Domperidon voor postoperatief nausea en braken, of toch maar niet? Minne Casteels Leuven, 5 oktober 2013

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1 Domperidon voor postoperatief nausea en braken, of toch maar niet? Minne Casteels Leuven, 5 oktober 2013

2 Domperidon is geïndiceerd (SPK Motilium 01/2013): o o bij volwassenen voor het verlichten van de symptomen van misselijkheid en braken, epigastrisch gevoel van volheid, bovenbuikklachten en regurgitatie van de maaginhoud bij kinderen (jonger dan 12 jaar en onder 35 kg) voor het verlichten van de symptomen van misselijkheid en braken

3 Geschiedenis in België zijn de orale en rectale vormen van domperidon vergund sinds 1978 vanaf 1980: publicaties over EPS door FDA nooit vergund geweest (min. 2 pogingen) 1985: IV-vorm van markt gehaald door VHB-houder na aantal reports van plotse dood/aritmie heel aantal publicaties over studies in postoperatief braken en nausea maar blijkbaar geen indicatie in SKP

4 FDA Warns Against Women Using Unapproved Drug, Domperidone, to Increase Milk Production June 7, The Agency also is issuing an Import Alert which alerts FDA field personnel to be on the lookout for attempts to import this drug so that it can be detained and refused admission into the U.S. if appropriate The agency is concerned with the potential public health risks associated with domperidone. There have been several published reports and case studies of cardiac arrhythmias, cardiac arrest, and sudden death in patients receiving an intravenous form of domperidone that has been withdrawn from marketing in a number of countries. FDA 17/09/ However, FDA recognized that there are some patients with severe gastrointestinal motility disorders that are difficult to manage with available therapy, who may benefit from domperidone and in whom domperidone s potential benefits outweigh its risks. FDA currently allows patients 12 years of age and older with various gastrointestinal (GI) conditions to be treated with domperidone through the Expanded Access to Investigational Drugs program. These conditions include gastroesophageal reflux disease with upper GI symptoms, gastroparesis, and chronic constipation. Patients must have failed standard therapies to be eligible to receive domperidone. This program facilitates access to investigational drugs, (such as domperidone) for patients with serious diseases or conditions when there is no comparable or satisfactory alternative therapy to diagnose, monitor, or treat the patient s disease or condition.

5 In februari 2004 is de SKP van deze geneesmiddelen aangepast om het risico van verlenging van het QTc-interval weer te geven. In 2008 werd meer informatie omtrent het risico van verlengd QTc-interval en het cardiale risico toegevoegd aan de productinformatie. In 2010 werden twee nieuwe epidemiologische studies gepubliceerd die handelen over het risico van ventriculaire (hart)aritmieën of plotse cardiale dood en een mogelijk verband met domperidon. Begin 2011 heeft het FAGG deze studies grondig geanalyseerd en voorgelegd aan de werkgroep van het EMA, verantwoordelijk voor de geneesmiddelenbewaking (Pharmacovigilance working Party, PhVWP).

6 Summary Assessment Report of the PhVWP October 2011 Domperidone - Risk of cardiac disorders Key message Domperidone should be used at the lowest effective dose in adults and children because of its use may be associated with an increased risk of serious ventricular arrhythmias or sudden cardiac death, particularly in patients older than 60 years or in patients taking daily doses of more than 30 mg.

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9 Domperidone Article-31 referral Notification EMA 8/3/2013 Domperidone is commonly used across Europe. Belgium is the Reference Member State (RMS) for the innovator product Motilium since Domperidone is indicated in adults for the relief of the symptoms of nausea and vomiting, epigastric sense of fullness, upper abdominal discomfort and regurgitation of gastric contents and in children for the relief of the symptoms of nausea and vomiting.

10 In the mid 1980s a possible association of QTprolongation, and cardiac adverse events, was identified when high and rapidly administered intravenous doses of domperidone were used as an anti-emetic during cytotoxic treatment in cancer patients. On recognition of this possible association, the intravenous formulation was voluntarily withdrawn worldwide by the Marketing Authorisation Holder, and no intravenous formulations have been manufactured since Domperidone Article-31 referral Notification EMA 8/3/2013

11 Over the last years, cardiovascular events including risk of QT-prolongation, arrhythmia, sudden death have been discussed by the Pharmacovigilance Working Party (PhVWP). This led to changes to the product information agreed by the PhVWP in October The MAH of the innovator was also requested to conduct a pharmacoepidemiological study and a thorough QTc study. Domperidone Article-31 referral Notification EMA 8/3/2013

12 Since then, new cases of cardiotoxicity related to domperidone have been reported. Some of these are included and assessed in the PSUR Work Sharing procedure covering the period January 2009 to January 2012 and for which Belgium acts as P-RMS. In this assesment report, Belgium, notably, proposed to contraindicate the use of domperidone in patients who have existing prolongation of cardiac conduction intervals, particulary QTc, patients with significant electrolyte disturbances or underlying cardiac diseases such as congestive heart failure. Domperidone Article-31 referral Notification EMA 8/3/2013

13 Furthermore, in 2012 a procedure referred to in article 45 of Regulation 1901/2006/EC, as amended, was performed and a conclusion was reached that high-dose paediatric regimen of domperidone was no longer considered as acceptable and therefore the section 4,2 paediatric posology of the SmPC should be modified. Domperidone Article-31 referral Notification EMA 8/3/2013

14 In light of the above, Belgium considers that it is in the interest of the Union to refer domperidone-containing medicinal products to the Pharmacovigilance Risk Assessment Committee and requests that it gives its recommendation under Article 31 of Directive 2001/83/EC on whether the balance of benefits and risks is positive for these products in the approved indications and whether the marketing authorisation for medicinal products containing domperidone should be maintained, varied, suspended or withdrawn. Domperidone Article-31 referral Notification EMA 8/3/2013

15 Postoperatief nausea en braken geen enkel schema reduceert risico op nausea en braken tot 0 geen sluitende studies 4 grote risicofactoren: vrouw niet-roker reisziekte-gevoelig perioperatieve opioïden in UZ Leuven: o o alizapride dexamethasone ondansetron niet volgens vast protocol

16 Domperidon voor postoperatief braken en nausea??? SKP ondansetron preventie en behandeling van nausea en braken na een operatieve ingreep gedurende de 24 uur die volgen op de inductie van de algemene anesthesie bij risicopatienten met een verlaagde emetogene drempel alizapride symptomatische behandeling van nausea en braken van verschillende oorsprong, bij volwassenen en kinderen, met name: nausea en braken ten gevolge van een anesthesie of een chirurgische ingreep; nausea en braken te wijten aan chemotherapie en radiotherapie. domperidon (bij volwassenen) het verlichten van de symptomen van misselijkheid en braken, epigastrisch gevoel van volheid, een vervelend gevoel in de bovenbuik, regurgitatie van de maaginhoud

17 Domperidon voor postoperatief braken en nausea??? domperidon o benefit: weinig evidentie voor gebruik bij postoperatief braken o risk? vooral: domperidon kan/mag geen comfortmedicatie zijn voorschriftplicht logisch en noodzakelijk cave interacties cave risicopopulaties

18 Wat bij gewijzigde benefit/risk verhouding, gewijzigd SKP, waarschuwingen Ema..? (herhaalde) communicatie naar artsen/apothekers/verpleging (zeker wanneer het gaat over farmaca die op verpleeglijstje staan) nood tot aanpassing van interne schemata/protocols wanneer benefit/risk gewijzigd blijkt: o doelpopulatie o voorschriftplicht arts o wijziging max. dosis. verantwoordelijkheid van MFC- artsen- (klinische) apothekers..

19 Domperidone should be restricted to patients in whom its benefit is proven to justify the risk. Availability without prescription and advertising as an innocent relief is incorrect and unsafe, and needs to be reconsidered.