Translated from Rev Prescrire December 2015; 35 (386): 911

Drug-induced non-immune-mediated angioedema • Combinations of drugs that increase with pruritus or urticaria. It often includes In practice. Angioedema is not always vascular permeability increase the risk bowel wall oedema with abdominal pain. immune-mediated. Concomitant use of of angioedema. The drugs implicated are mainly angio- several drugs known to increase vascular tensin-converting enzyme (ACE) inhibi- permeability increases the risk of ngioedema is a localised oedema tors and aliskiren, and more rarely angio- angioedema. Aof the skin or mucous membranes tensin II receptor blockers (ARBs or ACE inhibitors are the most commonly caused by extravasation of fluid into the sartans) and racecadotril (see also implicated drugs in non-allergic interstitial tissue due to loss of vascular below) (1,2). Antihistamines and cortico- angioedema. They also worsen angio­ integrity. It typically affects the face, lips, steroids are ineffective in treating this edema induced by other drugs. tongue, throat, ears, hands, feet and type of angioedema. ©Prescrire external genital organs (1). Some drugs cause histamine release through a direct pharmacological effect

Bradykinin accumulation or hista- on mast cells rather than through an Selected references from Prescrire’s literature mine release. Drug-induced angioedema allergic reaction. The main drugs impli- search. is often an immune-mediated allergic cated are and radiographic con- 1- Zuraw B et al. “An overview of angioedema: pathogenesis and causes” UpToDate. www.­ reaction. But some drugs cause angioede- trast media, the antifungal caspofungin, uptodate.com accessed 29 September 2015: ma through non-immune-mediated mech- nonsteroidal anti-inflammatory drugs 8 pages. anisms involving an influx of inflammatory (NSAIDs) and aspirin (1,3). 2- Prescrire Editorial Staff “Angioedema due to ACE inhibitors” Prescrire Int 1998; 7 (35): 92-93. mediators that increase capillary perme- The immunosuppressive agents siroli- 3- “Noscapine” + “” + “Pethi- ability: bradykinin or histamine (1). mus and everolimus provoke angio­ dine” + “” + “Sirolimus”. In: “Martin- dale The Complete Drug Reference” The Pharma- Angioedema due to drug-induced edema through an unknown non- ceutical Press, London. www.medicinescomplete. bradykinin­ accumulation is not associated immune-­mediated mechanism (1,3). com accessed 26 September 2015: 77 pages.

Translated from Rev Prescrire December Translated from Rev Prescrire December anism that involves reduced bradykinin 2015; 35 (386): 905 2015; 35 (386): 905 degradation rather than an allergic reac- tion (see also above) (2). Noscapine: angioedema Racecadotril + ACE About 10 years ago, the US Food and inhibitors: angioedema Drug Administration (FDA) denied a • Opioids can trigger angioedema. request for approval of omapatrilat, a • A combination that is best avoided. drug that inhibits both neutral endo­ Noscapine is an used peptidase and angiotensin-converting to treat (1). In April 2015, the French enzyme. The reason for this rejection was In July 2015, the Nether- Health Products Agency the higher risk of severe angioedema lands Pharmacovigilance (ANSM) reported evidence demonstrated in a head-to-head trial ver- Centre Lareb announced that it had of an increased risk of angio­ sus an ACE inhibitor (1). received 10 reports of angioedema asso- edema associated with concomitant use In practice, it is best that patients with ciated with the use of noscapine between of the antidiarrhoeal racecadotril and an hypertension or heart failure who are tak- 1987 and 2013 (2). angiotensin­­ -converting enzyme (ACE) ing an ACE inhibitor avoid using racecad- The underlying mechanism could be an inhibitor (1). otril if they develop diarrhoea. Patients immune-mediated allergic reaction or nos- An 80-year-old woman treated with an should be warned about this risk in capine-induced histamine release. Hista- ACE inhibitor had three episodes of advance, because some of them might mine increases vascular permeability. angioedema, two of which occurred when self-medicate with racecadotril without Morphine and other opioids cause dose-­ she was also taking racecadotril (1). seeking advice from a health professional. dependent histamine release provoking A search of the French national phar- ©Prescrire disorders such as pruritus, urti­caria, hypo- macovigilance database identified tension, flushing and angioedema. 11 reports of angioedema in patients tak- Selected references from Prescrire’s literature Opioids, including antitussives, are a ing both an ACE inhibitor and racecadotril; search. possible cause of angioedema. in 9 of these cases, the temporal relation- 1- ANSM “GT interactions médicamenteuses - Séance du 13 avril 2015. Racécadotril et inhibiteurs ©Prescrire ship between the use of this drug combi- de l’enzyme de conversion” 8 June 2015: 4-5. nation and the onset of angioedema was 2- “ACE inhibitors”. In: “Martindale The Com- plete Drug Reference” The Pharmaceutical Press, highly suggestive of a causal link (1). London. www.medicinescomplete.com accessed Selected references from Prescrire’s literature Racecadotril inhibits the neutral endo- 23 September 2015: 36 pages. search. 1- “Noscapine” + “Opioid analgesics”. In: “Martin- peptidase involved in the metabolism of dale The Complete Drug Reference” The Pharma- bradykinins, which are inflammatory medi- ceutical Press, London. www.medicinescomplete. ators that increase capillary permeabili- com accessed 26 September 2015: 77 pages. 2- Lareb “Noscapine and angioedema” 3 July ty (1). Angioedema is a known adverse 2015: 5 pages. effect of ACE inhibitors through a mech­

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