Anastrozole

Warnings and Precautions, Embryo-Fetal Toxicity (5.4) 12/2018

Anastrozole is an aromatase inhibitor indicated for:

• Adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer (
  
  
  
  
  
  
  1.1 Adjuvant Treatment

  Anastrozole is indicated for adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer.
  )
  
  
  
  
• First-line treatment of postmenopausal women with hormone receptor-positive or hormone receptor unknown locally advanced or metastatic breast cancer (
  
  
  
  
  
  
  1.2 First-Line Treatment

  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.
  )
  
  
  
  
• Treatment of advanced breast cancer in postmenopausal women with disease progression following tamoxifen therapy. Patients with ER-negative disease and patients who did not respond to previous tamoxifen therapy rarely responded to Anastrozole  (
  
  
  
  
  
  
  1.3 Second-Line Treatment

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

One 1 mg tablet taken once daily (

Anastrozole Tablets, USP 1 mg are white, circular, biconvex tablets, debossed with ‘YL’ on one side, and ‘111’ on the other side.

• Lactation: Do not breastfeed. (
  
  
  
  8.2 Lactation

  Risk Summary

  
  
  There are no data on the presence of anastrozole or its metabolites in human milk, or its effects on the breast-fed child or on milk production. Because many drugs are excreted in human milk and because of the tumorigenicity shown for anastrozole in animal studies, or the potential for serious adverse reactions in the breast-fed child from Anastrozole, advise lactating women not to breastfeed during treatment with Anastrozole and for 2 weeks after the last dose.
  )
  
  
• Females and Males of Reproductive Potential: Verify pregnancy status prior to initiation of Anastrozole Tablets. (
  
  
  
  8.3 Females and Males of Reproductive Potential

  Pregnancy Testing

  
  
  Verify the pregnancy status of females of reproductive potential prior to initiation of Anastrozole.
  
  

  Contraception

  
  
  

  Females

  
  
  Based on animal studies, Anastrozole can cause fetal harm when administered to a pregnant woman [

  see Use in Specific Populations (8.1)

  ]. Advise females of reproductive potential to use effective contraception during treatment with Anastrozole Tablets and for at least 3 weeks after the last dose.
  
  

  Infertility

  
  
  

  Females

  
  
  Based on studies in female animals, Anastrozole may impair fertility in females of reproductive potential [

  see Nonclinical Toxicology (13.1)

  ].
  )
  
  
• Pediatric patients: Efficacy has not been demonstrated for pubertal boys of adolescent age with gynecomastia or girls with McCune-Albright Syndrome and progressive precocious puberty. (
  
  
  
  8.4 Pediatric Use

  Clinical studies in pediatric patients included a placebo-controlled trial in pubertal boys of adolescent age with gynecomastia and a single-arm trial in girls with McCune-Albright Syndrome and progressive precocious puberty. The efficacy of Anastrozole Tablets in the treatment of pubertal gynecomastia in adolescent boys and in the treatment of precocious puberty in girls with McCune-Albright Syndrome has not been demonstrated.

  Gynecomastia Study

  A randomized, double-blind, placebo-controlled, multi-center study enrolled 80 boys with pubertal gynecomastia aged 11 to 18 years. Patients were randomized to a daily regimen of either Anastrozole tablets 1 mg or placebo. After 6 months of treatment there was no statistically significant difference in the percentage of patients who experienced a≥50% reduction in gynecomastia (primary efficacy analysis). Secondary efficacy analyses (absolute change in breast volume, the percentage of patients who had any reduction in the calculated volume of gynecomastia, breast pain resolution) were consistent with the primary efficacy analysis. Serum estradiol concentrations at Month 6 of treatment were reduced by 15.4% in the Anastrozole group and 4.5% in the placebo group.

  Adverse reactions that were assessed as treatment-related by the investigators occurred in 16.3% of the Anastrozole-treated patients and 8.1% of the placebo-treated patients with the most frequent being acne (7% Anastrozole and 2.7% placebo) and headache (7%Anastrozole and 0% placebo); all other adverse reactions showed small differences between treatment groups. One patient treated with Anastrozole tablets discontinued the trial because of testicular enlargement. The mean baseline-subtracted change in testicular volume after 6 months of treatment was + 6.6 ± 7.9 cm³in the Anastrozole-treated patients and + 5.2 ± 8.0 cm³in the placebo group.

  McCune-Albright Syndrome Study

  A multi-center, single-arm, open-label study was conducted in 28 girls with McCune-Albright Syndrome and progressive precocious puberty aged 2 to <10 years. All patients received a 1 mg daily dose of Anastrozole tablets. The trial duration was 12 months. Patients were enrolled on the basis of a diagnosis of typical (27/28) or atypical (1/27) McCune-Albright Syndrome, precocious puberty, history of vaginal bleeding, and/or advanced bone age. Patients’ baseline characteristics included the following: a mean chronological age of 5.9 ± 2.0 years, a mean bone age of 8.6 ± 2.6 years, a mean growth rate of 7.9 ± 2.9 cm/year and a mean Tanner stage for breast of 2.7 ± 0.81. Compared to pre-treatment data there were no on-treatment statistically significant reductions in the frequency of vaginal bleeding days, or in the rate of increase of bone age (defined as a ratio between the change in bone age over the change of chronological age). There were no clinically significant changes in Tanner staging, mean ovarian volume, mean uterine volume and mean predicted adult height. A small but statistically significant reduction of growth rate from 7.9 ± 2.9 cm/year to 6.5 ± 2.8 cm/year was observed but the absence of a control group precludes attribution of this effect to treatment or to other confounding factors such as variations in endogenous estrogen levels commonly seen in McCune-Albright Syndrome patients.

  Five patients (18%) experienced adverse reactions that were considered possibly related to Anastrozole tablets. These were nausea, acne, pain in an extremity, increased alanine transaminase and aspartate transaminase, and allergic dermatitis.

  Pharmacokinetics in Pediatric Patients

  Following 1 mg once daily multiple administration in pediatric patients, the mean time to reach the maximum anastrozole concentration was 1 hr. The mean (range) disposition parameters of anastrozole in pediatric patients were described by a CL/F of 1.54 L/h (0.77-4.53 L/h) and V/F of 98.4 L (50.7-330.0 L). The terminal elimination half-life was 46.8 h, which was similar to that observed in postmenopausal women treated with anastrozole for breast cancer. Based on a population pharmacokinetic analysis, the pharmacokinetics of anastrozole was similar in boys with pubertal gynecomastia and girls with McCune-Albright Syndrome.