Effectiveness of Danazol for Long-term Prophylaxis in Hereditary Angioedema
Danazol is highly effective for long-term prophylaxis in hereditary angioedema (HAE), reducing attack frequency by more than 90% in most patients, but should be considered a second-line option due to its significant side effect profile. 1
Efficacy of Danazol
- Double-blind, randomized controlled trials have demonstrated that danazol significantly reduces both the frequency and severity of HAE attacks, including potentially life-threatening laryngeal attacks 1
- At high doses, danazol is effective in more than 90% of patients with HAE 1
- Long-term studies show that 45.8% of patients become symptom-free or experience only one attack or less per year while on danazol therapy 2
- The frequency of acute attacks during danazol treatment is reduced to approximately 16.2% of pre-treatment levels, with attacks being considerably milder 2
- Danazol works by increasing intrinsic production of C1-inhibitor (C1-INH), which corrects the primary biochemical abnormality in HAE 3
Dosing Considerations
- The dose of danazol should be adjusted to the lowest possible amount that provides effective control of attacks 1
- Typical dosing ranges from 100 mg on alternate days to up to 600 mg per day, depending on individual patient requirements 1
- Dose adjustments should not occur more frequently than once per week, as the beneficial effects of danazol accrue slowly 1
- Some patients benefit from an "alternative prophylaxis" approach with dose adjustments according to known trigger exposures such as menstruation or infections 1
Side Effect Profile
- Common side effects include weight gain, acne, virilization, menstrual irregularities, hirsutism, hepatic abnormalities, growth retardation, behavioral and mood alterations, headache, and cardiovascular risk 1, 4
- Approximately 10% of patients experience masculinizing side effects such as acne, hirsutism, and voice deepening 4
- Side effects are dose-related and more common at doses higher than 200 mg per day 1, 4
- Long-term studies show that adverse effects occur in approximately 79% of patients and lead to discontinuation of therapy in about 25% of cases 2
- Despite concerns, long-term studies suggest that when administered at the lowest effective dose, danazol does not induce significant liver injury in HAE patients 5
Current Guidelines and Recommendations
- Current guidelines recommend that danazol be considered a second-line option for long-term prophylaxis due to its side effect profile 1, 6
- First-line prophylactic treatments are now subcutaneous C1-INH and lanadelumab due to their superior safety profiles 1
- Every patient should be evaluated for long-term prophylaxis based on attack frequency, severity, location, access to acute care, comorbid conditions, and patient preference 1, 6
- Guidelines strongly emphasize that all patients on long-term prophylaxis should still have access to acute "on-demand" treatment for breakthrough angioedema episodes 1
Monitoring and Follow-up
- Regular monitoring is essential for patients on long-term danazol therapy to avoid undesirable toxicity 4
- Monitoring should include liver function tests, lipid profiles, and regular clinical assessment for side effects 5, 7
- Despite concerns about lipid profile changes, long-term studies have not shown significant differences in HDL-C or carotid intima-media thickness compared to matched controls, though increased activation of coagulation has been observed 7
Special Considerations
- In resource-limited settings where first-line treatments are not available, the risk-benefit ratio may favor greater use of danazol despite its side effect profile 1
- Danazol is contraindicated during pregnancy due to potential masculinizing effects on the female fetus 1, 6
- In children, antifibrinolytic agents are generally preferred over androgens for long-term prophylaxis due to concerns about growth and development 6