Danazol (danazol)

Danazol is administered orally. For the treatment of endometriosis and fibrocystic breast disease, administration of the drug should be initiated during menstruation; otherwise, appropriate laboratory tests should be performed to ensure that the patient is not pregnant. Attempts should be made to determine the lowest possible effective dosage of the drug.

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

Danazol/Lovastatin (> 20 Mg); Simvastatin

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: Danazol may inhibit the metabolism of lovastatin(1) and simvastatin(2) by CYP3A4.

CLINICAL EFFECTS: Concurrent use of danazol may result in elevated levels of lovastatin(1) and simvastatin(2,3) and toxicity, including rhabdomyolysis. One case report of pancreatitis was possibly caused by the danazol/lovastatin interaction.(7)

PREDISPOSING FACTORS: Higher doses of lovastatin(1) or simvastatin(2,3) may increase the risk of myopathy. The risk for myopathy or rhabdomyolysis may also be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis.

PATIENT MANAGEMENT: The US manufacturer of lovastatin states that in patients receiving danazol, lovastatin should be started at a dose of 10 mg daily and that the dose of lovastatin should not exceed 20 mg daily. The benefits of concurrent use should be carefully weighed against the risk of the combination.(1) Do not use simvastatin with danazol.(2-4)

DISCUSSION: Concurrent use of danazol with lovastatin(1) or simvastatin(2-4) increases the risk of rhabdomyolysis. Rhabdomyolysis(5-7) and pancreatitis(5) have been reported with concurrent lovastatin and danazol and with concurrent simvastatin and danazol.(8,9) One case involved death.(8)

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

Selected Androgens/Cyclosporine

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

MECHANISM OF ACTION: Danazol and methyltestosterone may inhibit the metabolism of cyclosporine.

CLINICAL EFFECTS: Concurrent therapy may result in increased levels of cyclosporine, which may produce hepatic and renal dysfunction.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: If possible, avoid giving patients receiving cyclosporine danazol or methyltestosterone. If concurrent therapy is warranted, monitor cyclosporine levels as well as renal and hepatic function carefully. Cyclosporine dosage adjustments may be necessary when these agents are initiated or discontinued, as well as during concurrent therapy. Discontinuation of the androgen may be necessary.

DISCUSSION: Four case reports have documented increased cyclosporine levels during concurrent therapy with danazol.(1-4) In two of these reports, elevated cyclosporine levels persisted even after decreases in cyclosporine dosages.(1,2) One patient also experienced decreased renal function, as indicated by an increase in serum creatinine levels.(1) Cyclosporine levels returned to baseline following the discontinuation of danazol.(1-4) Two case reports have documented increased cyclosporine levels during concurrent therapy with methyltestosterone. Both patients experienced elevated cyclosporine, bilirubin, and serum creatinine levels during concurrent therapy.(5,6) In one patient, elevated cyclosporine levels persisted despite a 40% decrease in cyclosporine dosage.(5) Discontinuation of methyltestosterone resulted in a gradual return of cyclosporine levels to previous values.(5,6)

Slt Anabolic Steroids/Slt Anticoagulants (Vit K Antagonists)

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

MECHANISM OF ACTION: The exact mechanism is unknown. It has been hypothesized that the C-17 alkylated androgens may increase turnover of clotting factors and decrease their synthesis. Increased affinity for the anticoagulant receptor site has also been hypothesized. The C-17 alkylated androgens have not been shown to alter the metabolism of anticoagulants.

CLINICAL EFFECTS: The concurrent use of anticoagulants and anabolic steroids may result in an increased risk for bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Patients should be closely monitored for increased anticoagulant activity. The dose of the anticoagulant may need to be adjusted. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug. When concurrent therapy is warranted, also monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: Danazol, methandrostenolone, methyltestosterone, oxymetholone, and stanozolol have been shown to increase the hypoprothrombinemic actions of warfarin. Methyltestosterone has also been shown to increase the effects of dicumarol. Oxymetholone and ethylestrenol have been shown to increase the effects of phenindione. Limited data suggest that the non-C-17-alkylated androgens do not affect anticoagulants.

Moderate Interaction: Assess the risk to the patient and take action as needed.

Danazol/Carbamazepine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Danazol-induced inhibition of CYP3A4, resulting in a decrease in carbamazepine metabolism.

CLINICAL EFFECTS: May see an increase in the pharmacologic activity of carbamazepine, including carbamazepine toxicity.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: It may be necessary to reduce the dose of carbamazepine during concurrent administration of danazol. Monitor serum carbamazepine levels and monitor the patient for symptoms of carbamazepine toxicity. Adjust the dose accordingly.

DISCUSSION: In six patients with epilepsy and fibrocystic breast disease the concentration in serum of antiepileptic drugs was obtained before, during, and after danazol therapy. (1) Carbamazepine serum level increased almost twofold in the presence of danazol. Danazol led to a pronounced inhibition of CBZ metabolism in an epileptic patient. (2) During danazol coadministration, CBZ elimination half-life increased from a pretreatment value of 11 to 24.3 h. Carbamazepine plasma clearance decreased from 57.7 to 23.2 ml/h/kg. Observations in five other female patients confirm that the steady-state plasma concentrations of CBZ increase between 50 and 100% during coadministration of danazol.

Danazol/Lovastatin (<= 20 Mg)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Danazol may inhibit the metabolism of lovastatin by CYP3A4.(1)

CLINICAL EFFECTS: Concurrent use of danazol may result in elevated levels of lovastatin and toxicity, including rhabdomyolysis.(1) One case report also states pancreatitis may possibly be caused by the lovastatin danazol interaction.(4)

PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis.

PATIENT MANAGEMENT: The US manufacturer of lovastatin states that in patients receiving danazol, lovastatin should be started at a dose of 10 mg daily and that the dose of lovastatin should not exceed 20 mg daily. The benefits of concurrent use should be carefully weighed against the risk of the combination.(1)

DISCUSSION: Concurrent use of danazol with lovastatin increases the risk of rhabdomyolysis.(1) Rhabdomyolysis(2-4) and pancreatitis(2) have been reported with concurrent lovastatin and danazol.

Danazol/Tacrolimus

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Danazol may inhibit the metabolism of tacrolimus by CYP3A4.(1-3)

CLINICAL EFFECTS: Concurrent use of danazol may result in elevated levels of and toxicity from tacrolimus, including nephrotoxicity, neurotoxicity, and prolongation of the QTc interval and life-threatening cardiac arrhythmias, including torsades de pointes.(1-3)

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age. Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).

PATIENT MANAGEMENT: Monitor tacrolimus levels in patients receiving concurrent danazol. The dosage of tacrolimus may need to be adjusted if danazol is initiated or discontinued.(1) When concurrent therapy of danazol and tacrolimus is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Concurrent danazol has been shown to increase tacrolimus trough concentrations (Cmin) by more than 5-fold in patients and by 3-fold in rats.(1)

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• Chronic heart failure
• History of venous thromboembolism
• Lactation
• Porphyria
• Pregnancy
• Thromboembolic disorder

• Disease of liver

• Migraine
• Seizure disorder

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More Frequent

• Abnormal vaginal bleeding
• Amenorrhea
• Breast size decreased
• Irregular menstrual periods

Less Frequent

• Edema
• Virilism

Rare or Very Rare

• Abnormal hepatic function tests
• Acute arterial thromboembolism
• Acute intermittent porphyria
• Acute pancreatitis
• Carpal tunnel syndrome
• Cataracts
• Cerebrovascular accident
• Eosinophilia
• Gingival bleeding
• Hematuria
• Idiopathic intracranial hypertension
• Jaundice
• Leukocytosis
• Neoplasm of liver
• Nipple discharge
• Peliosis hepatis
• Rhabdomyolysis
• Skin rash
• Splenic peliosis
• Stevens-johnson syndrome
• Thrombocytopenic disorder
• Thromboembolic disorder
• Urticaria

More Frequent

• Acne vulgaris
• Weight gain

Less Frequent

• Alopecia
• Flushing
• Hypoestrogenism
• Vaginal dryness
• Voice change

Rare or Very Rare

• Hyperhidrosis
• Hyperlipidemia
• Mood changes
• Nervousness
• Oligospermia
• Pruritus of skin
• Skin photosensitivity

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Although there are no adequate and controlled studies to date in humans, danazol may cause fetal harm when administered to pregnant women. Androgenic effects including clitoral hypertrophy, labial fusion of the external genital fold to form a scrotal-like structure, ambiguous genitalia, abnormal vaginal development, and persistence of a urogenital sinus have occurred in the female offspring of women who were given danazol during pregnancy. Spontaneous abortions have also occurred in pregnant women who received the drug. Since the risks clearly outweigh the possible benefits in women who are or may become pregnant, danazol is contraindicated in such women. Women of childbearing age should be instructed to use an effective, nonhormonal method of contraception during danazol therapy and be informed of the potential hazard to the fetus should they become pregnant during therapy. In addition, a reliable pregnancy test (e.g., beta-subunit radioimmunoassay (RIA)) must be performed immediately prior to beginning danazol therapy. If the drug is inadvertently administered during pregnancy or if the patient becomes pregnant while receiving the drug, administration of danazol should be discontinued, and the woman should be apprised of the potential risk to the fetus.

Because of the potential for serious adverse reactions to danazol in nursing infants, a decision should be made whether to discontinue nursing or not use the drug, taking into account the importance of the drug to the woman.

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