Anastrozole Sandoz

Anastrozole Sandoz

anastrozole

Manufacturer:

Sandoz

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Anastrozole.
Description
Each film-coated tablet contains 1 mg anastrozole.
Excipients/Inactive Ingredients:Tablet core: Lactose monohydrate, cellulose microcrystalline, sodium starch glycollate type A, magnesium stearate, silica colloidal anhydrous, hydroxypropylcellulose.
Tablet coating: Opadry II white containing Lactose monohydrate, hypromellose, macrogol 4000, titanium dioxide E 171.
Action
Pharmacotherapeutic Group: Enzyme inhibitors. ATC Code: L02BG03.
Pharmacology: Pharmacodynamics: Mechanism of Action and Pharmacodynamic Effects: Anastrozole is a potent and highly selective non-steroidal aromatase inhibitor. In postmenopausal women, estradiol is produced primarily from the conversion of androstenedione to estrone through the aromatase enzyme complex in peripheral tissues. Estrone is subsequently converted to estradiol. Reducing circulating estradiol levels has been shown to produce a beneficial effect in women with breast cancer. In postmenopausal women, anastrozole at a daily dose of 1 mg produced estradiol suppression of greater than 80% using a highly sensitive assay.
Anastrozole does not possess any progestogenic, androgenic, or estrogenic activity.
Daily doses of anastrozole up to 10 mg do not have any effect on cortisol or aldosterone secretion, measured before or after standard adrenocorticotrophic hormone (ACTH) challenge testing. Corticoid supplements are therefore not needed.
Pharmacokinetics: Absorption: Absorption of anastrozole is rapid and maximum plasma concentrations typically occur within two hours of dosing (under fasted conditions). Food slightly decreases the rate but not the extent of absorption. The small change in the rate of absorption is not expected to result in a clinically significant effect on steady-state plasma concentrations during once daily dosing of anastrozole tablets. Plasma anastrozole steady-state concentrations are attained after 7 daily doses, and accumulation is 3- to 4-fold.
Distribution: Anastrozole is only 40% bound to plasma proteins.
Elimination: Anastrozole is eliminated slowly with a plasma elimination half-life of 50 hours. Anastrozole is extensively metabolized in the liver. Hepatic metabolism accounts for about 85% of the elimination of anastrozole, with renal excretion accounting for only 10% of total clearance. Metabolism of anastrozole occurs by N-dealkylation, hydroxylation and glucuronidation. The metabolites are excreted primarily via the urine. Triazole, the major metabolite in plasma, does not inhibit aromatase.
Renal or hepatic impairment: The apparent oral clearance of anastrozole was reduced by approximately 30% in individuals with stable hepatic cirrhosis related to alcohol abuse compared with controls with normal hepatic function. However, plasma anastrozole concentrations observed in individuals with hepatic cirrhosis were within the range of concentrations observed in normal individuals across all clinical trials.
Although the renal clearance of anastrozole decrease proportionally with creatinine clearance and is reduced by about 50% in individuals with severe renal impairment (cleatinine clearance less than 30 ml/minute per 1.73 m2) compared with controls, total body clearance of anastrozole is reduced by only 10% in patients with severe renal impairment.
Paediatric population: Following 1 mg once daily multiple administration in children, the mean Tmax was 1 hour. The mean (range) disposition parameters of anastrozole in children were described by a CL/F of 1.54 L/h (0.77 to 4.53 L/h) and apparent volume of distribution (V/F) of 98.4 L (50.7 to 330 L). The terminal elimination half-life was 46.8 hours, which was similar to that observed in postmenopausal women treated with anastrozole for breast cancer. Based on a population pharmacokinetic analysis, the pharmacokinetic of anastrozole were similar in boys with pubertal gynecomastia and girls with McCune Albright Syndrome.
Toxicology: Preclinical Safety Data: Reproductive toxicology: Anastrozole has been shown to cross the placenta in rats and rabbits receiving oral doses of 0.1 mg/kg (approximately 1 and 1.9 times the recommended human dose, respectively, on a mg/m2 basis). Increased pregnancy loss was demonstrated in rats and rabbits receiving anastrozole dosages equal to or exceeding 0.1 and 0.02 mg/kg daily, respectively (about one and one-third times the recommended human dosage, respectively, on a mg/m2 basis), during the period of organo genesis; in rats, this effects was dose-related.
Impairment of fertility and effects on the reproductive organ associated with anastrozole in female rats.
Indications/Uses
Anastrozole is indicated for: Adjuvant treatment of postmenopausal women with hormone receptor positive early invasive breast cancer.
Treatment of advanced breast cancer in post-menopausal women for which Anastrozole has efficacy at least as good as tamoxifen. Use in Oestrogen receptor negative patients is not recommended.
Adjuvant treatment of early breast cancer in hormone receptor positive post-menopausal woman who have received 2 to 3 years of adjuvant tamoxifen.
Dosage/Direction for Use
The recommended dose of anastrozole for adults including the elderly is one 1 mg tablet once a day.
For postmenopausal women with hormone receptor-positive early invasive breast cancer, the recommended duration of adjuvant endocrine treatment is 5 years.
Special populations: Paediatric population: Anastrozole is not recommended for use in children and adolescents due to insufficient data on safety and efficacy (see Interactions).
Renal impairment: No dose change is recommended in patients with mild or moderate renal impairment. In patients with severe renal impairment, administration of anastrozole should be performed with caution (see Interactions and Pharmacology: Pharmacokinetics under Actions).
Hepatic impairment: No dose change is recommended in patients with mild hepatic disease. Caution is advised in patients with moderate to severe hepatic impairment (see Interactions).
Method of administration: Anastrozole should be taken orally.
Overdosage
There is limited clinical experience of accidental overdose. In animal studies, anastrozole demonstrated low acute toxicity.
Clinical trials have been conducted with various dosages of anastrozole, up to 60 mg in a single dose given to healthy male volunteers and up to 10 mg daily given to postmenopausal women with advanced breast cancer; these dosages were well tolerated. A single dose of anastrozole that results in life-threatening symptoms has not been established. There is no specific antidote to overdose and treatment must be symptomatic.
In the management of an overdose, consideration should be given to the possibility that multiple agents may have been taken. Vomiting may be induced if the patient is alert. Dialysis may be helpful because anastrozole is not highly protein bound. General supportive care, including frequent monitoring of vital signs and close observation of the patient, is indicated.
Contraindications
Anastrozole is contraindicated in: Pregnant or breast-feeding women.
Patients with known hypersensitivity to anastrozole or to any of the excipients.
Special Precautions
General: Anastrozole should not be used in premenopausal women. The menopause should be defined biochemically (luteinizing-hormone [LH], follicle stimulating hormone [FSH], and/or estradiol levels) in any patient where there is doubt about menopausal status. There are no data to support the use of anastrozole with LHRH analogues.
Co-administration of tamoxifen or estrogen-containing therapies with anastrozole should be avoided as this may diminish its pharmacological action (see Use in Pregnancy & Lactation).
Effect on bone mineral density: As anastrozole lowers circulating estrogen levels it may cause a reduction in bone mineral density with a possible consequent increased risk of fracture (see Adverse Reactions).
Women with osteoporosis or at risk of osteoporosis, should have their bone mineral density formally assessed at the commencement of treatment and at regular intervals thereafter. Treatment or prophylaxis for osteoporosis should be initiated as appropriate and carefully monitored. The use of specific treatments, e.g., bisphosphonates, may stop further bone mineral loss caused by anastrozole in postmenopausal women and could be considered (see Adverse Reactions).
Hepatic impairment: Anastrozole has not been investigated in breast cancer patients with moderate or severe hepatic impairment. Exposure to anastrozole can be increased in subjects with hepatic impairment (see Pharmacology: Pharmacokinetics under Actions); administration of anastrozole in patients with moderate and severe hepatic impairment should be performed with caution (see Dosage & Administration). Treatment should be based on a benefit-risk evaluation for the individual patient.
Renal impairment: Anastrozole has not been investigated in breast cancer patients with severe renal impairment. Exposure to anastrozole is not increased in subjects with severe renal impairment (GRF < 30 ml/min, see Pharmacology: Pharmacokinetics under Actions); in patients with severe renal impairment, administration of anastrozole should be performed with caution (see Dosage & Administration).
Effects on ability to drive and use machines: Anastrozole has no or negligible influence on the ability to drive and use machines. However, asthenia and somnolence have been reported with the use of anastrozole and caution should be observed when driving or operating machinery while such symptoms persist.
Fertility:
The effects of anastrozole on fertility in humans have not been studied. Studies in animals have shown reproductive toxicity (see Pharmacology: Toxicology: Preclinical Safety Data under Actions).
Use in Children: Anastrozole is not recommended for use in children and adolescents as safety and efficacy have not been established in this group of patients.
Anastrozole should not be used in boys with growth hormone deficiency in addition to growth hormone treatment. In the pivotal clinical trial, efficacy was not demonstrated and safety was not established. Since anastrozole reduces estradiol levels, anastrozole must not be used in girls with growth hormone deficiency in addition to growth hormone treatment. Long-term safety data in children and adolescents are not available.
Use In Pregnancy & Lactation
Use in Pregnancy: There are no data from the use of anastrozole in pregnant women. Studies in animals have shown reproductive toxicity (see Pharmacology: Toxicology: Preclinical Safety Data under Actions). Anastrozole is contraindicated during pregnancy (see Precautions).
Use in Lactation: There are no data on the use of anastrozole during lactation. Anastrozole is contraindicated during breast-feeding (see Precautions).
Adverse Reactions
The following list presents adverse reactions from clinical trials, post-marketing studies or spontaneous reports. Unless specified, the 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 given adjuvant treatment for five years (the Anastrozole, Tamoxifen, Alone or in Combination [ATAC] study).
Adverse reactions listed below are classified according to frequency and System Organ Class (SOC). Frequency groupings are defined according to the following convention: 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), and very rare (<1/10,000).
The most frequently reported adverse reactions were headache, hot flushes, nausea, rash, arthralgia, joint stiffness, arthritis, and asthenia.
Metabolism and nutrition disorders: Common: Anorexia, hypercholesterolaemia.
Uncommon: Hypercalcaemia (with or without an increase in parathyroid hormone).
Nervous system disorders: Very common: Headache.
Common: Somnolence, Carpal Tunnel Syndrome*
Vascular disorders: Very common: Hot flushes.
Gastrointestinal disorders: Very common: Nausea.
Common: Diarrhoea, vomiting.
Hepatobiliary disorders: Common: Increases in alkaline phosphatase, alanine aminotransferase and aspartate aminotransferase.
Uncommon: Increases in gamma-GT and bilirubin, hepatitis.
Skin and subcutaneous tissue disorders: Very common: Rash.
Common: Hair thinning (Alopecia).
Allergic reactions: Uncommon: Urticaria.
Rare: Erythema multiforme, anaphylactoid reaction. Cutaneaous vasculitis (including some reports of Henoch-Schönlein purpura)**.
Very rare: Stevens-Johnson syndrome, angioedema.
Musculoskeletal and connective tissue disorders: Very common: Arthralgia/joint stiffness, arthritis, osteoporosis.
Common: Bone pain, myalgia.
Uncommon: Trigger finger.
Reproductive system and breast disorders: Common: Vaginal dryness, vaginal bleeding***.
General disorders and administration site conditions: Very common: Asthenia.
*Events of Carpal Tunnel Syndrome have been reported in patients receiving anastrozole treatment in clinical trials in greater numbers than those receiving treatment with tamoxifen. However, the majority of these events occurred in patients with identifiable risk factors for the development of the condition.
**Since cutaneous vasculitis and Henoch-Schonlein purpura was not observed in ATAC, the frequency category for these events can be considered as 'Rare' (≥ 0.01% and < 0.1%) based on the worst value of the point estimate.
***Vaginal bleeding has been reported commonly, mainly in patients with advanced breast cancer during the first few weeks after changing from existing hormonal therapy to treatment with anastrozole. If bleeding persists, further evaluation should be considered.
The table presents the frequency of pre-specified adverse events in the ATAC study after a median follow-up of 68 months, irrespective of causality, reported in patients receiving trial therapy and up to 14 days after cessation of trial therapy. (See Table.)

Click on icon to see table/diagram/image

Fracture rates of 22 per 1,000 patient-years and 15 per 1,000 patient-years were observed for the anastrozole and tamoxifen groups, respectively, after a median follow-up of 68 months. The observed fracture rate for anastrozole is similar to the range reported in age-matched postmenopausal populations. The incidence of osteoporosis was 10.5% in patients treated with anastrozole and 7.3% in patients treated with tamoxifen.
It has not been determined whether the rates of fracture and osteoporosis seen in ATAC in patients on anastrozole treatment reflect a protective effect of tamoxifen, a specific effect of anastrozole, or both.
Drug Interactions
Anastrozole inhibits CYPs 1A2, 2C8/9 and 3A4 in vitro. Clinical studies with antipyrine and warfarin showed that anastrozole at a 1 mg dose did not significantly inhibit the metabolism of antipyrine and R- and S-warfarin indicating the co-administration of anastrozole with other medicinal products is unlikely to result in clinically significant medicinal product interactions mediated by CYP enzymes.
The enzymes mediating metabolism of anastrozole have not been identified. Cimetidine, a weak, unspecific inhibitor of CYP enzymes, did not affect the plasma concentrations of anastrozole. The effect of potent CYP inhibitors is unknown.
A review of the clinical trial safety database did not reveal evidence of clinically significant interaction in patients treated with anastrozole who also received other commonly prescribed medicinal products.
There were no clinically significant interactions with bisphosphonates.
Co-administration of tamoxifen or estrogen-containing therapies with anastrozole is not recommended as this may diminish its pharmacological action (see previous text).
Caution For Usage
Incompatibilities: Not applicable.
Storage
Do not store above 30°C.
This medicinal product does not require any special storage conditions.
ATC Classification
L02BG03 - anastrozole ; Belongs to the class of enzyme inhibitors. Used in treatment of neoplastic diseases.
Presentation/Packing
FC tab 1 mg (white, round, biconvex without breaking notch and embossment "A1" on one side) x 2 x 14's.
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