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  • CLASSES

    Androgens
    Antigonadotropins and Similar Agents

    BOXED WARNING

    Hepatic disease, hepatotoxicity, jaundice

    Do not use danazol in patients with severe hepatic disease. Danazol should be used with caution, if at all, in patients with milder grades of hepatic disease. Danazol use can cause hepatotoxicity including cholestatic jaundice, peliosis of the liver, and benign hepatic adenoma. Peliosis and adenoma may not be apparent until patients present with life-threatening intra-abdominal hemorrhage. Regular liver function tests (LFTs) should be carried out in all patients.

    Increased intracranial pressure, papilledema, pseudotumor cerebri

    Danazol has been associated with cases of pseudotumor cerebri (benign increased intracranial pressure). Early signs and symptoms include headache, nausea/vomiting, visual disturbances, and papilledema. Patients with these signs and symptoms should be examined for papilledema, and if present, should discontinue the drug immediately and be referred for neurologic evaluation.

    Stroke, thromboembolic disease

    Thromboembolic disease such as thromboembolism or thrombotic events have occurred during danazol therapy. Cases of sagittal sinus thrombosis and fatal or life-threatening stroke have been reported.

    DEA CLASS

    Rx

    DESCRIPTION

    Synthetic steroid derived from ethisterone (ethinyl testosterone). Is antiestrogenic and weakly androgenic. Used for endometriosis, unless the process has advanced to the stage of surgical correction. Also used in the palliative treatment of fibrocystic breast disease and hereditary angioedema in both males and females.

    COMMON BRAND NAMES

    Danocrine

    HOW SUPPLIED

    Danazol/Danocrine Oral Cap: 50mg, 100mg, 200mg

    DOSAGE & INDICATIONS

    For the treatment of endometriosis.
    For mild cases.
    Oral dosage
    Adult females

    200 to 400 mg/day PO in 2 divided doses. Begin therapy during menstruation to ensure the patient is not pregnant. Subsequent doses may be adjusted depending upon the patient's response. Continue uninterrupted therapy for 3 to 6 months; may extend to 9 months as necessary. If symptoms persist following termination of therapy, treatment can be reinstituted.

    For moderate to severe cases.
    Oral dosage
    Adult females

    Initially, 800 mg/day PO in 2 divided doses. Begin therapy during menstruation to ensure the patient is not pregnant. Subsequent doses may be gradually reduced depending upon the patient's response. Continue uninterrupted therapy for 3 to 6 months; may extend to 9 months as necessary. If symptoms persist following termination of therapy, treatment can be reinstituted.

    For the treatment of fibrocystic breast disease.
    Oral dosage
    Adults

    100 to 400 mg/day PO in 2 divided doses. Begin therapy during menstruation to ensure the patient is not pregnant. Dosage should be adjusted according to the individual patient's need and response. Although symptoms may be relieved, and even eliminated in 3 months, up to 6 months of uninterrupted therapy may be required to eliminate nodularity. Since ovulation may not be suppressed at these dosages, an effective non-hormonal method of contraception is recommended during therapy.

    For angioedema prophylaxis in patients with hereditary angioedema.
    Oral dosage
    Adults

    Initially, 200 mg PO 2 to 3 times per day. If a favorable response is achieved, the dose may be reduced by half at intervals of 1 to 3 months. If there is an unfavorable response (in the form of an attack of angioedema during treatment), the dose may be increased by up to 200 mg per day. NOTE: If danazol therapy was initiated during an exacerbation of angioedema caused by trauma, stress, or other causes, periodic attempts to reduce or discontinue therapy should be considered.

    For the treatment of chronic immune thrombocytopenia/idiopathic thrombocytopenic purpura (ITP)†.
    Oral dosage
    Adults

    A dosage of 200 mg PO 4 times per day has been recommended. The drug should be administered for at least 6 months due to the slow response.

    For the treatment of mastalgia† associated with premenstrual syndrome (PMS)†; or for PMS-associated bloating and weight gain, anxiety, depressive symptoms, and/or global complaints.
    Oral dosage
    Adults

    The recommended dose is 50 to 100 mg PO twice daily. Dosages should be individually titrated to achieve desired effects. Danazol has also been found to decrease psychologic symptoms such as anxiety and depression, as well as global complaints. Therapy for weight gain and bloating should be limited to patients who demonstrate a premenstrual weight gain of more than 1.4 kg.

    For emergency postcoital contraception†.
    Oral dosage
    Adults

    Contradictory data exist regarding the efficacy of this drug for this use. A dosage of 800 to 1,200 mg PO every 12 hours for 2 doses and a dosage of 800 mg PO every 12 hours for 3 doses have been studied.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    800 mg/day PO; 2400 mg/day PO has been used for off-label emergency postcoital contraception.

    Geriatric

    Safety and efficacy have not been established.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Mild to moderate hepatic impairment: No adjustment is needed; use with caution.
    Severe hepatic impairment: Do not use.

    Renal Impairment

    CrCl >= 30 mL/min: No adjustment is needed.
    CrCl < 30 mL/min: Do not use.

    ADMINISTRATION

    Oral Administration

    Administer with meals to minimize indigestion or GI irritation.

    STORAGE

    Danocrine:
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Cardiac disease, migraine, renal disease, renal failure, renal impairment, seizure disorder

    Danazol should be used with caution in patients with seizure disorder, migraine headaches, cardiac disease, or renal impairment because the drug can increase fluid retention, which can exacerbate these conditions. Danazol should not be used in patients with severe cardiac disease or severe renal disease (including renal failure).

    Hepatic disease, hepatotoxicity, jaundice

    Do not use danazol in patients with severe hepatic disease. Danazol should be used with caution, if at all, in patients with milder grades of hepatic disease. Danazol use can cause hepatotoxicity including cholestatic jaundice, peliosis of the liver, and benign hepatic adenoma. Peliosis and adenoma may not be apparent until patients present with life-threatening intra-abdominal hemorrhage. Regular liver function tests (LFTs) should be carried out in all patients.

    Porphyria

    Danazol can induce ALA synthetase activity and porphyrin metabolism. For this reason, danazol should not be used in patients with acute intermittent porphyria because it can precipitate an attack.

    Pregnancy

    Danazol is contraindicated during pregnancy (FDA pregnancy category X), so care should be taken to ensure that the patient is not pregnant or becomes pregnant during therapy. Teratogenic effects have been associated with danazol treatment. In addition, androgens have caused virilization of the external genitalia of the female fetus, including clitoromegaly, abnormal vaginal development, and fusion of genital folds to form a scrotal-like structure. The degree of masculinization is dependent on the amount of drug given and the age of the fetus; these effects are most likely to occur in the female fetus when the drugs are given in the first trimester. Females of childbearing potential should use adequate methods of contraception, and should commence therapy during menstruation when possible to ensure a nonpregnant state. If pregnancy occurs, the drug should be immediately discontinued and the patient should be counseled concerning the potential risks to the fetus.

    Breast-feeding

    Danazol is excreted into human breast milk. Because of androgenic effects on the infant, its use is contraindicated during breast-feeding. An alternative method to breast-feeding should be found if the drug must be used.

    Vaginal bleeding

    Danazol can cause menstrual irregularity, breakthrough bleeding and other adverse reactions in women that could exacerbate or mask preexisting vaginal conditions. Therefore, danazol use is contraindicated in undiagnosed vaginal bleeding.

    Breast cancer

    Danazol should not be used for the treatment of fibrocystic breast disease until the possibility of breast cancer has been eliminated. If nodules persist or become enlarged during treatment, the possibility of cancer should be investigated.

    Geriatric, prostatic hypertrophy

    Geriatric patients should be treated with danazol cautiously as safety and effectiveness has not been determined in patients >= 65 years during clinical studies. Elderly male patients may be at risk of developing prostatic hypertrophy.

    Increased intracranial pressure, papilledema, pseudotumor cerebri

    Danazol has been associated with cases of pseudotumor cerebri (benign increased intracranial pressure). Early signs and symptoms include headache, nausea/vomiting, visual disturbances, and papilledema. Patients with these signs and symptoms should be examined for papilledema, and if present, should discontinue the drug immediately and be referred for neurologic evaluation.

    Stroke, thromboembolic disease

    Thromboembolic disease such as thromboembolism or thrombotic events have occurred during danazol therapy. Cases of sagittal sinus thrombosis and fatal or life-threatening stroke have been reported.

    ADVERSE REACTIONS

    Severe

    hepatoma / Delayed / Incidence not known
    pancreatitis / Delayed / Incidence not known
    Guillain-Barre syndrome / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    myocardial infarction / Delayed / Incidence not known
    thrombosis / Delayed / Incidence not known
    stroke / Early / Incidence not known
    thromboembolism / Delayed / Incidence not known
    teratogenesis / Delayed / Incidence not known
    papilledema / Delayed / Incidence not known
    visual impairment / Early / Incidence not known
    erythrocytosis / Delayed / Incidence not known

    Moderate

    elevated hepatic enzymes / Delayed / 1.0-10.0
    constipation / Delayed / 1.0-10.0
    fluid retention / Delayed / 1.0-10.0
    hypercholesterolemia / Delayed / 10.0
    edema / Delayed / Incidence not known
    anovulation / Delayed / Incidence not known
    hematuria / Delayed / Incidence not known
    cholestasis / Delayed / Incidence not known
    peliosis hepatis / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    hyperglycemia / Delayed / Incidence not known
    palpitations / Early / Incidence not known
    sinus tachycardia / Rapid / Incidence not known
    pseudotumor cerebri / Delayed / Incidence not known
    depression / Delayed / Incidence not known
    polycythemia / Delayed / Incidence not known
    eosinophilia / Delayed / Incidence not known
    leukopenia / Delayed / Incidence not known
    thrombocytopenia / Delayed / Incidence not known
    cataracts / Delayed / Incidence not known
    pneumonitis / Delayed / Incidence not known

    Mild

    seborrhea / Delayed / 1.0-10.0
    nausea / Early / 1.0-10.0
    headache / Early / 1.0-10.0
    dizziness / Early / 1.0-10.0
    fatigue / Early / 1.0-10.0
    hirsutism / Delayed / 10.0
    acne vulgaris / Delayed / 10.0
    weight gain / Delayed / 10.0
    amenorrhea / Delayed / 10.0
    menstrual irregularity / Delayed / 10.0
    alopecia / Delayed / Incidence not known
    oligospermia / Delayed / Incidence not known
    pharyngitis / Delayed / Incidence not known
    spermatogenesis inhibition / Delayed / Incidence not known
    hoarseness / Early / Incidence not known
    breakthrough bleeding / Delayed / Incidence not known
    breast discharge / Delayed / Incidence not known
    emotional lability / Early / Incidence not known
    flushing / Rapid / Incidence not known
    diaphoresis / Early / Incidence not known
    vomiting / Early / Incidence not known
    photosensitivity / Delayed / Incidence not known
    petechiae / Delayed / Incidence not known
    vesicular rash / Delayed / Incidence not known
    purpura / Delayed / Incidence not known
    maculopapular rash / Early / Incidence not known
    pruritus / Rapid / Incidence not known
    urticaria / Rapid / Incidence not known
    nasal congestion / Early / Incidence not known
    paresthesias / Delayed / Incidence not known
    anxiety / Delayed / Incidence not known
    tremor / Early / Incidence not known
    chills / Rapid / Incidence not known
    weakness / Early / Incidence not known
    pelvic pain / Delayed / Incidence not known
    back pain / Delayed / Incidence not known
    muscle cramps / Delayed / Incidence not known
    carpal tunnel syndrome / Delayed / Incidence not known
    leukocytosis / Delayed / Incidence not known
    fever / Early / Incidence not known

    DRUG INTERACTIONS

    Abarelix: (Major) Concomitant use of androgens or estrogens with abarelix is relatively contraindicated, as both could counteract the therapeutic effect of abarelix.
    Abciximab: (Moderate) Danazol can decrease hepatic synthesis of procoagulant factors, increasing the possibility of bleeding when used concurrently with anticoagulants, platelet inhibitors, or thrombolytic agents.
    Acalabrutinib: (Major) Decrease the acalabrutinib dose to 100 mg PO once daily if coadministered with danazol. Coadministration may result in increased acalabrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Acalabrutinib is a CYP3A4 substrate; danazol is a moderate CYP3A4 inhibitor. In physiologically based pharmacokinetic (PBPK) simulations, the Cmax and AUC values of acalabrutinib were increased by 2- to almost 3-fold when acalabrutinib was coadministered with moderate CYP3A inhibitors.
    Acarbose: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Danazol can decrease hepatic synthesis of procoagulant factors, increasing the possibility of bleeding when used concurrently with platelet inhibitors.
    Acetaminophen; Hydrocodone: (Major) Monitor for respiratory depression and sedation if hydrocodone and danazol are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as danazol, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Acetaminophen; Oxycodone: (Moderate) Concomitant use of oxycodone with danazol may increase oxycodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of oxycodone until stable drug effects are achieved. Discontinuation of danazol could decrease oxycodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to oxycodone. If danazol is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Oxycodone is a substrate for CYP3A4 and danazol is a CYP3A4 inhibitor.
    Alfentanil: (Moderate) Danazol is a CYP3A4 inhibitor and can decrease the hepatic metabolism of drugs metabolized by this enzyme including alfentanil. A dose reduction of one or both drugs may be warranted. Close monitoring for oversedation and respiratory depression is warranted if a CYP3A4 inhibitor is used with alfentanil.
    Aliskiren; Amlodipine: (Moderate) Coadministration of CYP3A4 inhibitors with amlodipine can theoretically decrease the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inhibitors, such as danazol , are coadministered with calcium-channel blockers. Monitor therapeutic response; a dose reduction of amlodipine may be required.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Coadministration of CYP3A4 inhibitors with amlodipine can theoretically decrease the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inhibitors, such as danazol , are coadministered with calcium-channel blockers. Monitor therapeutic response; a dose reduction of amlodipine may be required.
    Alogliptin: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia. However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Alogliptin; Metformin: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia. However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary. (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Alogliptin; Pioglitazone: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia. However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Alpha-glucosidase Inhibitors: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Alprazolam: (Moderate) Danazol is a CYP3A4 inhibitor and can decrease the hepatic metabolism of CYP3A4 substrates, including alprazolam.
    Alteplase, tPA: (Moderate) Danazol can decrease hepatic synthesis of procoagulant factors, increasing the possibility of bleeding when used concurrently with thrombolytic agents.
    Amiodarone: (Moderate) Danazol is a CYP3A4 inhibitor and can decrease the hepatic metabolism of CYP3A4 substrates, including amiodarone.
    Amitriptyline; Chlordiazepoxide: (Moderate) Danazol is a CYP3A4 inhibitor and can theoretically reduce the metabolism of CYP3A4 substrates, including chlordiazepoxide.
    Amlodipine: (Moderate) Coadministration of CYP3A4 inhibitors with amlodipine can theoretically decrease the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inhibitors, such as danazol , are coadministered with calcium-channel blockers. Monitor therapeutic response; a dose reduction of amlodipine may be required.
    Amlodipine; Atorvastatin: (Moderate) Coadministration of CYP3A4 inhibitors with amlodipine can theoretically decrease the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inhibitors, such as danazol , are coadministered with calcium-channel blockers. Monitor therapeutic response; a dose reduction of amlodipine may be required. (Moderate) The risk of myopathy and rhabdomyolysis is increased by concomitant administration of danazol with atorvastatin. Danazol is a CYP3A4 inhibitor and may inhibit the metabolism of atorvastatin, a CYP3A4 substrate. Until more data are available, danazol should be used very cautiously, if at all, in patients receiving statins which are CYP3A4 substrates.
    Amlodipine; Benazepril: (Moderate) Coadministration of CYP3A4 inhibitors with amlodipine can theoretically decrease the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inhibitors, such as danazol , are coadministered with calcium-channel blockers. Monitor therapeutic response; a dose reduction of amlodipine may be required.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Coadministration of CYP3A4 inhibitors with amlodipine can theoretically decrease the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inhibitors, such as danazol , are coadministered with calcium-channel blockers. Monitor therapeutic response; a dose reduction of amlodipine may be required.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Coadministration of CYP3A4 inhibitors with amlodipine can theoretically decrease the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inhibitors, such as danazol , are coadministered with calcium-channel blockers. Monitor therapeutic response; a dose reduction of amlodipine may be required.
    Amlodipine; Olmesartan: (Moderate) Coadministration of CYP3A4 inhibitors with amlodipine can theoretically decrease the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inhibitors, such as danazol , are coadministered with calcium-channel blockers. Monitor therapeutic response; a dose reduction of amlodipine may be required.
    Amlodipine; Telmisartan: (Moderate) Coadministration of CYP3A4 inhibitors with amlodipine can theoretically decrease the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inhibitors, such as danazol , are coadministered with calcium-channel blockers. Monitor therapeutic response; a dose reduction of amlodipine may be required.
    Amlodipine; Valsartan: (Moderate) Coadministration of CYP3A4 inhibitors with amlodipine can theoretically decrease the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inhibitors, such as danazol , are coadministered with calcium-channel blockers. Monitor therapeutic response; a dose reduction of amlodipine may be required.
    Anagrelide: (Moderate) Danazol can decrease hepatic synthesis of procoagulant factors, increasing the possibility of bleeding when used concurrently with anticoagulants, platelet inhibitors, or thrombolytic agents.
    Antithrombin III: (Major) Danazol can decrease hepatic synthesis of procoagulant factors, increasing the possibility of bleeding when used concurrently with anticoagulants.
    Aprepitant, Fosaprepitant: (Major) Avoid the concomitant use of danazol with aprepitant, fosaprepitant due to substantially increased exposure of aprepitant. After administration, fosaprepitant is rapidly converted to aprepitant. Danazol is a moderate CYP3A4 inhibitor and aprepitant is a CYP3A4 substrate. Coadministration of daily oral aprepitant with a moderate CYP3A4 inhibitor, diltiazem, increased the aprepitant AUC 2-fold with a concomitant 1.7-fold increase in the diltiazem AUC; clinically meaningful changes in ECG, heart rate, or blood pressure beyond those induced by diltiazem alone did not occur.
    Aripiprazole: (Moderate) Because aripiprazole is partially metabolized by CYP3A4, increased aripiprazole blood levels may occur when the drug is coadministered with inhibitors of CYP3A4 such as danazol. If these agents are used in combination, the patient should be carefully monitored for aripiprazole-related adverse reactions. Because aripiprazole is also metabolized by CYP2D6, patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adult patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. There are no dosing recommendations for Aristada during use of a mild to moderate CYP3A4 inhibitor.
    Artemether; Lumefantrine: (Moderate) Danazol is a inhibitor and artemether is a substrate of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased artemether concentrations. Concomitant use warrants caution due to the potential for increased side effects. (Moderate) Danazol is a inhibitor and lumefantrine is a substrate of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased lumefantrine concentrations. Concomitant use warrants caution due to the potential for increased side effects, including increased potentiation of QT prolongation.
    Aspirin, ASA: (Moderate) Danazol can decrease hepatic synthesis of procoagulant factors, increasing the possibility of bleeding when used concurrently with platelet inhibitors.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) Danazol can decrease hepatic synthesis of procoagulant factors, increasing the possibility of bleeding when used concurrently with platelet inhibitors.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Danazol can decrease hepatic synthesis of procoagulant factors, increasing the possibility of bleeding when used concurrently with platelet inhibitors.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Danazol can decrease hepatic synthesis of procoagulant factors, increasing the possibility of bleeding when used concurrently with platelet inhibitors.
    Aspirin, ASA; Carisoprodol: (Moderate) Danazol can decrease hepatic synthesis of procoagulant factors, increasing the possibility of bleeding when used concurrently with platelet inhibitors.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Danazol can decrease hepatic synthesis of procoagulant factors, increasing the possibility of bleeding when used concurrently with platelet inhibitors.
    Aspirin, ASA; Dipyridamole: (Moderate) Danazol can decrease hepatic synthesis of procoagulant factors, increasing the possibility of bleeding when used concurrently with platelet inhibitors. (Moderate) Danazol can decrease hepatic synthesis of procoagulant factors, increasing the possibility of bleeding when used concurrently with platelet inhibitors.
    Aspirin, ASA; Omeprazole: (Moderate) Danazol can decrease hepatic synthesis of procoagulant factors, increasing the possibility of bleeding when used concurrently with platelet inhibitors.
    Aspirin, ASA; Oxycodone: (Moderate) Concomitant use of oxycodone with danazol may increase oxycodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of oxycodone until stable drug effects are achieved. Discontinuation of danazol could decrease oxycodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to oxycodone. If danazol is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Oxycodone is a substrate for CYP3A4 and danazol is a CYP3A4 inhibitor. (Moderate) Danazol can decrease hepatic synthesis of procoagulant factors, increasing the possibility of bleeding when used concurrently with platelet inhibitors.
    Aspirin, ASA; Pravastatin: (Moderate) Danazol can decrease hepatic synthesis of procoagulant factors, increasing the possibility of bleeding when used concurrently with platelet inhibitors.
    Atazanavir: (Moderate) Danazol is a CYP3A4 inhibitor, and serum concentrations of atazanavir, a CYP3A4 substrate, may increase with co-administration. Co-administer these drugs with caution due to the potential for atazanavir toxicity.
    Atazanavir; Cobicistat: (Moderate) Caution is warranted when cobicistat is administered with danazol as there is a potential for elevated cobicistat concentrations. Danazol is a CYP3A4 inhibitor and cobicistat is a substrate of CYP3A4. (Moderate) Danazol is a CYP3A4 inhibitor, and serum concentrations of atazanavir, a CYP3A4 substrate, may increase with co-administration. Co-administer these drugs with caution due to the potential for atazanavir toxicity.
    Atorvastatin: (Moderate) The risk of myopathy and rhabdomyolysis is increased by concomitant administration of danazol with atorvastatin. Danazol is a CYP3A4 inhibitor and may inhibit the metabolism of atorvastatin, a CYP3A4 substrate. Until more data are available, danazol should be used very cautiously, if at all, in patients receiving statins which are CYP3A4 substrates.
    Atorvastatin; Ezetimibe: (Moderate) The risk of myopathy and rhabdomyolysis is increased by concomitant administration of danazol with atorvastatin. Danazol is a CYP3A4 inhibitor and may inhibit the metabolism of atorvastatin, a CYP3A4 substrate. Until more data are available, danazol should be used very cautiously, if at all, in patients receiving statins which are CYP3A4 substrates.
    Axitinib: (Moderate) Use caution if coadministration of axitinib with danazol is necessary, due to the risk of increased axitinib-related adverse reactions. Axitinib is a CYP3A4 substrate and danazol is a moderate CYP3A4 inhibitor. Coadministration with a strong CYP3A4/5 inhibitor, ketoconazole, significantly increased the plasma exposure of axitinib in healthy volunteers. The manufacturer of axitinib recommends a dose reduction in patients receiving strong CYP3A4 inhibitors, but recommendations are not available for moderate or weak CYP3A4 inhibitors.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Danazol is a CYP3A4 inhibitor and can decrease the hepatic metabolism of some drugs, such as ergot alkaloids, and lead to ergot toxicity.
    Boceprevir: (Moderate) Close clinical monitoring is advised when administering danazol with boceprevir due to an increased potential for boceprevir-related adverse events. If danazol dose adjustments are made, re-adjust the dose upon completion of boceprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathways of danazol and boceprevir. Danazol is an inhibitor of the hepatic isoenzyme CYP3A4; boceprevir is metabolized by this isoenzyme. When used in combination, the plasma concentrations of boceprevir may be elevated.
    Bosentan: (Moderate) Danazol is a CYP3A4 inhibitor, and may reduce the hepatic metabolism of CYP3A4 substrates including bosentan. Excessive bosentan dosage can result in hypotension or elevated hepatic enzymes.
    Brexpiprazole: (Moderate) Because brexpiprazole is primarily metabolized by CYP3A4 and CYP2D6, the manufacturer recommends that the brexpiprazole dose be reduced to one-quarter (25%) of the usual dose in patients receiving a moderate to strong inhibitor of CYP3A4 in combination with a moderate to strong inhibitor of CYP2D6. Danazol is a moderate inhibitor of CYP3A4. If danazol is used in combination with brexpiprazole and a moderate to strong CYP2D6 inhibitor, the brexpiprazole dose should be adjusted and the patient should be carefully monitored for brexpiprazole-related adverse reactions. A reduction of the brexpiprazole dose to 25% of the usual dose is also recommended in patients who are poor metabolizers of CYP2D6 and are receiving a moderate CYP3A4 inhibitor.
    Bromocriptine: (Major) When bromocriptine is used for diabetes, do not exceed a dose of 1.6 mg once daily during concomitant use of danazol. Use this combination with caution in patients receiving bromocriptine for other indications. Concurrent use may increase bromocriptine concentrations. Bromocriptine is extensively metabolized in the liver via CYP3A4; danazol is a moderate inhibitor of CYP3A4. Administration of bromocriptine with a moderate inhibitor of CYP3A4 increased the bromocriptine mean AUC and Cmax by 3.7-fold and 4.6-fold, respectively.
    Brompheniramine; Guaifenesin; Hydrocodone: (Major) Monitor for respiratory depression and sedation if hydrocodone and danazol are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as danazol, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and danazol are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as danazol, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Budesonide: (Moderate) Avoid coadministration of oral budesonide and danazol due to the potential for increased budesonide exposure. Use caution with inhaled forms of budesonide as systemic exposure to the corticosteroid may also increase. Budesonide is a CYP3A4 substrate; danazol is a moderate CYP3A4 inhibitor. In the presence of a strong CYP3A4 inhibitor, the systemic exposure to oral budesonide was increased by 8-fold.
    Budesonide; Formoterol: (Moderate) Avoid coadministration of oral budesonide and danazol due to the potential for increased budesonide exposure. Use caution with inhaled forms of budesonide as systemic exposure to the corticosteroid may also increase. Budesonide is a CYP3A4 substrate; danazol is a moderate CYP3A4 inhibitor. In the presence of a strong CYP3A4 inhibitor, the systemic exposure to oral budesonide was increased by 8-fold.
    Bupivacaine; Lidocaine: (Moderate) Danazol is a CYP3A4 inhibitor and may decrease the hepatic metabolism of lidocaine. Patients receiving lidocaine should be closely monitored for toxicity if danazol is added to therapy.
    Buspirone: (Minor) Danazol is a CYP3A4 inhibitor and can decrease the hepatic metabolism of buspirone, a CYP3A4 substrate.
    Cabazitaxel: (Major) Cabazitaxel is a CYP3A4 substrate, and concomitant use of cabazitaxel with strong CYP3A4 inhibitors such as danazol is expected to increase cabazitaxel concentrations. Concomitant administration of cabazitaxel and strong CYP3A4 inhibitors should be avoided. Consider alternative therapies with low enzyme induction potential.
    Cabozantinib: (Moderate) Monitor for an increase in cabozantinib-related adverse events if concomitant use with danazol is necessary. Cabozantinib is primarily metabolized by CYP3A4 and danazol is a CYP3A4 inhibitor. Coadministration with a strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), increased cabozantinib (single dose) exposure by 38%. The manufacturer of cabozantinib recommends a dose reduction when used with strong CYP3A4 inhibitors; however, recommendations are not available for concomitant use with a moderate inhibitor of CYP3A4.
    Caffeine; Ergotamine: (Major) Danazol is a CYP3A4 inhibitor and can decrease the hepatic metabolism of some drugs, such as ergot alkaloids, and lead to ergot toxicity.
    Canagliflozin: (Moderate) Canagliflozin is a substrate/weak inhibitor of drug transporter P glycoprotein (P-gp). Testosterone is a P-gp inhibitor/substrate. Theoretically, concentrations of canagliflozin may be increased. Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Canagliflozin; Metformin: (Moderate) Canagliflozin is a substrate/weak inhibitor of drug transporter P glycoprotein (P-gp). Testosterone is a P-gp inhibitor/substrate. Theoretically, concentrations of canagliflozin may be increased. Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary. (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Carbamazepine: (Moderate) Carbamazepine is metabolized by the hepatic isoenzyme CYP3A4. Danazol is known to inhibit CYP3A4 and may decrease carbamazepine metabolism and increase carbamazepine plasma concentrations.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and danazol are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as danazol, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and danazol are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as danazol, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Cariprazine: (Moderate) Cariprazine and its active metabolites are extensively metabolized by CYP3A4. Danazol inhibits CYP3A4 and may reduce the hepatic metabolism of CYP3A4 substrates, although the impact of moderate CYP3A4 inhibitors on cariprazine metabolism has not been studied. Monitoring for adverse effects, such as CNS effects and extrapyramidal symptoms, is advisable during coadministration.
    Chlordiazepoxide: (Moderate) Danazol is a CYP3A4 inhibitor and can theoretically reduce the metabolism of CYP3A4 substrates, including chlordiazepoxide.
    Chlordiazepoxide; Clidinium: (Moderate) Danazol is a CYP3A4 inhibitor and can theoretically reduce the metabolism of CYP3A4 substrates, including chlordiazepoxide.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and danazol are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as danazol, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Chlorpheniramine; Hydrocodone: (Major) Monitor for respiratory depression and sedation if hydrocodone and danazol are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as danazol, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and danazol are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as danazol, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and danazol are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as danazol, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Cilostazol: (Moderate) Danazol can decrease hepatic synthesis of procoagulant factors, increasing the possibility of bleeding when used concurrently with platelet inhibitors.
    Cisapride: (Severe) Cisapride is metabolized by the hepatic cytochrome P450 enzyme system, specifically the CYP3A4 isoenzyme. QT prolongation and ventricular arrhythmias, including torsade de pointes and death, have been reported when known and potent inhibitors of CYP3A4 are coadministered with cisapride. Danazol has the potential to inhibit the metabolism of cisapride through CYP3A4 and thus, should not be used with cisapride.
    Clevidipine: (Minor) Danazol is a CYP3A4 inhibitor and can decrease the hepatic metabolism of CYP3A4 substrates like calcium-channel blockers.
    Clindamycin: (Moderate) Concomitant use of clindamycin and danazol may decrease clindamycin clearance and increase the risk of adverse reactions. Clindamycin is a CYP3A4 substrate; danazol is a moderate inhibitor of CYP3A4. Caution and close monitoring are advised if these drugs are used together.
    Clonazepam: (Moderate) Danazol is a CYP3A4 inhibitor and can decrease the hepatic metabolism of clonazepam, a CYP3A4 substrate.
    Clopidogrel: (Moderate) Administer clopidogrel and danazol together with caution. Clopidogrel requires hepatic biotransformation via 2 cytochrome dependent oxidative steps. The CYP3A4 isoenzyme is involved in one of the metabolic steps. Danazol is an inhibitor of CYP3A4 and may decrease the hepatic metabolism of clopidogrel to its active metabolite. Therefore, the therapeutic effectiveness of clopidogrel should be monitored when used concomitantly with danazol.
    Clorazepate: (Moderate) Danazol is a CYP3A4 inhibitor and can decrease the hepatic metabolism of clorazepate, a CYP3A4 substrate.
    Clozapine: (Moderate) Caution is advisable during concurrent use of danazol and clozapine. Danazol is an inhibitor of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP3A4 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
    Cobicistat: (Moderate) Caution is warranted when cobicistat is administered with danazol as there is a potential for elevated cobicistat concentrations. Danazol is a CYP3A4 inhibitor and cobicistat is a substrate of CYP3A4.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Caution is warranted when cobicistat is administered with danazol as there is a potential for elevated cobicistat concentrations. Danazol is a CYP3A4 inhibitor and cobicistat is a substrate of CYP3A4. (Moderate) Caution is warranted when cobicistat is administered with danazol as there is a potential for elevated elvitegravir concentrations. Danazol is a CYP3A4 inhibitor and elvitegravir is a substrate of CYP3A4.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is warranted when cobicistat is administered with danazol as there is a potential for elevated cobicistat concentrations. Danazol is a CYP3A4 inhibitor and cobicistat is a substrate of CYP3A4. (Moderate) Caution is warranted when cobicistat is administered with danazol as there is a potential for elevated elvitegravir concentrations. Danazol is a CYP3A4 inhibitor and elvitegravir is a substrate of CYP3A4.
    Cobimetinib: (Major) Avoid the concurrent use of cobimetinib with chronic danazol therapy due to the risk of cobimetinib toxicity. If concurrent short-term (14 days or less) use of danazol is unavoidable, reduce the dose of cobimetinib to 20 mg once daily for patients normally taking 60 mg daily; after discontinuation of danazol, resume cobimetinib at the previous dose. Use an alternative to danazol in patients who are already taking a reduced dose of cobimetinib (40 or 20 mg daily). Cobimetinib is a CYP3A substrate in vitro, and danazol is a moderate inhibitor of CYP3A. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7).
    Conivaptan: (Moderate) Conivaptan is a substrate of CYP3A4. Coadministration of conivaptan with CYP3A4 inhibitors like danazol could lead to an increase in conivaptan serum concentrations.
    Conjugated Estrogens: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as danazol may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Conjugated Estrogens; Bazedoxifene: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as danazol may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Conjugated Estrogens; Medroxyprogesterone: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as danazol may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Crizotinib: (Moderate) Monitor for an increase in crizotinib-related adverse reactions if coadministration with danazol is necessary. Crizotinib is a CYP3A substrate and danazol is a moderate CYP3A inhibitor.
    Cyclosporine: (Major) Danazol has been reported to increase concentrations of cyclosporine. Danazol is an inhibitor of CYP3A4 while cyclosporine is a substrate of CYP3A4. In a patient stabilized on cyclosporine, the addition of danazol 200 mg every 8 hours yielded a 38% increase in the cyclosporine blood concentration and necessitated a cyclosporine dosage reduction from 250 mg twice daily to 200 mg twice daily. Close monitoring of cyclosporine concentrations is required when danazol is given concurrently with cyclosporine. Case reports suggest that methyltestosterone may also increase plasma concentrations of cyclosporine, potentially increasing the risk of nephrotoxicity. The mechanism has not been established but is thought to be due to inhibition of cyclosporine metabolism. No data are available to evaluate whether other androgens act similarly. Until further data are available, close monitoring of cyclosporine serum concentrations is prudent during coadministration with androgens.
    Dabigatran: (Major) Danazol can decrease hepatic synthesis of procoagulant factors, increasing the possibility of bleeding when used concurrently with anticoagulants.
    Daclatasvir: (Moderate) Concurrent administration of daclatasvir, a CYP3A4 substrate, with danazol, a moderate CYP3A4 inhibitor, may increase daclatasvir serum concentrations. If these drugs are administered together, monitor patients for daclatasvir-related adverse effects, such as headache, fatigue, nausea, and diarrhea. The manufacturer does not recommend daclatasvir dose reduction for adverse reactions.
    Dalteparin: (Major) Danazol can decrease hepatic synthesis of procoagulant factors, increasing the possibility of bleeding when used concurrently with anticoagulants.
    Danaparoid: (Major) Danazol can decrease hepatic synthesis of procoagulant factors, increasing the possibility of bleeding when used concurrently with anticoagulants.
    Dapagliflozin: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Dapagliflozin; Metformin: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary. (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Dapagliflozin; Saxagliptin: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia. However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary. Also, saxagliptin is primarily metabolized by CYP3A4/5; saxagliptin plasma concentrations may increase in the presence of moderate CYP3A4/5 inhibitors such as danazol. (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Darbepoetin Alfa: (Moderate) Androgens are known to stimulate erythropoiesis. Concurrent administration of androgens can increase the patient's response to darbepoetin alfa, reducing the amount required to treat anemia.
    Darunavir: (Moderate) Caution is warranted when darunavir is administered with danazol as there is a potential for elevated concentrations of darunavir. Danazol is a CYP3A4 inhibitor; darunavir is a substrate of CYP3A4.
    Darunavir; Cobicistat: (Moderate) Caution is warranted when cobicistat is administered with danazol as there is a potential for elevated cobicistat concentrations. Danazol is a CYP3A4 inhibitor and cobicistat is a substrate of CYP3A4. (Moderate) Caution is warranted when darunavir is administered with danazol as there is a potential for elevated concentrations of darunavir. Danazol is a CYP3A4 inhibitor; darunavir is a substrate of CYP3A4.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Concurrent administration of danazol with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of dasabuvir, paritaprevir, and ritonavir. Danazol is an inhibitor of the hepatic isoenzyme CYP3A4; ritonavir, paritaprevir and dasabuvir (minor) are substrates of this enzyme. Although therapy with dasabuvir; ombitasvir; paritaprevir; ritonavir did not prolong the QTc interval to a clinical relevant extent in healthy subjects, ritonavir has been associated with concentration-dependent QT prolongation in other trials. Caution and close monitoring are advised if these drugs are administered together. (Moderate) Concurrent administration of danazol with ritonavir may result in elevated plasma concentrations of ritonavir. Danazol is an inhibitor of the hepatic isoenzyme CYP3A4; ritonavir is a substrate of this enzyme. Ritonavir has been associated with concentration-dependent QT prolongation in trials. Caution and close monitoring are advised if these drugs are administered together.
    Dasatinib: (Moderate) Dasatinib is metabolized by CYP3A4. Concurrent administration of inhibitors of this isoenzyme, such as danazol, may increase concentrations of dasatinib.
    Deflazacort: (Major) Decrease deflazacort dose to one third of the recommended dosage when coadministered with danazol. Concurrent use may significantly increase concentrations of 21-desDFZ, the active metabolite of deflazacort, resulting in an increased risk of toxicity. Deflazacort is a CYP3A4 substrate; danazol is a moderate inhibitor of CYP3A4. Administration of deflazacort with clarithromycin, a strong CYP3A4 inhibitor, increased total exposure to 21-desDFZ by about 3-fold.
    Degarelix: (Major) Concomitant use of androgens with degarelix is relatively contraindicated, as androgens could counteract the therapeutic effect of degarelix.
    Desirudin: (Major) Danazol can decrease hepatic synthesis of procoagulant factors, increasing the possibility of bleeding when used concurrently with anticoagulants.
    Dextromethorphan; Quinidine: (Moderate) Danazol is a CYP3A4 inhibitor and can decrease the hepatic metabolism of CYP3A4 substrates including quinidine.
    Diazepam: (Moderate) Danazol is a CYP3A4 inhibitor and can decrease the hepatic metabolism of diazepam.
    Dienogest; Estradiol valerate: (Minor) As danazol inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives, including oral contraceptives.
    Dihydroergotamine: (Major) Danazol is a CYP3A4 inhibitor and can decrease the hepatic metabolism of some drugs, such as ergot alkaloids, and lead to ergot toxicity.
    Diltiazem: (Minor) Danazol is a CYP3A4 inhibitor and can decrease the hepatic metabolism of CYP3A4 substrates like calcium-channel blockers.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and danazol are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as danazol, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Dipyridamole: (Moderate) Danazol can decrease hepatic synthesis of procoagulant factors, increasing the possibility of bleeding when used concurrently with platelet inhibitors.
    Disopyramide: (Moderate) Danazol is a CYP3A4 inhibitor and can decrease the hepatic metabolism of disopyramide. Patients receiving disoyramide should be closely monitored for toxicity if danazol is added to therapy.
    Dofetilide: (Major) Danazol could significantly inhibit the CYP3A4 metabolism of dofetilide. The resultant increase in serum dofetilide concentrations could increase the risk of torsade de pointes.
    Doxercalciferol: (Moderate) CYP450 enzyme inhibitors, like danazol, may inhibit the 25-hydroxylation of doxercalciferol, thereby decreasing the formation of the active metabolite and thus, decreasing efficacy. Patients should be monitored for a decrease in efficacy if CYP450 inhibitors are coadministered with doxercalciferol.
    Doxorubicin: (Major) Danazol is a CYP3A4 inhibitor and doxorubicin is a major CYP3A4 substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP3A4, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of danazol and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Dronabinol, THC: (Major) Use caution if coadministration of dronabinol with danazol is necessary, and monitor for an increase in dronabinol-related adverse reactions (e.g., feeling high, dizziness, confusion, somnolence). Dronabinol is a CYP2C9 and 3A4 substrate; danazol is a moderate inhibitor of CYP3A4. Concomitant use may result in elevated plasma concentrations of dronabinol.
    Dronedarone: (Moderate) Dronedarone and danazol should be coadministered with caution. Dronedarone is metabolized by CYP3A. Danazol is an inhibitor of CYP3A4. Concomitant use of dronedarone with danazol may increase dronedarone concentrations.
    Drospirenone; Estradiol: (Minor) As danazol inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives, including oral contraceptives.
    Dutasteride; Tamsulosin: (Moderate) Use caution when administering tamsulosin with a moderate CYP3A4 inhibitor such as danazol. Tamsulosin is extensively metabolized by CYP3A4 hepatic enzymes. In clinical evaluation, concomitant treatment with a strong CYP3A4 inhibitor resulted in significant increases in tamsulosin exposure; interactions with moderate CYP3A4 inhibitors have not been evaluated. If concomitant use in necessary, monitor patient closely for increased side effects.
    Elbasvir; Grazoprevir: (Moderate) Administering elbasvir; grazoprevir with danazol may cause the plasma concentrations of elbasvir and grazoprevir to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Danazol is a moderate CYP3A inhibitor. Both elbasvir and grazoprevir are metabolized by CYP3A. If these drugs are used together, closely monitor for signs of hepatotoxicity.
    Eletriptan: (Major) Eletriptan is contraindicated for use within 72 hours of danazol. The concomitant use of medications that significantly inhibit the CYP3A4 isozyme, such as danazol, with eletriptan may result in elevations in eletriptan concentrations.
    Eliglustat: (Major) In intermediate or poor CYP2D6 metabolizers (IMs or PMs), coadministration of danazol and eliglustat is not recommended. In extensive CYP2D6 metabolizers (EMs), coadministration of the agents requires dosage reduction of eliglustat to 84 mg PO once daily. The coadministration of eliglustat with both danazol and a moderate or strong CYP2D6 inhibitor is contraindicated in all patients. Danazol is a moderate CYP3A inhibitor; eliglustat is a CYP3A and CYP2D6 substrate. Coadministration of eliglustat with CYP3A inhibitors may increase eliglustat exposure and the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias); this risk is the highest in CYP2D6 IMs and PMs because a larger portion of the eliglustat dose is metabolized via CYP3A.
    Elvitegravir: (Moderate) Caution is warranted when cobicistat is administered with danazol as there is a potential for elevated elvitegravir concentrations. Danazol is a CYP3A4 inhibitor and elvitegravir is a substrate of CYP3A4.
    Empagliflozin: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Empagliflozin; Linagliptin: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Empagliflozin; Metformin: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary. (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Close clinical monitoring is advised when administering danazol with rilpivirine due to an increased potential for rilpivirine-related adverse events. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Danazol is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Moderate) Close clinical monitoring is advised when administering danazol with rilpivirine due to an increased potential for rilpivirine-related adverse events. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Danazol is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
    Enalapril; Felodipine: (Minor) Danazol is a CYP3A4 inhibitor and can decrease the hepatic metabolism of CYP3A4 substrates like calcium-channel blockers.
    Enoxaparin: (Major) Danazol can decrease hepatic synthesis of procoagulant factors, increasing the possibility of bleeding when used concurrently with anticoagulants.
    Eplerenone: (Major) Eplerenone is metabolized by the CYP3A4 pathway. Danazol inhibits the hepatic CYP3A4 isoenzyme and therefore may increase the serum concentrations of eplerenone. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension. If these medications are given concurrently in post-myocardial infarction patients with heart failure, do not exceed an eplerenone dose of 25 mg PO once daily. If these medications are given concurrently, and eplerenone is used for hypertension, initiate eplerenone at 25 mg PO once daily. The dose may be increased to a maximum of 25 mg PO twice daily for inadequate blood pressure response.
    Epoetin Alfa: (Moderate) Androgens are known to stimulate erythropoiesis. Concurrent administration of androgens can increase the patient's response to epoetin alfa, reducing the amount required to treat anemia. Because adverse reactions have been associated with an abrupt increase in blood viscosity, this drug combination should be avoided, if possible. Further evaluation of this combination needs to be made.
    Eptifibatide: (Moderate) Danazol can decrease hepatic synthesis of procoagulant factors, increasing the possibility of bleeding when used concurrently with platelet inhibitors.
    Ergoloid Mesylates: (Major) Danazol is a CYP3A4 inhibitor and can decrease the hepatic metabolism of some drugs, such as ergot alkaloids, and lead to ergot toxicity.
    Ergonovine: (Major) Danazol is a CYP3A4 inhibitor and can decrease the hepatic metabolism of some drugs, such as ergot alkaloids, and lead to ergot toxicity.
    Ergot alkaloids: (Major) Danazol is a CYP3A4 inhibitor and can decrease the hepatic metabolism of some drugs, such as ergot alkaloids, and lead to ergot toxicity.
    Ergotamine: (Major) Danazol is a CYP3A4 inhibitor and can decrease the hepatic metabolism of some drugs, such as ergot alkaloids, and lead to ergot toxicity.
    Esterified Estrogens: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as danazol may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Esterified Estrogens; Methyltestosterone: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as danazol may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Estradiol Cypionate; Medroxyprogesterone: (Minor) As danazol inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives, including oral contraceptives.
    Estradiol: (Minor) As danazol inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives, including oral contraceptives.
    Estradiol; Levonorgestrel: (Minor) As danazol inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives, including oral contraceptives.
    Estradiol; Norethindrone: (Minor) As danazol inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives, including oral contraceptives.
    Estradiol; Norgestimate: (Minor) As danazol inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives, including oral contraceptives.
    Estropipate: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4, such as danazol, may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Ethinyl Estradiol; Etonogestrel: (Minor) Coadministration of etonogestrel and moderate CYP3A4 inhibitors such as danazol may increase the serum concentration of etonogestrel.
    Ethosuximide: (Minor) Danazol is a CYP3A4 inhibitor and can decrease the hepatic metabolism of ethosuximide, a CYP3A4 substrate. Patients receiving these agents should be closely monitored for toxicity if danazol is added to therapy. Conversely, a dose adjustment of either drug may be necessary if danazol therapy is discontinued.
    Etonogestrel: (Minor) Coadministration of etonogestrel and moderate CYP3A4 inhibitors such as danazol may increase the serum concentration of etonogestrel.
    Etoposide, VP-16: (Major) Monitor for an increased incidence of etoposide-related adverse effects if used concomitantly with danazol. Danazol is an inhibitor of CYP3A4 and etoposide, VP-16 is a CYP3A4 substrate. Coadministration may increase etoposide concentrations.
    Everolimus: (Major) Everolimus is a substrate of CYP3A4. Coadministration with strong or moderate inhibitors of CYP3A4, such as danazol, is not recommended. Patients may experience an increase in systemic exposure to everolimus if these drugs are coadministered.
    Ezetimibe; Simvastatin: (Severe) The use of simvastatin with danazol is contraindicated due to an increased risk of myopathy and rhabdomyolysis. A single case report has documented the onset of myositis that progressed to rhabdomyolysis with myoglobinuria after danazol was added to a regimen containing lovastatin. Although other drugs were in use concurrently, a drug interaction between danazol and lovastatin is suspected, as danazol (CYP3A4 inhibitor) is known to inhibit lovastatin metabolism.
    Felodipine: (Minor) Danazol is a CYP3A4 inhibitor and can decrease the hepatic metabolism of CYP3A4 substrates like calcium-channel blockers.
    Fentanyl: (Moderate) Danazol is a CYP3A4 inhibitor and can theoretically reduce the metabolism of other CYP3A4 substrates incuding fentanyl. Patients receiving these fentanyl should be closely monitored for toxicity if danazol is added to therapy. Conversely, a dose adjustment of either drug may be necessary if danazol therapy is discontinued.
    Flibanserin: (Severe) The concomitant use of flibanserin and moderate CYP3A4 inhibitors, such as danazol, is contraindicated. Moderate CYP3A4 inhibitors can increase flibanserin concentrations, which can cause severe hypotension and syncope. If initiating flibanserin following use of a moderate CYP3A4 inhibitor, start flibanserin at least 2 weeks after the last dose of the CYP3A4 inhibitor. If initiating a moderate CYP3A4 inhibitor following flibanserin use, start the moderate CYP3A4 inhibitor at least 2 days after the last dose of flibanserin.
    Flurazepam: (Moderate) Danazol is a CYP3A4 inhibitor and can decrease the hepatic metabolism of drugs metabolized by this enzyme, including flurazepam. Patients receiving these agents should be closely monitored for toxicity if danazol is added to therapy. Conversely, a dose adjustment of either drug may be necessary if danazol therapy is discontinued.
    Fondaparinux: (Major) Danazol can decrease hepatic synthesis of procoagulant factors, increasing the possibility of bleeding when used concurrently with anticoagulants.
    Food: (Moderate) The incidence of marijuana associated adverse effects may change following coadministration with danazol. Danazol is an inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of marijuana's most psychoactive compound, delta-9-tetrahydrocannabinol (Delta-9-THC). When given concurrently with danazol, the amount of Delta-9-THC converted to the active metabolite 11-hydroxy-delta-9-tetrahydrocannabinol (11-OH-THC) may be reduced. These changes in Delta-9-THC and 11-OH-THC plasma concentrations may result in an altered marijuana adverse event profile.
    Gefitinib: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and danazol are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and danazol is a moderate CYP3A4 inhibitor; coadministration may decrease the metabolism of gefitinib and increase gefitinib concentrations. While the manufacturer has provided no guidance regarding the use of gefitinib with mild or moderate CYP3A4 inhibitors, administration of a single 250 mg gefitinib dose with a strong CYP3A4 inhibitor (itraconazole) increased the mean AUC of gefitinib by 80%.
    Glipizide; Metformin: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Glyburide; Metformin: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Goserelin: (Major) Goserelin inhibits steroidogenesis. Concomitant use of androgens, like fluoxymesterone, with goserelin is relatively contraindicated and would defeat the purpose of goserelin therapy.
    Guaifenesin; Hydrocodone: (Major) Monitor for respiratory depression and sedation if hydrocodone and danazol are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as danazol, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and danazol are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as danazol, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Halofantrine: (Major) Danazol is a CYP3A4 inhibitor and can decrease the hepatic metabolism of CYP3A4 substrates. Examples of CYP3A4 substrates with potential for a narrow therapeutic index, include halofantrine.
    Haloperidol: (Moderate) Danazol is an inhibitor of CYP3A4, one of the isoenzymes responsible for the metabolism of haloperidol. Mild to moderate increases in haloperidol plasma concentrations have been reported during concurrent use of haloperidol and inhibitors of CYP3A4. Until more data are available, it is advisable to closely monitor for adverse events when these medications are co-administered.
    Heparin: (Major) Danazol can decrease hepatic synthesis of procoagulant factors, increasing the possibility of bleeding when used concurrently with anticoagulants.
    Histrelin: (Major) Gonadotropin releasing hormone (GnRH) agonists (i.e.,histrelin) inhibit steroidogenesis, therefore the concomitant use of these agents with androgens may counteract this therapeutic effect. Avoid concurrent use of androgens with GnRH agonists.
    Homatropine; Hydrocodone: (Major) Monitor for respiratory depression and sedation if hydrocodone and danazol are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as danazol, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Hydrocodone: (Major) Monitor for respiratory depression and sedation if hydrocodone and danazol are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as danazol, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Hydrocodone; Ibuprofen: (Major) Monitor for respiratory depression and sedation if hydrocodone and danazol are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as danazol, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Hydrocodone; Phenylephrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and danazol are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as danazol, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Hydrocodone; Potassium Guaiacolsulfonate: (Major) Monitor for respiratory depression and sedation if hydrocodone and danazol are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as danazol, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and danazol are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as danazol, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Hydrocodone; Pseudoephedrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and danazol are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as danazol, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Hydroxyprogesterone: (Minor) In vitro data indicate that the metabolism of hydroxyprogesterone is predominantly mediated by CYP3A4 and CYP3A5. The metabolism of progesterone is inhibited by ketoconazole, a known inhibitor of cytochrome P450 3A4 hepatic enzymes. Theoretically, the metabolism of hydroxyprogesterone may also be inhibited by ketoconazole. It has not been determined whether other drugs which inhibit CYP3A4 hepatic enzymes would have a similar effect. Other such drugs include cimetidine, clarithromycin, danazol, diltiazem, erythromycin, fluconazole, itraconazole, troleandomycin, verapamil, and voriconazole. This list is not inclusive of all drugs that inhibit CYP3A4.
    Ibrutinib: (Major) If coadministered with danazol, initiate ibrutinib therapy at a reduced dose of 140 mg/day PO for the treatment of B-cell malignancy or 420 mg/day PO for the treatment of chronic graft-versus-host disease; monitor patients more frequently for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate; danazol is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the Cmax and AUC values of ibrutinib were increased by 3.4-fold and 3-fold, respectively.
    Ibuprofen; Oxycodone: (Moderate) Concomitant use of oxycodone with danazol may increase oxycodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of oxycodone until stable drug effects are achieved. Discontinuation of danazol could decrease oxycodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to oxycodone. If danazol is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Oxycodone is a substrate for CYP3A4 and danazol is a CYP3A4 inhibitor.
    Incretin Mimetics: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Insulins: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Irinotecan Liposomal: (Moderate) Use caution if irinotecan liposomal is coadministered with danazol, a CYP3A4 inhibitor, due to increased risk of irinotecan-related toxicity. The metabolism of liposomal irinotecan has not been evaluated; however, coadministration of ketoconazole, a strong CYP3A4 and UGT1A1 inhibitor, with non-liposomal irinotecan HCl resulted in increased exposure to both irinotecan and its active metabolite, SN-38.
    Irinotecan: (Moderate) Danazol is a moderate inhibitor of CYP3A4; irinotecan is a CYP3A4 substrate. Coadministration may result in increased irinotecan exposure. Use caution if concomitant use is necessary and monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression.
    Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with danazol may result in increased serum concentrations of isavuconazonium. Isavuconazole, the active moiety of isavuconazonium, is a sensitive substrate of the hepatic isoenzyme CYP3A4; danazol is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
    Isradipine: (Minor) Danazol is a CYP3A4 inhibitor and can decrease the hepatic metabolism of CYP3A4 substrates like calcium-channel blockers.
    Ivabradine: (Major) Avoid coadminsitration of ivabradine and danazol as increased concentrations of ivabradine are possible. Ivabradine is primarily metabolized by CYP3A4; danazol inhibits CYP3A4. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Ivacaftor: (Major) Use caution when administering ivacaftor and danazol concurrently; increased monitoring and/or dose reduction of ivacaftor may be necessary. The manufacturer recommends administering ivacaftor at the usual recommended dose but reducing the frequency to once daily when used concurrently with a moderate CYP3A inhibitor. Ivacaftor is a CYP3A substrate, and danazol is a CYP3A inhibitor. Coadministration with fluconazole, a moderate CYP3A inhibitor, increased ivacaftor exposure by 3-fold.
    Ixabepilone: (Major) Ixabepilone is a CYP3A4 substrate, and concomitant use of ixabepilone with strong CYP3A4 inhibitors such as danazol should be avoided. Alternative therapies that do not inhibit the CYP3A4 isoenzyme should be considered. If concurrent treatment with a strong CYP3A4 inhibitor is necessary, strongly consider an ixabepilone dose reduction. Closely monitor patients for ixabepilone-related toxicities. If a strong CYP3A4 inhibitor is discontinued, allow 7 days to elapse before increasing the ixabepilone dose.
    Lapatinib: (Moderate) Lapatinib is a CYP3A4 substrate, and concomitant use of lapatinib with danazol, a CYP3A4 inhibitor, may result in decreased metabolism and increased serum concentrations of lapatinib.
    Leuprolide: (Major) Leuprolide inhibits steroidogenesis. While no drug interactions have been reported with leuprolide, therapy with androgens would be relatively contraindicated and would counteract the therapeutic effect of leuprolide.
    Leuprolide; Norethindrone: (Major) Leuprolide inhibits steroidogenesis. While no drug interactions have been reported with leuprolide, therapy with androgens would be relatively contraindicated and would counteract the therapeutic effect of leuprolide.
    Lidocaine: (Moderate) Danazol is a CYP3A4 inhibitor and may decrease the hepatic metabolism of lidocaine. Patients receiving lidocaine should be closely monitored for toxicity if danazol is added to therapy.
    Linagliptin: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Linagliptin; Metformin: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary. (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Loperamide: (Moderate) The plasma concentration of loperamide, a CYP3A4 substrate, may be increased when administered concurrently with danazol, a CYP3A4 inhibitor. If these drugs are used together, monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest).
    Loperamide; Simethicone: (Moderate) The plasma concentration of loperamide, a CYP3A4 substrate, may be increased when administered concurrently with danazol, a CYP3A4 inhibitor. If these drugs are used together, monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest).
    Lopinavir; Ritonavir: (Moderate) Concurrent administration of danazol with ritonavir may result in elevated plasma concentrations of ritonavir. Danazol is an inhibitor of the hepatic isoenzyme CYP3A4; ritonavir is a substrate of this enzyme. Ritonavir has been associated with concentration-dependent QT prolongation in trials. Caution and close monitoring are advised if these drugs are administered together.
    Lovastatin: (Major) The risk of myopathy and rhabdomyolysis is increased if danazol is used with lovastatin. In adult patients taking danazol, the initial lovastatin dose should not exceed 10 mg/day PO, and the total lovastatin dose should not exceed 20 mg/day PO. A single case report has documented the onset of myositis which progressed to rhabdomyolysis with myoglobinuria after danazol was added to a regimen containing lovastatin. Although other drugs were in use concurrently, a drug interaction between danazol and lovastatin is suspected since danazol (CYP3A4 inhibitor) is known to inhibit lovastatin metabolism. If concurrent use of lovastatin and danazol is desired, carefully weigh the benefit of lovastatin against the risk of myopathy and rhabdomyolysis.
    Lovastatin; Niacin: (Major) The risk of myopathy and rhabdomyolysis is increased if danazol is used with lovastatin. In adult patients taking danazol, the initial lovastatin dose should not exceed 10 mg/day PO, and the total lovastatin dose should not exceed 20 mg/day PO. A single case report has documented the onset of myositis which progressed to rhabdomyolysis with myoglobinuria after danazol was added to a regimen containing lovastatin. Although other drugs were in use concurrently, a drug interaction between danazol and lovastatin is suspected since danazol (CYP3A4 inhibitor) is known to inhibit lovastatin metabolism. If concurrent use of lovastatin and danazol is desired, carefully weigh the benefit of lovastatin against the risk of myopathy and rhabdomyolysis.
    Lumacaftor; Ivacaftor: (Major) Use caution when administering ivacaftor and danazol concurrently; increased monitoring and/or dose reduction of ivacaftor may be necessary. The manufacturer recommends administering ivacaftor at the usual recommended dose but reducing the frequency to once daily when used concurrently with a moderate CYP3A inhibitor. Ivacaftor is a CYP3A substrate, and danazol is a CYP3A inhibitor. Coadministration with fluconazole, a moderate CYP3A inhibitor, increased ivacaftor exposure by 3-fold.
    Lurasidone: (Major) Danazol is a moderate inhibitor of CYP3A4 and has the potential for interactions with substrates of CYP3A4 such as lurasidone. Concurrent use of these medications may lead to an increased risk of lurasidone-related adverse reactions. If a moderate inhibitor of CYP3A4 is being prescribed and lurasidone is added in an adult patient, the recommended starting dose of lurasidone is 20 mg/day and the maximum recommended daily dose of lurasidone is 80 mg/day. If a moderate CYP3A4 inhibitor is added to an existing lurasidone regimen, reduce the lurasidone dose to one-half of the original dose. Patients should be monitored for efficacy and toxicity.
    Maraviroc: (Moderate) Use caution if coadministration of maraviroc with danazol is necessary, due to a possible increase in maraviroc exposure. Maraviroc is a CYP3A substrate and danazol is a CYP3A4 inhibitor. Monitor for an increase in adverse effects with concomitant use.
    Mefloquine: (Moderate) Mefloquine is metabolized by CYP3A4. Danazol is an inhibitor of this enzyme and may decrease the clearance of mefloquine and increase mefloquine systemic exposure.
    Meglitinides: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Metformin: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Metformin; Pioglitazone: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Metformin; Repaglinide: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Metformin; Rosiglitazone: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Metformin; Saxagliptin: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia. However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary. Also, saxagliptin is primarily metabolized by CYP3A4/5; saxagliptin plasma concentrations may increase in the presence of moderate CYP3A4/5 inhibitors such as danazol. (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Metformin; Sitagliptin: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary. (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Methadone: (Moderate) Danazol is a CYP3A4 inhibitor and can decrease the hepatic metabolism of drugs that are CYP3A4 substrates including methadone.
    Methoxy polyethylene glycol-epoetin beta: (Moderate) Androgens are known to stimulate erythropoiesis. Despite the fact that endogenous generation of erythropoietin is depressed in patients with chronic renal failure, other tissues besides the kidney can synthesize erythropoietin, albeit in small amounts. Concurrent administration of androgens can increase the patient's response to MPG-epoetin beta, reducing the amount required to treat anemia. Because adverse reactions have been associated with an abrupt increase in blood viscosity, this drug combination should be avoided, if possible. Further evaluation of this combination needs to be made.
    Methylergonovine: (Major) Danazol is a CYP3A4 inhibitor and can decrease the hepatic metabolism of some drugs, such as ergot alkaloids, and lead to ergot toxicity.
    Methysergide: (Major) Danazol is a CYP3A4 inhibitor and can decrease the hepatic metabolism of some drugs, such as ergot alkaloids, and lead to ergot toxicity.
    Midazolam: (Moderate) Danazol is a CYP3A4 inhibitor and can decrease the hepatic metabolism of some drugs that are CYP3A4 substrates including midazolam.
    Miglitol: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Nafarelin: (Major) Gonadotropin releasing hormone (GnRH) agonists (i.e.,nafarelin) inhibit steroidogenesis, therefore the concomitant use of these agents with androgens may counteract this therapeutic effect. Avoid concurrent use of androgens with GnRH agonists.
    Naldemedine: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with danazol. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a CYP3A4 substrate; danazol is a moderate CYP3A4 inhibitor.
    Neratinib: (Major) Avoid concomitant use of danazol with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and danazol is a moderate CYP3A4 inhibitor. The effect of moderate CYP3A4 inhibition on neratinib concentrations has not been studied; however, coadministration with a strong CYP3A4 inhibitor increased neratinib exposure by 481%. Because of the significant impact on neratinib exposure from strong CYP3A4 inhibition, the potential impact on neratinib safety from concomitant use with moderate CYP3A4 inhibitors should be considered as they may also significantly increase neratinib exposure.
    Niacin; Simvastatin: (Severe) The use of simvastatin with danazol is contraindicated due to an increased risk of myopathy and rhabdomyolysis. A single case report has documented the onset of myositis that progressed to rhabdomyolysis with myoglobinuria after danazol was added to a regimen containing lovastatin. Although other drugs were in use concurrently, a drug interaction between danazol and lovastatin is suspected, as danazol (CYP3A4 inhibitor) is known to inhibit lovastatin metabolism.
    Nicardipine: (Minor) Danazol is a CYP3A4 inhibitor and can decrease the hepatic metabolism of CYP3A4 substrates like calcium-channel blockers.
    Nifedipine: (Minor) Danazol is a CYP3A4 inhibitor and can decrease the hepatic metabolism of CYP3A4 substrates like calcium-channel blockers.
    Nilotinib: (Moderate) Concomitant use of nilotinib, a substrate and moderate CYP3A4 inhibitor, and danazol, a CYP3A4 inhibitor, may result in increased nilotinib levels. Monitor patients for nilotinib toxicity (e.g., QT interval prolongation) if these drugs are used together.
    Nimodipine: (Minor) Danazol is a CYP3A4 inhibitor and can decrease the hepatic metabolism of CYP3A4 substrates like calcium-channel blockers.
    Nintedanib: (Moderate) Danazol is a moderate inhibitor of CYP3A4 and nintedanib is a substrate of P-glycoprotein (P-gp) and to a minor extent, CYP3A4. Concomitant use of P-gp and CYP3A4 inhibitors with nintedanib may increase exposure to nintedanib. It is not clear to what extent danazol might affect nintedanib exposure. If concomitant use of danazol and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of nintedanib therapy may be necessary.
    Nisoldipine: (Minor) Danazol is a CYP3A4 inhibitor and can decrease the hepatic metabolism of CYP3A4 substrates like calcium-channel blockers.
    Olaparib: (Major) Avoid coadministration of olaparib with danazol and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 150 mg twice daily; reduce the dose of olaparib capsules to 200 mg twice daily. Olaparib is a CYP3A4/5 substrate and danazol is a moderate CYP3A4 inhibitor.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Concurrent administration of danazol with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of dasabuvir, paritaprevir, and ritonavir. Danazol is an inhibitor of the hepatic isoenzyme CYP3A4; ritonavir, paritaprevir and dasabuvir (minor) are substrates of this enzyme. Although therapy with dasabuvir; ombitasvir; paritaprevir; ritonavir did not prolong the QTc interval to a clinical relevant extent in healthy subjects, ritonavir has been associated with concentration-dependent QT prolongation in other trials. Caution and close monitoring are advised if these drugs are administered together. (Moderate) Concurrent administration of danazol with ritonavir may result in elevated plasma concentrations of ritonavir. Danazol is an inhibitor of the hepatic isoenzyme CYP3A4; ritonavir is a substrate of this enzyme. Ritonavir has been associated with concentration-dependent QT prolongation in trials. Caution and close monitoring are advised if these drugs are administered together.
    Oxybutynin: (Moderate) Oxybutynin is metabolized by CYP3A4. Serum concentrations of oxybutynin may be increased if coadministered with inhibitors of CYP3A4 including danazol. The manufacturer recommends that caution when oxybutynin is co-administered with CYP3A4 inhibitors.
    Oxycodone: (Moderate) Concomitant use of oxycodone with danazol may increase oxycodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of oxycodone until stable drug effects are achieved. Discontinuation of danazol could decrease oxycodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to oxycodone. If danazol is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Oxycodone is a substrate for CYP3A4 and danazol is a CYP3A4 inhibitor.
    Paricalcitol: (Moderate) Care should be taken when dosing paricalcitol with strong CYP3A4 inhibitors, such as danazol. Dose adjustments of paricalcitol may be required. Monitor plasma PTH and serum calcium and phosphorous concentrations if a patient initiates or discontinues therapy with this combination.
    Pazopanib: (Moderate) Pazopanib is a substrate for CYP3A4. Danazol is an inhibitor of CYP3A4. Concurrent administration may result in increased pazopanib concentrations. Dose reduction of pazopanib may be necessary when coadministration of pazopanib and danazol is required.
    Pentosan: (Major) Danazol can decrease hepatic synthesis of procoagulant factors, increasing the possibility of bleeding when used concurrently with anticoagulants.
    Pergolide: (Major) Danazol is a CYP3A4 inhibitor and can decrease the hepatic metabolism of some drugs, such as ergot alkaloids, and lead to ergot toxicity.
    Perindopril; Amlodipine: (Moderate) Coadministration of CYP3A4 inhibitors with amlodipine can theoretically decrease the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inhibitors, such as danazol , are coadministered with calcium-channel blockers. Monitor therapeutic response; a dose reduction of amlodipine may be required.
    Pimozide: (Major) Concurrent use of pimozide and danazol should be avoided. Pimozide is metabolized primarily through CYP3A4, and danazol is a CYP3A4 inhibitor. Elevated pimozide concentrations occurring through inhibition of CYP3A4 can lead to QT prolongation, ventricular arrhythmias, and sudden death.
    Pramlintide: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Prasugrel: (Moderate) Danazol can decrease hepatic synthesis of procoagulant factors, increasing the possibility of bleeding when used concurrently with platelet inhibitors.
    Progesterone: (Minor) The metabolism of progesterone may be inhibited by danazol, a known inhibitor of cytochrome P450 3A4 hepatic enzymes.
    Quazepam: (Moderate) Danazol is a CYP3A4 inhibitor and can decrease the hepatic metabolism of benzodiazepines metabolized by oxidation, such as quazepam.
    Quinidine: (Moderate) Danazol is a CYP3A4 inhibitor and can decrease the hepatic metabolism of CYP3A4 substrates including quinidine.
    Ranolazine: (Major) Danazol is a CYP3A4 inhibitor, and may reduce the hepatic metabolism of CYP3A4 substrates. Moderate or potent CYP3A4 inhibitors are contraindicated for use with ranolazine, a CYP3A4 substrate. Inhibition of ranolazine metabolism could lead to increased ranolazine plasma concentrations and associated QTc prolongation. Avoid coadministration of ranolazine with danazol due to the potential for reduced metabolism of ranolazine and the risk of QT prolongation.
    Red Yeast Rice: (Major) Since certain red yeast rice products (i.e., pre-2005 Cholestin formulations) contain lovastatin, clinicians should use red yeast rice cautiously in combination with drugs known to interact with lovastatin. Danazol is a CYP3A4 inhibitor. CYP3A4 inhibitors have been shown to increase HMG-CoA reductase activity and potential for myopathy when coadministered with lovastatin. Because of these potential risks, red yeast rice is best avoided by patients taking CYP3A4 inhibitors.
    Reteplase, r-PA: (Moderate) Danazol can decrease hepatic synthesis of procoagulant factors, increasing the possibility of bleeding when used concurrently with thrombolytic agents.
    Ribociclib: (Moderate) Use caution if coadministration of ribociclib with danazol is necessary, as the systemic exposure of ribociclib may be increased resulting in an increase in ribociclib-related adverse reactions (e.g., neutropenia, QT prolongation). Ribociclib is extensively metabolized by CYP3A4 and danazol is a moderate CYP3A4 inhibitor.
    Ribociclib; Letrozole: (Moderate) Use caution if coadministration of ribociclib with danazol is necessary, as the systemic exposure of ribociclib may be increased resulting in an increase in ribociclib-related adverse reactions (e.g., neutropenia, QT prolongation). Ribociclib is extensively metabolized by CYP3A4 and danazol is a moderate CYP3A4 inhibitor.
    Rilpivirine: (Moderate) Close clinical monitoring is advised when administering danazol with rilpivirine due to an increased potential for rilpivirine-related adverse events. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Danazol is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
    Ritonavir: (Moderate) Concurrent administration of danazol with ritonavir may result in elevated plasma concentrations of ritonavir. Danazol is an inhibitor of the hepatic isoenzyme CYP3A4; ritonavir is a substrate of this enzyme. Ritonavir has been associated with concentration-dependent QT prolongation in trials. Caution and close monitoring are advised if these drugs are administered together.
    Rivaroxaban: (Major) Danazol can decrease hepatic synthesis of procoagulant factors, increasing the possibility of bleeding when used concurrently with anticoagulants. Coadministration of rivaroxaban and danazol may result in increases in rivaroxaban exposure and may also increase bleeding risk. Danazol is an inhibitor of CYP3A4, and rivaroxaban is a substrate of CYP3A4. If these drugs are administered concurrently, monitor the patient for signs and symptoms of bleeding.
    Romidepsin: (Moderate) Romidepsin is a substrate for CYP3A4. Danazol is an inhibitor of CYP3A4. Concurrent administration of romidepsin with an inhibitor of CYP3A4 may cause an increase in systemic romidepsin concentrations. Use caution when concomitant administration of these agents is necessary.
    Ruxolitinib: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors of CYP3A4 such as danazol, a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. There was an 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was given after a short course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3 inhibition was consistent with the increase in exposure.
    Saquinavir: (Moderate) Both saquinavir boosted with ritonavir and danazol are inhibitors of CYP3A4; an isoenzyme responsible for the metabolism of saquinavir. The use of saquinavir/ritonavir with danazol may result in large increases in saquinavir plasma concentrations, which could cause adverse events such as life threatening cardiac arrhythmias (e.g., torsades de pointes [TdP]).
    Saw Palmetto, Serenoa repens: (Major) Drug interactions with Saw palmetto, Serenoa repens have not been specifically studied or reported. Saw palmetto extracts appear to have antiandrogenic effects. The antiandrogenic effects of Saw palmetto, Serenoa repens would be expected to antagonize the actions of androgens; it would seem illogical for patients taking androgens to use this herbal supplement.
    Saxagliptin: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia. However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary. Also, saxagliptin is primarily metabolized by CYP3A4/5; saxagliptin plasma concentrations may increase in the presence of moderate CYP3A4/5 inhibitors such as danazol.
    Sildenafil: (Moderate) Danazol is a CYP3A4 inhibitor and can theoretically decrease the hepatic metabolism of CYP3A4 substrates including sildenafil.
    Silodosin: (Moderate) Silodosin is extensively metabolized by hepatic cytochrome P450 3A4. In theory, drugs that inhibit CYP3A4, such as danazol, may cause significant increases in silodosin plasma concentrations.
    Simeprevir: (Major) Avoid concurrent use of simeprevir and danazol. Inhibition of CYP3A4 by danazol may increase the plasma concentrations of simeprevir, resulting in adverse effects.
    Simvastatin: (Severe) The use of simvastatin with danazol is contraindicated due to an increased risk of myopathy and rhabdomyolysis. A single case report has documented the onset of myositis that progressed to rhabdomyolysis with myoglobinuria after danazol was added to a regimen containing lovastatin. Although other drugs were in use concurrently, a drug interaction between danazol and lovastatin is suspected, as danazol (CYP3A4 inhibitor) is known to inhibit lovastatin metabolism.
    Simvastatin; Sitagliptin: (Severe) The use of simvastatin with danazol is contraindicated due to an increased risk of myopathy and rhabdomyolysis. A single case report has documented the onset of myositis that progressed to rhabdomyolysis with myoglobinuria after danazol was added to a regimen containing lovastatin. Although other drugs were in use concurrently, a drug interaction between danazol and lovastatin is suspected, as danazol (CYP3A4 inhibitor) is known to inhibit lovastatin metabolism. (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Sirolimus: (Major) Agents that inhibit CYP3A4 and/or P-glycoprotein, such as danazol, may affect absorption and elimination of sirolimus leading to increased blood concentrations. Monitor sirolimus serum concentrations carefully if these drugs need to be coadministered.
    Sitagliptin: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Sofosbuvir; Velpatasvir: (Moderate) Use caution when administering velpatasvir with danazol. Taking these drugs together may increase velpatasvir plasma concentrations, potentially resulting in adverse events. Danazol is a CYP3A4 inhibitor; velpatasvir is a substrate of CYP3A4.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Use caution when administering velpatasvir with danazol. Taking these drugs together may increase velpatasvir plasma concentrations, potentially resulting in adverse events. Danazol is a CYP3A4 inhibitor; velpatasvir is a substrate of CYP3A4.
    Soy Isoflavones: (Moderate) Theoretically, the soy isoflavones may counteract the activity of the androgens.
    Streptokinase: (Moderate) Danazol can decrease hepatic synthesis of procoagulant factors, increasing the possibility of bleeding when used concurrently with thrombolytic agents.
    Sufentanil: (Moderate) Danazol is a CYP3A4 inhibitor and can theoretically decrease the hepatic metabolism of sufentanil, a CYP3A4 substrate.
    Sulfonylureas: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Sunitinib: (Moderate) Concurrent administration of sunitinib with inhibitors of cytochrome P450 3A4 such as danazol results in increased concentrations of sunitinib and its primary active metabolite. Whenever possible selection of an alternative concomitant medication with no or minimal enzyme inhibition potential is recommended. If an alternative therapy is not available, monitor patients closely for increased adverse reactions to sunitinib; a reduction in the dose of sunitinib may be required.
    Tacrolimus: (Major) Danazol is a CYP3A4 inhibitor and can decrease the hepatic metabolism of some drugs. Danazol has also been reported to increase tacrolimus whole blood concentrations. Patients receiving tacrolimus should be closely monitored for toxicity if danazol is added to therapy. Conversely, a dose adjustment of tacrolimus may be necessary if danazol therapy is discontinued.
    Tamoxifen: (Major) Danazol is a CYP3A4 inhibitor. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent by both CYP2C9 and CYP2C19, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Danazol may inhibit the CYP3A4 metabolism of tamoxifen to these metabolites. Concomitant use of danazol and tamoxifen may result in decreased concentrations of the active metabolites of tamoxifen, which can compromise efficacy. If it is not possible to avoid concomitant use, monitor patients for changes in therapeutic efficacy of tamoxifen.
    Tamsulosin: (Moderate) Use caution when administering tamsulosin with a moderate CYP3A4 inhibitor such as danazol. Tamsulosin is extensively metabolized by CYP3A4 hepatic enzymes. In clinical evaluation, concomitant treatment with a strong CYP3A4 inhibitor resulted in significant increases in tamsulosin exposure; interactions with moderate CYP3A4 inhibitors have not been evaluated. If concomitant use in necessary, monitor patient closely for increased side effects.
    Tasimelteon: (Moderate) Caution is recommended during concurrent use of tasimelteon and danazol. Because tasimelteon is partially metabolized via CYP3A4, use with CYP3A4 inhibitors, such as danazol, may increase exposure to tasimelteon with the potential for adverse reactions.
    Telaprevir: (Moderate) Close clinical monitoring is advised when administering danazol with telaprevir due to an increased potential for telaprevir-related adverse events. If danazol dose adjustments are made, re-adjust the dose upon completion of telaprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathways of danazol and telaprevir. Danazol is an inhibitor of the hepatic isoenzyme CYP3A4; telaprevir is metabolized by this isoenzyme. When used in combination, the plasma concentrations of telaprevir may be elevated.
    Telithromycin: (Moderate) Concentrations of telithromycin may be increased with concomitant use of danazol. Telithromycin is a substrate of CYP3A4 and danazol is a CYP3A4 inhibitor.
    Temsirolimus: (Moderate) Use caution if coadministration of temsirolimus with danazol is necessary, and monitor for an increase in temsirolimus-related adverse reactions. Temsirolimus is a CYP3A4 substrate and danazol is a moderate CYP3A4 inhibitor. The manufacturer of temsirolimus recommends a dose reduction if coadministered with a strong CYP3A4 inhibitor, but recommendations are not available for concomitant use of moderate inhibitors. Coadministration of temsirolimus with ketoconazole, a strong CYP3A4 inhibitor, had no significant effect on the AUC or Cmax of temsirolimus, but increased the sirolimus AUC and Cmax by 3.1-fold and 2.2-fold, respectively.
    Tenecteplase, TNK-tPA: (Moderate) Danazol can decrease hepatic synthesis of procoagulant factors, increasing the possibility of bleeding when used concurrently with thrombolytic agents.
    Terbinafine: (Moderate) Due to the risk for terbinafine related adverse effects, caution is advised when coadministering danazol. Although this interaction has not been studied by the manufacturer, and published literature suggests the potential for interactions to be low, taking these drugs together may increase the systemic exposure of terbinafine. Predictions about the interaction can be made based on the metabolic pathways of both drugs. Terbinafine is metabolized by at least 7 CYP isoenyzmes, with major contributions coming from CYP3A4; danazol is an inhibitor of this enzyme. Monitor patients for adverse reactions if these drugs are coadministered.
    Thiazolidinediones: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia. However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Thrombolytic Agents: (Moderate) Danazol can decrease hepatic synthesis of procoagulant factors, increasing the possibility of bleeding when used concurrently with thrombolytic agents.
    Ticagrelor: (Moderate) Danazol can decrease hepatic synthesis of procoagulant factors, increasing the possibility of bleeding when used concurrently with platelet inhibitors.
    Tinzaparin: (Major) Danazol can decrease hepatic synthesis of procoagulant factors, increasing the possibility of bleeding when used concurrently with anticoagulants.
    Tirofiban: (Moderate) Danazol can decrease hepatic synthesis of procoagulant factors, increasing the possibility of bleeding when used concurrently with platelet inhibitors.
    Tolvaptan: (Major) Tolvaptan is metabolized by CYP3A4. Danazol is a moderate inhibitor of CYP3A4. Coadministration may cause a marked increased in tolvaptan concentrations and should be avoided.
    Toremifene: (Moderate) Cytochrome P450 3A4 enzyme inhibitors, such as danazol, decrease the rate of toremifene metabolism.
    Trabectedin: (Moderate) Use caution if coadministration of trabectedin and danazol is necessary, due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and danazol is a moderate CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), a strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone. The manufacturer of trabectedin recommends avoidance of strong CYP3A inhibitors within 1 day before and 1 week after trabectedin administration; there are no recommendations for concomitant use of moderate or weak CYP3A inhibitors.
    Trandolapril; Verapamil: (Minor) Danazol is a CYP3A4 inhibitor and can decrease the hepatic metabolism of CYP3A4 substrates like calcium-channel blockers.
    Tretinoin, ATRA: (Moderate) The concomitant use of systemic tretinoin, ATRA and danazol should be done cautiously due to the potential for increased intracranial pressure and an increased risk of pseudotumor cerebri (benign intracranial hypertension). Early signs and symptoms of pseudotumor cerebri include papilledema, headache, nausea, vomiting, and visual disturbances.
    Triazolam: (Moderate) Danazol is a CYP3A4 inhibitor could theoretically reduce the metabolism of other CYP3A4 substrates including triazolam.
    Triptorelin: (Major) Gonadotropin releasing hormone (GnRH) agonists (i.e.,triptorelin) inhibit steroidogenesis, therefore the concomitant use of these agents with androgens may counteract this therapeutic effect. Avoid concurrent use of androgens with GnRH agonists.
    Ulipristal: (Minor) Ulipristal is a substrate of CYP3A4 and danazol is a CYP3A4 inhibitor. Concomitant use may increase the plasma concentration of ulipristal resulting in an increased risk for adverse events.
    Urokinase: (Moderate) Danazol can decrease hepatic synthesis of procoagulant factors, increasing the possibility of bleeding when used concurrently with thrombolytic agents.
    Vemurafenib: (Moderate) Concomitant use of vemurafenib and danazol may result in increased vemurafenib concentrations. Vemurafenib is CYP3A4 substrate and danazol is a CYP3A4 inhibitor. Use caution and monitor patients for increased side effects.
    Verapamil: (Minor) Danazol is a CYP3A4 inhibitor and can decrease the hepatic metabolism of CYP3A4 substrates like calcium-channel blockers.
    Vinca alkaloids: (Major) Danazol is a CYP3A4 inhibitor and can decrease the hepatic metabolism of vinca alkaloids. Patients receiving these agents should be closely monitored for toxicity.
    Vorapaxar: (Moderate) Danazol can decrease hepatic synthesis of procoagulant factors, increasing the possibility of bleeding when used concurrently with platelet inhibitors.
    Warfarin: (Moderate) Androgens are associated with potentiation of the hypoprothrombinemic effect of warfarin. These interactions have resulted in bleeding episodes in some patients receiving coumarin derivatives along with danazol, esthylestrenol, methyltestosterone, oxandrolone, oxymetholone, or stanozolol. A multidose study of oxandrolone in 15 healthy individuals concurrently treated with warfarin resulted in significant increases in warfarin half-life and AUC; a 5.5-fold decrease in the mean warfarin dosage from 6.13 mg/day to 1.13 mg/day (approximately 80-85% dose reduction) was necessary to maintain a target INR of 1.5. When oxandrolone is prescribed to patients being treated with warfarin, doses of warfarin may need to be decreased significantly to maintain a desirable INR level and diminish the risk of potentially serious bleeding. A case report describes an increased INR in a woman receiving topical testosterone propionate ointment and anticoagulation with warfarin. In addition, danazol and stanozolol (androgen-related compounds), are associated with potentiation of the hypoprothrombinemic effect of warfarin. Danazol may inhibit warfarin metabolism and/or may potentiate the anticoagulant effects by affecting the coagulation system, and has been associated with reports of serious bleeding events. When androgen therapy is initiated in a patient already receiving warfarin, the patient should be closely monitored with frequent evaluation of the INR and clinical parameters; the dosage of warfarin should be adjusted as necessary until a stable target INR is achieved. Careful monitoring of the INR and necessary adjustment of the warfarin dosage are also recommended when the androgen or androgen-related (danazol, stanozolol) therapy is changed or discontinued.
    Ziprasidone: (Major) Danazol is a CYP3A4 inhibitor and can decrease the hepatic metabolism of ziprasidone. Patients receiving ziprasidone should be closely monitored for toxicity if danazol is added to therapy.
    Zolpidem: (Moderate) It is advisable to closely monitor zolpidem tolerability and safety during concurrent use of danazol, a moderate CYP3A4 inhibitor, since CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism. There is evidence of an increase in pharmacodynamics effects and systemic exposure of zolpidem during co-administration with some potent inhibitors of CYP3A4, such as azole antifungals.

    PREGNANCY AND LACTATION

    Pregnancy

    Danazol is contraindicated during pregnancy (FDA pregnancy category X), so care should be taken to ensure that the patient is not pregnant or becomes pregnant during therapy. Teratogenic effects have been associated with danazol treatment. In addition, androgens have caused virilization of the external genitalia of the female fetus, including clitoromegaly, abnormal vaginal development, and fusion of genital folds to form a scrotal-like structure. The degree of masculinization is dependent on the amount of drug given and the age of the fetus; these effects are most likely to occur in the female fetus when the drugs are given in the first trimester. Females of childbearing potential should use adequate methods of contraception, and should commence therapy during menstruation when possible to ensure a nonpregnant state. If pregnancy occurs, the drug should be immediately discontinued and the patient should be counseled concerning the potential risks to the fetus.

    Danazol is excreted into human breast milk. Because of androgenic effects on the infant, its use is contraindicated during breast-feeding. An alternative method to breast-feeding should be found if the drug must be used.

    MECHANISM OF ACTION

    Through its action on the pituitary, danazol indirectly reduces estrogen production by lowering the output of follicle-stimulating hormone and luteinizing hormone. There is also evidence that danazol binds to sex hormone receptors in target tissues, thereby exibiting anabolic, antiestrognic and weakly androgenic activity. With higher doses, amenorrhea generally occurs after about 6 weeks of therapy; ovulation and cyclic bleeding returns to normal 60—90 days after therapy is discontinued. Danazol is used to treat endometriosis because it causes atrophy of ectopic endometrial tissue, which relieves symptoms completely. It also decreases the growth rate of abnormal breast tissue, making it useful in fibrocystic breast disease. Heriditary angioedema is an inherited disorder characterized by a deficiency in C1 esterase inhibitor (C1 INH), a serum inhibitor of the activated first component of complement. Danazol increases circulating levels of C1 INH and therby increases C4 of the complement system, which also is deficient in hereditary angioedema. Consequently, danazol prevents attacks of hereditary angioedema in both males and females. The exact mechanism by which danazol increases C1 INH is not known. Danazol does not possess any progestogenic activity, and does not suppress normal pituitary release of corticotropin, or release of cortisol by the adrenal glands.

    PHARMACOKINETICS

    Danazol is administered orally. Distribution data are limited, but extensive hepatic metabolism produces the primary metabolite, 2-hydroxymethylethisterone. Danazol is excreted in the urine and has an elimination half-life of 4—5 hours.
     
    Affected cytochrome P450 isoenzymes: CYP3A4
    Danazol inhibits the cytochrome P450 system isoenzyme CYP3A4, and may reduce the hepatic metabolism of CYP3A4 substrates.

    Oral Route

    The bioavailability of danazol is not directly dose-related; dosage increases are not proportional to increases in plasma concentrations. For example, doubling the dose may yield only a 30—40% increase in plasma concentration. Peak concentrations occur within 2 hours, but the onset of a therapeutic effect (anovulation or amenorrhea) does not occur for approximately 6—8 weeks after taking daily doses. Pain reduction in fibrocystic breast disease will begin to be realized at 1 month, with a peak effect at 2—3 months.