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This so-called non-inferiority trial included 600 pa- tients treated with dopaminergic therapy and ex- periencing end-of-dose motor fluctuations (6-8). After randomisation, in addition to the dopamin- ergic therapy, they received in double-blind manner either opicapone (5 mg per day, 25 mg per day, or 50 mg per day), or entacapone , or placebo.The dose of levodopa could be adjusted during the first two weeks after randomisation, but not thereafter (6). This article only reports the results obtained with opicapone 50 mg per day, the only dose recom- mended in the marketing authorisation. At baseline, the patients had on average received dopaminergic therapy for about 5 years and had been suffering from motor fluctuations for about 2 years.The average duration of “off” periods was about 6 hours per day in the different groups. Most of the patients were receiving other antiparkinsonian drugs (most often a dopaminergic agonist), with no notable difference between the groups (6). In this trial, the primary outcome measure was the mean reduction in the duration of “off” periods after 14 to 15 weeks of treatment, compared to baseline. This reduction was 117 minutes in the opicapone group, which was close to that in the entacapone group (96 minutes) and statistically significantly greater than that in the placebo group (56 minutes) (6). Dyskinesia twice as prevalent as with entacapone. The predictable adverse effect profile of opicapone is that of the other COMT inhibitors, mainly related to the increased dopaminergic action of levodopa : gastrointestinal disorders (including chronic diarrhoea and colitis), orthostatic hypotension, mental health problems (including compulsive disorders, insomnia, hallucinations and abnormal dreams), excessive drowsiness and suddenly falling asleep during the daytime, plus rhabdomyolysis and liver damage (especially with tolcapone ) (5,9).There is a possible increased risk of prostate cancer with entacapone . In the double-blind randomised trial versus enta- capone , the incidence of adverse effects was about 33% in the opicapone 50 mg per day group and in the entacapone group, but there was an increase in dyskinesia with opicapone : 15% versus 7% with entacapone , versus 4% with placebo. The other adverse effects more frequently reported in the entacapone and opicapone groups than in the pla- cebo group were constipation, nausea, insomnia and dizziness (7). Taking into account all the trials that evaluated opicapone , particularly those versus placebo, there was an indication of a possible increase in ischaemic heart disorders. Abnormal liver function has also been reported in a few patients treated with opica- pone (6). Beware of hypertensive crises when used in com- bination with a monoamine oxidase inhibitor (MAOI). As with the other COMT inhibitors, the combination of opicapone with a monoamine oxi- dase inhibitor (MAOI) leads to an inhibition of

catecholamine metabolism, exposing patients to the risk of hypertensive crises. Combination of opicapone with an MAOI (such as selegiline , an- other antiparkinsonian drug), a tricyclic antidepres- sant, a drug that has an inhibitory action on nor- adrenaline reuptake (such as the antidepressant venlafaxine ) or a drug metabolised by COMT (such as the antidepressant paroxetine ) should be avoid- ed, or if not, requires close clinical monitoring (5,9). Opicapone and its metabolites inhibit, in particu­ lar, the cytochrome P450 isoenzyme CYP 2C8, creating a risk of overdose when combined with substrates of this isoenzyme, such as repaglinide (a hypoglycaemic drug) (6,9). Convenience: just one administration per day, but cannot be taken simultaneously with levodopa. Opicapone is taken only once daily, but it must be taken at least one hour before or after levodopa . Entacapone, on the other hand, is taken up to 10 times per day, along with each dose of levodopa + peripheral dopa-decarboxylase inhibitor (9). In patients with Parkinson’s disease suffering from motor fluctuations despite optimised dopaminergic therapy, opicapone has not been shown to be more effective than entacapone in reducing the duration of “off” periods. Opicapone increases the risk of dyskinesia, and its adverse effect profile is less well known than that of entacapone . As of 2019, there is no reason to choose opicapone over entacapone , despite the significant reduction in the number of daily doses that need to be taken. ©Prescrire ▶ Translated from Rev Prescrire September 2019 Volume 39 N° 431 • Pages 652-654 In practice Literature search up to 8 July 2019 In response to our request for information, Bial Portela provided uswith administrative documents and published articles . 1- Prescrire Rédaction “Maladie de Parkinson: traitement initial des troubles moteurs” Premiers Choix Prescrire, updated January 2018: 4 pages. 2- Prescrire Rédaction “Traitement de la maladie de Parkinson. Deux- ième partie. Réduire les fluctuations motrices sous lévodopa” Rev Prescrire 2011; 31 (330): 273-279. 3- Prescrire Rédaction“Entacapone: une autre option dans lamaladie de Parkinson” Rev Prescrire 2013; 33 (353): 187-188. 4- Prescrire Rédaction “Stalevo°, un nième dosage: ça suffit!” Rev Prescrire 2013; 33 (359): 660. 5- Prescrire Rédaction“Patients parkinsoniens” InteractionsMédica- menteuses Prescrire 2019. 6- EMA - CHMP “Public assessment report for Ongentys. EMEA/ H/C/002790/0000” 28 April 2016: 140 pages. 7- HAS - Commission de la transparence “Avis-Ongentys 50 mg” 23 January 2019: 27 pages. 8- Ferreira JJ et al. “Opicapone as an adjunct to levodopa in patients with Parkinson’s disease and end-of-dose motor fluctuations: a ran- domised, double-blind, controlled trial” Lancet Neurol 2016; 15 (2): 154-165. 9- European Commission “SPC-Ongentys” 13 March 2019 + “SPC-­ Comtan” 19 April 2018: 37 pages. 10- Prescrire Editorial Staff “Levodopa + carbidopa + entacapone, Parkinson’s disease: amodest effect” Prescrire Int 2005; 14 (76): 51-54

Prescrire Int • January 2020

P age 6 • P rescrire I nternational S pecial E dition 2020