm in which follow up was approximately one third placebo, two-thirds letrozole. Median treatment duration for letrozole was 60 months; in the placebo arm, median duration of placebo until switch (if a switch occurred) was 37 months.
The updated final analysis, conducted at a median follow up of 62 months, confirmed the significant reduction in the risk of breast cancer recurrence with letrozole compared with placebo, despite 60% of women in the placebo arm switching to letrozole after the study was unblinded. The protocol specified 4 year DFS rate was identical in the letrozole arm for both the 2004 and 2008 analyses, confirming the stability of the data and robust effectiveness of letrozole long-term. In the placebo arm, the impact of the selective switch to letrozole is seen in the increase in 4 year DFS rate and in the apparent dilution in treatment difference.
In the original analysis, for the secondary endpoint overall survival (OS) a total 113 deaths were reported (51 letrozole, 62 placebo). Overall, there was no significant difference between treatments in OS (hazard ratio 0.82; P = 0.29). In node positive disease, letrozole significantly reduced the risk of all-cause mortality by approximately 40% (hazard ratio 0.61; P = 0.035), whereas no significant difference was seen in patients with node negative disease patients (hazard ratio 1.36; P = 0.385), in patients with prior chemotherapy or in patients with no prior chemotherapy. Tables 4 and 5 summarise the results.
In the updated analysis, as shown in Table 4, there was a significant reduction in the odds of an invasive contralateral breast cancer with letrozole compared with placebo, despite 60% of the patients in the placebo arm having switched to letrozole. There was no significant difference in overall survival.
There was no difference in safety and efficacy between patients aged < 65 versus ≥ 65 years.
The updated safety profile of letrozole did not reveal any new adverse event and was entirely consistent with the profile reported in 2004.
The following adverse events irrespective of causality were reported statistically significantly more often with letrozole (n = 2567) than with patients who elected not to switch to letrozole after the study was unblinded (n = 1026); hot flushes (letrozole, 60.9% versus placebo, 51.4%), arthralgia/arthritis (41.5% versus 27.2%), sweating (34.8% versus 29.7%), hypercholesterolemia (23.6% versus 15.3%) and myalgia (17.7% versus 9.4%). Most of these adverse events were observed during the first year of treatment.
For patients who elected to switch to letrozole after the study was unblinded, the pattern of general adverse events reported was similar to the pattern during the first two years of treatment in the double blind study.
Cardiovascular, skeletal and endometrial events were collected with dates of onset and it is possible to report according to the treatment received.
With respect to cardiovascular events, statistically significantly more patients reported overall cardiovascular events with letrozole (9.8%) than with placebo (7.0%). Overall cardiovascular events were reported for 6.2% of the patients who elected to switch to letrozole. Significantly more patients reported stroke/TIA with letrozole (1.5%) than with placebo (0.8%) (letrozole after switch, 0.7%); cardiac events (letrozole, 2.1% versus placebo, 1.0%) (letrozole after switch, 1.4%); and thromboembolic events (letrozole, 0.9% versus placebo, 0.3%) (letrozole after switch, 0.6%).
Fractures were reported significantly more often with letrozole (10.4%) than with placebo (5.8%) (letrozole after switch, 7.7%) as was new osteoporosis (letrozole, 12.2% versus placebo, 6.4%) (letrozole after switch, 5.4%). Irrespective of treatment, patients aged 65 years or older at enrolment experienced more bone fractures and more (new) osteoporosis than younger women.
Updated results (median duration of follow up was 61 months) from the bone substudy demonstrated that at 2 years, compared to baseline, patients receiving letrozole had a median decrease of 3.8% in hip bone mineral density (BMD) compared to 2.0% in the placebo group (P = 0.02). There was no significant difference between treatments in terms of changes in lumbar spine BMD at any time.
Updated results (median follow up was 62 months) from the lipid substudy showed no significant difference between the letrozole and placebo groups at any time in total cholesterol or in any lipid fraction. In the updated analysis the incidence of cardiovascular events (including cerebrovascular and thromboembolic events) during treatment with letrozole versus placebo until switch was 9.8% vs. 7.0%, a statistically significant difference.

First line treatment of advanced breast cancer.

One well controlled double blind trial (study 025) was conducted comparing letrozole 2.5 mg (n = 453) to tamoxifen 20 mg daily (n = 454) as first line therapy in postmenopausal women with locally advanced or metastatic breast cancer. The percentage of patients with hormone receptor positive tumours was 64% in the letrozole group and 67% in the tamoxifen group. Letrozole was superior to tamoxifen in time to progression (primary endpoint) and in overall objective tumour response and time to treatment failure. Time to response and duration of response were the same for both drugs. Specific results are presented in Table 6.
Both time to progression and objective response rate were significantly longer/higher for letrozole than for tamoxifen irrespective of receptor status (Table 7).
Study design allowed patients to crossover upon progression to the other therapy or discontinue from the study. Approximately 50% of patients crossed over to the opposite treatment arm and crossover was virtually completed by 36 months. The median time to crossover was 17 months (letrozole to tamoxifen) and 13 months (tamoxifen to letrozole). Letrozole treatment in the first line therapy of advanced breast cancer patients is associated with an early survival advantage over tamoxifen. The median survival was 34 months for letrozole and 30 months for tamoxifen. A significantly greater number of patients were alive on letrozole versus tamoxifen throughout the first 24 months of the study (repeated log rank test), see Table 8.
In patients who did not 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 15-18 months) than for tamoxifen (median 9.3 months, 95% CI 8 to 12 months) (logrank P = 0.0047).
Worsening of Karnofsky Performance Score (KPS) by 20 points or more occurred in significantly fewer patients on letrozole (19%) than tamoxifen first line (25%) (odds ratio 0.69 (0.50-0.94), P = 0.0208).

Second line treatment of advanced breast cancer.

In a well controlled double blind clinical trial (study AR/BC2), 551 postmenopausal women with advanced breast cancer who had relapse or disease progression following anti-oestrogen (e.g. tamoxifen) therapy were randomised to receive oral daily doses of either letrozole 0.5 mg, letrozole 2.5 mg or megestrol acetate 160 mg. Some of the patients had also received previous cytotoxic treatment. Patients were either ER positive or unknown status. Data were collected up to 9 months after the last patient was enrolled in the core trial. This was the 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 has not been demonstrated in the neoadjuvant treatment of breast cancer.

5.2 Pharmacokinetic Properties

Absorption.

Letrozole is rapidly and completely absorbed from the gastrointestinal tract (mean absolute bioavailability 99.9%). Food slightly decreases the rate of absorption (median tmax: 1 hour fasted versus 2 hours fed, and mean Cmax: 129 ± 20.3 nanomol/L fasted versus 98.7 ± 18.6 nanomol/L fed) but the extent of absorption (AUC) is not changed. The minor effect on the absorption rate is not considered to be of clinical relevance and, therefore, letrozole may be taken without regard to mealtimes.
In a separate bioequivalence study which involved the treatment of eighteen healthy adult female subjects with a single oral dose of 2.5 mg letrozole tablets under fasting conditions, the mean tmax was found to be approximately 2.5 hours, with a mean Cmax of 35.57 ± 5.913 nanogram/mL.

Distribution.

Plasma protein binding of letrozole is approximately 60%, mainly to albumin (55%). The concentration of letrozole in erythrocytes is about 80% of that in plasma. After administration of 2.5 mg 14C-labelled letrozole, approximately 82% of the radioactivity in plasma was unchanged compound. Systemic exposure to metabolites is therefore low. Letrozole is rapidly and extensively distributed to tissues. Its apparent volume of distribution at steady state is about 1.87 ± 0.47 L/kg.

Metabolism and elimination.

Metabolic clearance to a pharmacologically inactive carbinol metabolite is the major elimination pathway of letrozole (CLm = 2.1 L/h) but is relatively slow when compared to hepatic blood flow (about 90 L/h). The cytochrome P450 isoenzymes 3A4 and 2A6 were found to be capable of converting letrozole to this metabolite. Formation of minor unidentified metabolites and direct renal and faecal excretion play only a minor role in the overall elimination of letrozole. Within 2 weeks after administration of 2.5 mg 14C-labelled letrozole to healthy postmenopausal volunteers, 88.2 ± 7.6% of the radioactivity was recovered in urine and 3.8 ± 0.9% in faeces. At least 75% of the radioactivity recovered in urine up to 216 hours (84.7 ± 7.8% of the dose) was attributed to the glucuronide of the carbinol metabolite, about 9% to two unidentified metabolites and 6% to unchanged letrozole.
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.
In a separate bioequivalence study which involved the treatment of eighteen healthy adult female subjects with a single oral dose of 2.5 mg letrozole tablets under fasting conditions, the mean elimination half-life in plasma was 3 days.

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

In the study populations (adults ranging in age from 35 to > 80 years), no change in pharmacokinetic parameters was observed with increasing age. In a study involving volunteers with varying degrees of renal function (24 hour creatinine clearance 9-116 mL/min) no effect on the pharmacokinetics of letrozole was found after a single dose of 2.5 mg. In a similar study involving subjects with varying degrees of hepatic function, the mean AUC values of the volunteers with moderate hepatic impairment (Child-Pugh score B) was 37% higher than in normal subjects, but still within the range seen in subjects without impaired function. In a study comparing the pharmacokinetics of letrozole after a single oral dose in eight subjects with liver cirrhosis and severe hepatic cirrhosis (Child-Pugh score C) to those in healthy subjects (N = 8), AUC and t1/2 increased on average by 95 and 187%, respectively, although uncertainty exists about the exact figures because of the wide confidence intervals in the study. Breast cancer patients with this type of severe hepatic impairment are thus expected to be exposed to higher levels of letrozole than patients without severe hepatic dysfunction. The available data do not allow any conclusions to be drawn about patients with predominant hepatocellular damage, for example, those with hepatitis C. If the opinion of the treating doctor is that the risk is acceptable, a patient with severe hepatic impairment may be treated without dose reduction, but close monitoring of possible adverse drug reactions is recommended. In addition, in two well controlled studies involving 359 patients with advanced breast cancer, no effect of renal impairment (calculated creatinine clearance: 20-50 mL/min) or hepatic dysfunction was found on the letrozole concentration.

5.3 Preclinical Safety Data

Repeat dose toxicity studies of up to 12 months duration were conducted in rats and dogs. No effect levels were not established for letrozole, but changes observed at the lowest doses used (0.03 mg/kg/day) were related directly to the pharmacological properties of letrozole. In a study using another aromatase inhibitor (anastrozole) plasma levels of anastrozole at these doses in rats and dogs were similar to those expected in human postmenopausal women during treatment with letrozole.
At higher doses of letrozole, associated with plasma letrozole concentrations 3 to 100 times greater than those expected in humans, changes were observed in the liver (probably related to the enzyme inducing properties of letrozole), the pituitary gland, skin, salivary gland, thyroid gland, haematopoietic system, kidneys, adrenal cortex and skeletal system (increased bone fragility). Additional lesions observed at similar doses in studies of longer duration were ocular and cardiac lesions in mice.
In juvenile rats, letrozole treatment beginning on day 7 postpartum for 6-12 weeks resulted in skeletal, neuroendocrine and reproductive changes at all doses 0.003-0.3 mg/kg/day; below and similar to the human exposure). Bone growth was decreased in males and increased in females. Bone mineral density (BMD) was decreased in females. Decreased fertility was accompanied by hypertrophy of the hypophysis, testicular changes which included a degeneration of the seminiferous tubular epithelium and atrophy of the female reproductive tract and ovarian cysts. With the exception of bone size and morphological changes in the testes, all effects were at least partially reversible.

Genotoxicity.

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

Carcinogenicity.

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

6 Pharmaceutical Particulars

6.1 List of Excipients

Femolet tablet contains the following inactive ingredients: colloidal anhydrous silica, microcrystalline cellulose, lactose monohydrate, magnesium stearate, maize starch, sodium starch glycollate and Opadry II complete film coating system 40L38238 Yellow (ARTG PI No: 107043).

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. Store in original container.

6.5 Nature and Contents of Container

Pack sizes: 10 and 30 tablets (blister packs).
Some strengths, pack sizes and/or pack types may not be marketed.

Australian register of therapeutic goods (ARTG).

AUST R 166010 - Femolet letrozole 2.5 mg film-coated tablet blister pack.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Letrozole is sparingly soluble in methanol, slightly soluble in isopropyl alcohol, freely soluble in dichloromethane and N,N-dimethylformamide and practically insoluble in hexane, isopropyl ether and water.

Chemical structure.


Chemical name: 4,4'-[(1H-1,2,4-triazol-1-yl)-methylene]bis-benzonitrile.
Molecular formula: C17H11N5.
Molecular weight: 285.31.

CAS number.

112809-51-5.

7 Medicine Schedule (Poisons Standard)

S4 (Prescription Only Medicine).

Summary Table of Changes