Danazol for hereditary angioedema

Last updated Feb. 21, 2024, by Lindsey Shapiro, PhD
Fact-checked by Joana Carvalho, PhD

What is danazol for hereditary angioedema?

Danazol is an approved oral medication that’s used to prevent swelling attacks of all types, including those involving the skin, abdomen, and larynx, or voice box, in people with hereditary angioedema, or HAE.

In the U.S., it’s been used since the 1970s for various medical purposes, including the treatment of HAE. Danazol was originally marketed by Sanofi under the brand name Danocrine, but that product has since been discontinued. Its withdrawal from the market was deemed unrelated to concerns with safety or effectiveness in HAE patients.

Generic versions of the medicine are still available, including the ones marketed by Lannett and by Barr Pharmaceuticals, which was later acquired by Teva Pharmaceuticals.

Therapy snapshot

How does danazol work?

In the main types of HAE, genetic mutations lead to a lack of functional C1 esterase inhibitor (C1-INH), a protein that normally regulates pathways involved in inflammation and blood clotting. A lack of C1-INH leaves these pathways uncontrolled, driving the overproduction of a molecule called bradykinin, which is responsible for the pain and swelling that characterize an HAE attack.

Overactivation of the immune system’s complement cascade due to C1-INH deficiency causes C4, a complement protein, to be excessively used up. As a result, its levels are usually low in people with HAE.

Danazol is a synthetic, or lab-made, steroid that has a similar structure to testosterone, a male sex hormone or androgen. The medication suppresses hormone production by the pituitary and sex glands that are normally responsible for sexual development and reproduction.

It also increases C1-INH, and subsequently, C4 levels in the bloodstream, and is thus believed to be able to lower bradykinin production to prevent HAE attacks. Still, it is not exactly known how danazol is able to regulate these proteins.

Who with hereditary angioedema can take danazol?

Danazol was approved under the brand name Danocrine by the U.S. Food and Drug Administration (FDA) in June 1976 for the prevention of all types of HAE swelling attacks in male and female patients. Generic versions of the therapy also were approved for the same indication in the 1990s and early 2000s. The medicine can be used for cutaneous or skin-related, abdominal, and laryngeal attacks.

The medication also is approved in the U.S. to treat women with endometriosis, a tissue-related condition of the uterus, that is amenable to hormonal management.

Who should not take danazol?

Danazol is contraindicated, or not recommended, for patients with several medical conditions. These include:

• undiagnosed abnormal genital bleeding
• markedly impaired liver, kidney, or heart function
• pregnancy, or by people who are breastfeeding
• androgen-dependent tumors
• porphyria
• active blood clots or a history of such events
• hypersensitivity, or allergy to danazol.

The therapy’s prescribing information also comes with a boxed warning noting that danazol may cause female babies to be born with birth defects due to its androgenic effects. Its use during pregnancy is therefore contraindicated. It’s recommended that patients perform a test capable of detecting early pregnancy before starting treatment and remain on a nonhormonal method of contraception while on the therapy. If a patient becomes pregnant, treatment with danazol should be stopped immediately.

The boxed warning also notes the use of danazol is associated with an increased risk of blood clot-related events, certain liver conditions, and intracranial hypertension, which is characterized by increased pressure in the skull.

How is danazol administered in hereditary angioedema?

Danazol comes in oral capsules containing 50, 100, or 200 mg of its active ingredient, with individualized dosing based on a person’s clinical response.

The recommended starting dose for HAE patients is 200 mg, taken two to three times daily. If attacks are well-controlled, the dose should be slowly decreased to the lowest effective dosage for maintenance treatment. During that process, the dose should be decreased by no more than 50% at intervals of 1-3 months or longer. If an attack occurs, the dose can be increased by up to 200 mg.

During dose adjustment phases, a patient’s response should be closely monitored, particularly if the patient has a history of airway involvement.

Danazol capsules should be stored at room temperature in a container that protects them from light.

Danazol in hereditary angioedema clinical trials

Several studies dating back to the 1970s have assessed danazol for the management of HAE attacks. These include a small placebo-controlled clinical trial and a range of other open-label and observational studies. In an open-label study, both participants and researchers know the exact treatment being given.

In the randomized, controlled clinical trial, nine HAE patients received alternating courses of danazol at a dose of 600 mg per day — 200 mg taken three times daily — or a placebo. Treatment was stopped when an attack occurred, or after a month if no attack had occurred.

The results showed that, over 46 total courses of danazol, one HAE attack occurred (2.2%). That compared with 44 recorded attacks during 47 courses of the placebo (93.6%). C1-INH and C4 protein levels increased immediately upon starting danazol, reaching their maximum after about 1-2 weeks.

A number of prospective, open-label studies and retrospective analyses also have supported danazol’s ability to reduce the severity and frequency of HAE attacks.

One open-label study evaluated danazol’s effects in 12 HAE patients who received the therapy for up to 25 months, or just longer than two years. Patients received danazol at a daily dose of 600 mg in the first month, followed by repeated cycles of five days on treatment and five days off it. All but one patient achieved complete remission, with no attacks reported during the study. C1-INH and C4 protein levels also were found to increase.

A long-term survey retrospectively evaluated the real-world effects of danazol among 118 people with HAE in Germany and Denmark. These patients had used the therapy for as little as two months and as long as 30 years. Nearly all patients (111 of 118)  responded to treatment, with 54 (45.8%) having one or zero attacks per year. The overall frequency of attacks was reduced by 16.2%, and attacks were deemed to be milder in severity than they had been prior to treatment.

A more recent retrospective study aimed to assess the effects of danazol on the growth of 42 pediatric HAE patients, given the medication’s possible hormonal influence on development. The treatment, when used at its lowest effective dose, was not found to influence growth.

Common side effects of danazol

Side effects associated with danazol use include:

• acne
• weight gain
• oily skin or hair
• voice changes
• sore throat
• hair loss
• abnormal body hair growth in women, called hirsutism
• menstrual changes
• flushing or sweating
• vaginal dryness, itching, or bleeding
• decreased breast size
• nervousness, irritability, or other mood changes

Many side effects associated with danazol can be attributed to its androgen-like effects, or those associated with male hormone signaling, or a suppression of estrogen, a female sex hormone. Patients should be monitored closely for these effects, which may not always be reversible once treatment is stopped.

Pregnancy, breastfeeding, and contraception

Danazol can harm a developing fetus, and thus, comes with a boxed warning that it should not be used in women who are pregnant or may become pregnant. A test sensitive enough to detect early pregnancy is recommended immediately prior to the start of treatment in female patients.

Additionally, an effective method of birth control must be used during treatment. Because danazol may decrease the effectiveness of hormonal contraceptives (e.g. birth control pills, patches, rings, implants, or injections), a non-hormonal method, such as condoms or diaphragms, should always be used.

Women who become pregnant while taking the medication should tell their doctor immediately, and danazol should be stopped. Androgenic effects — physical changes related to the activity of male sex hormones — have been reported in female fetuses exposed to danazol in the womb. Such effects include enlargement of the clitoris, labial fusion, defects in the reproductive and urinary tract, narrowing of the vaginal opening, and ambiguous genitalia.

Danazol also should not be used in women who are breastfeeding.

Blood clots

Danazol may increase the risk that a person will develop blood clots in the arms, legs, lungs, heart, or brain, potentially leading to serious problems, such as a heart attack or stroke.

Symptoms of a blood clot may include warm, red, swollen, or tender legs; trouble speaking or understanding; paralysis or numbness in the face, arms, or legs; sudden and severe headache; and/or vision changes. Patients should contact their doctor immediately if these symptoms occur.

Liver problems

Certain liver complications have been observed with long-term use of danazol. These conditions may not be associated with overt symptoms until they are complicated by acute and potentially life-threatening abdominal bleeding. Symptoms of these conditions may include yellowing of the skin or eyes, abdominal pain, extreme tiredness, or unusual bleeding or bruising.

Patients who experience any such symptoms should contact their doctor immediately.

To avoid these complications, patients should use the lowest possible dose of danazol that will still provide protection against HAE attacks. If the medication was started during periods of HAE exacerbation, or worsening, due to trauma or stress, periodic attempts to lower the dose should be considered.

Periodic liver function tests also should be performed in patients using danazol.

Elevated pressure in the skull

Danazol use has been tied to several cases of benign intracranial hypertension, or pseudotumor cerebri, which is characterized by elevated pressure in the skull. Early symptoms may include swelling of the optic disc, headache, nausea or vomiting, and visual disturbances.

If evidence of this condition is observed, danazol should be stopped immediately and patients should be referred to a neurologist for further care.

Cholesterol changes

A temporary alteration of cholesterol levels, including decreases in so-called good cholesterol or high-density lipoprotein, has been reported with danazol use. Conversely, the medication’s use also has been reported to lead to increases in so-called bad cholesterol, or low density lipoproteins. A person’s doctor should consider the potential impact of these changes on the risk for cardiovascular disease in HAE patients.

Fluid retention

Danazol may increase fluid retention. Patients with diseases that could be influenced by fluid retention, such as epilepsy, migraine, and certain kidney conditions, should be closely monitored. The therapy should be used with caution in people with diabetes.

Lab tests

Danazol may interfere with lab tests measuring the levels of certain hormones, including testosterone. The medication also may influence the levels of certain proteins associated with thyroid gland function.

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