Q:

2/14/2018
In patients with hereditary angioedema requiring prophylactic treatment attenuated androgens and tranexamic acid can be used. Most authors (obviously taking into account age/gender/pubescence etc) recommend a trial of one, and if ineffective a switch to the other. This is my approach also. If these are ineffective prophylactic C1-inh is an option. However, I am interested in whether there is any evidence for the combined use of low-dose androgens and tranexamic acid together. At low dose this would presumably attenuate the side effects of each but provide additional benefit over either alone. Are you aware of any such evidence? Or is there a particular reason why this should be avoided?

A:

You raise an interesting option of minimizing side effects by combining two disparate therapies. The problem is that the two therapies work in different ways so I am not confident that adding low dose of one would permit successful reduction of the other. The dosing for androgens is highly variable and tranxenemic acid is not recommended for long term prophylaxis in the most recent international guideline (http://onlinelibrary.wiley.com/doi/10.1111/all.13384/epdf). A quote is provided…

Androgens
Attenuated androgens are traditionally used for long-term prophylaxis of HAE-1/2 [154-163]. Androgen derivatives have been demonstrated to be effective in HAE-1/2, and the oral administration facilitates their use [155, 157, 159]. However, androgens must be regarded critically, especially in light of their adverse androgenic and anabolic effects, drug interactions, and contraindications. Side effects are numerous and involve the majority of patients; in other words, the absence of side effects is exceptional [157, 164]. Side effects appear to be dose related. Virilization is the most feared complication in women; menstrual disorders and even amenorrhea as well as diminished libido and hirsutism are also common [165], as are weight gain, headache, myalgia, depression, and acne. Androgens may lead to virilization of the female fetus and are, therefore, absolutely contraindicated during pregnancy [166, 167]. In children and adolescents, therapy with androgens may interfere with the natural growth and maturation process. In addition, androgens are subject to numerous contraindications and show interactions with many other drugs (e.g. statins). Careful surveillance is imperative in long-term prophylaxis with androgens. In addition to clinical tests and examinations and questioning of the patient, semiannual blood and urine tests (standard urine test strip) are needed, and at least once a year, an ultrasound of the liver should be performed. It is unclear if stopping long term prophylaxis with attenuated androgens should be done by tapering off gradually over time [168, 169]. The dose of androgens needed to control HAE attacks can vary between the equivalent of 100 mg every other day and 200 mg of danazol 3 times a day. The minimal effective dose should be used. Dosages above 200 mg of danazol daily for extended periods of time are not recommended, because of side effects. The response to androgens varies considerably, and the dose required for long-term prophylaxis is variable. For this reason, the dosage should be adjusted according to clinical response and not adjusted based on C4 and C1-INH results [6, 8, 9, 13].

Anti-fibrinolytics
Antifibrinolytics are not recommended for long-term prophylaxis. Data for their efficacy are largely lacking, but some patients may find them helpful. They are primarily used when C1-INH concentrate is not available and androgens are contraindicated. Side effects are usually minor. They include gastrointestinal upsets (can be reduced by taking the drug with food), myalgia/creatine kinase elevation, and a theoretical risk of thrombosis. Contraindications/precautions include the presence of thrombophilia or increased thrombotic risk or acute thrombosis, e.g. deep venous thrombosis, pulmonary embolism. The doses of Tranexamic Acid (TA) used range from 30 to 50 mg/kg to 6 g daily. Dose ranging studies and comparisons with other prophylactic medications have not been performed [4, 6, 8, 9, 86, 170-172].”

I could not find any evidence of combining the two therapies for enhanced mutual efficacy and utilization of lower doses of each. I shared your question with Dr. Tim Craig, Professor and Program Director at Pennsylvania State University and one of the authors on the guidelines. His comments were:

A great question but no data exist. We often discuss this item but as of yet no definitive studies to prove synergy exist.

All my best.

Dennis K. Ledford, MD, FAAAAI

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