Danazol (Danocrine) - Uses, Dose, Side effects, MOA, Brands

Danazol (Danocrine) is a synthetic androgen like testosterone. It is used in the treatment of endometriosis, hereditary angioedema, and fibrocystic disease of the breast.

Danazol Uses:

  • Endometriosis:

    • For treating endometriosis susceptible to hormonal therapy.
  • Hereditary angioedema (HAE), prophylaxis:

    • Prophylaxis against all kinds of angioedema including, cutaneous abdominal, laryngeal in all genders.
    • Guideline recommendations:   Guidelines do not recommend treating HAE acute attacks. However, it may be used instead of CI inhibitor for long time prevention of HAE and temporary use against before procedure.
  • Off Label Use of Danazol in Adults:

    • Cyclic mastalgia secondary to benign breast disorders
    • Refractory immune thrombocytopenia.

Danazol (Danocrine) Dose in Adults

Note: start therapy during menstruation in women.

Danazol (Danocrine) Dose in the treatment of Cyclic breast pain (mastalgia) associated with benign breast disorders (off-label):

  • Use orally. Start with 100 mg twice daily on day 1 of menstruation.
  • Dosing range: 100 to 400 mg per day.
  • Duration of therapy: 3 to 6 months.
  • The dose was tapered before ending in a few research studies.

Danazol (Danocrine) Dose in the treatment of Endometriosis (females): Oral:

  • Mild disease:

    • Initial: 200 to 400 mg/day in 2 divided doses slowly down titrate while maintaining use for 3 -6 months straight, may continue till 9 months.
    • If symptoms develop again treatment can be started once more.
  • Moderate to severe disease or infertility:

    • Initial: 800 mg/day in 2 divided doses slowly down titrate while maintaining use for 3 -6 months straight, may continue till 9 months.
    • If symptoms develop again treatment can be started once more.

Danazol (Danocrine) Dose in the treatment of Hereditary angioedema (prophylaxis): Oral:

Note: Because of the adverse effect profile use the smallest possible dose. Multiple short spurts of therapy may lead to side effect frequency comparable to long-duration treatment.

  • Short-term/ preprocedural prophylaxis (off-label dose):

    • 5 to 10 mg/kg/day;
    • The dose can be adjusted according to feedback. (maximum: 600 mg/day).
    • Given 5 days prior to the procedure and 2 to 3 days post-procedure.
  • Long-term prophylaxis:

    • 100 mg on an alternate day up to 200 mg 2 to 3 times daily.
    • After achieving a positive response dose is reduced by half every 4 to 12 weeks or more based on attack timing
    •  >200 mg/day for an extended period of time is not recommended because of adverse effects.

Danazol (Danocrine) Dose in the treatment of refractory immune thrombocytopenia (off-label):

  • Oral: 200 mg 2 to 4 times/day (10 to 15 mg/kg/day in divided doses);
  • The response is seen in anywhere from 2 weeks to few months may take up to 6 months or 600 mg once daily for 6 months or more than 400 mg once daily for 3 months, later if remission maintained 200 mg once daily.

Danazol (Danocrine) Dose in Childrens

Danazol (Danocrine) Dose in the treatment of Hereditary angioedema: 

  • Adolescents ≥16 years:

    • Short-term prophylaxis (for patient-specific triggers, medical and dental procedures):
      • Oral: 2.5 to 10 mg/kg/day divided into 3 doses;
      • The maximum daily dose: 600 mg/day;
      • begin 5 days prior and continued for 2 to 5 days post procedure.
    • Long-term prophylaxis:
      • Oral: Initial: 2.5 mg/kg/day;
      • The maximum initial daily dose: 50 mg/day;
      • Every two weeks, the dose is gradually increased until it reaches the highest tolerated or recommended level or the symptoms stop.
    • The maximum daily dose: 5 mg/kg/day up to 200 mg/day.
    • After symptoms are improved down-titrate dose ;
    • The maximum dose: 100 mg/dose.

Danazol (Danocrine) Pregnancy Category: X

  • [US Boxed Warning]Pregnancy is not a good time to use Danazol.
  • Danazol exposure in utero can cause androgenic effects for the female fetus.
  • There have been reports of clitoral hypertrophy and labial fusion as well as urogenital sinus defect and vaginal atresia.
  • Eliminate any pregnancy before starting treatment. Throughout the course of the therapy, non-hormonal contraception may be employed.
  • If the patient becomes pregnant during treatment, discontinue immediately.
  • There are very few case reports that show pregnancy with danazol for non-responsive HAE.

Danazol use during breastfeeding:

  • Breastfeeding is not recommended. Before starting Danazol, you should use other agents or stop breastfeeding.

Dose in Kidney disease:

Contraindicated in severe renal failure.

Dose in Liver disease:

Contraindicated in severe liver dysfunction.

Side effects of Danazol (Danocrine):

  • Cardiovascular:

    • Edema
    • Flushing
    • Hypertension
    • Myocardial Infarction
    • Palpitations
    • Syncope
    • Tachycardia
  • Central Nervous System:

    • Depression
    • Dizziness
    • Emotional Lability
    • Fatigue
    • Headache
    • Nervousness
    • Paresthesia
    • Sleep Disorder
    • Voice Disorder (Deepening Of The Voice, Hoarseness, Instability, Sore Throat)
  • Dermatologic:

    • Acne Vulgaris
    • Alopecia
    • Diaphoresis
    • Maculopapular Rash
    • Papular Rash
    • Pruritus
    • Seborrhea
    • Urticaria
    • Vesicular Eruption
  • Endocrine & Metabolic:

    • Amenorrhea (May Continue Post-Therapy)
    • Change In Libido
    • Decreased Glucose Tolerance (And Glucagon Changes)
    • Decreased HDL Cholesterol
    • Decreased Thyroxine Binding Globulin
    • Hirsutism (Mild)
    • Increased LDL Cholesterol
    • Increased Thyroxine Binding Globulin
    • Menstrual Disease (Altered Timing Of Cycle, Spotting)
    • Weight Gain
  • Gastrointestinal:

    • Constipation
    • Gastroenteritis
    • Nausea
    • Vomiting
  • Genitourinary:

    • Asthenospermia
    • Breast Atrophy
    • Decreased Ejaculate Volume
    • Hematuria
    • Inhibition Of Spermatogenesis
    • Spermatozoa Disorder (Changes In Sperm Count And Semen Viscosity)
    • Vaginal Dryness
    • Vaginal Irritation
  • Hematologic & Oncologic:

    • Abnormal Erythrocytes (Increased)
    • Decreased Sex Hormone Binding Globulin
    • Eosinophilia
    • Increased Sex Hormone-Binding Globulin
    • Leukocytosis
    • Leukopenia
    • Malignant Neoplasm (After Prolonged Use)
    • Petechial Rash
    • Polycythemia
    • Purpuric Rash
    • Thrombocythemia
    • Thrombocytopenia
  • Hepatic:

    • Cholestatic Jaundice
    • Hepatic Adenoma
    • Hepatic Neoplasm (Malignant; After Prolonged Use)
    • Increased Liver Enzymes
    • Jaundice
    • Peliosis Hepatitis
  • Neuromuscular & Skeletal:

    • Ankylosing Spondylitis
    • Arthralgia
    • Back Pain
    • Increased Creatine Phosphokinase
    • Joint Swelling
    • Limb Pain
    • Muscle Cramps
    • Muscle Spasm
    • Neck Pain
    • Tremor
    • Weakness
  • Ophthalmic:

    • Visual Disturbance
  • Respiratory:

    • Interstitial Pneumonitis

Contraindications to Danazol (Danocrine):

  • Hypersensitivity to danazol
  • Undiagnosed abnormal Genital Bleeding.
  • pregnancy
  • Breastfeeding
  • porphyria
  • Severe renal, cardiac, or liver failure
  • androgen-dependent tumor
  • Current or past history of thrombosis/thromboembolic diseases

Canadian labeling: Additional contraindications not in the US labeling

  • Genital neoplasia
  • Simvastatin may be administered concurrently.

Warnings and precautions

  • Androgen effects:

    • It can cause permanent androgenic effects.
  • Changes in blood lipids:

    • Atherosclerosis and CAD risk increase due to decreased high-density and increased low-density cholesterol.
  • Hepatotoxicity: [US Boxed Warning]

    • When used for a prolonged period, peliosis liveritis and benign hepatic tumors have been reported. 
    • Although initial symptoms may not be apparent, they may lead to serious intraabdominal bleeding. 
    • Use minimum lowest effective dose. Do not delay in reducing the dose.
    • You should monitor your liver function and be on the lookout for potential hepatotoxicity while you are receiving treatment.
  • Intracranial hypertension [US Boxed Warning]

    • This condition may be linked to pseudotumor cerebri, which can cause headaches, nausea, vomiting, and visual impairments.
    • If you are experiencing signs and symptoms, it is important to have a neurology evaluation done immediately.
  • Thromboembolic Events: [US Boxed Warning]

    • There have been reports of thromboembolism, blood clots, and thrombotic events (including sagittal sinusthrombosis, life-threatening strokes, or fatal strokes).
  • A benign breast disorder is associated with cyclic breast pain (mastalgia).

    • Second-line agent for benign conditions only. This is when the pain is not responding to other analgesics.
  • Diabetes:

    • Diabetes patients may experience an increase in insulin use. Be careful.
  • Conditions that are edematous:

    • Patients with underlying conditions like migraine, heart disease, or renal impairment should be cautious when using edema.
  • Porphyria

    • Patients with porphyria should not be given this medication as it can worsen AIP.

Danazol: Drug Interaction

Note: Drug Interaction Categories:

  • Risk Factor C: Monitor When Using Combination
  • Risk Factor D: Consider Treatment Modification
  • Risk Factor X: Avoid Concomitant Use

Risk Factor C (Monitor therapy).

Ajmaline Ajmaline's toxic/adverse effects may be exacerbated by the use of androgens. Particularly, there may be an increase in the risk of cholestasis.
Antidiabetic Agents The therapeutic benefit of anti-diabetic agents may be reduced by hyperglycemia-associated agents.
ARIPiprazole ARIPiprazole serum levels may rise in the presence of weak CYP3A4 inhibitors.
It's crucial to keep an eye out for any heightened pharmacologic effects of aripiprazole.
C1 inhibitors C1 inhibitors could have a thrombogenic effect that is enhanced by the use of androgens.
CarBAMazepine Danazol could decrease CarBAMazepine metabolism
Corticosteroids (Systemic) Depending on the indication and concurrent medication, aripiprazole dosage modifications may be required. Consult the interaction monograph in its entirety for more details. Androgens' capacity to retain fluid might be improved.
Dofetilide Dofetilide may be increased by CYP3A4 inhibitors (Weak).
Flibanserin Flibanserin may be increased by CYP3A4 inhibitors (Weak).
NiMODipine NiMODipine serum levels may rise in response to weak CYP3A4 inhibitors.
Tacrolimus Systemic Tacrolimus serum concentrations may be increased by danazol (Systemic).
Tacrolimus (Topical) Danazol may raise the serum levels of Tacrolimus (Topical).
Vitamin D Analogs Danazol could increase the hypercalcemic effects of Vitamin D Analogs.There are exceptions Calcipotriene;Calcitriol(Topical); Tacalcitol.

Risk Factor D (Consider therapy modifications)

CycloSPORINE Systemic CycloSPORINE (Systemic) may have a hepatotoxic effect that can be enhanced by androgens. CycloSPORINE (Systemic) may be increased by androgens.
HMG-CoA Reductase Inhibitors (Statins) HMG-CoA Reductase Inhibitor serum concentrations can rise when danazol is used. Danazol and simvastatin should not be used together. Do not take more than 20mg of lovastatin and danazol per day if used together. Pravastatin, rosuvastatin, and fluvastatin might carry less risk. Fluvastatin, Pitavastatin, Pravastatin, and Rosuvastatin are exceptions.
Lomitapide CYP3A4 inhibitors may result in a rise in lomitapide (Weak).Patients who are currently taking lomitapide 5 mg/day can keep doing so.Patients must cut their lomitapide dosage in half if they are taking 10 mg or more per day. The lomitapide dosage can then be changed to 30 mg/day for adults.
Vitamin K antagonists (eg warfarin) Vitamin K Antagonists might have an anticoagulant effect that is enhanced by the use of androgens.

Risk Factor X (Avoid Combination)

Pimozide Pimozide may be increased by CYP3A4 inhibitors (Weak).
Simvastatin Simvastatin may be increased by Danazol.

 

Monitoring parameters:

  • Liver and kidney function tests (periodically);
  • hematologic parameters;
  • lipid panel.
  • Signs and symptoms of intracranial hypertension (papilledema, headache, nausea, vomiting), androgenic changes, and/or fluid retention.
  • Hereditary angioedema, long-term prophylaxis:
    • CBC, urinalysis, liver function test, and lipid profile (baseline, every 6 months while on therapy and 6 months following discontinuation);
    • liver ultrasound (baseline and then yearly);
    • blood pressure (every 6 months)

Cyclic breast pain (mastalgia) secondary to benign  breast disorders:

  • Pain and side effects; in most studies, this was done (at a minimum) following 1, 3, and 6 months of therapy.

How to administer Danazol (Danocrine)?

Endometriosis: therapy is started in menstruation. Pregnancy must be avoided during treatment.

Mechanism of action of Danazol (Danocrine):

  • Reduces abnormal breast tissue proliferation, atrophy local and ectopic endometrial growth, and increases C-4 complement levels to reduce hereditary angioedema spells.
  • This is done by suppressing FSH/LH production from pituitary.

The onset of action:

  • Immune thrombocytopenia (off-label use):
    • Initial response: 14 to 90 days;
    • Peak response: 28 to 180 days.

Metabolism:

  • major site: hepatic, mainly to 2-hydroxymethyl danazol and ethisterone

Half-life elimination:

  • 9.7 ± 3.29 hours (variable; up to 24 hours following long-term use for endometriosis)

Time to peak, serum:

  • 4 hours (range: 2 to 8 hours)

Excretion:

  • Urine and feces

International Brand Names of Danazol:

  • Cyclomen
  • Anargil
  • Azol
  • Cipladanogen
  • Cyclolady
  • D-Zol
  • Dana
  • Danamet
  • Danarem
  • Danasin
  • Danatrol
  • Danazol
  • Danazol Jean Marie
  • Danazol-ratiopharm
  • Danocil
  • Danocrine
  • Danodiol
  • Danogar
  • Danogen
  • Danokrin
  • Danol
  • Danoval
  • Dazol
  • Dorink
  • Ectopal
  • Elle
  • Gonablock
  • Gonablok
  • Gong Fu Yi Kang
  • Kupdina
  • Ladazol
  • Ladogal
  • Lozana
  • Mastodanatrol
  • Nazol
  • Novaprin
  • Vabon
  • Winobanin
  • Zendol

Danazol Brand Names in Pakistan:

Danazol 200 mg Tablets in Pakistan

Lozana Shrooq Pharmaceuticals

 

Danazol 100 mg Capsules in Pakistan

Danatris Sycom Pharmaceuticals
Danocrine Searle Pakistan (Pvt.) Ltd.
Danzol Platinum Pharmaceuticals (Pvt.) Ltd.

 

Danazol 200 mg Capsules in Pakistan

Danatris Sycom Pharmaceuticals
Danocrine Searle Pakistan (Pvt.) Ltd.
Danzol Platinum Pharmaceuticals (Pvt.) Ltd.