Testosterone-Anastrozole (testosterone/anastrozole)

Dosage of testosterone is variable and should be individualized according to the condition being treated; the severity of symptoms; the patient's age, gender, and history of prior androgenic therapy; and the specific testosterone preparation being used.

Various dosage regimens have been used to induce pubertal changes in hypogonadal males. Some clinicians recommend that lower dosages be used initially, followed by gradual increases in dosage as puberty progresses; subsequently, the dosage may be decreased to maintenance levels. Other clinicians state that higher dosages are required initially to induce pubertal changes and lower dosages can then be used for maintenance therapy after puberty. The chronologic and skeletal ages of the patient must be considered when determining the initial dosage and subsequent dosage adjustment.

Diagnosis of hypogonadism must be confirmed by laboratory testing prior to initiation of testosterone therapy. To confirm this diagnosis, serum testosterone concentrations should be measured in the morning on at least 2 separate days and must be consistently below the normal range. Serum testosterone concentrations may be low later in the day in men with or without hypogonadism; therefore, measuring testosterone concentrations later in the day should be avoided.

The manufacturers of testosterone enanthate injection, testosterone undecanoate injection, and testosterone transdermal system, topical gel, topical solution, nasal gel, and buccal tablets state that clinical studies involving patients with renal or hepatic impairment have not been conducted. Therefore, there are no special population dosage recommendations at this time.

Testosterone is administered by IM injection; percutaneously by topical application of a transdermal system, solution, or gel to the skin; intranasally; subcutaneously as a biodegradable implant; and intrabuccally (transmucosally) as a buccal tablet.

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.

No dosing information is available for this tab.

No dosing information is available for this tab.

Testosterone may potentiate the action of oral anticoagulants, causing bleeding in some patients. When testosterone therapy is initiated in patients receiving oral anticoagulants, dosage reduction of the anticoagulant may be required to prevent an excessive hypoprothrombinemic response. In patients receiving concomitant therapy with testosterone and anticoagulants, more frequent monitoring of INR and prothrombin time is recommended, especially during initiation or discontinuance of therapy.

Increased serum oxyphenbutazone concentrations have reportedly occurred in patients receiving androgens concurrently with oxyphenbutazone.

Changes in insulin sensitivity or glycemic control may occur in patients receiving androgen therapy. The metabolic effects of androgens may decrease blood glucose concentrations and insulin requirements in patients with diabetes.

Concomitant administration of testosterone with ACTH or corticosteroids may result in increased fluid retention and edema formation. Therefore, testosterone should be administered with caution in patients with cardiac, renal, and/or hepatic disease. Patients should be monitored for fluid retention and edema formation.

Administration of IM testosterone cypionate resulted in increased clearance of propranolol in one study. It is not known whether there is a potential for this interaction with topically administered testosterone gel.

Topical administration of 0.1% triamcinolone cream prior to application of a testosterone transdermal system did not alter absorption of testosterone; however, pretreatment with topical administration of triamcinolone ointment substantially reduced absorption of testosterone.

Administration of intranasal oxymetazoline, a sympathomimetic nasal decongestant, prior to administration of testosterone nasal gel (Natesto(R)) did not alter absorption of testosterone. Concomitant administration of testosterone nasal gel with other drugs administered intranasally has not been studied. The manufacturer does not recommend concomitant use with such drugs.

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)

Selected Steroids/Sodium Fusidate

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: Sodium fusidate and steroids may inhibit the biotransformation of each other by CYP P-450-3A4.(1)

CLINICAL EFFECTS: Concurrent use may result in toxicity from sodium fusidate and steroids.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The Australian manufacturer of sodium fusidate states that concurrent use of sodium fusidate and CYP P-450-3A4 biotransformed drugs such as steroids should be avoided.(1)

DISCUSSION: Although the specifics of sodium fusidate metabolic pathways are not known, an interaction between sodium fusidate and drugs that are biotransformed by CYP P-450-3A4 is suspected.(1)

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
• Malignant tumor of male breast
• Pregnancy
• Prostatic carcinoma

• Acute myocardial infarction
• Acutely decompensated chronic heart failure
• Benign prostatic hyperplasia
• Cerebrovascular accident
• Erythrocytosis
• Hyperlipidemia
• Myocardial ischemia
• Neoplasm of liver
• Polycythemia vera
• Pregnancy
• Pulmonary thromboembolism
• Venous thrombosis

• Chronic heart failure
• Chronic obstructive pulmonary disease
• Diabetes mellitus
• Disease of liver
• Edema
• Gynecomastia
• Humoral hypercalcemia of malignancy
• Hypercholesterolemia
• Hypertension
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Obesity
• Osteopenia
• Sleep apnea

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

• Amenorrhea
• Bladder irritability
• Irregular menstrual periods
• Priapism
• Urinary tract infection
• Virilism

Less Frequent

• Benign prostatic hyperplasia
• Dizziness
• Edema
• Epididymitis
• Fatigue
• Flushing
• Hypercalcemia
• Hypertension
• Nausea
• Prostatic carcinoma
• Raised prostate specific antigen
• Sleep apnea
• Vomiting

Rare or Very Rare

• Acute myocardial infarction
• Acute respiratory distress syndrome
• Cerebrovascular accident
• Cholestatic hepatitis
• Deep venous thrombosis
• Drug-induced hepatitis
• Erythrocytosis
• Heart failure
• Hepatic necrosis
• Hypersensitivity drug reaction
• Increased hemoglobin
• Jaundice
• Leukopenia
• Malignant neoplasm of liver
• Peliosis hepatis
• Pulmonary thromboembolism
• Suicidal ideation
• Venous thrombosis

More Frequent

• Gynecomastia
• Mastalgia

Less Frequent

• Abdominal pain with cramps
• Acne vulgaris
• Diarrhea
• Erectile dysfunction
• Headache disorder
• Increased pubic hair
• Injection site infection
• Injection site sequelae
• Insomnia
• Libido changes
• Testicular atrophy

Rare or Very Rare

• Aggressive behavior
• Anorexia
• Depression
• Hostility
• Hypercholesterolemia
• Irritability
• Oligospermia

No enhanced messaging available.

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.

Testosterone may cause fetal harm when administered to pregnant women due to the potential for virilization of a female fetus. Androgenic effects including clitoral hypertrophy, labial fusion of the external genital fold to form a scrotal-like structure, abnormal vaginal development, and persistence of a urogenital sinus have occurred in the female offspring of women who were given androgens during pregnancy. The degree of masculinization is related to the amount of drug given to the woman and the age of the fetus; masculinization is most likely to occur in a female fetus when exposure to androgens occurs during the first trimester. Since the risks clearly outweigh the possible benefits in women who are or may become pregnant, testosterone is contraindicated in such women. Women who become pregnant while receiving the drug should be informed of the potential hazard to the fetus.

Pregnant women or those who may become pregnant should be aware of the possibility that testosterone could be transferred from patients treated with topical preparations of the drug such as their sexual partners or other individuals in close physical contact. (See Cautions: Precautions and Contraindications.) Testosterone transdermal system (Androderm(R)) has an occlusive backing that prevents the partner from coming in contact with active ingredient in the system. Transdermal systems that inadvertently are transferred to a sexual partner should be removed immediately and the contacted skin washed. Pregnant women should avoid skin contact with testosterone topical gel application sites in men. (See Cautions: Precautions and Contraindications.) If unwashed or unclothed skin to which testosterone topical gel has been applied comes in direct contact with the skin of a pregnant woman, the general area of contact by the woman should be washed with soap and water immediately. In vitro studies show that residual testosterone is removed by such washing.

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 testosterone is distributed into milk. The manufacturers of testosterone enanthate injection (Delatestryl(R)) and testosterone pellets (Testopel(R)) state that because of the potential for serious adverse reactions to androgens in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman. The manufacturer of testosterone cypionate injection (Depo(R)-testosterone) states that use in nursing women is not recommended. Testosterone topical gel, topical solution, nasal gel, transdermal system, and buccal tablets and testosterone undecanoate injection (Aveed(R)) are not indicated for use in women. Testosterone topical gel, topical solution, nasal gel, and buccal tablets and testosterone undecanoate injection also are contraindicated in nursing women because of the potential for serious adverse reactions in nursing infants. Exposure of a female nursing infant to androgens may result in varying degrees of virilization. Testosterone and other androgens also may adversely affect lactation.

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.