QT time prolongation
Adverse drug events
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Explanations of the substances for patients
We have no additional warnings for the combination of donepezil and abarelix. Please also consult the relevant specialist information.
The reported changes in exposure correspond to the changes in the plasma concentration-time curve [ AUC ]. We do not expect any change in exposure for donepezil, when combined with abarelix (100%). We do not expect any change in exposure for abarelix, when combined with donepezil (100%).
The pharmacokinetic parameters of the average population are used as the starting point for calculating the individual changes in exposure due to the interactions.
Donepezil has a high oral bioavailability [ F ] of 90%, which is why the maximum plasma level [Cmax] tends to change little during an interaction. The terminal half-life [ t12 ] is rather long at 70 hours and constant plasma levels [ Css ] are only reached after more than 280 hours. The protein binding [ Pb ] is 96% strong. Since the substance has a low hepatic extraction rate of 0.09, displacement from protein binding [Pb] in the context of an interaction can lead to increased exposure. The metabolism takes place via CYP2D6 and CYP3A4, among others and the active transport takes place partly via BCRP and PGP.
The bioavailability of abarelix is unknown. The terminal half-life [ t12 ] is rather long at 316.8 hours and constant plasma levels [ Css ] are only reached after more than 1267.2 hours. The protein binding [ Pb ] is 97.5% strong. The metabolism via cytochromes is currently still being worked on.
|Serotonergic Effects a||0||Ø||Ø|
Rating: According to our knowledge, neither donepezil nor abarelix increase serotonergic activity.
|Kiesel & Durán b||0||Ø||Ø|
Rating: According to our knowledge, neither donepezil nor abarelix increase anticholinergic activity.
QT time prolongation
Rating: In combination, donepezil and abarelix can potentially trigger ventricular arrhythmias of the torsades de pointes type.
General adverse effects
|Side effects||∑ frequency||don||aba|
|Loss of appetite||5.0 %||5.0||n.a.|
|Weight loss||4.0 %||4.0||n.a.|
Hypertension (3%): donepezil
Syncope (2%): donepezil
Atrioventricular block: donepezil
Elevated creatine kinase (3%): donepezil
Dream disorder (3%): donepezil
Depression (2.5%): donepezil
Asthenia (1.5%): donepezil
Somnolence (1.5%): donepezil
Gastrointestinal hemorrhage: donepezil
Based on your answers and scientific information, we assess the individual risk of undesirable side effects. These recommendations are intended to advise professionals and are not a substitute for consultation with a doctor. In the restricted test version (alpha), the risk of all substances has not yet been conclusively assessed.
Abstract: AIMS: To investigate spontaneous reports of TdP present in the public version of the FDA Adverse Event Reporting System (AERS) in the light of what is already known on their TdP-liability. METHODS: Reports of TdP from January 2004 through December 2007 were retrieved from the public version of the AERS database. All reports were selected from REACTION files and the relevant suspected and/or interacting drugs were identified from DRUG files. Qualitative analysis was performed by the case/non-case method. Cases were represented by TdP reports, whereas non-cases were all reports of adverse drug reactions other than TdP. Quantitative analysis was assessed by calculating the crude and adjusted reporting odds ratio (ROR), as a measure of disproportionality, with the 95% confidence interval. RESULTS: Reports of TdP were 1665 over a 4-year period, involving 376 active substances. Thirty-five drugs with at least 10 reports were identified: amiodarone and methadone were associated with the highest number of cases (113 and 83 respectively) and most of the other reports were ascribable to antibacterials, antidepressants and antipsychotics; remarkable differences in number of cases and ROR were present among agents within each therapeutic class. A disproportionate reporting was also observed for other compounds such as donepezil, famotidine and mitoxantrone. CONCLUSIONS: Large spontaneous reporting databases represent an important source for signal detection of rare adverse drug reactions (ADR), such as TdP. The number of reports associated to donepezil, famotidine and mitoxantrone could be considered unexpected on the basis of current evidence and needs further investigations on their true TdP-liability.
Abstract: BACKGROUND: Anticholinergic drugs are often involved in explicit criteria for inappropriate prescribing in older adults. Several scales were developed for screening of anticholinergic drugs and estimation of the anticholinergic burden. However, variation exists in scale development, in the selection of anticholinergic drugs, and the evaluation of their anticholinergic load. This study aims to systematically review existing anticholinergic risk scales, and to develop a uniform list of anticholinergic drugs differentiating for anticholinergic potency. METHODS: We performed a systematic search in MEDLINE. Studies were included if provided (1) a finite list of anticholinergic drugs; (2) a grading score of anticholinergic potency and, (3) a validation in a clinical or experimental setting. We listed anticholinergic drugs for which there was agreement in the different scales. In case of discrepancies between scores we used a reputed reference source (Martindale: The Complete Drug Reference®) to take a final decision about the anticholinergic activity of the drug. RESULTS: We included seven risk scales, and evaluated 225 different drugs. Hundred drugs were listed as having clinically relevant anticholinergic properties (47 high potency and 53 low potency), to be included in screening software for anticholinergic burden. CONCLUSION: Considerable variation exists among anticholinergic risk scales, in terms of selection of specific drugs, as well as of grading of anticholinergic potency. Our selection of 100 drugs with clinically relevant anticholinergic properties needs to be supplemented with validated information on dosing and route of administration for a full estimation of the anticholinergic burden in poly-medicated older adults.
Abstract: An 80-year-old woman with Alzheimer's dementia presented with diarrhoea, vomiting and worsening confusion following an increase in donepezil dose from 5 to 10 mg. The ECG revealed prolongation of QTc interval. Soon after admission, she became unresponsive with polymorphic ventricular tachycardia (VT). Cardiopulmonary resuscitation with a 200 J shock was successful in establishing cardiac output. Following the discontinuation of donepezil, the QTc interval normalised and no further arrhythmias were recorded. Treatment with anticholinesterase inhibitors may result in life-threatening VT. Vigilance is required for the identification of this condition in patients presenting with presyncope, syncope or seizures.
Abstract: Transporters in proximal renal tubules contribute to the disposition of numerous drugs. Furthermore, the molecular mechanisms of tubular secretion have been progressively elucidated during the past decades. Organic anions tend to be secreted by the transport proteins OAT1, OAT3 and OATP4C1 on the basolateral side of tubular cells, and multidrug resistance protein (MRP) 2, MRP4, OATP1A2 and breast cancer resistance protein (BCRP) on the apical side. Organic cations are secreted by organic cation transporter (OCT) 2 on the basolateral side, and multidrug and toxic compound extrusion (MATE) proteins MATE1, MATE2/2-K, P-glycoprotein, organic cation and carnitine transporter (OCTN) 1 and OCTN2 on the apical side. Significant drug-drug interactions (DDIs) may affect any of these transporters, altering the clearance and, consequently, the efficacy and/or toxicity of substrate drugs. Interactions at the level of basolateral transporters typically decrease the clearance of the victim drug, causing higher systemic exposure. Interactions at the apical level can also lower drug clearance, but may be associated with higher renal toxicity, due to intracellular accumulation. Whereas the importance of glomerular filtration in drug disposition is largely appreciated among clinicians, DDIs involving renal transporters are less well recognized. This review summarizes current knowledge on the roles, quantitative importance and clinical relevance of these transporters in drug therapy. It proposes an approach based on substrate-inhibitor associations for predicting potential tubular-based DDIs and preventing their adverse consequences. We provide a comprehensive list of known drug interactions with renally-expressed transporters. While many of these interactions have limited clinical consequences, some involving high-risk drugs (e.g. methotrexate) definitely deserve the attention of prescribers.
Abstract: We report a case of torsades de pointes (TdP) induced by donepezil without QT prolongation. An 86-year-old woman was admitted to our hospital because of a syncopal attack. She had been treated for Alzheimer's disease with donepezil. Initial 12-lead electrocardiogram showed atrial fibrillation and normal corrected QT interval. After admission, atrial fibrillation spontaneously recovered to normal sinus rhythm on electrocardiographic monitoring. On the second day, electrocardiographic monitoring documented TdP. We discontinued donepezil immediately. After washout of donepezil, TdP was not observed again. Corrected QT interval was normal throughout hospitalization. This case suggests that donepezil may cause life-threatening ventricular arrhythmias without QT prolongation. Even if corrected QT interval is normal in patients taking donepezil and experiencing symptoms associated with TdP, electrocardiographic monitoring is recommended. <Donepezil may cause life-threatening ventricular arrhythmias without QT prolongation. Even if corrected QT interval is normal in patients taking donepezil and experiencing symptoms associated with torsades de pointes, electrocardiographic monitoring is recommended.>.