Anastrozole

Other less frequent (2% to 5%) adverse reactions reported in patients receiving anastrozole tablets l mg in either Trial 0004 or Trial 0005 are listed below. These adverse experiences are listed by body system and are in order of decreasing frequency within each body system regardless of assessed causality.

Cardiovascular: Hypertension; thrombophlebitis 

Hematologic: Anemia; leukopenia

Metabolic and Nutritional: Alkaline phosphatase increased; weight loss 

Mean serum total cholesterol levels increased by 0.5 mmol/L among patients receiving anastrozole tablets. Increases in LDL cholesterol have been shown to contribute to these changes.

Musculoskeletal: Myalgia; arthralgia; pathological fracture

Nervous: Somnolence; confusion; insomnia; anxiety; nervousness

Respiratory: Sinusitis; bronchitis; rhinitis

Skin and Appendages:  Hair thinning (alopecia); pruritus 

Urogenital: Urinary tract infection; breast pain

6.2 Post-Marketing 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 tablets.

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

Cases of allergic reactions including angioedema, urticaria and anaphylaxis have been reported in patients receiving anastrozole tablets. [see Contraindications (4.2)]

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

7 DRUG INTERACTIONS

7.1 Tamoxifen

Co-administration of anastrozole and tamoxifen in breast cancer patients reduced anastrozole plasma concentration by 27%.  However, the coadministration of anastrozole and tamoxifen did not affect the pharmacokinetics of tamoxifen or N-desmethyltamoxifen. At a median follow-up of 33 months, the combination of anastrozole tablets 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.  [see Clinical Studies (14.1)]. Based on clinical and pharmacokinetic results from the ATAC trial, tamoxifen should not be administered with anastrozole.

7.2 Estrogen

7.3 Warfarin

In a study conducted in 16 male volunteers, anastrozole did not alter the exposure (as measured by C_max and AUC) and anticoagulant activity (as measured by prothrombin time, activated partial thromboplastin  time, and thrombin time) of both R- and S-warfarin.

7.4 Cytochrome P450

Based on in vitro and in vivo results, it is unlikely that co-administration of anastrozole tablets 1 mg will affect other drugs as a result inhibition of cytochrome P450 [see Clinical Pharmacology (12.3)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

PREGNANCY CATEGORY X [see Contraindications (4.1)]

In animal reproduction studies, pregnant rats and rabbits received anastrozole during organogenesis at doses equal to or greater than 1 (rats) and 1/3 (rabbits) the recommended human dose on a mg/m² basis. In both species, anastrozole crossed the placenta, and therewas increased pregnancy loss (increased pre- and/or post-implantation loss, increased resorption, and decreased numbers of live fetuses).  In rats, these effects were dose related, and placental weights were significantly increased. Fetotoxicity, including delayed fetal development (i.e., incomplete ossification and depressed fetal body weights), occurred in rats at anastrozole doses that produced peak plasma levels 19 times higher than serum levels in humans at the therapeutic dose (AUC_0-24hr 9 times higher). In rabbits, anastrozole caused pregnancy failure at doses equal to or greater than 16 times the recommended human dose on a mg/m² basis. [see Animal Toxicology and/or Pharmacology (13.2)]

8.3 Nursing Mothers

  It is not known if anastrozole is excreted in human milk. 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 nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

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.

Labeling describing clinical trails and pharmacokinetic studies of anastrozole in pubertal boys of adolescent age with gynecomastia and in girls with McCune- Albright Syndrome and progressive precocious puberty is approved for AstraZeneca Pharmaceuticals LP’s Arimidex ^® _.  However, due to AstraZeneca Pharmaceuticals LP’s marketing exclusivity rights, a description of those trials and studies is not approved for this anastrozole labeling.

8.5 Geriatric Use

In studies 0030 and 0027 about 50% of patients were 65 or older. Patients ≥ 65 years of age had moderately better tumor response and time to tumor progression than patients < 65 years of age regardless of randomized treatment. In studies 0004 and 0005 50% of patients were 65 or older. Response rates and time to progression were similar for the over 65 and younger patients. 

8.6 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 [see Dosage and Administration (2.1) and  Clinical Pharmacology (12.3)].

8.7 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 tablets have not been studied in patients with severe hepatic impairment [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].

10 OVERDOSAGE

11 DESCRIPTION

Anastrozole is an off-white powder with a molecular weight of 293.4. Anastrozole has moderate aqueous solubility (0.5 mg/mL at 25ºC); solubility is independent of pH in the physiologica l range. Anastrozole is freely soluble in methanol, acetone, ethanol, and tetrahydrofuran, and very soluble in acetonitrile.

Each tablet contains as inactive ingredients: lactose monohydrate, magnesium stearate, hypromellose, polyethylene glycol, povidone, sodium starch glycolate and titanium dioxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The growth of many cancers of the breast is stimulated or maintained by estrogens. Treatment of breast cancer thought to be hormonally responsive (i.e., estrogen and/or progesterone receptor positive or receptor unknown) has included a variety of efforts to decrease estrogen levels (ovariectomy, adrenalectomy, hypophysectomy) or inhibit estrogen effects (antiestrogens and progestational agents). These interventions lead to decreased tumor mass or delayed progression of tumor growth in some women.

In postmenopausal women, estrogens are mainly derived from the action of the aromatase enzyme, which converts adrenal androgens (primarily androstenedione and testosterone) to estrone and estradiol. The suppression of estrogen biosynthesis in peripheral tissues and in the cancer tissue itself can therefore be achieved by specifically inhibiting the aromatase enzyme.

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.

12.2 Pharmacodynamics

Effect on Estradiol

Mean serum concentrations of estradiol were evaluated in multiple daily dosing trials with 0.5, 1, 3, 5, and 10 mg of anastrozole tablets 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 (3.7 pmol/L). The recommended daily dose, anastrozole tablets 1 mg, reduced estradiol by approximately 70% within 24 hours and 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 with anastrozole tablets 1 mg.

The effect of anastrozole tablets in premenopausal women with early or advanced breast cancer has not been studied. Because aromatization of adrenal androgens is not a significant source of estradiol in premenopausal women, anastrozole tablets would not be expected to lower estradiol levels in premenopausal women.

Effect 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 mineralocorticoid replacement therapy is necessary with anastrozole.

Other Endocrine Effects

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

12.3 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 radiolabeled 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 C_max of anastrozole decreased by 16% and the median T_max  was delayed from 2 to 5 hours when anastrozole was administered 30 minutes after food. The pharmacokinetics of anastrozole are linear over the dose range of 1 to 20 mg, and do not change with repeated dosing.  The pharmacokinetics of anastrozole were 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 tablets.  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 catalyzed by cytochrome P450 1A2, 2C8/9, and 3A4 in vitro with Ki values which were approximately 30 times higher than the mean steady-state C_max  values observed following a 1 mg daily dose. Anastrozole had no inhibitory effect on reactions catalyzed by cytochrome P450 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 radiolabeled anastrozole was recovered in feces 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 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.  

Effect of Race

Estradiol and estrone sulfate 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 have 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. [see Dosage and Administration (2.1) and Use in Specific Populations (8.6)]

Effect of Hepatic Impairment 

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, 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. [see Dosage and Administration (2.2) and Use in Specific Populations (8.7)]

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

A conventional carcinogenesis study in rats at doses of 1.0 to 25 mg/kg/day (about 10 to 243 times the daily maximum recommended human dose on a mg/m² basis) administered by oral gavage for up to 2 years revealed an increase in the incidence of hepatocellular adenoma and carcinoma and uterine stromal polyps in females and thyroid adenoma in males at the high dose. A dose related increase was observed in the incidence of ovarian and uterine hyperplasia in females. At 25 mg/kg/day, plasma AUC_{0-24 hr} levels in rats were 110 to 125 times higher than the level exhibited in postmenopausal volunteers at the recommended dose. A separate carcinogenicity study in mice at oral doses of 5 to 50 mg/kg/day (about 24 to 243 times the daily maximum recommended human dose on a mg/m² basis) for up to 2 years produced an increase in the incidence of benign ovarian stromal, epithelial and granulosa cell tumors at all dose levels. A dose related increase in the incidence of ovarian hyperplasia was also observed in female mice. These ovarian changes are considered to be rodent-specific effects of aromatase inhibition and are of questionable significance to humans. The incidence of lymphosarcoma was increased in males and females at the high dose. At 50mg/kg/day, plasma AUC levels in mice were 35 to 40 times higher than the level exhibited in postmenopausal volunteers at the recommended dose.

Anastrozole tablets have not been shown to be mutagenic in in vitro tests (Ames and E. coli bacterial tests, CHO-K1 gene mutation assay) or clastogenic either in vitro (chromosome aberrations in human lymphocytes) or in vivo (micronucleus test in rats).

13.2 Animal Toxicology and/or Pharmacology

Reproductive Toxicology

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 C_ssmax and AUC_{0-24 hr} that were 19 times and 9 times higher than the respective values found in postmenopausal volunteers at the recommended dose). There was no evidence of teratogenicity in rats administered doses up to 1.0 mg/kg/day. In rabbits, anastrozole caused pregnancy failure at doses equal to or greater than 1.0 mg/kg/day (about 16 times the recommended human dose on a mg/m² 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).

14 CLINICAL STUDIES

14.1 Adjuvant Treatment of Breast Cancer in Postmenopausal Women

A multicenter, double-blind trial (ATAC) randomized 9,366 postmenopausal women with operable breast cancer to adjuvant treatment with anastrozole tablets 1 mg daily, tamoxifen 20 mg daily, or a combination of the two treatments for five years or until recurrence of the disease.

Figure 2 — Disease-free Survival for Hormone Receptor-Positive Subpopulation of Patients Randomized to Anastrozole Tablets or Tamoxifen

The survival data with 68 months follow-up is presented in Table 9.

In the group of patients who had previous adjuvant chemotherapy (N=698 for anastrozole tablets and N=647 for tamoxifen), the hazard ratio for disease-free survival was 0.91(95% CI: 0.73 to 1.13) in the anastrozole tablets arm compared to the tamoxifen arm.

Table 8- All Recurrence and Death Events^*   

Table 9 - ATAC Efficacy Summary*  

14.2 First-Line Therapy in Postmenopausal Women with Advanced Breast Cancer

Two double-blind, controlled clinical studies of similar design (0030, a North American study and 0027, a predominately European study) were conducted to assess the efficacy of anastrozole tablets compared with tamoxifen as first-line therapy for hormone receptor positive or hormone receptor unknown locally advanced or metastatic breast cancer in postmenopausal women. A total of 1021 patients between the ages of 30 and 92 years old were randomized to receive trial treatment. Patients were randomized to receive 1 mg of anastrozole tablets once daily or 20 mg of tamoxifen once daily. The primary end points for both trials were time to tumor progression, objective tumor response rate, and safety.

Figure 4 - Kaplan-Meier probability of time to progression for all randomized patients (intent-to-treat) in Trial 0027

Results from the secondary endpoints were supportive of the results of the primary efficacy endpoints. There were too few deaths occurring across treatment groups of both trials to draw conclusions on overall survival differences.

14.3 Second-Line Therapy in Postmenopausal Women with Advanced Breast Cancer who had Disease Progression following Tamoxifen Therapy

16 HOW SUPPLIED/STORAGE AND HANDLING

These tablets are supplied in bottles of 30 tablets (NDC 16571-421-03)

Storage

Store at controlled room temperature, 20-25ºC (68-77ºF) [see USP].

17 PATIENT COUNSELING INFORMATION

17.1 Pregnancy

17.2 Allergic (Hypersensitivity) Reactions

Patients should be informed of the possibility of serious allergic reactions with swelling of the face, lips, tongue and/or throat (angioedema) which may cause difficulty in swallowing and/or breathing and to immediately report this to their doctor.

17.3 Ischemic Cardiovascular Events

Patients with pre-existing ischemic heart disease should be informed that an increased incidence of cardiovascular events has been observed with anastrozole tablets use compared to tamoxifen use.

17.4 Bone Effects

17.5 Cholesterol

Patients should be informed that an increased level of cholesterol might be seen while receiving anastrozole tablets.

17.6 Tamoxifen

17.7 FDA-Approved Patient Labeling

PATIENT INFORMATION

ANASTROZOLE TABLETS

Read the information that comes with anastrozole tablets before you start taking it and each time you get a refill.  The information may have changed.  This leaflet does not take the place of talking with your doctor about your medical condition or treatment.  Talk with your doctor about anastrozole tablets when you start taking it and at regular checkups.

What are anastrozole tablets? 

• treatment of early breast cancer
  • after surgery, with or without radiation 
  • in women whose breast cancer is hormone receptor-positive
•   first treatment of locally advanced or metastatic breast cancer, in women whose breast cancer is hormone receptor-positive or the hormone receptors are not known.
• treatment of advanced breast cancer, if the cancer has grown, or the disease has spread after tamoxifen therapy.

Anastrozole tablets do not work in women with breast cancer who have not finished menopause (premenopausal women).

Who should not take anastrozole tablets?

Do not take anastrozole tablets if you:

• are pregnant, think you may be pregnant, or plan to get pregnant.  Anastrozole tablets may harm your unborn child. If you become pregnant while taking anastrozole tablets, tell your doctor right away.
• have not finished menopause (are premenopausal)
• are allergic to any of the ingredients in anastrozole tablets. See the end of this leaflet for a list of the ingredients in anastrozole tablets.
• are a man or child

What is the most important information I should know about anastrozole tablets? 

Anastrozole tablets may cause serious side effects including:  

• Heart disease.  Women with early breast cancer, who have a history of blockages in heart arteries (ischemic heart disease) and who take anastrozole tablets may have a slight increase in this type of heart disease compared to similar patients who take tamoxifen.
  • Stop taking anastrozole tablets and call your doctor right away if you have chest pain or shortness of breath. These can be symptoms of heart disease. 
•   Osteoporosis (bone softening and weakening).  Anastrozole tablets lowers estrogen in your body, which may cause your bones to become softer and weaker.  This can increase your chance of fractures, specifically of the spine, hip and wrist. Your doctor may order a test for you called a bone mineral density study before you start taking anastrozole tablets and during treatment with anastrozole tablets as needed.

What should I tell my doctor before taking anastrozole tablets?

Anastrozole tablets may not be right for you.  Before taking anastrozole tablets, tell your doctor about all your medical conditions, including if you:

• have not finished menopause.  Talk to your doctor if you are not sure.  See “Who should not take anastrozole tablets?”
• have had a previous heart problem
• have a condition called osteoporosis
• have high cholesterol
• are pregnant, planning to become pregnant, or breast feeding.  See “Who should not take anastrozole tablets?”
• are nursing a baby. It is not known if anastrozole tablets pass into breast milk.  You and your doctor should decide if you will take anastrozole tablets or breast feed. You should not do both.

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your doctor if you take:  

• Tamoxifen.  You should not take anastrozole tablets with tamoxifen. Taking tamoxifen with anastrozole tablets may lower the amount of anastrozole tablets in your blood and may cause anastrozole tablets not to work as well. 

• Medicines containing estrogen. Anastrozole tablets may not work if taken with one of these medicines:    
  • hormone replacement therapy
  • birth control pills 
  • estrogen creams
  • vaginal rings
  • vaginal suppositories

Know the medicines you take. Keep a list of them and show it to your doctor and pharmacist each time you get a new medicine.

How should I take anastrozole tablets? 

• Take anastrozole tablets exactly as prescribed by your doctor. 

      Keep taking anastrozole tablets for as long as your doctor

      prescribes it for you.

• Take one anastrozole tablet each day.
• Anastrozole tablets can be taken with or without food.
• If you miss a dose, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose. Take your next regularly scheduled dose. Do not take two doses at the same time.  
• If you have taken more anastrozole tablets than your doctor has prescribed, contact your doctor right away. Do not take any additional anastrozole tablets until instructed to do so by your doctor.  

Talk with your doctor about any health changes you have while taking anastrozole tablets.  

What are possible side effects of anastrozole tablets?  

Anastrozole tablets can cause serious side effects including:

• See “What is the most important information I should know about anastrozole tablets?”
• increased blood cholesterol (fat in the blood).  Your doctor may check your cholesterol while you take anastrozole tablets therapy.
• skin reactions. Stop taking anastrozole tablets and call your doctor right away if you get any skin lesions, ulcers, or blisters.
• severe allergic reactions.  Get medical help right away if you have:
• swelling of the face, lips, tongue, or throat.
• trouble swallowing 
• trouble breathing 
• liver problems.  Anastrozole tablets can cause inflammation of the liver and changes in blood tests of the liver function.  Your doctor may monitor you for this. Stop taking anastrozole tablets and call your doctor right away if you have any of these signs or symptoms of a liver problem:
• a general feeling of not being well
• yellowing of the skin or whites of the eyes
• pain on the right side of your abdomen 

 Common side effects in women taking anastrozole tablets include:

• hot flashes 
• weakness
• joint pain 
• carpal tunnel syndrome (tingling, pain, coldness, weakness in parts of the hand)
• pain
• sore throat
• mood changes
• high blood pressure
• depression
• nausea and vomiting
• thinning of the hair (hair loss)
• rash
• back pain
• sleep problems
• bone pain
• headache
• swelling 
• increased cough
• shortness of breath
• lymphedema (build up of lymph fluid in the tissues of your affected arm)
• trigger finger (a condition in which one of your fingers or your thumb catches in a bent position)

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. 

HOW SHOULD I STORE ANASTROZOLE TABLETS?

• Store anastrozole tablets at 68ºF to 77ºF (20ºC to 25ºC).
• Keep anastrozole tablets and all medicines out of the reach of children.

 General information about anastrozole tablets.

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not take anastrozole tablets for a condition for which it was not prescribed. Do not give anastrozole tablets to other people, even if they have the same symptoms you have. It may harm them.

This patient information leaflet summarizes the most important information about anastrozole tablets. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about anastrozole tablets that is written for health professionals. For more information call 1-800-521-5340. 

What are the ingredients in anastrozole tablets?

Active ingredient: anastrozole  

Inactive ingredients: lactose monohydrate, magnesium stearate, hypromellose, polyethylene glycol, povidone, sodium starch glycolate and titanium dioxide.

Distributed by:

Pack Pharmaceuticals, LLC

Anastrozole Tablets 1 mg- Bottle of 30 tablets