Active ingredients: Exemestane
AROMASIN - 25 mg Coated Tablets
Why is Aromasin used? What is it for?
His medicine is called Aromasin. Aromasin belongs to the category of medicines known as aromatase inhibitors. These drugs interfere with a substance called aromatase, which is necessary for the production of the female sex hormone, estrogen, especially in postmenopausal women. The reduction in the level of estrogen in the body constitutes a modality to treat hormone-dependent breast cancer. Aromasin is used to treat early hormone-dependent breast cancer in postmenopausal women who have completed 2-3 years of therapy with the medicine tamoxifen.
Aromasin is also used to treat advanced hormone-dependent breast cancer in postmenopausal women when hormone therapy with another medicine has not worked well enough.
Contraindications When Aromasin should not be used
Do not take Aromasin
- If you are allergic to exemestane (active substance in Aromasin) or any of the other ingredients of this medicine (listed in section 6).
- If you have not already gone through menopause, that is, you have a regular menstrual cycle.
- If you are pregnant, if you are likely pregnant or if you are breastfeeding.
Precautions for use What you need to know before taking Aromasin
- Before treatment with Aromasin, your doctor may request blood samples to make sure you have reached menopause.
- Routine checks of your vitamin D levels will also be done before treatment, since they can be very low in the early stages of breast cancer. If the levels are below normal, you will be given a vitamin D supplement.
- Before taking Aromasin, tell your doctor if you have liver or kidney problems.
- Tell your doctor if you have a history of or suffer from any condition that affects the strength of your bones. Your doctor may find it necessary to measure your bone density before and during treatment with Aromasin. This is because medicines belonging to this class lower the level of female hormones and this can lead to the loss of the mineral content of the bones which can become less resistant.
Interactions Which drugs or foods can modify the effect of Aromasin
Other medicines and Aromasin
Tell your doctor if you are taking, have recently taken or might take any other medicines. Aromasin must not be given together with hormone replacement therapy (HRT).
The following medicines should be used with caution when taking Aromasin. Tell your doctor if you are taking:
- rifampicin (an antibiotic),
- carbamazepine or phenytoin (anticonvulsants used in the treatment of epilepsy),
- l "St. John's wort (Hypericum perforatum), or preparations containing it.
Warnings It is important to know that:
For those who carry out sporting activities: the use of the drug without therapeutic necessity constitutes doping and can in any case determine positive anti-doping tests.
Pregnancy and breastfeeding
Do not take Aromasin if you are pregnant or breastfeeding. Tell your doctor if you are pregnant or think you may be pregnant. Women who may become pregnant during treatment are advised to discuss the use of an effective method of contraception with their doctor. .
Driving and using machines
If you feel sleepy, dizzy or weak while taking Aromasin, you should not drive or use machines.
Aromasin contains sucrose and methyl para-hydroxybenzoate
- If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine. Aromasin tablets contain sucrose (a type of sugar), which can cause problems in a small number of patients with hereditary intolerance to some sugars (glucose-galactose malabsorption, fructose intolerance or sucrase-isomaltase insufficiency).
- Aromasin contains a small amount of methyl parahydroxybenzoate, which can cause allergic reactions (possibly delayed); if this happens to you, contact your doctor.
Dose, Method and Time of Administration How to use Aromasin: Posology
Adults and the elderly
Always take this medicine exactly as your doctor has told you. If in doubt, consult your doctor.
Aromasin tablets should be taken by mouth at about the same time each day after meals. Your doctor will advise you on how to take Aromasin and for how long.
The recommended dose is one 25 mg tablet once a day.
If you need to go to the hospital while being treated with Aromasin, please tell the medical staff what medicines you are taking.
Use in children
The use of Aromasin is not indicated in children.
Overdose What to do if you have taken too much Aromasin
If you take more Aromasin than you should
If you have accidentally taken too many tablets, contact your doctor immediately or go to the emergency department of the nearest hospital and show them the pack of Aromasin tablets.
If you forget to take Aromasin
Do not take a double dose to make up for a forgotten tablet. If you forget to take a tablet, take it as soon as you remember. If it is almost time for your next dose, just take it at the usual time.
If you stop taking Aromasin
Do not stop taking the tablets even if you feel well, unless your doctor tells you to
Side Effects What are the side effects of Aromasin
Like all medicines, Aromasin can cause side effects, although not everybody gets them. Aromasin is well tolerated and the side effects listed below observed in patients treated with Aromasin are mainly mild or moderate in severity. Most side effects are associated with estrogen deficiency (e.g. hot flashes).
Hypersensitivity, liver inflammation (hepatitis) and inflammation of the liver bile ducts which can cause yellowing of the skin (cholestatic hepatitis) may occur. Symptoms include generally feeling unwell, nausea, jaundice (yellowing of the skin and eyes), itching, pain on the right side of the abdomen and loss of appetite. If you think you have any of these symptoms, contact your doctor right away for urgent medical help.
Very common side effects (may affect more than one in 10 people):
- Depression
- Difficulty sleeping
- Headache
- Hot flashes
- Dizziness
- Nausea
- Increased sweating
- Muscle and joint pain (including: osteoarthritis, back pain, arthritis and joint stiffness)
- Tiredness
- Reduction in the number of white blood cells
- Abdominal pain
- Elevated level of liver enzymes
- High level of a breakdown product of hemoglobin in the blood
- High level of an enzyme in the blood due to liver damage
- Ache
Common side effects (may affect up to 1 in 10 people):
- Loss of appetite
- Carpal tunnel syndrome (a pins-and-needles sensation, numbness and pain in the hand with the exception of the little finger) or tingling / pricking of the skin
- Stomach pain, vomiting (nausea), constipation, indigestion, diarrhea
- Hair loss
- Skin rash, hives and itching
- Thinning of the bones that can weaken (osteoporosis), in some cases leading to bone fractures (breaks or cracks)
- Pain, swelling in the hands and feet
- Reduction in the number of platelets in the blood
- Muscle weakness
Uncommon side effects (may affect up to 1 in 100 people):
- Hypersensitivity
Rare side effects (may affect up to 1 in 1,000 people):
- Appearance of a "skin rash with small blisters
- Drowsiness
- Liver inflammation
- Inflammation of the liver bile ducts which can cause yellowing of the skin
Not known side effects (frequency cannot be estimated from the available data):
- Low level of a certain type of white blood cell in the blood
Changes in the number of some blood cells (lymphocytes) and circulating platelets may also be observed, especially in patients with pre-existing lymphopenia (reduction in the number of lymphocytes in the blood).
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. Side effects can also be reported directly via the national reporting system at https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse. By reporting side effects you can help provide more information on safety of this medicine.
Expiry and Retention
- Keep this medicine out of the sight and reach of children.
- Do not use this medicine after the expiry date which is stated on the carton and blister after "EXP". The expiry date refers to the last day of that month.
- This medicine does not require any special storage conditions.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Composition and pharmaceutical form
What Aromasin contains
- The active ingredient is exemestane. Each coated tablet contains 25 mg of exemestane.
- The other ingredients are: colloidal hydrated silica, crospovidone, hypromellose, magnesium stearate, mannitol, microcrystalline cellulose, carboxymethyl starch sodium (type A), polysorbate, polyvinyl alcohol, simethicone, macrogol sucrose, light magnesium carbonate, methyl parahydroxybenzoate (E218) wax, talc, carnauba wax, ethyl alcohol, lacquer, titanium dioxide (E171) and iron oxides (E172).
What Aromasin looks like and contents of the pack
Aromasin tablets are coated, round shaped, biconvex, off-white in color, marked 7663 on one side.
Aromasin is available in blister packs of 15, 20, 30, 90, 100 and 120 tablets.
Not all pack sizes may be marketed
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
AROMASIN 25 MG COATED TABLETS
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Active ingredient: exemestane.
Each coated tablet contains: 25 mg exemestane.
Each tablet contains 30.2 mg of sucrose and 0.003 mg of methyl parahydroxybenzoate (E 218).
For the full list of excipients see section 6.1.
03.0 PHARMACEUTICAL FORM
Coated tablets.
Round shaped, off-white coated, biconvex tablets, marked 7663 on one side.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Aromasin is indicated for the adjuvant treatment of postmenopausal women with invasive early stage breast cancer (early breast cancer, EBC) and with positive estrogen receptors, after initial adjuvant therapy with tamoxifen for 2-3 years.
AROMASIN is indicated for the treatment of advanced breast cancer in women in a natural or induced postmenopausal state, whose disease has progressed after treatment with anti-estrogen therapy.
Efficacy has not been demonstrated in patients with estrogen receptor negative.
04.2 Posology and method of administration
Dosage
Adult and elderly patients
The recommended dose of AROMASIN is 1 tablet of 25 mg to be taken once a day, preferably after a meal.
In patients with early breast cancer, treatment with Aromasin should continue until completion of five years of sequential combined adjuvant hormone therapy (tamoxifen followed by Aromasin) of five years or shorter in the event of cancer recurrence.
In patients with advanced breast cancer, treatment with AROMASIN should continue until tumor progression is evident.
No dose adjustments are required for patients with hepatic or renal insufficiency (see section 5.2).
Pediatric population
Use in children is not recommended.
04.3 Contraindications
The use of AROMASIN tablets is contraindicated in patients with known hypersensitivity to the active substance or to any of the excipients listed in section 6.1, in pre-menopausal, pregnant or lactating women.
04.4 Special warnings and appropriate precautions for use
AROMASIN should not be administered to women with pre-menopausal endocrine status. Therefore, if considered appropriate from a clinical point of view, the postmenopausal status should be verified by evaluating the levels of LH, FSH and estradiol.
AROMASIN should be used with caution in patients with impaired liver or kidney function.
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 and therefore may cause allergic reactions (possibly delayed).
Aromasin is a potent agent that reduces the level of estrogen, and a reduction in bone mineral density has been observed following administration (bone mineral density, BMD) and an increase in the fracture rate (see section 5.1). At initiation of adjuvant treatment with Aromasin in women with osteoporosis or at risk of osteoporosis, the mineral condition of the bones at treatment initiation should be assessed according to current practice and guidelines. In patients with advanced disease, bone mineral density should be assessed on a case-by-case basis. by chance. Although insufficient data are available to show the effects of treatment for the reduction in bone mineral density caused by Aromasin, patients treated with Aromasin should be closely monitored and osteoporosis treatment or prophylaxis initiated. in patients at risk.
Due to the high prevalence of severe 25 hydroxy vitamin D deficiency in women with early breast cancer, routine evaluation of this parameter should be considered prior to initiation of treatment with an aromatase inhibitor. with vitamin D deficiency, a vitamin D supplement should be given.
04.5 Interactions with other medicinal products and other forms of interaction
Studies conducted in vitro showed that the drug is metabolised by 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 did not show significant effects on the pharmacokinetics of exemestane.
In an interaction study with rifampicin, a potent CYP450 inducer, given at a dose of 600 mg / day and a single dose of 25 mg exemestane, the AUC of exemestane was reduced by 54% and Cmax by 41%. As the clinical relevance of this interaction has not been evaluated, concomitant administration of drugs such as rifampicin, anticonvulsants (e.g. phenytoin and carbamazepine) and herbal preparations containing hypericum perforatum (St. John's wort) known to induce CYP3A4, may reduce the effectiveness of AROMASIN.
AROMASIN should be used with caution with drugs which are metabolised via the CYP3A4 pathway and which have a narrow therapeutic window. There is no clinical experience with the concomitant use of AROMASIN with other anticancer drugs.
AROMASIN should not be administered concomitantly with estrogen-containing medicines as these would nullify its pharmacological action.
04.6 Pregnancy and lactation
Pregnancy
No clinical data are available on pregnant women exposed to AROMASIN. Animal studies have shown toxic effects on reproduction (see section 5.3). Therefore AROMASIN is contraindicated in pregnancy.
Feeding time
It is not known whether exemestane is excreted in human milk. AROMASIN should not be administered during lactation.
Women in perimenopause or of childbearing age
Physicians should assess the need for effective contraception for women of childbearing potential including women who have perimenopause, or who have recently reached menopause, at least until postmenopausal status has been fully established (see sections 4.3 and 4.4). .
04.7 Effects on ability to drive and use machines
Following the use of the drug, cases of drowsiness, drowsiness, asthenia and dizziness have been reported. Patients should be informed that if such effects occur, their physical and / or mental capacities necessary for driving vehicles or using machinery can be reduced.
04.8 Undesirable effects
Aromasin was generally well tolerated in all clinical studies conducted with Aromasin at the standard dose of 25 mg / day, and undesirable effects generally were mild to moderate in severity.
The incidence of discontinuation 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 flushing of heat (22%), arthralgia (18%) and fatigue (16%).
The incidence of treatment discontinuation due to adverse events was 2.8% in the entire advanced breast cancer patient population. The most common adverse reactions were hot flashes (14%) and nausea (12 %).
Most adverse reactions can be attributed to the normal pharmacological consequences of estrogen deprivation (eg hot flashes).
Adverse reactions reported from clinical and post-marketing studies are listed below by system organ class and frequency.
Frequencies were defined as follows: very common (≥ 1/10); common (≥1 / 100,
Disorders of the blood and lymphatic system:
Very common: leukopenia (**)
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: drowsiness
Vascular disorders:
Very common: hot flashes
Gastrointestinal disorders:
Very common: abdominal pain, nausea
Common: vomiting, diarrhea, constipation, dyspepsia
Hepatobiliary disorders:
Very common: liver enzymes 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, itching
Rare: acute generalized exanthematous pustulosis (†)
Musculoskeletal system disorders:
Very common: musculoskeletal and joint pain (*)
Common: fractures, osteoporosis
General disorders and administration site conditions:
Very common: achiness, fatigue
Common: peripheral edema, asthenia
(*) Includes: arthralgia, and less frequently limb pain, osteoarthritis, back pain, arthritis, myalgia and joint stiffness
(**) Cases of thrombocytopenia and leukopenia have rarely been reported in patients with advanced breast cancer. An occasional decrease in the number of lymphocytes was observed in approximately 20% of patients receiving AROMASIN, particularly in those with pre-existing lymphopenia; however, in these patients the mean lymphocyte values did not change significantly over time and no corresponding increase in viral infections was observed.
These effects were not seen in patients treated in early breast cancer studies.
(†) Frequency calculated with the 3 / X rule.
The table below shows the frequency of adverse events and diseases specified above in the Intergroup Exemestane Study (IES) in early breast cancer, regardless of causality, reported in patients receiving study drug and up to 30 days after the end of the study. therapy.
In the IES study, the frequency of cardiac ischemic events was 4.5% vs 4.2% in patients treated with exemestane and tamoxifen, respectively. No significant difference was observed for individual cardiovascular events including hypertension (9.9% vs 8.4%), myocardial infarction (0.6% vs 0.2%) and heart failure (1.1% vs 0. , 7%).
In the IES study, exemestane was associated with a higher incidence of hypercholesterolemia than tamoxifen (3.7% vs 2.1%).
In another randomized, double-blind study in postmenopausal women with low-risk early breast cancer who were treated with exemestane (N = 73) or placebo (N = 73) for 24 months, exemestane was was associated with an average reduction in plasma HDL cholesterol levels of 7-9%, versus a 1% increase in the placebo group. A 5-6% reduction in apolipoprotein A1 was also observed in the group treated with exemestane. vs 0-2% in the placebo group. The effect on the other lipid parameters examined (total cholesterol, LDL cholesterol, triglycerides, apolipoprotein B and lipoprotein a) was very similar in both treatment groups. The clinical significance of these results is unclear.
In the IES study, a higher frequency of gastric ulcer was found in the exemestane arm compared to the tamoxifen arm (0.7% vs gastric ulcer were on concomitant NSAIDs and / or had a previous medical history.
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address" www.agenziafarmaco.gov.it/it/responsabili ".
04.9 Overdose
Clinical studies were performed with administration of AROMASIN up to a dose of 800 mg as a single dose to healthy female volunteers and up to a dose of 600 mg per day to postmenopausal women with advanced breast cancer; these dosages were well tolerated. It is not known what single dose of AROMASIN could cause the patient's life-threatening symptoms. In rats and dogs, lethality was observed after single oral doses equivalent to 2,000 and 4,000 times the recommended human dose, respectively, calculated on a mg / m2 basis. There is no specific antidote to overdose and treatment should be symptomatic.
General supportive care is indicated, including frequent monitoring of vital signs and close observation of the patient.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: steroid aromatase inhibitor; antineoplastic agent.
ATC code: L02BG06.
Mechanism of action
Exemestane is an irreversible steroidal aromatase inhibitor, structurally related to the natural substrate androstenedione. In postmenopausal women, estrogens are mainly produced by the conversion of androgens to estrogen by 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. In postmenopausal women, AROMASIN administered orally significantly reduces serum estrogen concentrations starting from a dose of 5 mg, reaching maximum suppression (> 90%) with a dose of 10-25 mg. In postmenopausal breast cancer patients treated with the daily dose of 25 mg, the body's aromatase activity is reduced by 98%.
Exemestane does not possess any progestin or estrogenic properties. A slight androgenic activity was observed probably due to the 17-hydro derivative, especially at high doses. In studies conducted with multiple daily doses, AROMASIN did not demonstrate detectable effects on the adrenal biosynthesis of cortisol or aldosterone, measured before or after ACTH stimulation, thus demonstrating its selectivity with regard to the other enzymes involved in the synthesis of steroids.
Therefore, glucocorticoid or mineralocorticoid replacement therapy is not necessary. A slight non-dose-dependent increase in serum levels of LH and FSH has also been observed at low doses: however, this effect is expected given the drug class it belongs to and is probably the result of feedback at the pituitary level due to the reduction of estrogen levels that stimulate the pituitary secretion of gonadotropins even in postmenopausal women.
Clinical efficacy and safety
Treatment of early stage breast cancer
In a multicentre, randomized, double-blind (IES) study of 4,724 postmenopausal patients with estrogen receptor positive or unknown primary breast cancer, patients free of the disease following adjuvant tamoxifen therapy for 2-3 years were randomized to a subsequent 3-2 year treatment with Aromasin (25 mg / day) or tamoxifen (20 or 30 mg / day) to complete a total 5-year course of hormone therapy.
IES - median follow-up at 52 months
After a median duration of therapy of approximately 30 months and a median follow-up of approximately 52 months, the results demonstrated that sequential treatment with Aromasin after 2-3 years of adjuvant tamoxifen therapy was associated with a clinically and statistically improved. significant for disease-free survival (DFS) compared with continued tamoxifen therapy. The analysis performed showed that over the study period Aromasin reduced the risk of breast cancer recurrence by 24% compared to tamoxifen (Hazard Ratio 0.76, p = 0.00015).
The beneficial effect of exemestane over tamoxifen with respect to disease-free survival (DFS) was evident regardless of nodal status or previous chemotherapy.
Furthermore, Aromasin significantly reduced the risk of contralateral breast cancer (Hazard Ratio 0.57, p = 0.04158).
In the whole study population, there was a trend towards better overall survival for exemestane (222 deaths) than for tamoxifen (262 deaths) with a hazard ratio of 0.85 (log-rank test: p = 0.07362 ), which represents a 15% reduction in the risk of death in favor of exemestane. A statistically significant 23% reduction in the risk of death was observed (hazard ratio for overall survival of 0.77; Wald chi square test: p = 0.0069) for exemestane versus tamoxifen when corrected for predetermined prognostic factors (ER status, nodal status, previous chemotherapy, HRT and bisphosphonate use).
Main efficacy results at 52 months in all patients (intention to treat population) and in patients with estrogen receptor positive.
* Log-rank test; ER + patients = estrogen receptor positive patients;
a Disease-free survival is defined as the first occurrence of local recurrence or distant metastasis, contralateral breast cancer, or death from any cause;
b Breast cancer free survival is defined as the first occurrence of local recurrence or distant metastasis, contralateral breast cancer, or breast cancer death;
c Distant metastasis-free survival is defined as the first occurrence of distant metastasis or death from breast cancer;
d Overall survival is defined as occurrence of death from any cause.
In the further analysis of the subgroup of patients with positive or unknown estrogen receptors, the uncorrected hazard ratio for overall survival was 0.83 (log-rank test: p = 0.04250), which represents a reduction clinically and statistically significant risk of death by 17%.
The results of the IES bone substudy showed that a moderate reduction in bone mineral density is observed in women treated with Aromasin after 2-3 years of tamoxifen therapy.In the overall study, the incidence of on-treatment fractures evaluated over 30 months of treatment was higher in patients treated with Aromasin than in those treated with tamoxifen (4.5% and 3.3% respectively, p = 0.038).
Results from the IES endometrial substudy indicate that after 2 years of treatment there was a median reduction in endometrial thickness of 33% in patients treated with Aromasin compared with an undetectable change in patients treated with tamoxifen. The endometrial thickening, detected at the beginning of the treatment, has normalized (
IES - median follow-up of 87 months After a median duration of therapy of approximately 30 months and a median follow-up of approximately 87 months, the results showed that sequential treatment with exemestane after 2 or 3 years of adjuvant tamoxifen therapy was associated with a clinically and statistically significant improvement in disease-free survival (DFS) compared with continued tamoxifen therapy. The results showed that, over the observed study period, Aromasin significantly reduced the risk of breast cancer recurrence by 16% compared to tamoxifen (hazard ratio 0.84; p = 0.002).
Overall, the beneficial effect of exemestane over tamoxifen with respect to DFS was evident regardless of node status or previous chemotherapy or hormone therapy. Statistical significance was not maintained in some subgroups with small sample sizes. These showed the trend in favor of exemestane in patients with more than 9 positive lymph nodes, or with previous CMF chemotherapy. In patients with unknown lymph node status, with another type of previous chemotherapy, as well as with an unknown / absent condition related to hormone therapy a non-statistically significant trend in favor of tamoxifen was observed. Furthermore, the use of exemestane also significantly prolonged breast cancer-free survival (hazard ratio 0.82, p = 0.00263) and relapse-free survival at distance (hazard ratio 0.85, p = 0.02425). Aromasin 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 entire study population it was observed. a trend towards better overall survival for exemestane (373 deaths) compared to tamoxifen (420 deaths) with a hazard ratio of 0.89 (log rank test: p = 0.08972), which represents an 11% reduction in risk of death in favor of exemestane. In the entire study population, a statistically significant 18% reduction in the risk of death was observed (hazard ratio for overall survival equal to 0.82; Wald chi square test: p = 0 , 0082) for exemestane versus tamoxifen when corrected for predetermined prognostic factors (such as ER status, lymph node status, previous chemotherapy, use of hormone replacement therapy and bisphosphonates).
In the further subgroup analysis of patients with positive or unknown estrogen receptors, the unadjusted hazard ratio for overall survival was 0.86 (log rank test: p = 0.04262), which represents a clinically and statistically significant 14% risk of death.
Results from a bone substudy indicate that treatment with exemestane for 2-3 years after 3-2 years of tamoxifen treatment increased bone loss during treatment (mean% change in bone mineral density (BMD) from baseline at 36 months: -3.37 [spine], - 2.96 [hip] for exemestane and -1.29 [spine], -2.02 [hip], for tamoxifen). 24 months post-treatment period, there were minimal differences in BMD change from baseline in both treatment groups, presenting the tamoxifen arm with slightly greater final reductions in BMD at all sites (mean% change from baseline for BMD at 24 months after treatment -2.17 [column], -3.06 [hip] for exemestane and -3.44 [column], -4.15 [hip] for tamoxifen).
Total fractures reported during treatment and during follow-up were significantly more in the exemestane group than in the tamoxifen group (169 [7.3%] vs 122 [5.2%]; p = 0.004), but no differences were noted in the number of osteoporotic fractures.
Treatment of advanced breast cancer
In a randomized controlled clinical trial validated by a review committee, AROMASIN administered at a daily dose of 25 mg was shown to statistically significantly prolong survival, Time to Progression (TTP), Time to Relapse (TTF) if compared to standard hormone treatment with megestrol acetate in postmenopausal patients with advanced breast cancer who had progressed after or during treatment with tamoxifen given as adjuvant therapy or as first-line treatment for advanced disease.
05.2 "Pharmacokinetic properties
Absorption
Following oral administration of AROMASIN tablets, exemestane is rapidly absorbed. The fraction of the dose absorbed via the gastrointestinal tract is high. Absolute bioavailability in humans is unknown, although it is assumed to be limited by a large first pass effect. . A similar effect resulted in an absolute bioavailability of 5% in rats and dogs. After a single dose of 25 mg, maximum plasma levels of 18 ng / ml were reached after 2 hours. Concomitant food intake increases bioavailability by 40%.
Distribution
The volume of distribution of exemestane, not adjusted for oral bioavailability, is approximately 20,000 L. The kinetics are linear and the terminal elimination half-life is 24 hours. Plasma protein binding is 90% and is independent of concentration. Exemestane and its metabolites do not bind to erythrocytes.
After repeated administration, there is no accumulation of exemestane in unexpected ways.
Elimination
Exemestane is metabolized by oxidation of the methylene group in position 6 by the isoenzyme CYP3A4 and / or reduction of the 17-keto group by aldoketoreductase followed by conjugation. The clearance of exemestane, not adjusted for oral bioavailability, is about 500 l / hour. The metabolites are either inactive or less active than the parent drug in inhibiting aromatase. The amount of unchanged drug excreted in the urine is 1% of the dose. In faeces and urine, equal amounts (40%) of C14-labeled exemestane were excreted within one week.
Particular patient populations
Age
No significant correlation was observed between the systemic exposure of AROMASIN and the age of the subjects.
Renal impairment
In patients with severe renal impairment (CLcr
Hepatic impairment
In patients with moderate to severe hepatic impairment, the exposure of exemestane is 2-3 times higher than that seen in healthy volunteers. In view of the safety profile of exemestane, no dose adjustment is considered necessary.
05.3 Preclinical safety data
Toxicological studies
THE results of repeat dose toxicity studies in rats and dogs, such as effects on reproductive and related organs, were generally attributable to the pharmacological activity of exemestane. 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), Chinese hamster V79 cells, rat hepatocytes, and mouse micronucleus test. in vitro exemestane is clastogenic in lymphocytes, it was not clastogenic in two studies in vivo.
Reproductive toxicology
Exemestane was embryotoxic in rats and rabbits at systemic exposure levels similar to those obtained in humans at the dose of 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 ended after 92 weeks, due to their premature death from chronic kidney disease. In a two-year carcinogenicity study in mice, an increase in the incidence of liver tumors in both sexes was observed at intermediate and high doses (150 and 450 mg / kg / day). This result is considered to be related to the induction of microsomal liver enzymes, an effect observed in mice but not in clinical studies. An increased incidence of renal tubule adenomas was also noted in male mice at high doses (450 mg / kg / day). This change is considered species- and sex-specific and occurred at a dose representing 63 times the drug exposure in humans. None of the observed effects are considered clinically related to treatment with exemestane.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Core of the tablet:
Colloidal silica hydrates
Crospovidone
Hypromellose
Magnesium stearate
Mannitol
Microcrystalline cellulose
Sodium carboxymethyl starch (type A)
Polysorbate.
Coating:
Hypromellose
Polyvinyl alcohol
Simethicone
Macrogol
Sucrose
Lightweight magnesium carbonate
Titanium dioxide (E171)
Methyl parahydroxybenzoate (E218)
Cetyl esters of wax
Talc
Carnauba wax.
Ink for impression:
Ethyl alcohol
Lacquer
Iron oxides (E172)
Titanium dioxide (E171).
06.2 Incompatibility
Not relevant.
06.3 Period of validity
3 years.
06.4 Special precautions for storage
This medicine does not require any special storage conditions
06.5 Nature of the immediate packaging and contents of the package
Aluminum-PVDC / PVC-PVDC blister.
Cartons of 15, 20, 30, 90, 100 and 120 tablets.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
No special instructions.
07.0 MARKETING AUTHORIZATION HOLDER
Pfizer Italia S.r.l. - via Isonzo, 71 - 04100 Latina
08.0 MARKETING AUTHORIZATION NUMBER
Box of 15 tablets, AIC n. 034678019
Box of 20 tablets, AIC n. 034678021
Box of 30 tablets, AIC n. 034678033
Box of 90 tablets, AIC n. 034678045
Box of 100 tablets, AIC n. 034678058
Box of 120 tablets, AIC n. 034678060
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
March 15, 2000 / December 16, 2008
10.0 DATE OF REVISION OF THE TEXT
14 October 2015
