Consumer medicine information

APO-Exemestane

Exemestane

BRAND INFORMATION

Brand name

APO-Exemestane

Active ingredient

Exemestane

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using APO-Exemestane.

What is in this leaflet

Read this leaflet carefully before taking your medicine. This leaflet answers some common questions about exemestane. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

The information in this leaflet was last updated on the date listed on the last page. More recent information on this medicine may be available.

Ask your doctor or pharmacist:

  • if there is anything you do not understand in this leaflet,
  • if you are worried about taking your medicine, or
  • to obtain the most up-to-date information.

You can also download the most up to date leaflet from www.apotex.com.au.

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

Pharmaceutical companies cannot give you medical advice or an individual diagnosis.

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

What this medicine is used for

The name of your medicine is APO-Exemestane. It contains the active ingredient exemestane.

It is used to:

  • Treat breast cancer in women who no longer have their menstrual periods, either naturally due to their age (after menopause) or because they have had their ovaries surgically removed.
  • Reduce the risk of recurrence or spreading of the breast cancer. It is also used when the cancer has not responded or has returned after treatment with another medicine or medicines.

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

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

How it works

Exemestane is an aromatase inactivator. It works by significantly reducing the supply of estrogen to cancer cells.

This stops the growth of those cancer cells which need estrogen, a natural female sex hormone, to grow.

There is no evidence that this medicine is addictive.

Use in children

This medicine is not recommended for use in children.

Before you take this medicine

When you must not take it

Do not take this medicine if:

  • You are pregnant.
    Exemestane may affect your developing baby if you take it during pregnancy.
  • You are breastfeeding.
    Exemestane may pass into human breast milk.
  • The expiry date (EXP) printed on the pack has passed.
  • The packaging is torn, shows signs of tampering or it does not look quite right.
  • You are hypersensitive to, or have had an allergic reaction to, exemestane or any of the ingredients listed at the end of this leaflet.
    Symptoms of an allergic reaction may include cough, shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue, throat or other parts of the body, rash, itching or hives on the skin; fainting or hayfever-like symptoms.
    If you think you are having an allergic reaction, do not take any more of the medicine and contact your doctor immediately or go to the Accident and Emergency department at the nearest hospital.

Before you start to take it

Before you start taking this medicine, tell your doctor if:

  1. You have allergies to:
  • any other medicines
  • any other substances, such as foods, preservatives or dyes.
  1. You have or have had any medical conditions, especially the following:
  • you are still having your monthly period
  • kidney problems
  • liver problems
  • osteoporosis (disease which causes bones to be more brittle and likely to break)
  • a deficiency in vitamin D, your doctor may give you a blood test to determine your vitamin D levels.
  1. You are currently pregnant or you plan to become pregnant. Do not take this medicine whilst pregnant.
  2. You are currently breast-feeding or you plan to breast-feed. Do not take this medicine whilst breast-feeding.
  3. You are planning to have surgery or an anaesthetic.
  4. You are currently receiving or are planning to receive dental treatment.
  5. You are taking or are planning to take any other medicines, This includes vitamins and supplements that are available from your pharmacy, supermarket or health food shop.

Some medicines may interact with exemestane. These include:

  • medicines which contain estrogen, such as hormone replacement therapy (HRT)
  • oral contraceptives.

Some health food products for menopausal symptoms contain natural estrogens.

If you are taking any of these you may need a different dose or you may need to take different medicines.

Other medicines not listed above may also interact with exemestane.

How to take this medicine

Follow carefully all directions given to you by your doctor. Their instructions may be different to the information in this leaflet.

How much to take

The recommended dosage is one 25 mg tablet taken once daily.

Your doctor will tell you how much of this medicine you should take. This will depend on your condition and whether you are taking any other medicines.

Do not stop taking your medicine or change your dosage without first checking with your doctor.

When to take it

Take this medicine at the same time each day, preferably after a meal. Taking it at the same time each day will help you remember when to take it.

How long to take it for

Continue taking your medicine for as long as your doctor tells you.

Make sure you have enough to last over weekends and holidays.

If you forget to take it

If it is almost time to take your next dose, skip the missed dose and take your next dose at the usual time. Otherwise take it as soon as you remember and then go back to taking your medicine as you would normally.

Do not take a double dose to make up for missed doses. This may increase the chance of you experiencing side effects.

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

If you take too much (overdose)

If you think that you or anyone else may have taken too much of this medicine, immediately telephone your doctor or the Poisons Information Centre (Tel: 13 11 26 in Australia) for advice. Alternatively go to the Accident and Emergency Department at your nearest hospital.

Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are taking this medicine

Things you must do

Tell your doctor that you are taking this medicine if:

  • you are about to be started on any new medicine
  • you are pregnant or are planning to become pregnant
  • you are breast-feeding or are planning to breast-feed
  • you are about to have any blood tests
  • you are going to have surgery or an anaesthetic or are going into hospital.

Your doctor may occasionally do tests to make sure the medicine is working and to prevent side effects. Go to your doctor regularly for a check-up.

Tell any other doctors, dentists and pharmacists who are treating you that you take this medicine.

Things you must not do

Do not:

  • Give this medicine to anyone else, even if their symptoms seem similar to yours
  • Take your medicine to treat any other condition unless your doctor or pharmacist tells you to
  • Stop taking your medicine, or change the dosage, without first checking with your doctor.

Things to be careful of

Be careful when driving or operating machinery until you know how this medicine affects you. Exemestane may cause tiredness or dizziness in some people.

Possible side effects

Tell your doctor as soon as possible if you do not feel well while you are taking exemestane or if you have any questions or concerns.

Do not be alarmed by the following lists of side effects. You may not experience any of them. All medicines can have side effects. Sometimes they are serious but most of the time they are not.

Tell your doctor as soon as possible if you notice any of the following:

  • hot flushes
  • nausea, vomiting, loss of appetite, indigestion, pain (including stomach ache)
  • constipation
  • diarrhoea
  • tiredness and feelings of weakness
  • dizziness and headache
  • increased sweating
  • increase in weight
  • skin rash
  • hair loss

Tell your doctor as soon as possible if you notice any of the following.

These may be serious side effects and you may need medical attention:

  • pain in your muscle or joints
  • difficulty sleeping
  • increased drowsiness
  • depression
  • swelling in your legs
  • disturbed vision such as blurriness
  • bleeding or bruising more easily than normal
  • pain and/or numbness of hands, loss of feeling in fingers/thumb
  • frequent infections such as fever, severe chills, sore throat or mouth ulcers
  • symptoms of gastric ulcer such as blood in stools, black tarry stools or vomiting of blood
  • abnormal vaginal bleeding.

If you experience any of the following, stop taking your medicine and contact your doctor immediately or go to the Accident and Emergency department at your nearest hospital.

These are very serious side effects and you may need urgent medical attention or hospitalisation:

  • hepatitis, yellowing of the skin or eyes, also called jaundice
  • rapid appearance of many pustules and fever (a type of allergic reaction).

Other side effects not listed above may occur in some patients.

Allergic reactions

If you think you are having an allergic reaction to exemestane, do not take any more of this medicine and tell your doctor immediately or go to the Accident and Emergency department at your nearest hospital.

Symptoms of an allergic reaction may include some or all of the following:

  • cough, shortness of breath, wheezing or difficulty breathing.
  • swelling of the face, lips, tongue, or other parts of the body
  • rash, itching or hives on the skin
  • fainting
  • hayfever-like symptoms

Storage and disposal

Storage

Keep your medicine in its original packaging until it is time to take it.

If you take your medicine out of its original packaging it may not keep well.

Keep your medicine in a cool dry place where the temperature will stay below 30°C.

Do not store your medicine, or any other medicine, in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

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

Disposal

If your doctor or pharmacist tells you to stop taking this medicine or they have passed their expiry date, your pharmacist can dispose of the remaining medicine safely.

Product description

What APO-Exemestane looks like

Exemestane 25 mg tablets are white to off-white, circular, biconvex and are sugar-coated.

Ingredients

Each tablet contains 25 mg of exemestane as the active ingredient.

It also contains the following inactive ingredients:

  • microcrystalline cellulose
  • crospovidone
  • polysorbate 80
  • mannitol
  • colloidal anhydrous silica
  • magnesium stearate
  • sucrose
  • acacia
  • purified talc
  • titanium dioxide
  • ethanol
  • shellac
  • white beeswax
  • carnauba wax

This medicine is gluten-free, lactose-free, tartrazine-free and free of other azo dyes.

Australian Registration Numbers

APO-Exemestane 25 mg tablets (blister pack of 30s): AUST R 177312.

Sponsor

Arrotex Pharmaceuticals Pty Ltd
15-17 Chapel Street
Cremorne VIC 3121
www.arrotex.com.au

This leaflet was last updated in:
November 2023.

Published by MIMS January 2024

BRAND INFORMATION

Brand name

APO-Exemestane

Active ingredient

Exemestane

Schedule

S4

 

1 Name of Medicine

Exemestane.

2 Qualitative and Quantitative Composition

Each tablet contains 25 mg exemestane, as the active ingredient.
For the full list of excipients see Section 6.1 List of Excipients.

3 Pharmaceutical Form

White to off-white, circular, biconvex tablets coated with sugar.

4 Clinical Particulars

4.1 Therapeutic Indications

Exemestane is indicated for:
Sequential adjuvant treatment of estrogen receptor positive early breast cancer in postmenopausal women who have received prior adjuvant tamoxifen therapy.
Treatment of estrogen receptor positive advanced breast cancer in women with natural or induced postmenopausal status whose disease has progressed following antiestrogen therapy.

4.2 Dose and Method of Administration

APO-Exemestane tablets are intended for oral administration.

Dosage.

Adults.

The recommended dose of exemestane in adults is one 25 mg tablet taken once daily, preferably after a meal.
In patients with early breast cancer, treatment should continue until completion of five years adjuvant hormonal therapy or until tumour relapse occurs.
In patients with advanced breast cancer, treatment with exemestane should continue until tumour progression is evident.

Renal impairment.

No dose adjustments are required for patients with renal insufficiency.

Hepatic impairment.

No dose adjustments are required for patients with hepatic insufficiency.

Paediatric use.

Not recommended for use in children.

4.3 Contraindications

Exemestane tablets are contraindicated in pregnant or lactating women and patients with a known hypersensitivity to the drug or to any of the excipients.

4.4 Special Warnings and Precautions for Use

Check the following before use.

Because of its mode of action, exemestane should not be administered to women with premenopausal endocrine status. Whenever clinically appropriate, confirmation of post-menopausal status may be assisted by laboratory tests, such as assessment of luteinising (LH), follicle stimulating hormone (FSH) and oestradiol levels.
Routine assessment of 25 hydroxy vitamin D levels prior to the start of aromatase inhibitor treatment should be considered, due to the high prevalence of severe deficiency associated in women with early breast cancer (EBC). Women with vitamin D deficiency should receive supplementation with vitamin D.

Bone mineral density and fracture risk.

Overall, in trial 031, the incidence of fracture was greater in patients treated with exemestane than tamoxifen (see Section 4.8 Adverse Effects (Undesirable Effects)). Treatment-emergent fractures were more frequent in exemestane patients (4.5%) than in tamoxifen patients (3.3%). When all fractures reported on-treatment and during follow-up are considered, the incidence was significantly greater in exemestane patients (7.3%) compared with tamoxifen patients (5.2%), p=0.004.
Reductions in bone mineral density (BMD) over time are seen with exemestane use. In a sub-study of trial 031 in early breast cancer, patients who received 2-3 years of exemestane after 2-3 years of tamoxifen (n = 86) had a higher loss of bone mineral density while on treatment than patients who received continuous tamoxifen (n = 100) (mean % change from baseline for BMD at 36 months: -3.37 [spine], -2.96 [total hip] for exemestane and -1.29 [spine], -2.02 [total hip], for tamoxifen).
As exemestane is a potent estrogen lowering agent, reduction in bone mineral density can be anticipated. During adjuvant treatment with exemestane, women with osteoporosis or at risk of developing osteoporosis should have their bone mineral density formally assessed by bone densitometry at the commencement of treatment and at regular intervals thereafter. Treatment or prophylaxis for osteoporosis should be initiated as appropriate and carefully monitored.

Use in hepatic impairment.

See Section 5.2 Pharmacokinetic Properties.

Use in renal impairment.

See Section 5.2 Pharmacokinetic Properties.

Use in the elderly.

No data available.

Paediatric use.

Not recommended for use in children.

Effects on laboratory tests.

Elevation of serum hepatic function tests (especially ALT and GGT) and alkaline phosphatase have been occasionally observed. In the pivotal controlled study these elevations occurred mainly in patients with liver or bone metastasis or other impaired liver conditions, except for the elevations in GGT. Decreases in WBC, especially lymphocytes, were also observed.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Exemestane should not be coadministered with estrogen containing products as these would negate its pharmacological action.
No formal drug interaction studies have been carried out. In vitro evidence showed that the drug is metabolised through cytochrome P450 (CYP) 3A4 and aldoketoreductases and does not inhibit any of the major CYP isoenzymes. In a clinical pharmacokinetic study, the specific inhibition of CYP3A4 by ketoconazole showed no significant effects on the pharmacokinetics of exemestane. A possible decrease of exemestane plasma levels by known inducers of CYP3A4 cannot be excluded. Exemestane should be used cautiously with drugs that are metabolised via CYP3A4 and have a narrow therapeutic window.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Untreated female rats showed reduced fertility when mated to males treated with exemestane 500 mg/kg/day (approximately 200 times the recommended human dose on a mg/m2 basis). Exemestane given to female rats showed no effects on female fertility parameters (e.g. ovarian function, mating behaviour, conception rate) at doses up to 20 mg/kg/day (approximately eight times the human dose on a mg/m2 basis), but mean litter size was decreased at this dose. In general toxicology studies, changes in the ovary, including atrophy, tubulostromal hyperplasia, an increase in ovarian cysts and a decrease in corpora lutea were observed with variable frequency in mice, rats and/or dogs at doses that ranged from 3 to 20 times the human dose on a mg/m2 basis.
(Category C)
Exemestane should not be used in women who are or may become pregnant because it may cause harm to the foetus (see Section 4.3 Contraindications). Exemestane disrupts estrogen dependent metabolism and may result in abortion. It is contraindicated in pregnant women. Studies in animals have shown reproductive toxicity.
In animal reproduction studies in rats and rabbits, exemestane was embryotoxic, fetotoxic, and abortifacient. In rats the concentration of exemestane and its metabolites was approximately equivalent in maternal and foetal blood. When rats were administered exemestane from 14 days prior to mating until either days 15 or 20 of gestation, and resuming for the 21 days of lactation, an increase in placental weight was seen at 4 mg/kg/day (approximately 1.5 times the recommended human daily dose on a mg/m2 basis). Prolonged gestation and abnormal or difficult labour were observed at doses equal to or greater than 20 mg/kg/day. Increased resorption, reduced number of live foetuses, decreased foetal weight and retarded ossification were also observed at these doses. No malformations were noted when exemestane was administered to pregnant rats during the organogenesis period at doses up to 810 mg/kg/day (approximately 320 times the recommended human dose on a mg/m2 basis). Daily doses of exemestane given to rabbits during organogenesis caused a decrease in placental weight at 90 mg/kg/day (approximately 70 times the recommended human daily dose on a mg/m2 basis). In the presence of maternal toxicity, abortions, an increase in resorptions and a reduction in foetal bodyweight were seen at 270 mg/kg/day (approximately 210 times the recommended human dose on a mg/m2 basis). There was no increase in the incidence of malformations in rabbits at doses up to 270 mg/kg/day.
There are no studies in pregnant women using exemestane. Exemestane is indicated for postmenopausal women. If there is exposure to exemestane during pregnancy, the patient should be advised of the potential hazard to the foetus and potential risk for loss of the pregnancy.
Exemestane is contraindicated in pregnant women and only indicated in postmenopausal women. Exemestane and/or its metabolites appeared in rat milk within 15 minutes of oral administration of radiolabelled exemestane. Concentrations of exemestane and its metabolites were approximately equivalent in the milk and plasma of rats for 24 hours after a single oral dose of 1 mg/kg 14C-exemestane. It is not known whether exemestane is excreted in human milk. Because many drugs are excreted in human milk, Exemestane should not be used in women who are lactating.

4.7 Effects on Ability to Drive and Use Machines

Exemestane is unlikely to impair the ability of patients to drive and operate machinery. However, drowsiness, somnolence, asthenia and dizziness have been reported with the use of the drug. Patients should be advised that, if these events occur, their physical and/or mental abilities required for operating machinery or driving a car may be impaired.

4.8 Adverse Effects (Undesirable Effects)

Exemestane was generally well tolerated across all clinical studies; adverse events were usually mild to moderate. The discontinuation rate due to adverse events was 7.4% in patients with early breast cancer receiving adjuvant treatment with exemestane following initial adjuvant tamoxifen therapy. The most commonly reported adverse reactions were hot flush (22%), arthralgia (18%) and fatigue (16%). The discontinuation rate due to adverse events was 2.8% in the overall patient population with advanced breast cancer. The most commonly reported adverse reactions were hot flush (14%) and nausea (12%). Most adverse reactions can be attributed to the normal pharmacological consequences of estrogen deprivation (e.g. hot flush).
Adverse events in which causal relationship with exemestane could not be excluded are listed below by system organ class and by frequency. Frequencies are defined as follows: very common (≥ 10%), common (≥ 1%, < 10%), uncommon (≥ 0.1%, < 1%), rare (≥ 0.01%, < 0.1%).

General disorders and administration site conditions.

Very common: pain, fatigue. Common: peripheral oedema (including leg oedema), asthenia.

Gastrointestinal disorders.

Very common: abdominal pain, nausea. Common: vomiting, constipation, dyspepsia, diarrhoea.

Hepatobiliary disorders.

Very common: hepatic enzyme increased (including ALT increase, GGT increase#), blood bilirubin increased, blood alkaline phosphatase increase.

Metabolism and nutrition disorders.

Common: anorexia.

Nervous system disorders.

Very common: dizziness, headache. Common: carpal tunnel syndrome. Rare: somnolence.

Psychiatric disorders.

Very common: insomnia, depression.

Vascular disorders.

Very common: hot flush.

Skin and subcutaneous tissue disorders.

Very common: hyperhidrosis. Common: alopecia, rash.

Musculoskeletal and connective tissue disorders.

Very common: joint and musculoskeletal pain*. Common: osteoporosis, fracture.

Blood and lymphatic system disorders.

Very common: leukopenia#. Uncommon: thrombocytopenia#. Unknown: lymphocyte decrease#.
*Includes arthralgia and less frequently pain in limb, osteoarthritis, back pain, arthritis, myalgia and joint stiffness.
#Events observed in patients with advanced breast cancer.
Treatment emergent adverse events and illnesses including all causalities and occurring with an incidence of ≥ 5% in either treatment group in study 031 during or within one month of the end of the study are shown in Table 1.
The incidence of myocardial infarction (0.6% versus 0.2%, p = 0.030) and cardiac failure (1.1% versus 0.7%, p = 0.123) in patients treated with exemestane compared with those treated with tamoxifen was not significant at the nominal significance level of 0.01 used to allow for multiple testing.

Post-marketing experience.

Immune system disorders.

Hypersensitivity.

Nervous system disorders.

Paraesthesia.

Hepatobiliary disorders.

Rare cases of hepatitis including cholestatic hepatitis have been observed in clinical trials and reported through post-marketing surveillance.

Skin and subcutaneous tissue disorders.

Urticaria, pruritus, acute generalised exanthematous pustulosis.
Musculoskeletal and connective tissue disorders. Trigger finger, tenosynovitis stenosans.

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 https:// www.tga.gov.au/reporting-problems and contact Arrotex Medical Information Enquiries/Adverse Drug Reaction Reporting on 1800 195 055.

4.9 Overdose

Clinical trials have been conducted with exemestane given up to 800 mg in a single dose to healthy female volunteers and up to 600 mg daily to postmenopausal women with advanced breast cancer. These dosages were well tolerated. The single dose of exemestane that could result in life threatening symptoms is not known.
There is no specific antidote to overdosage and treatment should be symptomatic. General supportive care, including frequent monitoring of vital signs and close observation of the patient, is indicated. Consider administration of activated charcoal in the event of a potentially toxic ingestion. Activated charcoal is most effective when administered within one hour of ingestion. In patients who are not fully conscious or have impaired gag reflex, consideration should be given to administering activated charcoal via nasogastric tube once the airway is protected. Haemodialysis is not expected to significantly enhance the clearance of exemestane due to extensive protein binding.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Exemestane is an irreversible, steroidal aromatase inactivator, structurally related to the natural substrate androstenedione. In postmenopausal women, estrogens are produced primarily from the conversion of androgens into estrogens through the aromatase enzyme in peripheral tissues. Estrogen deprivation through aromatase inhibition is an effective and selective treatment for hormone dependent breast cancer in postmenopausal women. Exemestane acts by binding irreversibly to the active site of the enzyme causing its inactivation. Such type of inactivation is also known as "suicidal inhibition". In postmenopausal women, exemestane significantly lowered serum estrogen concentrations starting from a 5 mg dose, reaching maximal suppression (80 to 90%) with a dose of 10 to 25 mg. In postmenopausal breast cancer patients treated with the 25 mg daily dose, whole body aromatisation was reduced by 98%.
Exemestane does not possess any progestogenic or estrogenic activity. A slight androgenic activity, probably due to the 17-hydro derivative, has been observed mainly, at high doses. In trials with multiple daily doses, exemestane had no detectable effects on adrenal biosynthesis of cortisol or aldosterone, measured before or after adrenocorticotrophic hormone (ACTH) challenge, thus demonstrating its selectivity with regard to the other enzymes involved in the steroidogenic pathway. Glucocorticoid or mineralocorticoid replacements are therefore not needed.
A non-dose dependent slight increase in serum luteinising hormone (LH) and follicle stimulating hormone (FSH) levels has been observed even at low doses. This effect is expected for the pharmacological class and is probably the result of feedback at the pituitary level due to reduction in estrogen levels stimulating pituitary secretion of gonadotropins. A dose related decrease in sex hormone binding globulin (SHBG) was observed, which occurred with exemestane 25 mg/day.
A sub-study of endometrial thickness was done in the early breast cancer trial 031 in patients who had received two to three years of tamoxifen treatment. The sub-study contained 113 patients, 61 of whom received exemestane and 52 continued on tamoxifen. At baseline, 64% of exemestane patients and 63% of tamoxifen patients had abnormal endometrial thickening (≥ 5 mm on ultrasound). After two years, the proportion of exemestane patients with abnormal endometrial thickening had decreased to 36% whereas the proportion of tamoxifen patients with abnormal endometrial thickening remained near baseline at 64%. The difference between treatments after adjusting for baseline was statistically significant (p = 0.0025).

Clinical trials.

Sequential adjuvant treatment of early breast cancer. In a multicentre, randomised, double blind study (number 031), conducted in 4,724 postmenopausal patients with estrogen receptor positive or unknown primary breast cancer, patients who had remained disease free after receiving adjuvant tamoxifen therapy for two to three years were randomised to receive 2-3 years of exemestane (25 mg/day) or tamoxifen (20 or 30 mg/day) to complete a total of five years of hormonal therapy.

87-month median follow-up.

After a median duration of therapy of about 30 months and a median follow-up of about 87 months, results showed that sequential treatment with exemestane after 2 to 3 years of adjuvant tamoxifen therapy was associated with a clinically and statistically significant improvement in disease-free survival (DFS) compared with continuation of tamoxifen therapy (Table 2, Figure 1).
Results showed that in the observed study period exemestane significantly reduced the risk of breast cancer recurrence by 16% compared with tamoxifen (hazard ratio 0.84; p = 0.002).
Overall, the beneficial effect of exemestane over tamoxifen with respect to DFS was apparent regardless of nodal status or prior chemotherapy or hormonal therapy. Statistical significance was not maintained in a few sub-groups with small sample sizes. These showed a trend favouring exemestane in patients with more than 9 nodes positive, or previous chemotherapy CMF. In patients with nodal status unknown, previous chemotherapy other, as well as unknown/missing status of previous hormonal therapy a non statistically significant trend favouring tamoxifen was observed.
In addition, exemestane also significantly prolonged breast cancer-free survival (hazard ratio 0.82, p = 0.00263), and distant recurrence-free survival (hazard ratio 0.85, p = 0.02425).
Exemestane also reduced the risk of contralateral breast cancer, although the effect was no longer statistically significant in this observed study period (hazard ratio 0.74, p = 0.12983). In the whole study population, a trend for improved overall survival was observed for exemestane (373 deaths) compared to tamoxifen (420 deaths) with a hazard ratio 0.89 (log rank test: p = 0.08972), representing an 11% reduction in the risk of death in favour of exemestane. When adjusting for the pre-specified prognostic factors (i.e. ER status, nodal status, prior chemotherapy, use of HRT and use of bisphosphonates), a statistically significant 18% reduction in the risk of dying (hazard ratio for overall survival 0.82; Wald chi square test: p = 0.0082) was observed for exemestane compared to tamoxifen in the whole study population.
In the additional analysis for the subset of patients with estrogen receptor positive or unknown status, the unadjusted overall survival hazard ratio was 0.86 (log-rank test: p = 0.04262), representing a clinically and statistically significant 14% reduction in the risk of dying.
Results from a bone sub-study indicate that treatment with exemestane for 2 to 3 years following 2 to 3 years of tamoxifen treatment increased bone loss while on treatment (mean % change from baseline for BMD at 36 months: -3.37 [spine], -2.96 [total hip] for exemestane and -1.29 [spine], -2.02 [total hip], for tamoxifen). However, by the end of the 24 month post treatment period there were minimal differences in the change in BMD from baseline for both treatment groups, the tamoxifen arm having slightly greater final reductions in BMD at all sites (mean % change from baseline for BMD at 24 months post treatment -2.17 [spine], -3.06 [total hip] for exemestane and -3.44 [spine], -4.15 [total hip] for tamoxifen).
The all fractures reported on-treatment and during follow-up was significantly higher in the exemestane group than on tamoxifen (169 [7.3%] versus 122 [5.2%]; p = 0.004), but no difference was noted in the number of fractures reported as osteoporotic.

119-month final follow-up.

After a median duration of therapy of about 30 months and a median follow-up of about 119 months, results showed that sequential treatment with exemestane after 2 to 3 years of adjuvant tamoxifen therapy was associated with a clinically and statistically significant improvement in DFS compared with continuation of tamoxifen therapy. Analysis showed that over the observed study period exemestane reduced the risk of breast cancer recurrence by 14% compared with tamoxifen (hazard ratio 0.86, p = 0.00393). The beneficial effect of exemestane over tamoxifen with respect to DFS was apparent regardless of nodal status or prior chemotherapy.
Exemestane also significantly prolonged breast cancer-free survival (hazard ratio 0.83, p < 0.00152), and distant recurrence-free survival (hazard ratio 0.86, p = 0.02213). Exemestane also reduced risk of contralateral breast cancer; however, the effect was no longer statistically significant (hazard ratio 0.75, p = 0.10707).
In the whole study population, overall survival was not statistically different between the two groups with 467 deaths (19.9%) occurring in the exemestane group and 510 deaths (21.5%) in the tamoxifen group (hazard ratio 0.91, p = 0.15737, not adjusted for multiple testing). For the subset of patients with estrogen receptor positive or unknown status, the unadjusted overall survival hazard ratio was 0.89 (log-rank test: p = 0.07881) in the exemestane group relative to the tamoxifen group.
In the whole study population, a statistically significant 14% reduction in the risk of dying (hazard ratio for OS 0.86; Wald chi square test: p = 0.0257) was observed for exemestane compared with tamoxifen when adjusting for the prespecified prognostic factors (i.e. ER status, nodal status, prior chemotherapy, use of HRT and use of bisphosphonates).
A lower incidence of other second (non-breast) primary cancers was observed in exemestane-treated patients compared with tamoxifen only-treated patients (9.9% vs. 12.4%).
In the main study, which had a median follow-up in all participants of 119 months (0 - 163.94) and median duration of exemestane treatment of 30 months (0 - 40.41), the incidence of bone fractures was reported on 169 (7.3%) patients in the exemestane group compared with 122 (5.2%) patients in the tamoxifen group (p = 0.004).
Treatment of advanced breast cancer. Efficacy data in patients progressing while on anti-estrogen therapy (second line treatment) include results from a phase III study (multicentre, multinational, peer reviewed, randomised, double blind, controlled) with exemestane 25 mg daily versus megestrol acetate 40 mg qid (four times daily) in 763 patients. All patients had failed on prior tamoxifen treatment. The population characteristics were representative of postmenopausal patients with relapsed advanced breast cancer. The median age was 65 years. Various races were represented, the majority being Caucasian. Most patients (70%) were estrogen receptor/ progesterone receptor positive and most had measurable disease. Almost 50% had predominantly visceral disease.
The peer reviewed results of this controlled study indicate that exemestane and megestrol acetate are equivalent in terms of objective responses, with objective response rates of 12.4% for megestrol acetate versus 15.0% for exemestane (confidence interval (CI) for difference: -7.5 + 2.3). Overall success rates (complete response, partial response or no change) are also comparable, 37.4% for exemestane versus 34.6% for megestrol acetate.
Conversely, duration of overall success (median: 60.1 versus 49.1 weeks, p = 0.025), time to progression (median: 20.3 versus 16.6 weeks, p = 0.037), time to treatment failure (median: 16.3 versus 15.7 weeks, p = 0.042), and survival (median not yet achieved versus 123.4 weeks, p = 0.039) are significantly longer in exemestane treated patients than in those treated with megestrol acetate. The point estimates for survival at the 25th percentile (75% survival) are 74.6 weeks (95% CI 59.1 to 91.0) for exemestane and 55.0 weeks (95% CI 46.1 to 70.3) for megestrol acetate. The Kaplan-Meier curve for time to tumour progression is shown in Figure 2.
Efficacy was also observed in patients having progressed following multiple hormone therapies (third line therapy). Three peer reviewed uncontrolled phase II studies were conducted at the recommended dose of exemestane 25 mg. In the combined analysis, which was of the descriptive type, exemestane induced objective response, with a median duration of 61 weeks, in 9% of the patients (95% CI 6 to 12) and overall clinical benefit, with a median duration of 37 weeks, in 26% of the cases (95% CI 22 to 31). Although survival cannot yet be estimated in each of the three studies, median survival in the overall population (intent to treat) was approximately 30 months (131.1 weeks, 95% CI 100.0 to 147.1 weeks). Exemestane was effective both in patients experiencing failure of megestrol acetate and failure of other nonsteroidal aromatase inhibitors.

5.2 Pharmacokinetic Properties

Absorption.

Following oral administration, exemestane is rapidly and extensively absorbed, although animal data suggest that the absolute bioavailability was low due to an extensive first pass effect. At a single dose of 25 mg given after a meal, average peak plasma levels of 18 nanogram/mL are achieved within two hours post-dosing. Food was shown to enhance absorption, resulting in plasma levels 30 to 40% higher than those observed in subjects under fasting conditions.

Distribution.

After the peak, plasma levels of exemestane decline in a polyexponential manner with a terminal half-life of approximately 24 hours. The plasma protein binding of exemestane is approximately 90% and the fraction bound is independent of total concentration. The distribution of the drug and/or its metabolites into blood cells is negligible.

Metabolism and excretion.

No significant deviations from dose proportional pharmacokinetics were observed in healthy volunteers up to a 50 mg oral dose. Following repeated daily administration of 25 mg, plasma concentrations of the unchanged drug were of a similar order to those measured after single dosing. Following oral administration of a single dose of radiolabelled exemestane, the elimination of drug related products was shown to be essentially complete within one week, with approximately equal proportions of the dose eliminated in urine and faeces. The amount of drug excreted unchanged in urine is less than 1% of the dose. The biotransformation proceeds through oxidation of the methylene group at position 6 via the CYP3A4 isoenzyme and/or reduction of 17-keto group by aldoketoreductases. Subsequently, many secondary metabolites are formed, each accounting for a limited amount of the dose. The metabolites are either inactive or less active than the parent drug in inhibiting aromatase.

Special populations.

Age.

No significant correlation between the systemic exposure of exemestane and the age of subjects has been observed.

Renal insufficiency.

Exemestane pharmacokinetics have been investigated in subjects with severe renal insufficiency (CLCR ≤ 30 mL/minute). In these subjects the systemic exposure to exemestane after a single dose was found to be approximately double that of healthy volunteers. This difference, although pharmacokinetically significant, is unlikely to require dose adjustment, given the good tolerability observed in humans at doses up to eight times the recommended dose. However, exemestane should be used with caution in patients with renal insufficiency.

Hepatic insufficiency.

Exemestane pharmacokinetics have been investigated in subjects with moderate and severe hepatic insufficiency. The systemic exposure to exemestane was two to three times higher than in healthy volunteers. As for renal insufficiency, dose adjustment is unlikely to be required. However, exemestane should be used with caution in patients with hepatic impairment.

5.3 Preclinical Safety Data

Genotoxicity.

Exemestane was not mutagenic in bacteria (Ames test), in V79 Chinese hamster cells nor did it cause DNA damage in rat hepatocytes. Although exemestane was clastogenic in lymphocytes in vitro, it was not clastogenic in two in vivo studies.

Carcinogenicity.

A two year carcinogenicity study in mice at doses of exemestane 50, 150 and 450 mg/kg/day (gavage) resulted in an increased incidence of hepatocellular adenomas and/or carcinomas at doses > 50 mg/kg/day in males and > 150 mg/kg/day in females. Exposures (plasma AUC) at these doses were 4 and 37 times, respectively, exposure in patients at the recommended dose. However, statistical significance was only reached at the high dose exposures (approximately 34 (male) and 75 (female) fold the AUC in patients). An increased incidence of renal tubular adenomas was observed in male mice at the high dose of 450 mg/kg/day.
A carcinogenicity study was conducted in rats at doses of 30, 100 and 315 mg/kg/day (gavage) for 92 weeks in males and two years in females. No evidence of carcinogenic activity up to the highest dose tested (315 mg/kg/day) was observed. At the highest dose, plasma AUC0 to 24 hour levels in male and female rats were 19 and 31-fold higher than those measured in the postmenopausal cancer patients receiving the recommended clinical dose.

6 Pharmaceutical Particulars

6.1 List of Excipients

Microcrystalline cellulose, crospovidone, polysorbate 80, mannitol, colloidal anhydrous silica, magnesium stearate, sucrose, acacia, purified talc, titanium dioxide, ethanol, shellac, white beeswax, carnauba wax.

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 in a cool dry place below 30°C.

6.5 Nature and Contents of Container

APO-Exemestane tablets.

Blister pack of 30 tablets.
AUST R: 177312.

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

Exemestane is a white or yellowish white powder, which is freely soluble in N,N-dimethylformamide, soluble in methanol and practically insoluble in water. Due to the very low solubility in water, the drug is micronised.

Chemical structure.


Chemical name: 6-methylenandrosta-1,4-diene-3,17-dione.
Molecular formula: C20H24O2.
Molecular weight: 296.4.

CAS number.

107868-30-4.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes