AROMASIN

Patient leaflet in accordance with the Pharmacists' Regulations (Preparations) - 1986

This medicine is dispensed with a doctor’s prescription only

Aromasin

®

Coated tablets 25 mg

The active ingredient and its quantity:

Each coated tablet contains:

exemestane 25 mg

Inactive ingredients and allergens: See section 2 "Important information about some of this

medicine’s ingredients", section 6 "Additional information".

Read the entire leaflet carefully before you start using this medicine. This leaflet

contains concise information about this medicine. If you have any further questions, consult

your doctor or pharmacist.

This medicine has been prescribed to treat your illness. Do not pass it on to others. It may

harm them, even if it seems to you that their illness is similar to yours.

This medicine is not intended for children.

1. What is this medicine intended for?

Aromasin

is used to treat hormone dependent early breast cancer in postmenopausal

women after they have completed 2-3 years of treatment with the medicine tamoxifen.

Additionally, Aromasin

is used for the treatment of hormone dependent advanced breast

cancer in women in postmenopausal status (natural or induced) whose disease has

progressed following a single hormonal (anti-estrogen) therapy or several hormonal therapies.

Therapeutic group: Steroidal inhibitors of the enzyme aromatase, anti-neoplastic (anti-

cancer) agents.

Aromasin

belongs to a group of medicines known as aromatase inhibitors; aromatase is an

enzyme required for the production of the female sex hormones, estrogens, especially in

postmenopausal women. Reduction in estrogen levels in the body is a way of treating

hormone dependent breast cancer.

2. Before using this medicine

Do not use this medicine if:

you are or have previously been sensitive (allergic) to the active ingredient

(exemestane) or to any of the other ingredients of this medicine. For additional

information, please see section 6.

you are pregnant, likely to be pregnant or breastfeeding.

you are not postmenopausal (you are still having your monthly period).

Special warnings about using this medicine

Before using Aromasin

®

, tell your doctor if:

You have liver or kidney problems.

You are suffering or have suffered in the past from a condition which affects the strength

of your bones. Your doctor may want to perform bone mineral density tests before and

during treatment with Aromasin

. This is because this class of medicines lowers the

levels of female sex hormones, which may lead to a loss of the mineral content of bones,

which might decrease their strength.

Tests and follow up

Tests to be performed before using the medicine:

Your doctor may take blood samples from you to ensure you have reached

menopause.

Routine checking of vitamin D level. In the early stages of breast cancer, your

vitamin D level may be very low. The doctor will give you a vitamin D supplement if

your vitamin D level is below normal.

Drug interactions

If you are taking or have recently taken other medicines, including nonprescription

medications and dietary supplements, tell your doctor or pharmacist. Particularly if you

are taking:

medicines containing estrogen

rifampicin (an antibiotic)

phenytoin or carbamazepine (anticonvulsants used to treat epilepsy)

herbal preparations containing Hypericum (St. John’s Wort)

Aromasin

should not be taken at the same time with hormone replacement therapy (HRT).

Using this medicine and food

Swallow the medicine after a meal.

Pregnancy and breastfeeding

Do not take Aromasin

if you are pregnant or breastfeeding.

If you are pregnant or think you might be pregnant, tell the doctor.

If there is any possibility that you may become pregnant, consult with the doctor regarding

contraception.

Driving and using machines

If you feel drowsy, dizzy or weak while taking Aromasin

, you must not drive or operate

machines.

Important information about some of this medicine’s ingredients

Aromasin

contains sucrose. If you have been told by the doctor that you have an

intolerance to certain sugars, contact your doctor before taking this medicine.

Aromasin

contains a small amount of sodium, less than 1 mmol (23 mg), therefore it

is considered "sodium free".

Aromasin

contains a small amount of methyl parahydroxybenzoate, which may

cause allergic reactions (possibly delayed). If this should happen, contact your

doctor.

3. How to use this medicine?

Always use this medicine according to your doctor's instructions. Check with your doctor

or pharmacist if you are not sure about your dose or about how to take this medicine.

Only your doctor will determine your dose and how you should take this medicine.

The recommended dosage is usually:

One 25 mg tablet daily taken orally after a meal, at approximately the same time each day.

Your doctor will determine the manner and duration of treatment.

Do not exceed the recommended dose!

There is no information regarding crushing/ splitting/ chewing Aromasin

®

tablets

Swallow the medicine with a little water.

If you need to go to the hospital while taking Aromasin

, inform the medical staff about

the medicines you are taking.

If you have accidentally taken a higher dose or if you have taken an overdose, or if a

child has accidentally swallowed some medicine, immediately see a doctor or go to a

hospital emergency room and bring the medicine package with you.

If you forget to take this medicine at the designated time, do not take a double dose to

make up for the forgotten dose. Take the forgotten tablet as soon as you remember. If it is

nearly time for the next dose, take the tablet at the usual time.

Adhere to the treatment as recommended by your doctor.

Do not stop taking the medicine even if you feel well, unless instructed to do so by the

doctor.

Do not take medicines in the dark! Check the label and dose every time you take

medicine. Wear glasses if you need them.

If you have any further questions about using this medicine, consult your doctor or

pharmacist.

4. Side effects

Like with all medicines, using Aromasin

may cause side effects in some users. Do not be

alarmed by this list of side effects; you may not experience any of them.

Contact your doctor immediately if you suffer from:

Hypersensitivity, inflammation of the liver (hepatitis) and inflammation of the bile ducts of the

liver which cause yellowing of the skin. Symptoms include a general unwell feeling, nausea,

jaundice (yellowing of the skin and eyes), itching, right sided abdominal pain and loss of

appetite.

Generally, Aromasin

is well tolerated and the following side effects observed in patients

treated with Aromasin

are mainly mild or moderate. Most of the side effects are associated

with a shortage of estrogen (such as hot flushes).

Additional side effects:

Very common side effects (may affect more than 1 in 10 users):

Depression

Difficulty falling asleep

Headache

Hot flushes

Dizziness

Nausea

Increased sweating

Muscle and joint pain (including osteoarthritis, back pain, arthritis and joint stiffness)

Tiredness

A reduction in the number of white blood cells

Abdominal pain

Elevated level of liver enzymes

Elevated level of hemoglobin breakdown in the blood

High level of alkaline phosphatase enzyme in the blood due to liver damage

Pain

Common side effects (may affect up to 1 in 10 users):

Lack of appetite

Carpal tunnel syndrome (a combination of “pins and needles”, numbness and pain

affecting all of the hand except the little finger) or pricking or tingling of the skin

Vomiting, constipation, indigestion, diarrhea

Hair loss

Skin rash, hives and itchiness

Bone depletion which might decrease their strength (osteoporosis), leading in some

cases to bone fractures (breaks or cracks)

Swollen hands and feet

A reduction in blood platelet count

Feeling of weakness

Uncommon side effects (may affect up to 1 in 100 users):

Hypersensitivity

Rare side effects (may affect up to 1 in 1,000 users):

A breakout of small blisters in a

certain area of the skin in a rash

Drowsiness

Inflammation of the liver

Inflammation of the bile ducts of the liver which causes yellowing of the skin

Side effects of unknown frequency (the frequency of these effects has not been

established yet):

Low level of certain white blood cells in the blood

It is possible that there may be changes in the level of certain blood cells (lymphocytes) and

platelets circulating in your blood, especially in patients with a pre-existing lymphopenia (low

level of lymphocytes in the blood).

If you experience any side effect, if any side effect gets worse, or if you experience a

side effect not mentioned in this leaflet, consult your doctor.

Side effects may be reported to the Ministry of Health by following the link ‘Reporting Side

Effects of Drug Treatment’ on the Ministry of Health home page (www.health.gov.il

) which

links to an online form for reporting side effects, or by using this link:

https://sideeffects.health.gov.il/

5.

How to store the medicine?

Avoid poisoning! To avoid poisoning, keep this, and all other medicines, in a closed

place, out of the reach and sight of children and/or infants. Do not induce vomiting

unless explicitly instructed to do so by a doctor.

Do not use the medicine after the expiry date (exp. date) that appears on the

package. The expiry date refers to the last day of that month.

Storage conditions

Store below 30°C.

Do not throw away any medicines via wastewater or household waste. Ask the

pharmacist how to discard medicines no longer used. These measures will help

protect the environment.

6. Additional information

In addition to the active ingredient, this medicine also contains:

Sucrose; mannitol; microcrystalline cellulose; titanium dioxide; hypromellose; sodium starch

glycollate; crospovidone; magnesium carbonate, light; polyvinyl alcohol; magnesium

stearate; macrogol 6000; silica, colloidal hydrated; polysorbate 80; simethicone emulsion;

methyl-p-hydroxybenzoate

What the medicine looks like and contents of the pack:

Aromasin

are round, biconvex, off-white (cream colored), coated tablets marked with “7663”

on one side.

Aromasin

is available in blister packs. Each pack contains 15, 30, 60, 90 or 120 tablets. Not

all pack sizes may be marketed.

Registration holder’s name and address: Pfizer PFE Pharmaceuticals Israel Ltd., 9

Shenkar St., Herzliya Pituach, 46725

Manufacturer’s name and address: Pfizer Italia S.r.l., 63100 Ascoli piceno, Italy

Registration number of the medicine in the National Drug Registry of the Ministry of

Health:

0005

Revised in July 2020.

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י"ע עבקנ הז ןולע טמרופ

ב רשואו קדבנ ונכותו תואירבה דרשמ ץרמ

2016

Prescribing Information

1. TRADE NAME OF THE MEDICINAL PRODUCT

Aromasin

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each coated tablet contains 25 mg exemestane.

Each tablet contains 30.2 mg of sucrose and 0.003 mg of methyl parahydroxybenzoate (E218).

For full list of Excipients, see section 6.1

3. PHARMACEUTICAL FORM

Coated tablets.

Round, biconvex, off-white coated tablet marked 7663 on one side.

4. CLINICAL PARTICULARS

4.1 Therapeutic Indications

Aromasin

is indicated for the adjuvant treatment of postmenopausal women with oestrogen

receptor positive invasive early breast cancer, following 2 – 3 years of initial adjuvant

tamoxifen therapy.

Aromasin is indicated for the treatment of advanced breast cancer (ABC) in women with

natural or induced postmenopausal status whose disease has progressed following anti-

oestrogen therapy alone. Aromasin is also indicated for the treatment of postmenopausal

women with ABC whose disease has progressed following multiple hormonal therapies.

4.2 Posology and Method of Administration

Adult and elderly patients

The recommended dose of Aromasin is one 25 mg tablet to be taken once daily, preferably

after a meal.

In patients with early breast cancer, treatment with Aromasin should continue until

completion of five years of adjuvant endocrine therapy, or until local or distant recurrence or

new contralateral breast cancer. In patients with advanced breast cancer, treatment with

Aromasin should continue until tumour progression is evident.

No dose adjustments are required for patients with hepatic or renal insufficiency (see section

5.2).

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Paediatric population

Not recommended for use in children.

4.3 Contraindications

Aromasin tablets are contraindicated in patients with a known hypersensitivity to the active

substance or to any of the excipients listed in section 6.1, in pre-menopausal women and in

pregnant or lactating women.

4.4 Special warnings and precautions for use

Aromasin should not be administered to women with pre-menopausal endocrine status.

Therefore, whenever clinically appropriate, the post-menopausal status should be ascertained

by assessment of LH, FSH and oestradiol levels.

Aromasin should be used with caution in patients with hepatic or renal impairment.

Aromasin tablets contain sucrose and should not be administered to patients with rare

hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-

isomaltase insufficiency.

Aromasin tablets contain methyl-p-hydroxybenzoate which may cause allergic reactions

(possibly delayed).

Aromasin is a potent oestrogen lowering agent, and a reduction in bone mineral density

(BMD) and an increased fracture rate have been observed following administration (see

section 5.1). At the commencement of adjuvant treatment with Aromasin, women with

osteoporosis or at risk of osteoporosis should have treatment baseline bone mineral health

assessment based on current clinical guidelines and practice. Patients with advanced disease

should have their bone mineral density assessed on a case-by-case basis. Although adequate

data to show the effects of therapy in the treatment of the bone mineral density loss caused by

Aromasin are not available, patients treated with Aromasin should be carefully monitored and

treatment for, or prophylaxis of, osteoporosis should be initiated in at risk patients.

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.

4.5 Interactions with other medicaments and other forms of interaction

In vitro evidence showed that the drug is metabolised through cytochrome P450 CYP3A4 and

aldoketoreductases (see section 5.2) 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.

In an interaction study with rifampicin, a potent CYP450 inducer, at a dose of 600 mg daily

and a single dose of exemestane 25 mg, the AUC of exemestane was reduced by 54% and

Cmax by 41%. Since the clinical relevance of this interaction has not been evaluated, the co-

administration of drugs, such as rifampicin, anticonvulsants (e.g., phenytoin and

carbamazepine) and herbal preparations containing hypericum perforatum (St John’s Wort)

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known to induce CYP3A4 may reduce the efficacy of Aromasin.

Aromasin should be used cautiously with drugs that are metabolised via CYP3A4 and have a

narrow therapeutic window. There is no clinical experience of the concomitant use of

Aromasin with other anticancer drugs.

Aromasin should not be coadministered with oestrogen-containing medicines as these would

negate its pharmacological action.

4.6 Fertility, pregnancy and lactation

Pregnancy

No clinical data on exposed pregnancies are available with Aromasin. Studies on animals

have shown reproductive toxicity (see section 5.3). Aromasin is therefore contraindicated in

pregnant women.

Breast-feeding

It is not known whether exemestane is excreted into human milk. Aromasin should not be

administered to lactating woman.

Women of perimenopausal status or child-bearing potential

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 have

recently become postmenopausal, until their postmenopausal status is fully established (see

sections 4.3 and 4.4).

4.7 Effects on Ability to Drive and Use Machines

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 Undesirable Effects

Aromasin was generally well tolerated across all clinical studies conducted with Aromasin at a

standard dose of 25mg/day and undesirable effects were usually mild to moderate.

The withdrawal rate due to adverse events was 7.4% in patients with early breast cancer

receiving adjuvant treatment with Aromasin following initial adjuvant tamoxifen therapy. The

most commonly reported adverse reactions were hot flushes (22%), arthralgia (18%), and

fatigue (16%).

The withdrawal 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 flushes

(14%) and nausea (12%).

Most adverse reactions can be attributed to the normal pharmacological consequences of

oestrogen deprivation (e.g., hot flushes).

The reported adverse reactions from clinical studies and post-marketing experience are listed

below by system organ class and by frequency.

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Frequencies are defined as: Very common (≥1/10); Common ( ≥1/100 to <1/10) ; Uncommon

(≥1/1,000 to <1/100) ; Rare ( ≥1/10,000 to <1/1,000) ; Very rare (<1/10,000); Not known

(cannot be estimated from the available data).

Blood and lymphatic system disorders:

Very common

Leucopenia

Common

Thrombocytopenia

Not known

Lymphocyte count decreased

Immune system disorders:

Uncommon

Hypersensitivity

Metabolism and nutrition disorders:

Common

Anorexia

Psychiatric disorders:

Very common

Depression, insomnia

Nervous system disorders:

Very common

Headache, dizziness

Common

Carpal tunnel syndrome, paraesthesia

Rare

Somnolence

Vascular disorders:

Very common

Hot flushes

Gastrointestinal disorders:

Very common

Abdominal pain, nausea

Common

Vomiting, diarrhoea, constipation, dyspepsia

Hepatobiliary disorders:

Very common

Hepatic enzyme increased, blood bilirubin

increased, blood alkaline phosphatase increased

Rare

Hepatitis

(†)

, cholestatic hepatitis

(†)

Skin and subcutaneous tissue disorders:

Very common

Increased sweating

Common

Alopecia, rash, urticaria, pruritus

Rare

Acute generalised exanthematous pustulosis

(†)

Musculoskeletal and bone disorders:

Very common

Joint and musculoskeletal pain

Common

Fracture, osteoporosis

General disorders and administration site conditions:

Very common

Pain, fatigue

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Common

Oedema peripheral, asthenia

(*) Includes: arthralgia, and less frequently pain in limb, osteoarthritis, back pain, arthritis,

myalgia and joint stiffness.

In patients with advanced breast cancer thrombocytopenia and leucopenia have been

rarely reported. An occasional decrease in lymphocytes has been observed in approximately

20% of patients receiving Aromasin, particularly in patients with pre-existing lymphopenia;

however, mean lymphocyte values in these patients did not change significantly over time and

no corresponding increase in viral infections was observed. These effects have not been

observed in patients treated in early breast cancer studies.

(†)

Frequency calculated by rule of 3/X.

The table below presents the frequency of pre-specified adverse events and illnesses in the

early breast cancer study Intergroup Exemestane Study (IES), irrespective of causality,

reported in patients receiving trial therapy and up to 30 days after cessation of trial therapy.

Adverse events and illnesses

Exemestane

(N = 2249)

Tamoxifen

(N = 2279)

Hot flushes

491 (21.8%)

457 (20.1%)

Fatigue

367 (16.3%)

344 (15.1%)

Headache

305 (13.6%)

255 (11.2%)

Insomnia

290 (12.9%)

204 (9.0%)

Sweating increased

270 (12.0%)

242 (10.6%)

Gynaecological

235 (10.5%)

340 (14.9%)

Dizziness

224 (10.0%)

200 (8.8%)

Nausea

200 (8.9%)

208 (9.1%)

Osteoporosis

116 (5.2%)

66 (2.9%)

Vaginal haemorrhage

90 (4.0%)

121 (5.3%)

Other primary cancer

84 (3.6%)

125 (5.3%)

Vomiting

50 (2.2%)

54 (2.4%)

Visual disturbance

45 (2.0%)

53 (2.3%)

Thromboembolism

16 (0.7%)

42 (1.8%)

Osteoporotic fracture

14 (0.6%)

12 (0.5%)

Myocardial infarction

13 (0.6%)

4 (0.2%)

In the IES study, the frequency of ischemic cardiac events in the exemestane and tamoxifen

treatment arms was 4.5% versus 4.2%, respectively. No significant difference was noted for

any individual cardiovascular event including hypertension (9.9% versus 8.4%), myocardial

infarction (0.6% versus 0.2%) and cardiac failure (1.1% versus 0.7%).

In the IES study, exemestane was associated with a greater incidence of hypercholesterolemia

compared with tamoxifen (3.7% vs. 2.1%).

In a separate double blinded, randomized study of postmenopausal women with early breast

cancer at low risk treated with exemestane (N=73) or placebo (N=73) for 24

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months, exemestane was associated with an average 7-9% mean reduction in plasma HDL-

cholesterol, versus a 1% increase on placebo. There was also a 5-6% reduction in

apolipoprotein A1 in the exemestane group versus 0-2% for placebo. The effect on the other

lipid parameters analysed (total cholesterol, LDL cholesterol, triglycerides, apolipoprotein-B

and lipoprotein-a) was very similar in the two treatment groups. The clinical significance of

these results is unclear.

In the IES study, gastric ulcer was observed at a higher frequency in the exemestane arm

compared to tamoxifen (0.7% versus <0.1%). The majority of patients on exemestane with

gastric ulcer received concomitant treatment with non-steroidal anti-inflammatory agents

and/or had a prior history.

Reporting suspected adverse reactions after authorisation of the medicinal product is

important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

Any suspected adverse events should be reported to the Ministry of Health according to

the National Regulation by using an online form

getsequence.aspx?formType

http://forms.gov.il/globaldata/getsequence/

=AdversEffectMedic@moh.gov.il

4.9 Overdose

Clinical trials have been conducted with Aromasin 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 Aromasin that could

result in life-threatening symptoms is not known. In rats and dogs, lethality was observed

after single oral doses equivalent respectively to 2000 and 4000 times the recommended

human dose on a mg/m

basis. There is no specific antidote to overdosage and treatment must

be symptomatic. General supportive care, including frequent monitoring of vital signs and

close observation of the patient, is indicated.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: steroidal aromatase inhibitor; anti-neoplastic agent

ATC: LO2BG06

Mechanism of action

Exemestane is an irreversible, steroidal aromatase inhibitor, structurally related to the natural

substrate androstenedione. In post-menopausal 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. In

postmenopausal women, Aromasin p.o significantly lowered serum oestrogen concentrations

starting from a 5 mg dose, reaching maximal suppression (>90%) with a dose of 10-25 mg. In

postmenopausal breast cancer patients treated with the 25 mg daily dose, whole body

aromatization was reduced by 98 %.

Exemestane does not possess any progestogenic or oestrogenic activity. A slight androgenic

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activity, probably due to the 17-hydro derivative, has been observed mainly at high doses. In

multiple daily doses trials, Aromasin 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 non dose-

dependent slight increase in serum LH and FSH levels has been observed even at low doses:

this effect is, however, expected for the pharmacological class and is probably the result of

feedback at the pituitary level due to the reduction in oestrogen levels that stimulate the

pituitary secretion of gonadotropins also in postmenopausal women.

Clinical Studies and safety

Adjuvant Treatment of Early Breast Cancer

In a multicentre, randomized, double-blind study (IES), 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

randomized to receive 3 to 2 years of Aromasin (25 mg/day) or tamoxifen (20 or 30 mg/day)

to complete a total of 5 years of hormonal therapy.

IES 52-month median follow-up

After a median duration of therapy of about 30 months and a median follow-up of about 52

months, results showed that sequential treatment with Aromasin

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. Analysis

showed that in the observed study period Aromasin

reduced the risk of breast cancer

recurrence by 24% compared with tamoxifen (hazard ratio 0.76; p = 0.00015). The beneficial

effect of exemestane over tamoxifen with respect to DFS was apparent regardless of nodal

status or prior chemotherapy.

Aromasin also significantly reduced the risk of contralateral breast cancer (hazard ratio 0.57,

p = 0.04158).

In the whole study population, a trend for improved overall survival was observed for

exemestane (222 deaths) compared to tamoxifen (262 deaths) with a hazard ratio 0.85 (log-

rank test: p = 0.07362), representing a 15% reduction in the risk of death in favour of

exemestane. A statistically significant 23% reduction in the risk of dying (hazard ratio for

overall survival 0.77; Wald chi square test: p = 0.0069) was observed for exemestane

compared to tamoxifen when adjusting for the pre-specified prognostic factors (i.e., ER status,

nodal status, prior chemotherapy, use of HRT and use of bisphosphonates).

52 month main efficacy results in all patients (intention to treat population) and

oestrogen receptor positive patients

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Endpoint

Population

Exemestane

Events /N (%)

Tamoxifen

Events /N (%)

Hazard Ratio

(95% CI)

p-value*

Disease-free survival

a

All patients

354 /2352 (15.1%)

453 /2372 (19.1%)

0.76 (0.67-0.88)

0.00015

ER+ patients

289 /2023 (14.3%)

370 /2021 (18.3%)

0.75 (0.65-0.88)

0.00030

Contralateral breast cancer

All patients

20 /2352 (0.9%)

35 /2372 (1.5%)

0.57 (0.33-0.99)

0.04158

ER+ patients

18 /2023 (0.9%)

33 /2021 (1.6%)

0.54 (0.30-0.95)

0.03048

Breast cancer free survival

b

All patients

289 /2352 (12.3%)

373 /2372 (15.7%)

0.76 (0.65-0.89)

0.00041

ER+ patients

232 /2023 (11.5%)

305 /2021 (15.1%)

0.73 (0.62-0.87)

0.00038

Distant recurrence free survival

c

All patients

248 /2352 (10.5%)

297 /2372 (12.5%)

0.83 (0.70-0.98)

0.02621

ER+ patients

194 /2023 (9.6%)

242 /2021 (12.0%)

0.78 (0.65-0.95)

0.01123

Overall survival

d

All patients

222 /2352 (9.4%)

262 /2372 (11.0%)

0.85 (0.71-1.02)

0.07362

ER+ patients

178 /2023 (8.8%)

211 /2021 (10.4%)

0.84 (0.68-1.02)

0.07569

Log-rank test; ER+ patients = oestrogen receptor positive patients;

Disease-free survival is defined as the first occurrence of local or distant recurrence, contralateral breast cancer, or death

from any cause;

Breast cancer free survival is defined as the first occurrence of local or distant recurrence, contralateral breast cancer or

breast cancer death;

Distant recurrence free survival is defined as the first occurrence of distant recurrence or breast cancer death;

Overall survival is defined as occurrence of death from any cause.

In the additional analysis for the subset of patients with oestrogen receptor positive or

unknown status, the unadjusted overall survival hazard ratio was 0.83 (log-rank test: p =

0.04250), representing a clinically and statistically significant 17% reduction in the risk of

dying.

Results from the IES bone substudy demonstrated that women treated with Aromasin

following 2 to 3 years of tamoxifen treatment experienced moderate reduction in bone

mineral density. In the overall study, the treatment emergent fracture incidence evaluated

during the 30 months treatment period was higher in patients treated with Aromasin compared

with tamoxifen (4.5% and 3.3% correspondingly, p = 0.038).

Results from the IES endometrial substudy indicate that after 2 years of treatment there was a

median 33% reduction of endometrial thickness in the Aromasin-treated patients compared

with no notable variation in the tamoxifen-treated patients. Endometrial thickening, reported

at the start of study treatment, was reversed to normal (<5 mm) for 54% of patients treated

with Aromasin.

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

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improvement in disease-free survival (DFS) compared with continuation of tamoxifen

therapy. Results showed that over the observed study period Aromasin 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).

Aromasin also reduced risk of contralateral breast cancer, although the effect was no longer

statistically significant (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 favor 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 analysisfor 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 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 BMD from baseline, with 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.

In a randomized peer reviewed controlled clinical trial, Aromasin at the daily dose of 25 mg

demonstrated statistically significant prolongation of survival, Time to Progression (TTP),

Time to Treatment Failure (TTF) as compared to a standard hormonal treatment with

megestrol acetate in postmenopausal patients with advanced breast cancer that had progressed

following, or during, treatment with tamoxifen either as adjuvant therapy or as first-line

treatment for advanced disease.

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5.2 Pharmacokinetic Properties

Absorption

After oral administration of Aromasin tablets, exemestane is absorbed rapidly. The fraction of

the dose absorbed from the gastrointestinal tract is high. The absolute bioavailability in

humans is unknown, although it is anticipated to be limited by an extensive first pass effect. A

similar effect resulted in an absolute bioavailability in rats and dogs of 5%. After a single

dose of 25 mg, maximum plasma levels of 18 ng/ml are reached after 2 hours.Concomitant

administration with food increases the bioavailability by approximately 40%.

Distribution

The volume of distribution of exemestane, not corrected for the oral bioavailability (V/F), is

ca 20.000L. The kinetics is linear and the terminal elimination half-life is 24 h. Binding to

plasma proteins is 90% and is concentration independent. Exemestane and its metabolites do

not bind to red blood cells.

Exemestane does not accumulate in an unexpected way after repeated dosing.

Elimination:

Exemestane is metabolised via oxidation of the methylene moiety on the 6 position by

CYP3A4 isoenzyme and/or reduction of the 17-keto group by aldoketoreductase followed by

conjugation. The clearance of exemestane is ca 500 l/h, not corrected for the oral

bioavailability.

The metabolites are inactive or the inhibition of aromatase is less than the parent compound.

The amount excreted unchanged in urine is 1% of the dose. In urine and faeces equal amounts

(40%) of

C-labeled exemestane were eliminated within a week.

Special populations

Age:

No significant correlation between systemic exposure of Aromasin and the age of subjects has

been observed.

Renal insufficiency:

In patients with severe renal impairment (CL

< 30 ml/min) the systemic exposure to

exemestane was 2-times higher compared with healthy volunteers.

Given the safety profile of exemestane, no dose adjustment is considered to be necessary.

Hepatic insufficiency:

In patients with moderate or severe hepatic impairment the exposure of exemestane is 2-3 fold

higher compared with healthy volunteers. Given the safety profile of exemestane, no dose

adjustment is considered to be necessary.

5.3 Preclinical Safety Data

Toxicological studies:

Findings in the repeat dose toxicology studies in rat and dog were generally attributable to the

pharmacological activity of exemestane, such as effects on reproductive and accessory organs.

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Other toxicological effects (on liver, kidney or central nervous system) were observed only at

exposures considered sufficiently in excess of the maximum human exposure indicating little

relevance to clinical use.

Mutagenicity:

Exemestane was not genotoxic in bacteria (Ames test), in V79 Chinese hamster cells, in rat

hepatocytes or in the mouse micronucleus assay. Although exemestane was clastogenic in

lymphocytes in vitro, it was not clastogenic in two in vivo studies.

Reproductive toxicology:

Aromasin was embryotoxic in rats and rabbits at systemic exposure levels similar to those

obtained in humans at 25 mg/day. There was no evidence of teratogenicity.

Carcinogenicity:

In a two-year carcinogenicity study in female rats, no treatment-related tumors were observed.

In male rats the study was terminated on week 92, because of early death by chronic

nephropathy. In a two-year carcinogenicity study in mice, an increase in the incidence of

hepatic neoplasms in both genders was observed at the intermediate and high doses (150 and

450 mg/kg/day). This finding is considered to be related to the induction of hepatic

microsomal enzymes, an effect observed in mice but not in clinical studies. An increase in the

incidence of renal tubular adenomas was also noted in male mice at the high dose (450

mg/kg/day). This change is considered to be species- and gender-specific and occurred at a

dose which represents 63-fold greater exposure than occurs at the human therapeutic dose.

None of these observed effects is considered to be clinically relevant to the treatment of

patients with exemestane.

6. PHARMACEUTICAL PARTICULARS

6.1 List of Excipients

Silica, colloidal hydrated; crospovidone; hypromellose; magnesium carbonate, light;

magnesium stearate; mannitol; microcrystalline cellulose; methyl-p-hydroxybenzoate;

macrogol 6000; polysorbate 80; polyvinyl alcohol; simethicone emulsion; sodium starch

glycollate; sucrose; titanium dioxide

6.2 Incompatibilities

Not applicable.

6.3 Special Precautions for Storage

Store below 30

6.4 Nature and Contents of Container

15, 30, 60, 90, and 120 tablets in blister packs (Aluminium-PVDC/PVC-PVDC).

Not all pack sizes may be marketed.

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6.5 Special precautions for disposal and other handling

No special requirements.

Manufacturer:

Pfizer Italia S.r.l , Italy

For:

Pfizer PFE Pharmaceuticals Israel Ltd.