Anastroz

Anastroz

Anastroz

Anastroz

Admin / June 17, 2015 / Photography, Video

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Composition

Each film coated tablet contains Anastrozole 1mg IP.

Description

Anastroz tablets for oral administration contain 1 mg of Anastrozole, a non – steroidal aromatase inhibitor. It is chemically described as 1. 3 – Benzenediacetonitrile, a, a, a'. a' –tetramethyl-5- (1H- 1 ,2,4 –triazol – I –yImethyl). Its molecular formula is C I 7 H I 9 N 5 and its structural formula is:

Anastroz description

Mechanism of Action / Pharmcodynamics

Many breast cancers have estrogen  receptors and growth of these tumors can be stimulated by estrogen. In  postmenopausal women, the principal sources of circulating estrogen (primarily  estradiol) is conversion of adrenally  -  generated androstenedione to estrone by aromatase in peripheral tissues, “such  as adipose tissue” with further conversion of estrone to estradiol. Many breast  cancers also contain aromatase; the importance of tumor - generated estrogens  is uncertain.

Treatment of breast cancer has  included efforts to decrease estrogen levels, by ovariectomypremenopausally and  by use of anti - estrogens and progestational agents both pre- and post  –menopausally; and these interventions lead to decreased tumor mass or delayed  progression of tumor growth in some women.

Anastrozole is a potent and  selective non-steroidal aromatase inhibitor. It significantly lowers serum  estradiol concentrations and has no detectable effect on formation of adrenal  corticosteroids or aldosterone.

Pharmacokinetics

The orally administered  Anastrozole is well absorbed into the systemic circulation with 83% to 85% of  the radiolabel recovered in urine and feces. Food does not affect the extent of  absorption.

Elimination of  Anastrozole is primarily via hepatic  metabolism (approximately 85% ) and to a lesser extent, renal excretion  (approximately 11% ), Anastrozole has a mean terminal elimination half –life of  approximately 50 hours in postmenopausal women. The major circulating  metabolite of Anastrozole is triazole, lacks pharmacologic activity. The  pharmacokinetic parameters are similar in patients and in healthy  postmenopausal volunteers. The pharmacokinetis of Anastrozole  are linear over the dose range of 1 to 20 mg  and do not change with repeated dosing. Consistent with the approximately 2  –day terminal elimination half –life, plasma concentrations approach steady –  state levels at about 7 days of once daily dosing and steady- state levels are  approximately three- to four- fold higher than levels observed after a single  dose of Anastrozole is 40% bound to plasma proteins in the therapeutic range.

METABOLISM AND EXCRETION

Anastrozole is extensively  metabolized with about 10%  of the dose  excreted in the urine as unchanged drug within 72 hours of dosing, and the  remainder (about 60% of the dose) is excreted in urine as metabolites .  Metabolism of Anastrozole occurs by N –dealkylation, hydroxylation and  glucuronidation. Three metabolites of Anastrozole have been identified in human  plasma and urine. The known metabolites are triazole, a glucuronide conjugate  of hydroxy – Anastrozole, and a glucuronide of Anastrozole itself. Sereval  minor (less than 5% of the radioactive dose)  metabolites have not been identified.

Because renal elimination is not  a significant pathway of elimination, total body clearance of Anastrozole is  unchanged even in severe (creatinine clearance less than 30ml/min/1.73m2) renal  impairment, dosing adjustment in patients with renal dysfunction is not  necessary. Dosage adjustment is also unnecessary in patients with stable  hepatic cirrhosis.

SPECIAL POPULATIONS GERIATRIC

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

RACE

Estradiol and estrone sulfate  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 30.4ng/ml, respectively.

RENAL INSUFFICIENCY

Anastrozole pharmacokinetics have  been investigated in subjects with renal insufficiency. 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. Since only about 10% of  Anastrozole is excreted uncharged in the urine, the reduction in renal  clearance did not influence the total body clearance.

HEPATIC INSUFFICIENCY

Hepatic metabolism accounts for  approximately 85% of Anastrozole elimination. Anastrozole pharmacokinetics have  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, plasma Anastrozole concentrations in the subjects  with  hepatic cirrhosis were within the  range of concentrations seen in normal subjects across all clinical trials, so  that no “dosage” adjustment is needed.

PHARMACODYNAMICS

EFFECT ON ESTRADIOL

Mean serum concentrations of  estradiol was  evaluated in multiple  daily dosing trials with 0.5, 1, 3, 5, and 10mg of Anastrozole in  postmenopausal women with advanced breast cancer. Clinically significant  suppression of serum estradiol was seen with all doses. Doses of 1 mg and  higher resulted in suppression of mean serum concentrations of estradiol to the  lower limit of detection  (3.7pmol/L).  The recommended daily dose, Anastrozole 1 mg, reduced estradiol by approximately70%  within 24 hours by approximately 80% after 14 days of daily dosing. Suppression  of serum estradiol was maintained for up to 6 days after cessation of daily  dosing Anastrozole 1 mg.

The effect of Anastrozole on  estradiol levels in premenopausal women has not been studied. Because aromatization  of adrenal androgens is not a significant sources of estradiol in premenopausal  women (women with functioning ovaries as evidenced by menstruation and/ or  premenopausal LH, FSH and estradiol levels), Anastrozole would not be expected  to lower estradiol levels in premenopausal women.

EFFECTS ON CORTICOSTEROIDS

In multiple daily dosing trials  with 3, 5 and 10 mg, the selectivity of Anastrozole was assessed by examining  effects on corticosteroid synthesis. For all doses, Anastrozole did not affect  cortisol or aldosterone secretion at baseline or in response to ACTH. No  glucocorticoid or mineral ocorticoid replacement therapy is necessary with  Anastrozole.

OTHER ENDOCRINE EFFECTS

In multiple daily dosing trials  with 5 and 10 mg, thyroid-stimulating hormone (TSH) is measured; there was no  increase in TSH during the administration of Anastrozole. Anastrozole does not  possess direct progestogenic, androgenic, or estrogenic activity in animals,  but does perturb the circulating levels of progesterone, androgens, and  estrogens.

Indications

Anastrozole is indicated for adjuvant treatment of postmenopausal women with hormone receptor positive early breast cancer.

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

Anastrozole is indicated for the treatment of advanced breast cancer in postmenopausal women with dieases progression following tamoxifen therapy. Patients with ER-negative disease and paitents who did not respond to previous tamoxifen therapy rarely responded to Anastrozole.

Dosage & Administration

The dose of Anastrozole is one 1 mg tablet taken once a day. For patients with advanced breast cancer. Anastrozole should be continued until tumor progression.

For adjuvant treatment of early breast cancer in postmenopausal women, the optimal duration of therapy is unknown. In the ATAC trial Anastrozole was administered for five years.

PATIENTS WITH HEPATIC IMPAIRMENT

Hepatic metabolism accounts for approximately 85% of Anastrozole elimination.  Although clearance of Anastrozole was decreased in patient with cirrhosis due to alcohol abuse, plasma Anastrozole concentrations stayed in the usual range seen in patients without liver disease. Therefore, no changes in dose are recommrnded for patients with mild - to - moderate hepatic impairment, although patients should be monitored for side effects. Anastrozole has not been studied in patients with severe hepatic impairment.

PATIENTS WITH RENAL IMPAIRMENT

No changes in dose are necessary for patients with renal impairment.

USE IN THE ELDERLY

No dosage adjustment is necessary.

Warnings

Evidence of fetotoxicity, including delayed fetal development (i.e., incomplete ossification and depressed fetal body weights), was observed in rats administered doses of 1 mg/kg/day (which produced plasma Anastrozole Cssmax and AUCO- 24 hr that were 19 times and 9 times higher than the respective values found in the postmenopausal volunteers at recommended dose). There was no evidence of teratogenicity in rats administered dose up to 1.0 mg/kg/day. In rabbits, Anastrozole caused pregnancy failure at dose equal to or greater than 1.0 mg/kg/day (about 16 times the recommended human dose on a mg/m basis); there was no evidence of teratogenicity in rabbits administered 0.2 mg/kg/day (about 3 times the recommended human dose on a mg/m2 basis).                                           

There are no adequate and well - controlled studies in pregnant women using Anastrozole.If Anastrozole is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be appraised of the potential hazard to the fetus or potential risk for loss of the pregnancy.

Precautions

General
Anastrozole is not recommended  for use in premenopausal women as safety and efficacy has not been established  Before starting treatment with Anastrozole, pregnancy must be excluded.  Anastrozole should be administered under the supervision of a qualified  physician experienced in the use of anticancer agents.

PREGNANCY -   PREGNANCY CATEGORY D -  NURSING MOTHERS

It is not known if Anastrozole is  excreted in human milk. Because many drugs are excreted in human milk, caution  should be exercised when Anastrozole is administered to a nursing woman.

PEDIATRIC USE

The safety and efficacy of  Anastrozole in pediatric patients have not been established.

Adverse Reactions (Side Effects)

The most commonly reported events with Anastrozole are Hot flushes, Asthenia, Pain, Back pain, headache, Abdominal pain, Infection, accidental injury, Flu syndrome, Chest pain, Vasodilation, Hypertension, Nausea, Constipation, Diarrhea, Dyspepsia, Gastrointestinal disorder, Lymphoedma, Peripheral edema, Weight gain, Hypercholesteremia, Arthritis, Arthalgia, Osteoporosis, Fracture, Bone pain, Arthrosis, Depression,  Insomnia, dizziness, Anxiety, Paraesthesia. Pharyngitis, increased Cough, Dyspnea, Rash , Sweating, Leukorrhea, Urinary Tract Injection, Breast pain, Vulvovaginitis, Vaginal Discharge, Hair Thinning, Vaginal bleeding, Anorexia, Vomiting, Somnolence, Erythema Multiforme, Steven Johnson syndrome, Angioedema, Utricaria, Anaphylaxis, Mood disturbances, Cataracts, Venous thromboembolic events, Ischemic cerebrovascular  events, and Endometrial cancer.

Drug Interactions

Anastrozole inhibitied in vitro  metabolic reactions catalyzed by cytochromes P450 1A2, 2C8/9,and 3A4 but  only  at relatively high concentrations.  Anastrozole did not inhibit P450 2A6 or the polymorphic P450 2D6 in human liver  microsomes.  Anastrozole did not alter  the pharmacokinetics of antipyrine. Although there have been no formal  interaction studies other than with antipyrine, based on these in vivo and in  vitro studies, it is unlikely that co - administration of a 1 mg dose of  Anastrozole with other drugs will result in clinically significant drug  inhibition of cytochrome P450 – medicated metabolism of the other drugs. An  interaction study with warfarin showed no clinically significant effect of  Anastrozole on warfarin pharmacokinetics or anticoagulant activity. At a median  follow-up of 33 months, the combination of Anastrozole and tamoxifen did not  demonstrate any efficacy benefit when compared with tamoxifen in all patients  as well as in the hormone receptor-positive subpopulation. This treatment arm  was discontinued from the trial. Based on clinical and pharmacokinetic results  from the ATAC trail, tamoxifen should not be administered with Anastrozole.  Co-adminintration of Anastrozole and tamoxifen resulted in reduction of  Anastrozole plasma levels by 27% compared  with those achieved with Anastrozole alone.

  Estrogen-containing therapies  should not be used with Anastrozole as they may diminish its pharmacologic  action.

Overdose & Contradiction

Clinical trials 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 well tolerated. A single dose of Anastrozole that result in life – threatening symptoms has not been established. In rats, lethality was observed after single oral doses that were greater than 100 mg/kg (about 800 times the recommended human dose on a mg/m2 basis) and was associated with severe  irritation to the stomach (necrosis, gastritis, ulceration, and hemorrhage).  In an oral acute toxicity study in the dog the median lethal dose was greater than 45 mg/kg/day. There is no specific antidote to over dosage 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.

CONTRAINDICATIONS

Anastrozole is contraindicated in any patient who has shown a hypersensitivity reaction to the drug or to any of the excipients.

Storage

Store at controlled room temperature, 20-250 C (68-770 F) 

Presentation

Blister  of 10 Tablets

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