eMedicine Specialties > Dermatology > Allergy & Immunology
Angioedema, Acquired: Treatment & Medication
Updated: Aug 18, 2009
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
- Follow-up
Treatment
Medical Care
- Depending on the symptoms and the site of the angioedema, intensive support may be necessary, including intravenous fluids.
- When possible, the underlying disorder should be treated. The resolution of angioedema has been reported with the treatment of underlying disease, although recurrences have occurred despite appropriate treatment of the disorder.
- In acquired angioedema type I (AAE-I), treatment of the associated lymphoproliferative process may result in correction of the abnormality.
Surgical Care
- Intubation may be necessary in cases of laryngeal edema.
Medication
In acquired angioedema, therapy for acute attacks may be aborted with C1-INH concentrates or, if unavailable, fresh-frozen plasma. However, rapid catabolism of C1-INH occurs in acquired angioedema, so higher doses of C1-INH plasma concentrate may be needed.
Androgens, such as danazol or stanozolol, may be beneficial in acquired angioedema type I but are of no value in acquired angioedema type II (AAE-II). Prostate cancer and pregnancy preclude the use of androgens.
Antifibrinolytics, such as epsilon-aminocaproic acid and tranexamic acid, have been found to be more effective for long-term prophylaxis in those with acquired angioedema.
Immunosuppressive therapy directed toward decreasing autoantibody production may be of value in patients with acquired angioedema type II, which may be accomplished by the use of plasmapheresis with cyclophosphamide.
In recent years, 2 papers have reported effective treatment of acquired angioedema cases with a series of 4 weekly injections with rituximab (a chimeric monoclonal antibody to CD20). In one study, 3 patients with severe acquired angioedema were treated with rituximab, which resulted in normalization of C1-INH and C4 levels. Long-term remission of angioedema attacks was achieved.3 In a second study, a patient with acquired angioedema type II refractory to standard treatment was treated with rituximab, which allowed for a 6-month attack-free interval.4
New medications are currently being studied for the treatment of acquired angioedema. One such treatment is a synthetic kallikrein inhibitor, Ecallantide (DX-88), produced by Dyax (Cambridge, Mass). The drug is able to stop the generation of bradykinin by inhibiting kallikrein activation. This decreases the rate of C1-INH catabolism, allowing for C1-INH concentrate to be more effective. US Food and Drug Administration (FDA) approval for DX-88 is expected in December, 2009 (personal communication, Dyax; July 31, 2009).
Other new products in trial are a genetically engineered C1 esterase inhibitor and a bradykinin B2 receptor antagonist. The recombinant C1 esterase inhibitor, a drug called Rhucin produced by Pharming (Leiden, The Netherlands), is still in a dialogue with the FDA regarding the anticipated approval time. Pharming is expected to submit a Biologic License Application to the FDA sometime in the second half of 2009.5 The bradykinin B2 receptor antagonist, a drug called Icatibant produced by Jerini (Berlin, Germany), received a "nonapprovable" letter from the FDA in April 2008. Phase III clinical trials are anticipated in the United States, but the drug is currently only available in Europe.6
Two clinical trials include C1-Esteraseremmer-N for the Treatment of Hereditary (and Acquired) Angioedema (completed) and Effectiveness of Bradykinin Receptor Blocker at Reducing Swelling Associated With Angiotensin Converting Enzyme (ACE) Inhibitor-Associated Angioedema (recruiting).
Alkylating agents
Some agents in this class have potent immunosuppressive activity.
Cyclophosphamide (Cytoxan, Neosar)
Chemically related to nitrogen mustards. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells.
Adult
500-750 mg IV
Pediatric
Administer as in adults
Allopurinol may increase risk of bleeding or infection and enhance myelosuppressive effects; may potentiate doxorubicin-induced cardiotoxicity; may reduce digoxin serum levels and antimicrobial effects of quinolones; chloramphenicol may increase half-life while decreasing metabolite concentrations; may increase effect of anticoagulants; coadministration with high doses of phenobarbital may increase rate of metabolism and leukopenic activity; thiazide diuretics may prolong cyclophosphamide-induced leukopenia and neuromuscular blockade by inhibiting cholinesterase activity
Documented hypersensitivity; severely depressed bone marrow function
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Regularly examine hematologic profile (particularly neutrophils and platelets) to monitor for hematopoietic suppression; regularly examine urine for RBCs, which may precede hemorrhagic cystitis; hematologic myelosuppression, primarily leukopenia, is most common adverse effect; thrombocytopenia and anemia occur less frequently; gastrointestinal adverse effects include anorexia, nausea, emesis, and stomatitis; urologic adverse effects include dysuria, urgency, hematuria, bladder fibrosis, and necrosis; death from hemorrhagic cystitis has occurred; encourage excessive fluid intake; interferes with oogenesis and spermatogenesis; may cause irreversible sterility in both sexes
Antifibrinolytic agents
Act through the inhibition of plasmin; tend to be more effective than androgens for prophylaxis.1
Aminocaproic acid (Amicar)
Lysine analog that inhibits fibrinolysis via inhibition of plasminogen activator substances; to a lesser degree, through antiplasmin activity.
Widely distributed. Half-life is 1-2 h. Peak effect occurs within 2 h. Hepatic metabolism is minimal. Can be used PO/IV.
Adult
8 g q4h IV, then 16 g/d in acute attacks
6-10 g/d PO maintenance
Pediatric
8-10 g/d PO
Not recommended in newborns
Coadministration with estrogens may cause increase in clotting factors, leading to a hypercoagulable state; coadministration with tretinoin my increase risk of both venous and arterial thrombosis
Documented hypersensitivity; evidence of active intravascular clotting process; coadministration with factor IX complex concentrates or anti-inhibitor coagulant complexes; injection in premature neonates (injectable product contains benzyl alcohol)
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Do not administer unless a definite diagnosis of hyperfibrinolysis has been made; caution in cardiac, hepatic or renal disease; because aminocaproic acid can be fatal in patients with DIC, important to differentiate between hyperfibrinolysis and DIC; thrombi that form during treatment are not lysed and effectiveness is uncertain; associated adverse effects are postural hypotension, thrombosis, and muscular pain and weakness; monitor CK levels; caution in patients with upper urinary tract bleeding; caution with rapid infusions; do not administer with factor IX complex concentrates or anti-inhibitor coagulant complexes; adverse effects include bradyarrhythmia, drug-induced myopathy, and hypotension
Tranexamic acid (Cyklokapron)
Alternative to aminocaproic acid. Inhibits fibrinolysis by displacing plasminogen from fibrin.
Adult
Up to 8 g PO/IV for acute attacks
1-2 g PO for maintenance
3-4.5 g PO/IV qd divided tid/qid pc; continue for period long enough for at least 3-4 attacks to have normally occurred
Pediatric
12-25 mg/kg/dose (not to exceed 1.5 g) PO tid/qid for acute attack or as prophylaxis for 5 d
Not established
Documented hypersensitivity; active intravascular clotting process; acquired defective color vision; subarachnoid hemorrhage
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Caution in renal impairment; adverse effects are not common but include headaches, nausea, abdominal pain, and diarrhea; evidence of tumor formation in retina and liver found in experimental animal models after long-term use; although no evidence has supported these findings in humans, annual funduscopic examinations and LFT monitoring recommended q6mo if on long-term therapy; perform baseline ophthalmologic examination before initiating therapy; caution in history of thromboembolic disease and disseminated intravascular coagulation
Antigonadotropic agents
These agents have immunosuppressive properties.
Danazol (Danocrine)
Increases levels of C4 component of complement and prevents attacks associated with angioedema.
Adult
200 mg PO bid/tid initially; if efficacious, taper dose by 50% over following 2-3 mo
Pediatric
Not established
Decreases insulin requirements and increases effects of anticoagulants; concomitant administration with carbamazepine may result in toxicity; coadministration with HMG-CoA reductase inhibitors may increase risk for rhabdomyolysis; cyclosporine and/or tacrolimus toxicity may increase if coadministered with danazol; concomitant use with carbamazepine may increase risk of carbamazepine toxicity; concomitant administration with cyclosporine or tacrolimus and anabolic steroids may result in increased cyclosporine or tacrolimus blood levels and toxicity; may result in increased lovastatin plasma concentrations when administered concurrently (use only if potential benefit justifies potential risk of developing myopathy/rhabdomyolysis)
Documented hypersensitivity; seizure disorders; renal or hepatic insufficiency; cardiac disease; breastfeeding; conditions influenced by edema; undiagnosed genital bleeding; porphyria; carcinoma of the breast
Pregnancy
X - Contraindicated; benefit does not outweigh risk
Precautions
Caution in renal, hepatic, or cardiac insufficiency and seizure disorders; peliosis hepatitis and benign hepatic adenoma have been observed with long-term therapy; thromboembolic events and pseudotumor cerebri reported; androgenlike effects, including weight gain, acne, hirsutism, edema, hair loss, voice change, and menstrual disturbances, occur; temporary alteration of lipoproteins may occur; consider the impact on the risk of atherosclerosis and coronary artery disease; serum total testosterone values may be falsely elevated if radioimmunoassay done to measure testosterone in women taking danazol
Anabolic Steriod
Stanozolol
Synthetic androgen with immunosuppressive properties. Increases levels of C1 esterase inhibitor and C4 component of the complement. No longer available in the United States.
Adult
2 mg PO tid and reduce to maintenance dose of 2 mg/d or 2 mg qod after 1-3 mo
Pediatric
<6 years: 1 mg/d PO
6-12 years: 2 mg/d PO
Increases hypoprothrombinemic effects of oral anticoagulants and hypoglycemic effects of insulin and sulfonylureas; concomitant administration with carbamazepine may result in toxicity; coadministration with HMG-CoA reductase inhibitors may increase risk for rhabdomyolysis; cyclosporine and/or tacrolimus toxicity may increase if coadministered with danazol; concomitant use with carbamazepine may increase risk of carbamazepine toxicity; concomitant administration with cyclosporine or tacrolimus and anabolic steroids may result in increased cyclosporine or tacrolimus blood levels and toxicity; may result in increased lovastatin plasma concentrations when administered concurrently (use only if potential benefit justifies potential risk of developing myopathy/rhabdomyolysis)
Documented hypersensitivity; nephrosis, breast or prostate cancer
Pregnancy
X - Contraindicated; benefit does not outweigh risk
Precautions
May cause peliosis hepatitis, liver cell tumors, and blood lipid changes with increased risk of arteriosclerosis; caution in cardiac, renal, or hepatic disease or epilepsy; may increase PT; phallic or clitoral enlargement, hirsutism, gynecomastia, acne, edema, nausea, vomiting, and diarrhea may occur
More on Angioedema, Acquired |
| Overview: Angioedema, Acquired |
| Differential Diagnoses & Workup: Angioedema, Acquired |
 Treatment & Medication: Angioedema, Acquired |
| Follow-up: Angioedema, Acquired |
| References |
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References
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Leiden, The Netherlands. Biotech company Pharming Group NV ("Pharming" or "the Company") (NYSE Euronext: PHARM) today announces that, in agreement with the European Medicines Agency (EMEA), the dossier for the European Marketing Authorisation Application (MAA) of Rhucin(R) will be submitted in September 2009. CheckOrphan. Available at http://www.checkorphan.org/news/pharming_confirms_rhucin_european_maa_filing_timeline. Accessed 8/5/2009.
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Further Reading
Keywords
angioedema, acquired angioedema, AAE, Caldwell syndrome, acquired angioedema
