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Five products have recently been approved by the FDA to treat acute Hereditary Angioedema (HAE) attacks:
As might be expected from its different pathogenesis, angioedema seen in HAE does NOT respond to the drugs employed in treating other forms of urticaria/angioedema such as antihistamines, epinephrine, and corticosteroids. While epinephrine, in particular, may have a transient effect on swelling, it does not alter the course of an attack.1
Maintaining airway patency is the primary concern for patients with laryngeal edema. If the airway is threatened, the patient should be intubated by an experienced physician. In addition, the capability for emergency tracheostomy should be readily available.2 Because gastrointestinal edema usually involves excruciating pain, frequent vomiting, and the potential for hypotension, therapy should include aggressive fluid replacement and pain management. Clinicians report that Zofran, Compazine, and Phenergan are effective in reducing nausea and vomiting, while morphine or other narcotics are routinely used to relieve attack related abdominal pain. In the past, some physicians have used fresh frozen plasma in the acute attack setting, but this therapy is considered controversial because in addition to C1-inhibitor, fresh frozen plasma contains substrates of the complement and kinin systems that could produce a vasoactive peptide and cause an attack exacerbation.3
The approval of Firazyr®, Cinryze™ , Berinert®, Kalbitor®, and Ruconest® has changed the landscape of HAE therapeutic options in the US.
Short-term therapy is imperative to prevent attacks of angioedema when the patient is at high risk of swelling, particularly before expected trauma such as surgery or dental procedures. Historically, daily high dose androgen therapy (600-800mgs of danazol) was recommended for at least four days prior to surgery and four days afterward.4 Fresh frozen plasma can be used to prevent attacks when a patient is facing an emergency procedure. This is because administering fresh frozen plasma prophylactically to an asymptomatic patient does not pose the risk of exacerbation that is seen when given during an acute attack.
Berinert® and Kalbitor®, and Firazyr® are the first FDA-approved medicines for the acute treatment of HAE attacks. Professor Bruce Zuraw, US HAEA Medical Advisor, submits that the efficacy of these drugs is highest when used early in an HAE attack when it is impossible to predict which attacks may become severe or life-threatening.5 The advent of these new therapies, offers new choices for treating acute attacks of HAE.
Over the past 25 years, studies have confirmed the efficacy of plasma C1-Inhibitor as replacement therapy for acute attacks of HAE.6 Symptom relief is usually seen within 30-60minutes of intravenous administration of C1-Inhibitor. In studies, Berinert® showed significant reduction in the time to onset of relief to symptoms.
Clinical and lab study have show that bradykinin is a primary mediator of swelling in HAE.7 This information has led to new therapeutic strategies for treating HAE by preventing bradykinin-mediated enhancement in vascular permeability using Kalbitor®. Administration of Kalbitor is subcutaneous and is required to be administered in a healthcare setting.
Some patients experience only infrequent and mild attacks and therefore require no long-term therapy. Clinicians generally recommend long-term therapy for patients who experience more than one attack per month, or who believe that the disease significantly interferes with their life style.
Drugs historically available for long-term therapy have been the 17 alpha alkylated androgens danazol and oxandrolone. 17 alpha alkylated androgens produce an increase in C1-inhibitor levels, but the exact mechanism of how they do so has not been precisely defined.
The dose of anabolic androgens used to treat HAE should be titrated down to find the lowest dose that prevents attacks. A reasonable starting dose for danazol is 200 mg/day and 5 mg/day for oxandrolone. If good control is obtained, it is reasonable to try and reduce the dosages by 50 mg/week and 2.5 mg/week respectively after 4 weeks. Clinicians report that many patients are well controlled on 200 mg/day danazol or 2.5 mg/day oxandrolone, but it is not unusual to see patients that require higher or lower doses. NOTE: There is subset of patients for whom androgens are not effective at any dose.
Professor Zuraw notes that it is important to base androgen dosages on the clinical effect and not laboratory values. In addition, the side effects of anabolic androgens are dose related, with the most important side effects being hepatotoxicity and virilization. Professor Zuraw advises that patients taking anabolic androgens should have their liver enzymes checked every six months. Since hepatic adenomas have been reported as a consequence of anabolic androgens, Professor Zuraw also recommends ultrasound examination of the liver in the presence of consistently elevated liver enzymes.8 A class of drugs called antifibrinolytics have been shown to prevent attacks in some patients, but their use has largely been abandoned in the US because androgens have proven to be much more effective than antifibrinolytics.
Cinryze™ is an FDA-approved therapy for long-term prophylaxis. Patients with more than 2 attacks per month are potential candidates for prophylactic treatment. Professor Zuraw notes that individualization of dosage and frequency of administration will be necessary to achieve the optimal response.9 Cinryze™ is delivered intravenously and is approved for home infusion.
Fortunately, most prepubescent children with HAE do not suffer from frequent attacks and infrequent flares affecting the abdomen can be managed by using pain relievers and anti nausea agents. The small number of severely affected children who experience frequent and severe attacks must be managed on a case by case basis. Professor Zuraw noted good results in past years using 2.5 mg of oxandralone once or twice a week in treating severely affected children.1011 But the adverse effect of 17a-alkulated androgens on growth and development, including premature puberty make steroids a questionable choice.12 Every physician will need to discern for him or herself how the new FDA-approved medications may prove most useful for treating their young patients.
As with children, treating HAE in women presents its own particular challenges.
Steroids, or 17a-alkylated androgens, are contra-indicated for women due to their well-documented side effects. Fertility and the rate of miscarriage are the same as noted in the general public. It has been observed that HAE attacks frequency and severity may not change, may increase or may decrease during pregnancy. A recent study indicates that attack rates increase especially during the third trimester of pregnancy. The Caesarean section rate is no higher for women with HAE than in the general public, according to Bouillet.13
There is no restriction on breast-feeding for HAE mothers, according to the current literature, but 17a-alkylated androgens are contra-indicated as they are secreted in maternal milk.14
Although menopause does not alter the disease in most women with HAE, HRT (hormone replacement therapy) should not be prescribes as estrogen has been seen to exacerbate the symptoms of HAE.15 The same holds true of the estrogen found in most contraceptive pills. An alternative form of birth control may be recommended.
The incidence of breast cancer is not higher in women than HAE, but the medicine Tamoxifen has been shown to worsen symptoms.16
As stated earlier, the approval of Cinryze™, Berinert®, Kalbitor®, Firazyr®, and Ruconest® has changed the landscape of HAE therapeutic options in the US. The variability of HAE, including attack frequency and severity, individual response to therapies, as well as gender, age, other medical conditions and access to medical care, according to Professor Zuraw, highlight the need for a treatment approach uniquely tailored to the needs of each HAE patient.17
New HAE medicines are still being developed.