17-alpha-alkylated anabolic androgens
Attenuated androgens such as Danazol and Stanozolol are the usual agents with methyltestosterone and oxandrolone as alternatives. Androgens are generally more effective than antifibrinolytic agents [8, 17–19, 40]. Androgen contraindications usually include pregnancy, lactation, cancer, hepatitis, and childhood (until finished growing) [8, 15, 17–19, 29, 31, 32]. Side effects may include virilization, weight gain, acne, hair growth, altered libido, voice deepening, decreased breast size, menstrual irregularities, vasomotor symptoms, hypertension, atherogenesis, altered lipid metabolism, altered liver enzymes, cholestasis, hepatic necrosis, liver neoplasms (hepatocellular adenomas or carcinomas), erythrocytosis, hemorrhagic cystitis, and ambiguous genitalia in newborns if mothers treated with androgens during pregnancy [8, 17, 19, 28, 37, 40, 41, 55, 56]. Androgen induction can be with high dose and reduce or low dose and escalate aiming to achieve the lowest effective dose (maximum long term doses recommended are 200 mg daily for Danazol and 2 mg daily for Stanozolol) [17–19, 28, 29, 31, 35, 37, 40, 55]. Androgen therapy is not recommended for children but has been used in the prepubertal setting [8, 17, 19, 29, 31, 35]. If patients are exposed to a precipitating factor such as infection or if the sensation of prodromal attack symptoms or mild clinical manifestations developing, then doubling the dose for several days has been tried. The lowest effective maintenance dose including trying alternate day or twice weekly should be tried [19, 28, 29]. Danazol has been used in children [8, 31, 35] but pdC1INH may be the safest long term approach [8, 31, 35]. Danazol has been used for prophylaxis in HAE type III as have progesterone and tranexamic acid .
every six months: liver enzymes (ALT, AST, alk phos), lipid profile, complete blood cell count, and urinalysis. For adults with a dose of 200 mg or less per day Danazol: suggest an annual liver spleen ultrasound. In prepubertal patients or in adults with doses higher than 200 mg Danazol daily: suggest six monthly liver spleen ultrasound for the detection of focal lesions and annual alpha fetoprotein [8, 19, 29, 31, 35, 57–60].
Antifibrinolytic Agents (AFs;)
Tranexamic acid (TA; Cyklokapron®) is more effective than epsilon aminocaproic acid (EACA; Amicar®;) and has mostly replaced EACA outside the USA. AFs may not be as effective as androgen therapy in HAE but may be useful in AAE [10, 17, 19, 28]. TA is mostly used for prophylaxis in children before Tanner V puberty stage or if not wanting to risk androgen prophylaxis [8, 17, 19, 29, 31, 35]. Dyspepsia is common and can be reduced by taking the drug with food. Other side effects may include myalgia, muscle weakness, elevated serum creatine phosphokinase or aldolase, rhabdomyolysis (EACA particularly), hypotension, fatigue, and retinal changes (seen in animals) [19, 35, 44, 45]. TA dosage is not well established [4, 8, 17, 19, 29, 31, 35, 45] aiming for the lowest effective maintenance with recommended starting dose of 20 to 50 mg/kg/day (split 2 to 3 times daily, taken with food, with daily maximum of 4 to 6 g; [4, 8, 17, 19, 35, 44, 45]. The dose may be able to be reduced to 0.5 g once or twice daily or even alternate-day or twice weekly regimens . TA Monitoring: six monthly CK, urinalysis, liver and renal function; annual ophthalmology check for eye pressure (risk of glaucoma) [8, 19, 29, 31, 35]. AFs have not been associated with excess thrombosis or myocardial infarction in controlled trials [61–64], but there are case reports of thrombosis in patients with hypercoagulable states treated with AFs [65, 66], so it is prudent to use it cautiously if there is a family history of thrombophilia or active thromboembolic disease [35, 45, 65, 66]. TA was reported effective long-term prophylaxis in HAE type III .
Plasma-derived C1 inhibitor - pdC1INH
Home pdC1INH self-infusion programs should be offered to patients (created similar to hemophilia self-infusion programs which have existed for 35 years; [8, 12, 17, 19, 29, 31, 36, 37, 52, 68, 69]. The dose including dose per kg for prophylaxis has not been fully established [12, 14, 36, 37, 70]. We recommend 500 units (if less than 50 kg, 110 lb) or 1000 units (if greater than 50 kg, 110 lb) [1, 12, 14, 19].
from ViroPharma is FDA approved for adolescent and adult prophylaxis at a dose of 1000 units every three or four days (see FDA approved package insert:
http://www.fda.gov/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/FractionatedPlasmaProducts/ucm150480.htm). Prophylaxis with pdC1INH is not 100% effective http://www.cinryze.com/documents/cinryze-prescribing-information.pdf. Cetor® from Sanquin is licensed in the Netherlands http://www.sanquinreagents.com/sanquin-eng/sqn_products_plasma.nsf/8551110e498bd2c8c12572110034decf/11343072be4286d2c125702a004a4e50/$FILE/Cetor%20SPC.pdf.
from CSL Behring is approved for therapy in many countries around the world including Europe and by USA FDA (see FDA approved package insert:
http://www.fda.gov/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/FractionatedPlasmaProducts/ucm186264.htm). Reconstitution and administration of PdC1INH as per package inserts (see above web links; [18, 19, 35]). DO NOT SHAKE as this will denature the protein. Administration should be via peripheral vein (usually over ten minutes) (see product package insert references above for administration details) [8, 18, 19, 29, 31, 35].