When is Danocrine (danazol) appropriate to use in hereditary angioedema?

Appropriate Use of Danocrine (Danazol) in Hereditary Angioedema

Danazol is appropriate as a second-line long-term prophylactic treatment for hereditary angioedema when first-line therapies are unavailable or not tolerated. 1

Indications for Danazol in HAE

• Danazol is FDA-approved for the prevention of all types of angioedema attacks (cutaneous, abdominal, laryngeal) in both males and females with hereditary angioedema 2
• It should be considered as a second-line option for long-term prophylaxis after plasma-derived C1INH and lanadelumab, which are the preferred first-line treatments 3
• Danazol is particularly valuable in resource-limited settings where first-line therapies are unavailable 1
• It may be appropriate for patients with frequent or severe attacks who cannot access or tolerate first-line therapies 3

Dosing Protocol

• Initial recommended dose is 200 mg two or three times daily 2
• After a favorable initial response, the dose should be titrated down by 50% or less at intervals of one to three months 2
• If an attack occurs during dose adjustment, the daily dosage may be increased by up to 200 mg 2
• The minimum effective dose varies between patients, ranging from 100-400 mg/day, and should be the lowest dose that prevents attacks 4
• Some patients can maintain control with as little as 200 mg twice weekly 5

Monitoring Requirements

• Close monitoring is required during the dose adjustment phase, particularly for patients with a history of airway involvement 2
• Regular monitoring for side effects is essential, including liver function tests, lipid profiles, and complete blood counts 6, 7
• Periodic hepatic ultrasounds should be performed to monitor for liver adenomas 7

Contraindications and Special Populations

• Danazol is contraindicated during pregnancy and breastfeeding due to potential teratogenic effects and risk of masculinizing the female fetus 1
• It should be discontinued at least 2 months before attempting conception 3
• In children, tranexamic acid is preferred for long-term prophylaxis where first-line agents are unavailable 8
• Danazol should generally be avoided in children before Tanner Stage V of puberty due to potential effects on growth and development 1

Side Effects and Risks

• Common side effects include weight gain, myalgias, headaches, microscopic hematuria, abnormal liver function tests, anxiety, altered libido, dizziness, and nausea 6
• Women commonly experience menstrual irregularities 6, 7
• Approximately 10% of patients develop masculinizing side effects such as acne, hirsutism, and voice deepening 6
• More serious adverse effects include liver adenomas, which require monitoring 7
• In a long-term survey of 118 patients, adverse effects occurred in 93 patients (79%) and led to discontinuation in 30 patients (25%) 7

Efficacy

• Danazol is highly effective, with studies showing that 45.8% of patients become symptom-free or have one or fewer attacks per year during treatment 7
• It reduces the frequency of acute attacks to approximately 16.2% of pre-treatment levels 7
• Attacks that do occur during treatment tend to be considerably milder 7
• Laryngeal edema incidence is reduced to 4.8% during treatment 7
• Danazol works by increasing the levels of deficient C1 esterase inhibitor (C1EI) 2

Important Considerations

• Danazol is not effective for treating acute HAE attacks - it is only for prophylaxis 1
• For acute attacks, plasma-derived C1INH, icatibant, or ecallantide are recommended first-line treatments 1, 3
• In settings where these are unavailable, fresh frozen plasma (10-15 ml/kg) may be considered for acute attacks 3
• Standard angioedema treatments (antihistamines, corticosteroids, epinephrine) are ineffective for HAE attacks and should not be used 1, 8

Alternative Prophylactic Options

• First-line prophylactic options include plasma-derived C1INH and lanadelumab 3
• Tranexamic acid may be considered as an alternative prophylactic agent when first-line treatments and danazol are unavailable or contraindicated 1
• For short-term prophylaxis before procedures, plasma-derived C1INH is the first-line option 3, 8