ARMOTRAZ Tablets (Anastrozole)

Table of Content

Composition

ARMOTRAZ Tablets

Each film-coated tablet contains:

Anastrozole IP ……………….... 1 mg

Dosage Form

Oral tablet

Pharmacology

Pharmacodynamics

Anastrozole is a potent and highly selective non-steroidal aromatase inhibitor. In postmenopausal women, oestradiol is produced primarily from the conversion of androstenedione to oestrone through the aromatase enzyme complex in peripheral tissues. Oestrone is subsequently converted to oestradiol. Reducing circulating oestradiol 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 oestradiol suppression of greater than 80%, using a highly sensitive assay.

Anastrozole does not possess any progestogenic, androgenic or oestrogenic activity, but does perturb the circulating levels of progesterone, androgens and oestrogens.

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

Inhibition of aromatase activity is primarily due to anastrozole, the parent drug. Absorption of anastrozole is rapid and maximum plasma concentrations typically occur within 2 hours of dosing under fasted conditions. Studies with radiolabelled drug have demonstrated that orally administered anastrozole is well absorbed into the systemic circulation. Food reduces the rate but not the overall extent of anastrozole absorption. The mean Cmax of anastrozole decreased by 16% and the median Tmax was delayed from 2 to 5 hours when anastrozole was administered 30 minutes after food. The pharmacokinetics of anastrozole is linear over the dose range of 1 to 20 mg, and does not change with repeated dosing. The pharmacokinetics of anastrozole was similar in patients and healthy volunteers.

Distribution

Steady-state plasma levels are approximately 3- to 4-fold higher than levels observed after a single dose of anastrozole. Plasma concentrations approach steady-state levels at about 7 days of once daily dosing. Anastrozole is 40% bound to plasma proteins in the therapeutic range.

Metabolism

Metabolism of anastrozole occurs by N-dealkylation, hydroxylation and glucuronidation. Three metabolites of anastrozole (triazole, a glucuronide conjugate of hydroxy-anastrozole, and a glucuronide conjugate of anastrozole itself) have been identified in human plasma and urine. The major circulating metabolite of anastrozole, triazole, lacks pharmacologic activity.

Anastrozole inhibited reactions catalysed by cytochrome (CY) P450 1A2, 2C8/9, and 3A4 in vitro with Ki values which were approximately 30 times higher than the mean steady-state Cmax values observed following a 1 mg daily dose. Anastrozole had no inhibitory effect on reactions catalysed by CYP450 2A6 or 2D6 in vitro. Administration of a single 30 mg/kg or multiple 10 mg/kg doses of anastrozole to healthy subjects had no effect on the clearance of antipyrine or urinary recovery of antipyrine metabolites.

Excretion

Eighty-five percent of radiolabelled anastrozole was recovered in faeces and urine. Hepatic metabolism accounts for approximately 85% of anastrozole elimination. Renal elimination accounts for approximately 10% of total clearance. The mean elimination half-life of anastrozole is 50 hours.

Effect of Gender and Age

Anastrozole pharmacokinetics has been investigated in postmenopausal female volunteers and patients with breast cancer. No age-related effects were seen over the range <50 to >80 years.

Paediatric Population

In boys with pubertal gynaecomastia (aged 10 to 17 years), anastrozole was rapidly absorbed, was widely distributed, and was eliminated slowly with a half-life of approximately 2 days. Clearance of anastrozole was lower in girls (aged 3 to 10 years) than in the older boys and exposure higher. Anastrozole in girls was widely distributed and slowly eliminated.

Effect of Race

Oestradiol and oestrone sulphate serum levels were similar between Japanese and Caucasian postmenopausal women who received 1 mg of anastrozole daily for 16 days. Anastrozole mean steady-state minimum plasma concentrations in Caucasian and Japanese postmenopausal women were 25.7 and 30.4 ng/mL, respectively.

Effect of Renal Impairment

Anastrozole pharmacokinetics has been investigated in subjects with renal impairment. Anastrozole renal clearance decreased proportionally with creatinine clearance and was approximately 50% lower in volunteers with severe renal impairment (creatinine clearance <30 mL/min/1.73m2) compared to controls. Total clearance was only reduced 10%. No dosage adjustment is needed for renal impairment.

Effect of Hepatic Impairment

Anastrozole pharmacokinetics has been investigated in subjects with hepatic cirrhosis related to alcohol abuse. The apparent oral clearance (CL/F) of anastrozole was approximately 30% lower in subjects with stable hepatic cirrhosis than in control subjects with normal liver function. However, these plasma concentrations were still with the range of values observed in normal subjects. The effect of severe hepatic impairment was not studied. No dose adjustment is necessary for stable hepatic cirrhosis.

Indications

Adjuvant Treatment

ARMOTRAZ Tablets are indicated for adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer.

First-Line Treatment

ARMOTRAZ Tablets are indicated for the first-line treatment of postmenopausal women with hormone receptor-positive or hormone receptor unknown locally advanced or metastatic breast cancer.

Second-Line Treatment

ARMOTRAZ Tablets are indicated for the treatment of advanced breast cancer in postmenopausal women with disease progression following tamoxifen therapy. Patients with ER (estrogen receptor)-negative disease and patients who did not respond to previous tamoxifen therapy rarely responded to anastrozole.

Dosage and Administration

Recommended Dose

The dose of ARMOTRAZ Tablets is one 1 mg tablet taken once a day. For patients with advanced breast cancer, ARMOTRAZ Tablets should be continued until tumour progression. ARMOTRAZ Tablets can be taken with or without food.

For adjuvant treatment of early breast cancer in postmenopausal women, the optimal duration of therapy is unknown. In the ATAC (the Anastrozole, Tamoxifen, Alone or in Combination study) trial, anastrozole was administered for 5 years.

Special Populations

Paediatric

Anastrozole is not recommended for use in children and adolescents due to insufficient data on safety and efficacy.

Geriatric

No dosage adjustment is necessary for elderly patients.

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.

Hepatic Impairment

No dose change is recommended in patients with mild-to-moderate hepatic disease. Caution is advised in patients with moderate to severe hepatic impairment.

Contraindications

Pregnancy and Premenopausal Women

ARMOTRAZ Tablets may cause foetal harm when administered to a pregnant woman and offers no clinical benefit to premenopausal women with breast cancer. ARMOTRAZ Tablets are contraindicated in women who are or may become pregnant. There are no adequate and well-controlled studies in pregnant women using anastrozole. If ARMOTRAZ Tablets is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a foetus or potential risk for loss of the pregnancy.

Lactation

Anastrozole is contraindicated in lactating women.

Hypersensitivity

ARMOTRAZ Tablets are contraindicated in any patient who has shown a hypersensitivity reaction to the drug or to any of the excipients. Observed reactions include anaphylaxis, angio-oedema, and urticaria.

Warnings and Precautions

General

Anastrozole should not be used in premenopausal women. The menopause should be defined biochemically (luteinizing-hormone , follicle-stimulating hormone , and/or oestradiol levels) in any patient where there is doubt about menopausal status. There are no data to support the use of anastrozole with LHRH (luteinizing hormone-releasing hormone) analogues.

Drug Interactions

Tamoxifen

Co-administration of tamoxifen or oestrogen-containing therapies with anastrozole should be avoided as this may diminish its pharmacological action.

Oestrogen

Oestrogen-containing therapies should not be used with anastrozole as they may diminish its pharmacological action.

Warfarin

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 that the co-administration of anastrozole with other medicinal products is unlikely to result in clinically significant medicinal product interactions mediated by CYP enzymes.

CYP450

Based on in vitro and in vivo results, it is unlikely that co-administration of anastrozole 1 mg will affect other drugs as a result inhibition of CYP450. Anastrozole inhibits CYPs 1A2, 2C8/9 and 3A4 in vitro. Cimetidine, a weak, unspecific inhibitor of CYP enzymes, did not affect the plasma concentrations of anastrozole. The effect of potent CYP inhibitors is unknown.

There were no clinically significant interactions with bisphosphonates.

Ischaemic Cardiovascular Events

In women with pre-existing ischaemic heart disease, an increased incidence of ischaemic cardiovascular events was observed with anastrozole in the ATAC trial (17% of patients on anastrozole and 10% of patients on tamoxifen). Consider risk and benefits of anastrozole therapy in patients with pre-existing ischaemic heart disease.

Bone Effects

As anastrozole lowers circulating oestrogen levels, it may cause a reduction in bone mineral density with a possible consequent increased risk of fracture.

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.

Cholesterol

During the ATAC trial, more patients receiving anastrozole were reported to have elevated serum cholesterol compared to patients receiving tamoxifen (9% versus 3.5%, respectively.

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.

Renal Impairment

Since only about 10% of anastrozole is excreted unchanged in the urine, the renal impairment does not influence the total body clearance. Dosage adjustment in patients with renal impairment is not necessary. 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 (Glomerular filtration rate <30 ml/min); in patients with severe renal impairment, administration of anastrozole should be performed with caution.

Hepatic Impairment

The plasma anastrozole concentrations in the subjects with hepatic cirrhosis were within the range of concentrations seen in normal subjects across all clinical trials. Therefore, dosage adjustment is also not necessary in patients with stable hepatic cirrhosis. 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 administration of anastrozole in patients with moderate and severe hepatic impairment should be performed with caution. Treatment should be based on a benefit-risk evaluation for the individual patient.

Pregnancy

Pregnancy Category X

Anastrozole may cause foetal harm when administered to a pregnant woman and offers no clinical benefit to premenopausal women with breast cancer. Anastrozole is contraindicated in women who are or may become pregnant. There are no studies of anastrozole use in pregnant women. If anastrozole is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the foetus and potential risk for pregnancy loss.

Lactation

There are no data on the use of anastrozole during lactation. Anastrozole is contraindicated during breastfeeding.

Fertility

The effects of anastrozole on fertility in humans have not been studied. Studies in animals have shown reproductive toxicity.

Paediatric Use

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. The efficacy of anastrozole in the treatment of pubertal gynaecomastia in adolescent boys and in the treatment of precocious puberty in girls with McCune-Albright syndrome has not been demonstrated. Long-term safety data in children and adolescents are not available.

Geriatric Use

In clinical studies, patients who are ≥65 years of age had moderately better tumour response and time to tumour progression than patients <65 years of age, regardless of randomized treatment. Response rates and time to progression were similar for patients over 65 years and younger.

The pharmacokinetics of anastrozole is not affected by age.

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.

Undesirable Effects

The following table presents adverse reactions from clinical trials, postmarketing 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 5 years (the 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.

Adverse reactions by system/organ class and frequency

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*,

Sensory disturbances (including paraesthesia, taste loss and taste perversion)

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

Cutaneous vasculitis (including some reports of Henoch-Schönlein purpura)**

Very rare

Stevens-Johnson syndrome Angio-oedema

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-Schönlein 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.

Adverse reactions occurring with an incidence of at least 5% during treatment or within 14 days of the end of treatment in the ATAC trial were as follows: Asthenia, pain, back pain, headache, abdominal pain, infection, accidental injury, flu syndrome, chest pain, neoplasm, cyst, vasodilatation, hypertension, nausea and vomiting, constipation, diarrhoea, dyspepsia, gastrointestinal disorder, lymphoedema, anaemia, peripheral oedema, weight gain, hypercholesterolaemia, arthritis, arthralgia, osteoporosis, fracture (spine, hip, wrist/colles’, etc), bone pain, arthrosis, joint disorder, joint pain/stiffness, myalgia, depression, insomnia, dizziness, anxiety, paraesthesia, hypertonia, pharyngitis, cough increased, dyspnoea, sinusitis, bronchitis, rash, sweating, cataract specified, leucorrhoea, urinary tract infection, breast pain, breast neoplasm, vulvovaginitis, vaginal haemorrhage, vaginitis, hot flushes, and vaginal bleeding.

Adverse reactions occurring with an incidence of less than 5% were ischaemic cardiovascular disease, angina pectoris, myocardial infarct, coronary artery disorder, myocardial ischaemia, any venous thromboembolic event, deep-venous thromboembolic events including pulmonary embolism, ischaemic cerebrovascular events, and endometrial cancer.

Apart from the above mentioned adverse effects, in clinical trials 0030 and 0027, pelvic pain, hypertonia, tumour flare, paraesthesia, sweating, increased appetite, neck pain, malaise, weight loss, insomnia, confusion, anxiety, rhinitis, and pruritus were observed.

Postmarketing Experience

Hepatobiliary events, including increases in alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase have been reported (>1% and <10%) and gamma-GT, bilirubin and hepatitis have been reported (>0.1% and <1%) in patients receiving anastrozole.

Anastrozole may also be associated with rash, including cases of mucocutaneous disorders such as erythema multiforme and Stevens-Johnson syndrome.

Cases of allergic reactions, including angio-oedema, urticaria and anaphylaxis have been reported in patients receiving anastrozole.

Trigger finger has been reported (>0.1% and <1%) in patients receiving anastrozole.

If you experience any side effects, talk to your doctor or pharmacist or write to drugsafety@cipla.com. You can also report side effects directly via the national pharmacovigilance program of India by calling on 1800 180 3024.  

By reporting side effects, you can help provide more information on the safety of this product.

Overdosage

Clinical trials have been conducted with 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 tolerated. A single dose of anastrozole that results in life-threatening symptoms has not been established.

There is no specific antidote to overdosage and treatment must be symptomatic. In the management of an overdose, consider 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.

Shelf-Life

3 years

Storage and handling instructions 

Store in cool dry place.

Any unused product or waste material should be disposed of in accordance with local requirements.

Packaging Information

ARMOTRAZ Tablets …………………………Blister pack of 10 Tablets

 Last Updated: Jul 2015

Last Reviewed: Dec 2017