Active ingredients: Anastrozole
Arimidex 1 mg film-coated tablets
Why is Arimidex used? What is it for?
Arimidex contains a substance called anastrozole, which belongs to a group of medicines called “aromatase inhibitors.” Arimidex is used to treat breast cancer in postmenopausal women.
Arimidex works by reducing the amount of hormones called estrogens produced by the body. This happens by blocking a natural substance (enzyme) in your body, called "aromatase".
Contraindications When Arimidex should not be used
Do not take Arimidex:
- if you are allergic to anastrozole or any of the other ingredients of this medicine
- if you are pregnant or breast-feeding (see section "Pregnancy and breast-feeding").
Do not take Arimidex if any of the above apply to you. If in doubt, consult your doctor or pharmacist before taking Arimidex.
Precautions for use What you need to know before taking Arimidex
Talk to your doctor, pharmacist or nurse before taking Arimidex:
- if you are still menstruating and are not yet in menopause.
- if you are taking a medicine that contains tamoxifen or medicines containing estrogen (see section "Other medicines and ARIMIDEX").
- if you have or have ever had a condition that affects the strength of your bones (osteoporosis).
- if you have liver or kidney problems.
If you are not sure whether any of the above apply to you, consult your doctor or pharmacist before taking Arimidex.
If you are hospitalized, tell the medical staff that you are taking Arimidex.
Interactions Which drugs or foods can modify the effect of Arimidex
Tell your doctor or pharmacist if you are taking or have recently taken any other medicines.
These include medicines you can buy without a prescription and herbal remedies. This is because Arimidex can affect the way some medicines work and some medicines can have an effect on Arimidex.
Do not take Arimidex if you are already taking any of the following medicines:
- Some medicines used to treat breast cancer (selective estrogen receptor modulators), for example medicines containing tamoxifen. This is because these medicines can prevent Arimidex from working properly.
- Medicines containing estrogen, for example hormone replacement therapy (HRT).
If any of these apply to you, ask your doctor or pharmacist for advice. Tell your doctor or pharmacist if you are taking the following:
- A medicine known as an "LHRH analogue". This includes gonadorelin, buserelin, goserelin, leuprorelin and triptorelin. These medicines are used to treat breast cancer, certain female (gynecological) diseases and infertility.
Warnings It is important to know that:
Pregnancy and breastfeeding
Do not take Arimidex if you are pregnant or breast-feeding. Stop Arimidex if you become pregnant and talk to your doctor.
Ask your doctor or pharmacist for advice before taking any medicine.
Driving and using machines
Arimidex is unlikely to affect your ability to drive or use tools or machines. However, some people may occasionally feel faint or sleepy while taking Arimidex. If this happens, ask your doctor or pharmacist for advice.
Arimidex contains lactose
Arimidex contains lactose, a type of sugar. If you have been told by your doctor that you have an "intolerance to some sugars, consult your doctor before taking this medicine.
Dose, Method and Time of Administration How to use Arimidex: Posology
Always take Arimidex exactly as your doctor or pharmacist has told you. If in doubt, consult your doctor or pharmacist.
- The recommended dose is one tablet once a day.
- Try to take the tablet at the same time each day.
- Swallow the tablet whole with a drink of water.
- It does not matter if you take Arimidex before, with or after meals.
Continue to take Arimidex for as long as your doctor or pharmacist tells you. It is a long-term treatment and may need to be taken for several years. If in doubt, consult your doctor or pharmacist.
Use in children and adolescents
Arimidex should not be given to children and adolescents.
Overdose What to do if you have taken too much Arimidex
If you take more Arimidex than you should
If you take more Arimidex than you should, tell your doctor immediately.
If you forget to take Arimidex
If you forget to take a dose, just take the next dose as usual. Do not take a double dose (two doses at the same time) to make up for a forgotten dose.
If you stop taking Arimidex
Do not stop taking the tablets unless your doctor tells you to.
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.
Side Effects What are the side effects of Arimidex
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Very common side effects (affect more than 1 in 10 people)
- Headache.
- Hot flashes.
- Feeling sick (nausea).
- Rash.
- Joint pain or stiffness.
- Joint inflammation (arthritis).
- Feeling of weakness.
- Loss of bone density (osteoporosis).
Common side effects (affects 1 to 10 users in 100)
- Loss of appetite.
- Increase or elevated levels in the blood of a fatty substance known as cholesterol, which can be checked with a blood test.
- Feeling sleepy.
- Carpal tunnel syndrome (tingling, pain, cold sensation in parts of the hand).
- Tickling, tingling or numbness of the skin, loss / lack of taste.
- Diarrhea.
- Feeling sick (vomiting).
- Changes in blood tests related to how your liver is working.
- Hair thinning (hair loss).
- Allergic (hypersensitivity) reactions including to the face, lips and tongue.
- Bone pain.
- Vaginal dryness.
- Vaginal bleeding (usually in the first few weeks of treatment - if bleeding continues, talk to your doctor).
- Muscular pain.
Uncommon side effects (affects 1 to 10 users in 1,000)
- Changes in some specific blood tests that show your liver is working (gamma-GT and bilirubin).
- Inflammation of the liver (hepatitis).
- Urticaria.
- Snap fingers (condition in which one of your fingers or thumb takes a curved position).
- Increase the amount of calcium in your blood. If you feel sick, vomit and thirsty, tell your doctor or pharmacist or nurse as blood tests may need to be done.
Rare side effects (affects 1 to 10 users in 10,000)
- Unusual inflammation of the skin which may include red spots or blisters.
- Skin erythema caused by hypersensitivity (this can be caused by an allergic or anaphylactic reaction).
- Inflammation of the capillaries which causes a red or purple discoloration of the skin. Very rarely, pain in the joints, stomach and kidneys may occur; it is known as "Henoch Schönlein purpura".
Very rare side effects (affects less than 1 in 10,000 people)
- Extremely severe skin reaction, with the appearance of ulcers or blisters on the skin. It is known as "Stevens-Johnson syndrome".
- Allergic (hypersensitivity) reaction with swelling of the throat, which may cause difficulty in swallowing or breathing. Known as "angioedema". If any of these happen, call an ambulance or see a doctor immediately - urgent medical treatment may be needed.
Effects on the bones
Arimidex reduces the amount of hormones called estrogen in the body. This can reduce the mineral content of bones; therefore, bones may be less strong and more prone to fractures. Your doctor will monitor these risks according to treatment guidelines. for the management of bone health in postmenopausal women. Consult with your doctor about these risks and treatment options.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.
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. You can also report side effects directly via the national reporting system on the website of the Italian Medicines Agency: https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.
By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Do not store above 30 ° C
Keep this medicine out of the sight and reach of children.
Keep the tablets in a safe place where children cannot see or reach them. Tablets can be dangerous for them.
Do not use this medicine after the expiry date which is stated on the carton and blister. The expiry date refers to the last day of the month.
Keep the tablets in the original package.
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.
What Arimidex contains
- The active ingredient is anastrozole. Each film-coated tablet contains 1 mg of anastrozole.
- The other ingredients are: lactose monohydrate, povidone, sodium starch glycolate, magnesium stearate, hypromellose, macrogol 300 and titanium dioxide.
What Arimidex looks like and contents of the pack
The film-coated tablets are white, round, biconvex, approximately 6.1 mm marked with "A" on one side and "Adx1" on the other side.
Arimidex is supplied in blister packs of 28 tablets.
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
ARIMIDEX 1 MG TABLETS COATED WITH FILM
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 1 mg of anastrozole.
Excipients with known effects
Each film-coated tablet contains 93 mg of lactose monohydrate (see section 4.4).
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Film-coated tablet.
White, round, biconvex film-coated tablets of approximately 6.1 mm marked with "A" on one side and "Adx1" on the other side.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Arimidex is indicated in:
• Treatment of hormone receptor positive advanced breast cancer in postmenopausal women.
• Adjuvant treatment of the early stages of hormone receptor positive invasive breast cancer in postmenopausal women.
• Adjuvant treatment of early stages of hormone receptor positive invasive breast cancer in postmenopausal women who have received 2 or 3 years of adjuvant tamoxifen therapy.
04.2 Posology and method of administration
Dosage
The recommended dosage of Arimidex in adults including the elderly is one 1 mg tablet once a day.
In postmenopausal women with hormone receptor positive early invasive breast cancer, the recommended duration of adjuvant endocrine treatment is 5 years.
Special populations
Pediatric population
Arimidex is not recommended in children and adolescents due to insufficient data on safety and efficacy (see sections 4.4 and 5.1).
Kidney failure
No dosage adjustments are recommended in patients with mild or moderate renal impairment. In patients with severe renal insufficiency, administration of Arimidex should be performed with caution (see sections 4.4 and 5.2).
Hepatic insufficiency
No dosage adjustments are recommended in patients with mild hepatic impairment. Caution is advised in patients with moderate or severe hepatic impairment (see section 4.4).
Method of administration
Arimidex must be taken orally.
04.3 Contraindications
Arimidex is contraindicated in:
• Pregnancy or in women who are breastfeeding.
• Patients with known hypersensitivity to anastrozole or to any of the excipients mentioned in section 6.1.
04.4 Special warnings and appropriate precautions for use
In general
Arimidex should not be used in premenopausal women. Menopause must be biochemically ascertained (by means of luteinizing hormone [LH], follicle stimulating hormone [FSH] and / or estradiol levels) in those patients in whom there is some doubt about the state of menopause. data supporting the use of Arimidex with LHRH analogues.
Concomitant administration of Arimidex with tamoxifen or estrogen-containing therapies should be avoided as this may decrease its pharmacological action (see sections 4.5 and 5.1).
Effect on bone mineral density
Since Arimidex lowers circulating levels of estrogen, it may cause a decrease in bone mineral density with a possible consequent increased risk of fractures (see section 4.8).
Women with osteoporosis or at risk of osteoporosis should have bone mineral density assessment at the start of treatment and at regular intervals thereafter. Osteoporosis treatment or prophylaxis should be initiated appropriately and monitored closely. The use of specific treatments, eg bisphosphonates may be considered, as they may halt the further loss of bone mineral density caused by Arimidex in postmenopausal women (see section 4.8).
Hepatic insufficiency
Arimidex has not been evaluated in breast cancer patients with moderate or severe hepatic impairment. Anastrozole exposure may be increased in subjects with hepatic impairment (see section 5.2); administration of Arimidex in patients with moderate or severe hepatic impairment should be performed with caution (see section 4.2). Treatment should be based on assessment of the benefit / risk of each individual patient.
Kidney failure
Arimidex has not been evaluated in breast cancer patients with severe renal insufficiency. Anastrozole exposure was not increased in subjects with severe renal impairment (GRF
Pediatric population
Arimidex is not recommended for use in girls and adolescents as safety and efficacy in this patient group have not been established (see section 5.1).
Arimidex should not be used in male children with growth hormone deficiency as an adjunct to growth hormone treatment. Efficacy has not been demonstrated and safety has not been established in the pivotal clinical study (see section 5.1). Since anastrozole reduces estradiol levels, Arimidex should not be used in girls with growth hormone deficiency as an adjunct to growth hormone treatment. Long-term safety data are not available in pediatric and adolescent subjects.
Hypersensitivity to lactose
This product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
04.5 Interactions with other medicinal products and other forms of interaction
Anastrozole inhibits CYPs, 1A2, 2C8 / 9 and 3A4 in vitro. Clinical studies with antipyrine and warfarin indicate that anastrozole 1 mg does not significantly inhibit the metabolism of antipyrine and R- and S-warfarin demonstrating that co-administration of Arimidex with other medicinal products is unlikely to result in a CYP enzyme mediated interaction clinically. significant.
The enzymes that mediate the metabolism of anastrozole have not been identified. Cimetidine, a weak, non-specific inhibitor of CYP enzymes, does not alter the plasma concentrations of anastrozole. The effect of potent CYP inhibitors is unknown.
A review of the safety data from clinical trials revealed no clinically significant interactions in patients treated with Arimidex and concomitantly with other commonly prescribed medicinal products. There are no clinically significant interactions with bisphosphonates (see section 5.1).
Co-administration of Arimidex with tamoxifen or estrogen-containing therapies should be avoided as this may decrease its pharmacological action (see sections 4.4 and 5.1).
04.6 Pregnancy and lactation
Pregnancy
There are no data on the use of Arimidex in pregnant women. Animal studies have shown reproductive toxicity (see section 5.3). Arimidex is contraindicated during pregnancy (see section 4.3).
Breastfeeding
There are no data on the use of Arimidex during lactation. Arimidex is contraindicated in breastfeeding women (see section 4.3).
Fertility
The effects of Arimidex on human fertility have not been studied. Studies in animals have shown reproductive toxicity (see section 5.3).
04.7 Effects on ability to drive and use machines
Arimidex has no or negligible influence on the ability to drive or use machines. However, as asthenia and somnolence have been reported with the use of Arimidex, care should be taken when driving or operating machinery if these symptoms persist.
04.8 Undesirable effects
The following table reports adverse reactions from clinical trials, post-marketing studies or spontaneous reports. Unless specified, the following frequency categories were calculated from the number of adverse events reported in a large phase III study conducted in 9,366 postmenopausal women with operable breast cancer on adjuvant therapy for 5 years (Study Arimidex, Tamoxifen, Alone or in Combination [ATAC]).
The adverse reactions listed below are classified according to frequency and organ and system class (SOC). Frequency classes are defined according to the following convention: very common (≥ 1/10), common (≥ 1/100 to headache, flushing, nausea, skin rash, arthralgia, joint pain / stiffness, arthritis and asthenia.
* Carpal tunnel events have been reported in patients receiving Arimidex in clinical trials in more patients than those receiving tamoxifen. However, the majority of these events occurred in patients with identifiable risk factors for developing this condition.
** Since cutaneous vasculitis and Henoch-Schönlein purpura were not observed in the ATAC study, the frequency category for these events can be considered as "Rare" (≥ 0.01% and
*** Vaginal bleeding reported frequently especially in patients with advanced breast cancer during the first few weeks, after modification of existing hormone therapy in treatment with Arimidex. If bleeding persists, further evaluation should be considered.
The following table reports the frequency of pre-defined adverse events in the ATAC study after a median follow-up of 68 months, reported in patients treated with study therapy and up to 14 days after discontinuation of study therapy, regardless of causality. .
After a median follow-up of 68 months, fracture rates of 22 and 15 per 1,000 patient-years, respectively, were observed for the Arimidex and tamoxifen groups. The observed fracture rate for Arimidex is similar to the range reported in postmenopausal populations of the same age. The incidence of osteoporosis was 10.5% in patients treated with Arimidex and 7.3% in those treated with tamoxifen.
It has not been determined whether the fracture and osteoporosis rates observed in the ATAC study in patients treated with Arimidex reflect a protective effect of tamoxifen or a specific effect of Arimidex or both.
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 https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.
04.9 Overdose
Clinical experience with accidental overdose is limited. In animal studies, anastrozole has shown low acute toxicity. Clinical studies have been conducted with various doses of Arimidex, up to 60 mg as a single dose in healthy male volunteers and up to 10 mg per day in postmenopausal women with advanced breast cancer; these dosages were well tolerated. The single dose of Arimidex capable of causing symptoms that could be life threatening has not been established. There is no specific antidote to overdose and treatment should be symptomatic.
When managing an overdose, consideration should be given to the possibility that several drugs have been taken. If the person is alert, vomiting may be induced. Dialysis may help, as Arimidex does not bind highly to plasma proteins. General supportive measures are indicated, including frequent monitoring of vital signs and careful observation of the subject.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: enzyme inhibitors.
ATC code: L02B G03.
Mechanism of action and pharmacodynamic effects
Arimidex is a potent and highly selective non-steroidal aromatase inhibitor. In postmenopausal women, estradiol is produced mainly in peripheral tissues following the conversion of androstenedione to estrone by the aromatase enzyme. Estrone is then subsequently converted to estradiol. Reduction in plasma levels of estradiol has been shown to have a beneficial effect in women with breast cancer. In postmenopausal women, Arimidex at a daily dose of 1 mg resulted in suppression of estradiol levels above 80%, measured with a highly sensitive test.
Arimidex does not possess progestogenic, androgenic or estrogenic activity.
Daily doses of Arimidex up to 10 mg have shown no effect on cortisol or aldosterone secretion, measured before or after standard adrenocorticotropic hormone (ACTH) stimulation tests. Therefore no additional administration of corticosteroids is required.
Clinical efficacy and safety
Advanced breast cancer
First-line therapy in postmenopausal women with advanced breast cancer
Two controlled, double-blind, clinical trials with a similar experimental design (Study 1033IL / 0030 and Study 1033IL / 0027) were performed to evaluate the efficacy of Arimidex compared to tamoxifen as first-line therapy in postmenopausal women with breast cancer. metastatic or locally advanced with positive or unknown hormone receptors. A total of 1,021 patients were randomized to receive 1 mg of Arimidex once daily or 20 mg of tamoxifen once daily. The primary endpoints for both studies were the time to disease progression, the objective response rate of the disease and the safety of treatment.
For the primary endpoints, Study 1033IL / 0030 showed a statistically significant advantage for Arimidex over tamoxifen with respect to time to disease progression (Hazard ratio (HR) 1.42, 95% Confidence Interval (CI) [1.11 , 1.82], median time to progression 11.1 and 5.6 months for Arimidex and tamoxifen respectively, p = 0.006); the objective disease response rate was similar for both Arimidex and tamoxifen. Study 1033IL / 0027 showed that Arimidex and tamoxifen had similar disease response rate and time to progression. The results from the secondary endpoints supported the outcomes of the primary efficacy goals. Few deaths occurred in the treatment groups of both studies, so no conclusions could be drawn about any differences in overall survival.
Second-line treatment in postmenopausal women with advanced breast cancer
Arimidex was tested in two controlled clinical trials (Study 0004 and Study 0005) in postmenopausal women with advanced breast cancer who had progressed after tamoxifen therapy for both advanced and early cancer. A total of 764 patients were randomized to receive a single daily dose of 1 mg or 10 mg of Arimidex or 40 mg of megestrol acetate four times a day. The primary efficacy variables were time to progression and objective disease response rate. Prolonged disease stability rate (more than 24 weeks), progression rate and survival were also calculated. In both studies, there were no significant differences between the treatment arms with respect to any of the efficacy parameters.
Adjuvant treatment in patients with invasive early stage hormone receptor positive breast cancer
In a large phase III study in 9,366 postmenopausal women with operable breast cancer treated for 5 years (see table below), Arimidex was statistically superior to tamoxifen in disease-free survival. The observed disease-free survival benefit was greater for Arimidex than for tamoxifen in the prospectively defined hormone receptor positive patient population.
a Disease-free survival includes all relapse-type events and is defined as the first event of locoregional relapse, new contralateral breast cancer, distant recurrence or death (from any cause).
b Distant disease-free survival is defined as the first event of distant recurrence or death (from any cause).
c Time to recurrence is defined as the first event of locoregional recurrence, new contralateral breast cancer, distant recurrence or breast cancer death.
d Time to distant recurrence is defined as the first event of distant recurrence or death from breast cancer.
e Number (%) of patients who died.
The combination of Arimidex and tamoxifen showed no efficacy benefit compared to tamoxifen alone in all patients, including those with hormone receptor positive. This treatment group discontinued the study.
With an updated median follow-up of 10 years, long-term comparison, the effects of treatment with Arimidex versus tamoxifen were shown to be consistent with previous analyzes.
Adjuvant treatment of early stages of breast cancer in hormone receptor positive patients receiving adjuvant tamoxifen treatment
In a phase III study (Austrian Breast and Colorectal Cancer Study Group [ABCSG] 8) conducted in 2,579 postmenopausal women with early hormone receptor positive breast cancer who had undergone surgery with or without radiotherapy and without chemotherapy (see table below), replacement of Arimidex, after 2 years of adjuvant treatment with tamoxifen, was statistically superior to continuation with tamoxifen, in terms of disease-free survival, after a median follow-up of 24 months.
These results are supported by two further similar studies (GABG / ARNO 95 and ITA), in one of which the patients underwent surgery and chemotherapy, and by the combined analysis of the ABCSG 8 and GABG / ARNO 95 studies.
The safety profile of Arimidex in these 3 studies was in line with the safety profile previously found in postmenopausal women with hormone receptor positive early stage breast cancer.
Bone Mineral Density (DMO)
In the phase III / IV study (Study of Anastrozole with the Bisphosphonate Risedronate [SABER]), 234 postmenopausal women with hormone receptor-positive early stage breast cancer candidates for treatment with Arimidex 1 mg / day, were stratified into low, moderate and high risk groups according to their existing risk of fragility fractures. The primary efficacy parameter was analysis of spine bone mass density by DEXA scanning. All patients received treatment with vitamin D and calcium. Patients in the low-risk group received only Arimidex (N = 42), those in the moderate group were randomized to Arimidex plus risedronate 35 mg once weekly (N = 77) or Arimidex plus placebo (N = 77), and those at high risk received Arimidex plus risedronate 35 mg once weekly (N = 38) The primary endpoint was the change in spine bone mass density from baseline to 12 months.
The main analysis at 12 months showed that patients already at moderate or high risk for fragility fractures did not show a reduction in bone mass density (as measured by bone mineral density at the spine by DEXA scanning), when treated. with Arimidex 1 mg / day in combination with risedronate 35 mg once weekly In addition, a statistically insignificant decrease in bone mineral density (BMD) was observed in the low-risk group treated with Arimidex 1 mg / day alone. Identical results were obtained in the secondary efficacy variable of the change from baseline in total BMD in the hip at 12 months.
This study highlights that the use of bisphosphonates could be considered in the treatment of possible bone mineral depletion in postmenopausal women with early stage breast cancer, in anticipation of treatment with Arimidex.
Pediatric population
Arimidex is not indicated for use in pediatric and adolescent subjects. Efficacy has not been established in the pediatric population studied (see below). The number of subjects treated was too small to draw reliable conclusions on safety. No data are available on the potential long-term effects of Arimidex treatment in pediatric and adolescent subjects (see also section 5.3).
The European Medicines Agency has granted the exemption from the obligation to file the results of studies with Arimidex in one or more subsets of pediatric populations with short stature due to growth hormone deficiency (GHD), testotoxicosis, gynecomastia and McCune-Albright syndrome (see section 4.2).
Short stature due to growth hormone deficiency
In a randomized, double-blind, multicenter study, 52 pubertal males (aged 11-16 years) with GHD were evaluated for 12 to 36 months with Arimidex 1 mg / day or placebo in combination. with growth hormone. Only 14 subjects treated with Arimidex completed 36 months.
No statistically significant differences were observed compared to placebo for growth related parameters such as estimated adult height, height, SDS height (standard deviation score) and growth rate. Final height data were not available. While the number of children treated was too small to draw reliable safety conclusions, there was an increase in the fracture rate and a trend towards a decrease in bone mineral density in the Arimidex group compared with to placebo.
Testotoxicosis
An open-label, non-comparative, multicenter study evaluated 14 male patients (aged 2 to 9 years) with familial male sexual precocity, also known as testotoxicosis, treated in combination with Arimidex and bicalutamide. The primary objective was to verify the efficacy and safety of this combination during the 12 months. Thirteen of the 14 enrolled patients completed 12 months of combined treatment (one patient lost to follow-up). There was no significant difference in the growth rate after 12 months of treatment compared to the growth rate during the 6 months prior to study entry.
Studies in gynecomastia
Study 0006 was a randomized, double-blind, multicenter study conducted in 82 boys of pubertal age (aged 11-18 years) with gynecomastia lasting more than 12 months, treated with Arimidex 1mg / day or placebo every day for up to 6 months. No significant difference was observed in the number of patients who had a 50% or greater reduction in total breast volume after 6 months of treatment between the Arimidex 1 mg group and the placebo group.
Trial 0001 was an open multiple-dose pharmacokinetic study of Arimidex 1 mg / day in 36 pubertal boys with gynecomastia of less than 12 months duration. Secondary objectives were to assess the proportion of patients who had a reduction from baseline, the calculated volume of gynaecomastia of both breasts combined by at least 50% between the first day and after 6 months of treatment, as well as tolerability and patient safety. A 50% or greater reduction in total breast volume was observed in 56% (20/36) of boys after 6 months.
Studies in McCune-Albright Syndrome
Trial 0046 was an international, multicenter, exploratory, open-label study of Arimidex in 28 girls (aged 2 to ≤ 10 years) with McCune-Albrigth syndrome (MAS). The primary objective was to evaluate the tolerability and efficacy of Arimidex 1 mg / day in patients with MAS. The efficacy of study treatment was based on the proportion of patients meeting defined criteria for vaginal bleeding, bone age and growth rate. No statistically significant change was observed in the frequency of vaginal bleeding days on treatment. There were no clinically significant changes in Tanner staging, mean ovarian volume, or mean uterine volume. No statistically significant difference was observed in the on-treatment rate of bone age increase from baseline. growth rate (in cm / year) decreased significantly (p
05.2 Pharmacokinetic properties
Absorption
Absorption of anastrozole is rapid and maximum plasma concentrations are generally achieved within two hours of administration (fasting). Food slightly decreases the rate but not the extent of absorption. This slight change in the rate of absorption is believed to be. does not have a clinically significant effect on steady-state plasma concentrations when dosed once daily with Arimidex tablets. Approximately 90-95% of steady-state plasma anastrozole concentrations are achieved after 7 days, and accumulation is been 3- to 4- times. There is no evidence of time or dose dependence of the pharmacokinetic parameters of anastrozole.
The pharmacokinetics of anastrozole are independent of age in postmenopausal women.
Distribution
Anastrozole is only 40% bound to plasma proteins.
Elimination
Anastrozole is eliminated slowly with a plasma elimination half-life of 40 to 50 hours.
Anastrozole is extensively metabolised in postmenopausal women with less than 10% of the dose excreted unchanged in the urine within 72 hours of ingestion. Metabolism of anastrozole occurs by N-dealkylation, hydroxylation and glucuronidation. The metabolites are excreted primarily via the metabolites. urine Triazole, the major metabolite in plasma, does not inhibit the aromatase enzyme.
Renal or hepatic insufficiency
The apparent clearance (CL / F) of anastrozole following oral administration was approximately 30% lower in volunteers with stable liver cirrhosis than in the control group (Study 1033IL / 0014). However, plasma concentrations of anastrozole in volunteers with liver cirrhosis remained within the concentration range observed in normal subjects in other studies. Plasma concentrations of anastrozole observed during long-term efficacy studies in patients with hepatic insufficiency remained within the range of plasma concentrations of anastrozole observed in patients without hepatic insufficiency.
The apparent clearance (CL / F) of anastrozole following oral administration was not altered in volunteers with severe renal impairment (GFR
Pediatric population
In boys with pubertal gynecomastia (10-17 years), anastrozole was rapidly absorbed, widely distributed and slowly eliminated with a half-life of approximately 2 days. Anastrozole clearance was slower in girls (3-10 years) than in girls. older male boys and the highest exposure. In girls, anastrozole was widely distributed and slowly eliminated.
05.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, reproductive and developmental toxicity for the predicted population.
Acute toxicity
In animal studies, toxicity was observed only at high doses. In acute toxicity studies in rodents, the median lethal dose of anastrozole was greater than 100 mg / kg / day orally and greater than 50 mg / kg / day intraperitoneally. In an acute toxicity study in dogs, the median lethal dose was greater than 45 mg / kg / day orally.
Chronic toxicity
In animal studies, adverse effects were observed only at high doses. Multiple dose toxicity studies were performed in both rats and dogs. No-effect doses were not established in these studies; however, the effects seen at low doses (1 mg / kg / day) and medium doses (dog 3 mg / kg / day; rat 5 mg / kg / day) were related to both the pharmacological and enzyme-inducing properties of anastrozole and they were not associated with significant toxicological or degenerative changes.
Mutagenesis
Genetic toxicity studies with anastrozole showed that the product is neither mutagenic nor clastogenic.
Reproductive toxicity
In a fertility study, oral doses of 50 or 400 mg / l of anastrozole were administered via drinking water to newly weaned male rats for 10 weeks. Mean plasma concentrations were respectively 44.4 (± 14 , 7) ng / ml and 165 (± 90) ng / ml. Reproduction indices were adversely affected in both dose groups, while a reduction in fertility was evident only at the 400 mg / l dose. was transient, as all reproductive and fertility parameters were similar to the control group values after a drug-free recovery period of 9 weeks.
Oral administration of anastrozole 1 mg / kg / day to female rats induced a high incidence of infertility and at a dose of 0.02 mg / kg / day an increase in pre-implantation loss. These effects occurred. at clinically relevant doses. An effect in humans cannot be excluded. These effects were related to the pharmacological effects of the product and completely regressed after a 5-week withdrawal period.
Oral administration of anastrozole to pregnant rats and rabbits did not cause teratogenic effects at doses up to 1 and 0.2 mg / kg / day, respectively. The observed effects (such as placental enlargement in rats and termination of pregnancy in rabbits) were related to the pharmacological effects of the product.
Survival of offspring to female rats treated with anastrozole at doses equal to or greater than 0.02 mg / kg / day (from day 17 of pregnancy to day 22 after parturition) was compromised. These effects were related to the pharmacological effects of the product on delivery. There was no adverse effect on the behavior or reproductive performance of the first generation offspring attributable to maternal treatment with anastrozole.
Carcinogenesis
A two-year carcinogenicity study in rats showed an increased incidence of hepatic neoplasms and uterine stromal polyps in females and thyroid adenomas in males, only at the high dose (25 mg / kg / day). These changes occurred. at a dose that corresponds to an exposure 100 times higher than that which occurs with therapeutic doses in humans and are not considered clinically relevant for the treatment of patients with anastrozole.
A two-year carcinogenicity study in mice showed induction of benign ovarian tumors and an "altered" incidence of lymphoreticular neoplasms (fewer histiocytic sarcomas in females and more deaths due to lymphoma). These changes are considered to be species-specific of aromatase inhibition in mice and are not considered clinically relevant for the treatment of patients with anastrozole.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Lactose monohydrate
Povidone
Sodium starch glycolate
Magnesium stearate
Hypromellose
Macrogol 300
Titanium dioxide
06.2 Incompatibility
Not relevant.
06.3 Period of validity
5 years.
06.4 Special precautions for storage
Do not store above 30 ° C.
06.5 Nature of the immediate packaging and contents of the package
PVC / Aluminum blister. Packs of 20, 28, 30, 84, 98, 100, 300 tablets contained in a box. Not all pack sizes may be marketed.
06.6 Instructions for use and handling
Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.
07.0 MARKETING AUTHORIZATION HOLDER
AstraZeneca UK Limited
600 Capability Green
Luton LU1 3LU
United Kingdom
Representative for Italy:
AstraZeneca S.p.A,
Volta Palace,
Via F. Sforza,
Basiglio (MI)
08.0 MARKETING AUTHORIZATION NUMBER
031809041 1 mg film-coated tablets 20 tablets
031809015 1 mg film-coated tablets 28 tablets
031809027 1 mg film-coated tablets 30 tablets
031809039 1 mg film-coated tablets 84 tablets
031809054 1 mg film-coated tablets 100 tablets
031809066 1 mg film-coated tablets 300 tablets
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
20 tablets of 1 mg:
Date A.I.C. 11.12.97 / Renewal date: 12 May 2015
28 tablets of 1 mg:
Date A.I.C. 23.05.96 / Renewal date: 12 May 2015
30 tablets of 1 mg:
Date A.I.C. 11.12.97 / Renewal date: 12 May 2015
84 tablets of 1 mg:
Date A.I.C. 11.12.97 / Renewal date: 12 May 2015
100 tablets of 1 mg:
Date A.I.C. 11.12.97 / Renewal date: 12 May 2015
300 tablets of 1 mg:
Date A.I.C. 11.12.97 / Renewal date: 12 May 2015
10.0 DATE OF REVISION OF THE TEXT
12 May 2015
