Adverse Effects

Translated from Rev Prescrire February 2016; Translated from Rev Prescrire December Selected references from Prescrire’s literature 36 (388): 108 2015; 35 (386): 905 search. 1- U.S. Food and Drug Administration “FDA drug safety communication: FDA warns that DPP-4 inhibitors for type 2 diabetes may cause severe SSRI : Gliptins: disabling joint pain joint pain” 8 August 2015. www.fda.gov accessed extrapyramidal reactions. 25 September 2015: 4 pages. • Poor harm-benefit balance. 2- Prescrire Rédaction “4-1-9. Patients sous sita- Dose increase. gliptine, vildagliptine, saxagliptine ou linaglip- • tine” Rev Prescrire 2014; 34 (374 suppl. interac- In August 2015, the US tions médicamenteuses). A review published in 2015 Food and Drug Administra- identified 91 reports of tion (FDA) issued a safety extrapyramidal reactions warning about 33 reports of Translated from Rev Prescrire January 2016; attributed to serotonin severe joint pain linked to gliptins, a 36 (387): 19 reuptake inhibitor antidepressants pub- group of glucose-lowering drugs (1). lished between 1998 and May 2015 (1). The pain started within the first month Mirabegron: , The extrapyramidal reactions reported of treatment in 22 cases. 10 patients stroke were akathisia (17 patients), dyskinesia were hospitalised for disabling pain. In (18 patients) including tardive dyskinesia, 23 cases, the pain regressed within a • A poor option in urinary inconti- dystonia (27 patients), parkinsonism month after gliptin cessation. Joint pain nence. (19 patients), and a combination of sev- recurred in all 8 cases of gliptin rechal- eral types of extrapyramidal reac- lenge, including 6 cases in which a differ- Mirabegron is a beta-3 tion (10 patients). In half of the cases, the ent gliptin was used (1). adrenoceptor agonist disorder occurred within 7 days after ini- Manifestations suggestive of inflamma- approved for the symptom- tiating the treatment or increasing the tion or an immune reaction were atic relief of certain types of dose (1). observed in some patients: fever, rash, urinary incontinence. Cardiovascular In most cases, the drug implicated was oedema, elevated erythrocyte sedimen- adverse effects are expected, given its a “selective” serotonin reuptake inhibitor tation rate (1 case) or elevated C-reactive mechanism of action and the fact that, in (SSRI): citalopram or its enantiomer protein (CRP) (1 case). Some findings clinical use, receptor selectivity is only escitalopram (22% of cases), fluoxetine suggested an autoimmune reaction: anti- relative (1). (21%) or sertraline (15%). Serotonin and nuclear antibodies (2 cases), and anti- Initial evaluation data showed that noradrenaline reuptake inhibitors were neutrophil cytoplasmic antibodies mirabegron can provoke arrhythmia, QT also implicated: venlafaxine (12%) or (1 case). Certain patients received cortico- prolongation and hypertension (1). duloxetine (5%). In 14% of cases the steroids, methotrexate or another immu- Since its market introduction, mirabe- patient was taking no other medica- nosuppressant to treat their joint pain. gron has been implicated in cases of tion (1). Gliptins inhibit dipeptidyl dipeptidase severe hypertension and hypertensive Extrapyramidal disorders are known (DPP-4) and thereby prolong the action of crisis associated with cardiovascular adverse effects of antidepressants with gut hormones (incretins) that stimulate ­disorders, including stroke (2). serotonergic effects. In the 1950s, cases insulin secretion (2). DPP-4 is similar to In October 2015, the European public of “muscle hypertonia” and “hypermotility” CD26, a protein on the surface of lymph­ ­pharmacovigilance database (www.­ were described with monoamine oxidase ocytes that modulates their function. The adrreports.eu) contained 130 reports inhibitors (MAOIs) (2). Cases of extra­ action of gliptins on CD26 is prob­ably of hypertension linked to mirabegron pyramidal reactions were later linked to implicated in their immunological ­submitted­­ by health professionals and (2). effects (2). On the one hand they provoke 43 submitted by patients, and 14 cases If tremor, dystonia or abnormal move- hypersensitivity reactions, and on the of hypertensive crisis (3). ments develop in a patient taking a sero- other hand they have immunosuppressant The efficacy of mirabegron in urinary tonergic , the role of the effects and increase the risk of infection, incontinence is minimal, and similar to drug must be suspected and its discon- in particular urinary and upper respira­tory that of antimuscarinic drugs. Drugs are tinuation suggested, at least temporarily, tract infections. These apparently inflam- of little value in this situation. Mirabe- to test this hypothesis, while bearing in matory gliptin-associated joint disorders gron’s minor efficacy will not usually mind the risk of a withdrawal syndrome. may share a similar mechan­ism. ­justify exposing patients to the risk of ©Prescrire Gliptins have a long list of adverse hypertensive crisis, even for severe effects and any long-term clinical benefits ­urinary incontinence. A better choice in Selected references from Prescrire’s literature have yet to be proven (2). Gliptins have these cases is a better established anti- search. an unfavourable harm-benefit balance. muscarinic drug. 1- Hawthorne JM and Caley CF “Extrapyramidal If a gliptin-treated patient develops joint ©Prescrire reactions associated with serotoninergic anti­ depressants” Ann Pharmacother 2015; 49 (10): pain, recognising the drug’s role and 1136-1152. stopping this treatment can relieve the 2- Prescrire Rédaction “Effets extrapyramidaux Selected references from Prescrire’s literature des antidépresseurs inhibiteurs de la recapture de pain and avoid exposure to antirheumat- search. 1- Prescrire Editorial Staff “Mirabegron. Poorly la sérotonine” Rev Prescrire 2001; 21 (215): 201- ic or anti-inflammatory drugs and to their effective in urge urinary incontinence” Prescrire Int 203. adverse effects. 2016; 25 (167): 8-9. ©Prescrire 2- MHRA “Mirabegron (Betmiga): risk of severe hypertension and associated cerebrovascular and cardiac events” Drug Safety Update 2015; 9 (3): 1. 3- EMA “Suspected adverse drug reaction reports for substances. Mirabegron” October 2015. www. adrreports.eu accessed 23 November 2015.

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