Consumer medicine information

Exemestane Sandoz

Exemestane

BRAND INFORMATION

Brand name

Exemestane Sandoz

Active ingredient

Exemestane

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Exemestane Sandoz.

WHAT IS IN THIS LEAFLET

This leaflet answers some common questions about Exemestane Sandoz.

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

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

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

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

WHAT EXEMESTANE SANDOZ IS USED FOR

This medicine 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
  • to reduce the risk of recurrence or spreading of the breast cancer
  • when the cancer has not responded or has returned after treatment with another medicine or medicines.

It contains the active ingredient exemestane.

Exemestane is an aromatase inactivator.

It works by significantly reducing the supply of oestrogen to cancer cells. This stops the growth of those cancer cells which need oestrogen, a natural female sex hormone, to grow.

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

This medicine is not addictive.

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

BEFORE YOU TAKE EXEMESTANE SANDOZ

When you must not take it

Do not take this medicine if you have an allergy to:

  • exemestane, the active ingredient, or to any of the other ingredients listed at the end of this leaflet under Product Description.

Some of the symptoms of an allergic reaction may include:

  • 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.

Do not take this medicine if you are pregnant or intend to become pregnant. It may affect your developing baby if you take it during pregnancy.

Do not breastfeed if you are taking this medicine. The active ingredient in Exemestane Sandoz passes into breast milk and there is a possibility that your baby may be affected.

Exemestane Sandoz is not recommended for use in children.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you:

  • are still having your monthly period
  • have or have had kidney problems
  • have or have had liver problems
  • have osteoporosis (disease which causes bones to be more brittle and likely to break).

If you have not told your doctor about any of the above, tell him/her before you start taking Exemestane Sandoz.

Taking other medicines

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

Some medicines and Exemestane Sandoz may interfere with each other. These include:

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

Some health food products for menopausal symptoms contain natural oestrogens.

Tell your doctor or pharmacist if you are taking any medicines or health food products containing oestrogens.

These medicines may be affected by Exemestane Sandoz or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

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

HOW TO TAKE EXEMESTANE SANDOZ

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

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

How much to take

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

Ask your doctor or pharmacist if you are unsure of the correct dose for you. They will tell you exactly how much to take.

Follow the instructions they give you. If you take the wrong dose, Exemestane Sandoz may not work as well and your problem may not improve.

When to take Exemestane Sandoz

Take the tablet once daily after a meal at about the same time each day. Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

How long to take Exemestane Sandoz

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

Do not stop taking this medicine unless your doctor tells you to, even if you feel better.

If you forget to take it

Take your dose as soon as you remember, and continue to take it as you would normally.

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

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

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

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

If you take too much (overdose)

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

WHILE YOU ARE TAKING EXEMESTANE SANDOZ

Things you must do

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

Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

If you go into hospital whilst taking this medicine, let the medical staff know that you are taking Exemestane Sandoz.

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

Keep all of your doctor's appointments so that your progress can be checked.

Things you must not do

Do not take Exemestane Sandoz to treat any other complaints unless your doctor tells you to.

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

Do not stop taking your medicine or lower the dosage without checking with your doctor.

Things to be careful of

Be careful driving or operating machinery until you know how Exemestane Sandoz affects you. This medicine may cause dizziness or tiredness in some people. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

If this medicine makes you feel dizzy, be careful when getting up from a sitting or lying position.

SIDE EFFECTS

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

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

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

Tell your doctor or pharmacist if you notice any of the following and they worry you:

  • hot flushes
  • nausea, vomiting, loss of appetite, indigestion, pain (including stomach ache)
  • constipation
  • diarrhoea
  • tiredness
  • swelling in your legs
  • dizziness and headache
  • increased sweating
  • difficulty sleeping
  • depression
  • disturbed vision such as blurriness
  • pain in your muscle or joints
  • increase in weight
  • skin rash
  • hair loss
  • 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
  • hepatitis, yellowing of the skin or eyes, also called jaundice.

Tell your doctor or pharmacist if you notice anything else that is making you feel unwell. Other side effects not listed above may also occur in some people. Some of these side effects can only be found when your doctor does tests from time to time to check your progress.

AFTER TAKING EXEMESTANE SANDOZ

Storage

Keep your medicine in the original container.

If you take it out of its original container it may not keep well.

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

Do not store Exemestane Sandoz 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 it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

PRODUCT DESCRIPTION

What it looks like

Exemestane Sandoz comes in one strength:

Exemestane Sandoz 25mg - white to off-white, round biconvex film-coated tablets, marked with 'E25' on one side and plain on the other.

Available in blisters of 30 film-coated tablets.

Ingredients

Active ingredient:

  • Exemestane Sandoz 25mg - 25mg exemestane.

Inactive ingredients:

  • mannitol
  • microcrystalline cellulose
  • crospovidone
  • sodium starch glycollate (type A)
  • hypromellose
  • polysorbate 80
  • colloidal anhydrous silica
  • magnesium stearate
  • macrogol 400
  • titanium dioxide.

This medicine does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

Supplier

Sandoz Pty Ltd
ABN 60 075 449 553
54 Waterloo Road
Macquarie Park, NSW 2113
Australia
Tel: 1800 726 369

This leaflet was revised in February 2019.

Australian Register Number

25mg film-coated tablets: AUST R 174337 (blisters)

Published by MIMS April 2019

BRAND INFORMATION

Brand name

Exemestane Sandoz

Active ingredient

Exemestane

Schedule

S4

 

1 Name of Medicine

Exemestane.

6.7 Physicochemical Properties

Exemestane is a white to ivory-white powder, which is freely soluble in methylene chloride, sparingly soluble in alcohol and practically insoluble in water. Due to the very low solubility in water, the drug is micronised.
The chemical name of Exemestane is 6-methylenandrosta-1,4-diene-3,17-dione. Its empirical formula is C20H24O2 (MW: 296.4) and its chemical structure is:

Chemical structure.


CAS number.

107868-30-4.

2 Qualitative and Quantitative Composition

Each Exemestane Sandoz 25 mg tablet contains 25 mg exemestane.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Exemestane Sandoz 25 mg film-coated tablets.

White to off-white round, biconvex film-coated tablet, debossed with ‘E25’ on one side and plane on the other.

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, oestrogens are produced primarily from the conversion of androgens into oestrogens through the aromatase enzyme in peripheral tissues. Oestrogen 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 oestrogen concentrations starting from a 5 mg dose, reaching maximal suppression (80-90%) with a dose of 10-25 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 oestrogenic 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 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 nondose dependent slight increase in serum LH and 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 oestrogen levels stimulating pituitary secretion of gonadotropins. A dose related decrease in SHBG was observed, which occurred with exemestane 25 mg/day.
A substudy of endometrial thickness was done in the early breast cancer trial 031 in patients who had received 2-3 years of tamoxifen treatment. The substudy 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 2 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, randomized, double blind study (number 031), conducted in 4724 postmenopausal patients with oestrogen receptor positive or unknown primary breast cancer, patients who had remained disease free after receiving adjuvant tamoxifen therapy for 2 to 3 years were randomised to receive 3 to 2 years of exemestane (25 mg/day) or tamoxifen (20 or 30 mg/day) to complete a total of 5 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 (see 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 oestrogen 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 3 to 2 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 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 antioestrogen 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 a day) 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 oestrogen 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 (C.I. 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% C.I. 59.1-91.0) for exemestane and 55.0 weeks (95% C.I. 46.1-70.3) 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 25 mg exemestane. 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% C.I. 6-12) and overall clinical benefit, with a median duration of 37 weeks, in 26% of the cases (95% C.I. 22-31). 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% C.I. 100.0-147.1 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 2 hours postdosing. Food was shown to enhance absorption, resulting in plasma levels 30-40% 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.

The biotransformation proceeds through oxidation of the methylene group at position 6 via the CYP 3A4 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.

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 1 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.

Special populations.

Age.

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

Renal insufficiency.

Exemestane pharmacokinetics has been investigated in subjects with severe renal insufficiency (CLCR ≤ 30 mL/min). 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 8 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 2-3 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 50, 150 and 450 mg/kg/day exemestane (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 2 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 AUC(0-24 hr) 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.

4 Clinical Particulars

4.1 Therapeutic Indications

Exemestane Sandoz is indicated for the sequential adjuvant treatment of oestrogen receptor positive early breast cancer in postmenopausal women who have received prior adjuvant tamoxifen therapy.
Exemestane Sandoz is indicated for the treatment of oestrogen receptor positive advanced breast cancer in women with natural or induced postmenopausal status whose disease has progressed following antioestrogen therapy.

4.3 Contraindications

Exemestane Sandoz tablets are contraindicated in pregnant or lactating women and in patients with a known hypersensitivity to the active ingredient 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 pre-menopausal endocrine status. Whenever clinically appropriate, confirmation of post-menopausal status may be assisted by laboratory tests, such as assessment of luteinising hormone (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.

Reductions in bone mineral density (BMD) over time are seen with exemestane use. In a substudy of trial 031 in early breast cancer, patients who received 2 years of exemestane after 2-3 years of tamoxifen (n = 86) had a higher loss of bone mineral density in the spine, hip, femoral neck and Ward's triangle 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 Aromasin and -1.29 (spine), -2.02 (total hip), for tamoxifen).
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)). The impact of exemestane on long-term fracture risk remains to be determined. Treatment-emergent fractures were more frequent in exemestane patients (4.5%) than in tamoxifen patients (3.3%). When 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.
As exemestane is a potent oestrogen 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.
Patients with advanced disease should have their bone mineral density assessed on a case by case basis.

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 oestrogen 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 CYP 3A4 by ketoconazole showed no significant effects on the pharmacokinetics of exemestane. A possible decrease of exemestane plasma levels by known inducers of CYP 3A4 cannot be excluded. Exemestane should be used cautiously with medicines that are metabolised via CYP 3A4 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 500 mg/kg/day exemestane (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 8 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 3-20 times the human dose on a mg/m2 basis.
(Category C)
Australian pregnancy category C: drugs, which, owing to their pharmacological effects, have caused or may be suspected of causing, harmful effects on the human foetus or neonate without causing malformations.
Exemestane disrupts oestrogen dependent metabolism and may result in abortion. Exemestane should not be used in women who are or may become pregnant because it may cause harm to the fetus (see Section 4.3 Contraindications). 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 (approximately 7.5 times the recommended human daily dose on a mg/m2 basis). 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). 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, caution should be exercised if a nursing woman is inadvertently exposed to exemestane.

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 effects were hot flushes (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 effects were hot flushes (14%) and nausea (12%). Most adverse effects can be attributed to the normal pharmacological consequences of oestrogen deprivation (e.g. hot flushes).
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: 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).

Gastrointestinal disorders.

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

Hepatobiliary disorders.

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

Metabolism and nutrition disorders.

Common: anorexia.

Autonomic nervous system.

Very common: increased sweating.

Nervous system disorders.

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

Psychiatric disorders.

Very common: depression, insomnia.

Vascular disorders.

Very common: hot flushes.

Skin and sub-cutaneous tissue disorders.

Very common: increased sweating.
Common: rash, alopecia.

Musculoskeletal and bone disorders.

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

Blood and lymphatic system disorders.

Very common: lymphocyte decrease.#
Uncommon: leukopenia, thrombocytopenia.#
+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% vs 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.
Treatment emergent fractures were more frequent in exemestane patients (4.5%) than in tamoxifen patients (3.3%). When fractures reported on treatment and during follow-up are considered, the incidence was significantly greater in exemestane patients (7.0%) compared with tamoxifen patients (4.9%), p = 0.002.

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.

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 http://www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

Dosage.

Adults.

The recommended dose of Exemestane Sandoz in adults is one 25 mg tablet.
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 Sandoz should continue until tumour progression is evident.
No dose adjustments are required for patients with hepatic or renal insufficiency.
Not recommended for use in children.

Method of administration.

Taken once daily, preferably after a meal.

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 medicine. 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.

4.9 Overdose

Symptoms.

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.

Treatment.

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 1 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 Poison Information Centre on 131126 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Exemestane Sandoz tablets also contain the following inactive ingredients: mannitol, microcrystalline cellulose, crospovidone, sodium starch glycollate type A, hypromellose, polysorbate 80, colloidal anhydrous silica, magnesium stearate, macrogol 400 and titanium dioxide.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.
For information on interactions with other medicines and other forms of interactions, see Section 4.5.

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Store below 25°C.
Protect from moisture.

6.5 Nature and Contents of Container

Exemestane Sandoz 25 mg film-coated tablets are available in PVC/PVDC/Al blister packs of 15, 30 and 90 tablets.
Not all presentation maybe marketed in Australia.

6.6 Special Precautions for Disposal

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

Summary Table of Changes