Anastrozole (anastrozole)

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Anastrozole is administered orally.

Food does not affect the absorption of anastrozole, and the drug may be administered without regard to meals.

Commercially available anastrozole tablets should be stored at a controlled room temperature of 20-25degreesC.

Anastrozole has been shown to inhibit in vitro metabolic reactions catalyzed by cytochrome P-450 (CYP) isoenzymes 1A2, 2C8/9, and 3A4, but only at relatively high concentrations. It is considered unlikely that anastrozole, when administered at the recommended dosage, will result in clinically important interactions with drugs metabolized by CYP enzymes.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Anastrozole; Letrozole/Tamoxifen

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Tamoxifen may induce the metabolism of anastrozole(1) and letrozole(2) by induction of CYP3A4.

CLINICAL EFFECTS: Concurrent use of tamoxifen may result in decreased plasma levels and effectiveness of anastrozole(1,3) and letrozole.(2,3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturers of anastrozole(1) and tamoxifen(3) state that these agents should not be coadministered. The manufacturer of letrozole does not recommend concurrent therapy with tamoxifen(4) and the manufacturer of tamoxifen states they should not be used concurrently.(3) Patients may benefit more from sequential therapy, rather than concurrent therapy.(2,5)

DISCUSSION: Based on clinical and pharmacokinetic data from the ATAC trial, tamoxifen should not be administered with anastrozole. Concurrent use decreased anastrozole plasma levels by 27%. The combination had no efficacy benefit when compared to tamoxifen administration alone. Tamoxifen pharmacokinetics were not affected.(1,3) A study in 12 subjects examined the concurrent administration of tamoxifen and letrozole for six weeks. Concurrent use decreased the mean concentration of letrozole by 37.6%.(3,4) Although suppression of estradiol, estrone, and estrone sulfate were not effected, the authors speculated that patients may not receive the full benefit of combination therapy.(4) A study in 23 patients found that letrozole had no effect on tamoxifen levels. However, the antitumor effects of combination therapy were less than expected.(6) The therapeutic effect of letrozole is not affected if letrozole is administered immediately after tamoxifen.(5)

Selected Anti-Aromatase Agents/Estrogens

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Aromatase inhibitors(1-6) and inactivators(7-10) treat breast cancer by inhibiting estrogen synthesis therefore lowering serum estrone and estradiol levels. In postmenopausal women, androgens are metabolized to estrogens via the primary pathway of the aromatase enzyme.

CLINICAL EFFECTS: Concurrent administration of estrogen may decrease the effectiveness of aromatase inhibitors.(1-6)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The Canadian,(1) UK,(2) and US(3) manufacturers of anastrozole state that estrogen containing therapies should not be used during anastrozole therapy. The Australian,(7) Canadian,(8) UK,(9) and US(10) manufacturers of exemestane state that exemestane should not be administered with estrogen containing therapies. The Canadian(4) and UK(5) manufacturer of letrozole state that estrogen containing therapies should be avoided during letrozole therapy.

DISCUSSION: Many breast cancers have estrogen receptors and their growth can be stimulated by estrogen. Anastrozole is a potent and selective non-steroidal aromatase inhibitor that lowers serum estradiol levels. Concurrent use of estrogen may diminish the effects of anastrozole.(1-3) Exemestane is a steroidal aromatase inactivator that lowers serum estradiol levels. Concurrent use of estrogen may diminish the effects of exemestane.(7-10)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Selected Anti-Aromatase Agents/Selected Vaginal Estrogens

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Aromatase inhibitors(1-6) and inactivators(7-10) treat breast cancer by inhibiting estrogen synthesis therefore lowering serum estrone and estradiol levels. In postmenopausal women, androgens are metabolized to estrogens via the primary pathway of the aromatase enzyme.

CLINICAL EFFECTS: Concurrent administration of estrogen may decrease the effectiveness of aromatase inhibitors.(1-6)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The Canadian,(1) UK,(2) and US(3) manufacturers of anastrozole state that estrogen containing therapies should not be used during anastrozole therapy. The Australian,(7) Canadian,(8) UK,(9) and US(10) manufacturers of exemestane state that exemestane should not be administered with estrogen containing therapies. The Canadian(4) and UK(5) manufacturer of letrozole state that estrogen containing therapies should be avoided during letrozole therapy. A clinical consensus from the American College of Obstetricians and Gynecologists states that low-dose vaginal estrogen may be used in patients on aromatase inhibitors who have failed non-hormonal treatment after shared decision making.(11) The Fifth International Consultation on Sexual Medicine also made recommendations on treatment of genitourinary syndrome of menopause (GSM). They state that local estrogen therapy cannot be a first line treatment for GSM in women on adjuvant hormone therapy but low- and ultra-low dose local estrogens can be used after trying non-hormonal approaches, and after a discussion of risks and benefits with the patient.(12)

DISCUSSION: Many breast cancers have estrogen receptors and their growth can be stimulated by estrogen. Anastrozole is a potent and selective non-steroidal aromatase inhibitor that lowers serum estradiol levels. Concurrent use of estrogen may diminish the effects of anastrozole.(1-3) Exemestane is a steroidal aromatase inactivator that lowers serum estradiol levels. Concurrent use of estrogen may diminish the effects of exemestane.(7-10) Several meta-analyses and systematic reviews have concluded that vaginal estrogens are likely to be safe in women on aromatase inhibitors. Nevertheless, they recommend using vaginal estrogens after a trial with nonhormonal therapies has failed and following shared decision making including a discussion with the patient of the risks and benefits of treatment.(13-16)

There are no moderate interactions for this drug.

* Known hypersensitivity to anastrozole or any ingredient in the formulation.

• Lactation

• Myocardial ischemia
• Pregnancy

• Hypercholesterolemia
• Osteopenia

In the early breast cancer study (ATAC), the most common adverse effects (occurring in 10% or more of patients) included hot flashes, asthenia, arthritis, pain, arthralgia, pharyngitis, hypertension, depression, nausea, vomiting, rash, osteoporosis, fractures, back pain, insomnia, headache, peripheral edema, and lymphedema.

In advanced breast cancer studies, the most common adverse effects (occurring in 10% or more of patients) included hot flashes, nausea, asthenia, pain, headache, back pain, bone pain, increased cough, dyspnea, pharyngitis, and peripheral edema.

More Frequent

• Chest pain
• Dyspnea
• Fracture
• Hypertension

Less Frequent

• Anemia
• Angina
• Cataracts
• Leukopenia
• Thromboembolic disorder
• Thrombophlebitis
• Tumor flare reaction

Rare or Very Rare

• Anaphylaxis
• Angioedema
• Erythema multiforme
• Hepatitis
• Hyperbilirubinemia
• Jaundice
• Myocardial ischemia
• Stevens-johnson syndrome
• Tendon rupture
• Tenosynovitis
• Urticaria

More Frequent

• Abdominal pain with cramps
• Arthralgia
• Arthritis
• Back pain
• Bone pain
• Cough
• Depression
• Diarrhea
• Dizziness
• Drug-induced hot flash
• Flushing
• Gastrointestinal irritation
• General weakness
• Headache disorder
• Insomnia
• Lymphedema
• Nausea
• Osteoporosis
• Pain
• Paresthesia
• Peripheral edema
• Pharyngitis
• Skin rash
• Vomiting
• Xerostomia

Less Frequent

• Abnormal vaginal bleeding
• Alopecia
• Carpal tunnel syndrome
• Constipation
• Dyspepsia
• Flu-like symptoms
• Hyperhidrosis
• Mastalgia
• Mood changes
• Myalgia
• Pelvic pain
• Pruritus of skin
• Rhinitis
• Sinusitis
• Urinary tract infection
• Vaginal discharge
• Vaginal dryness
• Vulvovaginitis
• Weight gain

Rare or Very Rare

• Abnormal hepatic function tests
• Acute cognitive impairment
• Drowsy
• Hypercalcemia
• Hypercholesterolemia
• Tendonitis
• Trigger finger

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Efficacy of anastrozole for the treatment of pubertal gynecomastia+ in adolescent males and for the treatment of progressive precocious puberty associated with McCune-Albright syndrome+ in girls has not been established.

Results of a randomized, double-blind, placebo-controlled trial in 80 adolescent males 11-18 years of age with pubertal gynecomastia failed to establish efficacy of anastrozole (1 mg daily for 6 months) in reducing gynecomastia or relieving breast pain. Serum estradiol concentrations were reduced by 15.4 or 4.5% in patients receiving anastrozole or placebo, respectively. Patients receiving anastrozole were more likely to experience treatment-related adverse effects (16.3 versus 8.1%), and the difference was related mainly to higher rates of acne and headache in those receiving anastrozole. One patient discontinued anastrozole therapy because of testicular enlargement.

Results of a noncomparative open-label trial of anastrozole (1 mg daily for 12 months) in 28 girls (2 to less than 10 years of age) with McCune-Albright syndrome and progressive precocious puberty showed no reduction from baseline in the frequency of vaginal bleeding days or in the rate of increase in bone age and no clinically important changes in Tanner staging, mean ovarian or uterine volume, or mean predicted adult height. A small reduction in growth rate was observed; however, because the study was uncontrolled, it is unclear whether this effect was related to anastrozole or to other confounding factors (e.g., variations in endogenous estrogen levels commonly observed in patients with McCune-Albright syndrome). Adverse effects (i.e., nausea, acne, extremity pain, increased aminotransferase concentrations, allergic dermatitis) were reported in 18% of patients.

Pharmacokinetics of anastrozole were similar in adolescent males with pubertal gynecomastia and in girls with McCune-Albright syndrome, and the elimination half-life in these pediatric populations (about 47 hours) was similar to that observed in postmenopausal women with breast cancer.

Anastrozole may cause fetal harm; the drug has been shown to be embryotoxic, fetotoxic, and abortifacient in animals. The manufacturer states that a pregnancy test should be performed prior to initiation of anastrozole therapy in females of reproductive potential and that such women should be advised to use effective contraceptive methods while receiving the drug and for at least 3 weeks after discontinuance of therapy. If the drug is administered during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be informed of the potential hazard to the fetus and the potential risk for loss of the pregnancy.

Adequate, well-controlled studies of anastrozole in pregnant women have not been conducted. 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 (increased preimplantation and/or postimplantation loss, increased resorption, and decreased numbers of live fetuses) 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 organogenesis; in rats, this effect was dose-related. In rats receiving dosages equal to or exceeding 0.1 mg/kg daily, placental weights were increased.

In rats, anastrozole dosages of 1 mg/kg daily (which produced steady-state peak plasma anastrozole concentrations and AUC0-24h values that were 19 and 9 times higher, respectively, than those observed in healthy postmenopausal women receiving the recommended dose) resulted in fetotoxicity, including delayed fetal development (i.e., incomplete ossification and depressed fetal body weights). In rats, no evidence of teratogenicity was observed at dosages of up to 1 mg/kg daily. In rabbits, anastrozole dosages equal to or exceeding 1 mg/kg daily (about 16 times the recommended human dosage on a mg/m2 basis) caused pregnancy failure. No evidence of teratogenicity was observed in rabbits receiving anastrozole 0.2 mg/kg daily (about 3 times the recommended human dosage on a mg/m2 basis).

It is not known whether anastrozole or its metabolites are distributed into human milk or if the drug has any effect on nursing infants or on milk production. Because many drugs are distributed into milk and because tumorigenic effects of anastrozole have been observed in animals and anastrozole has the potential to cause serious adverse reactions in nursing infants, women should be advised to discontinue breast-feeding during anastrozole therapy and for 2 weeks after discontinuance of the drug.

Because no evidence of altered pharmacokinetics has been observed in women older than 80 years of age compared with women younger than 50 years of age, the manufacturer states that adjustment of anastrozole dosage is not necessary in geriatric patients.

Among patients receiving anastrozole as adjuvant therapy for early-stage breast cancer in the ATAC trial, 45% were 65 years of age or older. Subgroup analysis showed that anastrozole did not provide the same benefit for disease-free survival in women 65 years of age or older (hazard ratio of 0.93 with a 95% confidence interval of 0.8-1.08) that it provided in postmenopausal women younger than 65 years of age (hazard ratio of 0.79 with a 95% confidence interval of 0.67-0.94).

Among patients receiving anastrozole as first-line or second-line therapy in clinical trials, about 50% were 65 years of age or older. No difference in efficacy was observed for geriatric patients (65 years or older) compared with younger patients receiving anastrozole as second-line therapy for advanced breast cancer; moderately greater efficacy was observed for geriatric patients (65 years or older) receiving either anastrozole or tamoxifen as first-line therapy for advanced breast cancer.