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 abarelix and flecainide. 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 abarelix, when combined with flecainide (100%). We do not expect any change in exposure for flecainide, when combined with abarelix (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.
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.
Flecainide has a high oral bioavailability [ F ] of 95%, which is why the maximum plasma level [Cmax] tends to change little during an interaction. The terminal half-life [ t12 ] is 8.8 hours and constant plasma levels [ Css ] are reached after approximately 35.2 hours. The therapeutic window is narrow and the safety margin is therefore small. Even small changes in exposure can increase the risk of toxicity. The protein binding [ Pb ] is rather weak at 40% and the volume of distribution [ Vd ] is very large at 546 liters. About 30.0% of an administered dose is excreted unchanged via the kidneys and this proportion is seldom changed by interactions. The metabolism mainly takes place via CYP2D6 and the active transport takes place partly via BCRP and PGP.
|Serotonergic Effects a||0||Ø||Ø|
Rating: According to our knowledge, neither abarelix nor flecainide increase serotonergic activity.
|Kiesel & Durán b||0||Ø||Ø|
Rating: According to our knowledge, neither abarelix nor flecainide increase anticholinergic activity.
QT time prolongation
Rating: In combination, abarelix and flecainide can potentially trigger ventricular arrhythmias of the torsades de pointes type.
General adverse effects
|Side effects||∑ frequency||aba||fle|
|Blurred vision||24.0 %||n.a.||24.0|
|Cardiac arrest||0.0 %||n.a.||0.01|
|Cardiogenic shock||0.0 %||n.a.||0.01|
Heart failure: flecainide
Ventricular fibrillation: flecainide
Ventricular tachycardia: flecainide
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: We have studied the effects of quinidine on ECG intervals and on the pharmacokinetics of flecainide and its two metabolites in 6 healthy men in an open randomized crossover study. Flecainide acetate (150 mg) was given as a constant rate i.v. infusion over 30 min. Quinidine (50 mg orally), given the previous evening, did not change the volume of distribution of flecainide (7.9 vs 7.4 l.kg-1), but significantly increased its half-life (8.8 vs 10.7 h). This was attributable to a reduction in total clearance (10.6 vs 8.1 ml.min-1 x kg-1), most of it being accounted for by a reduction in non-renal clearance (7.2 vs 5.2 ml.min-1 x kg-1). The excretion of the metabolites of flecainide over 48 h was significantly reduced. These findings suggest that quinidine inhibits the first step of flecainide metabolism, although it may also reduce its renal clearance, but to a lesser extent (3.5 vs 2.9 ml.min-1 x kg-1). The effects of flecainide on ECG intervals were not altered by quinidine. Thus, quinidine tends to shift extensive metabolizer status for flecainide towards poor metabolizer status and may also alter its renal excretion.
Abstract: No Abstract available
Abstract: The pharmacokinetics and urinary excretion of flecainide (50 mg administered orally) were investigated in five extensive metabolizers (EMs) and five poor metabolizers (PMs) of the sparteine/debrisoquin type of polymorphism under conditions of controlled urinary pH. Flecainide disposition was altered in the PMs. The AUC was higher (1462 +/- 407 versus 860 +/- 256 hr ng/ml), the elimination half-life prolonged (11.8 versus 6.8 hours), and the amount excreted in the urine was higher (26.7 +/- 7.2 versus 15.4 +/- 1.3 mg) in PMs compared with EMs (p less than 0.05). Oral clearance of flecainide was reduced (p less than 0.019) in PMs (600 +/- 139 versus 1041 +/- 307 ml/min in EMs). The renal clearance was similar (p greater than 0.05) in PMs (308 +/- 70 ml/min) and EMs (315 +/- 69 ml/min) and, consequently, PMs had a lower (p less than 0.008) metabolic clearance of flecainide (292 +/- 136 versus 726 +/- 240 ml/min in EMs). Under conditions of uncontrolled urinary flow and pH, renal excretion of flecainide will be reduced and the difference in disposition will be greater. In PMs with renal impairment, accumulation of flecainide to very high serum concentrations may be anticipated, and this may result in proarrhythmic effects.
Abstract: This case report describes a 68-year-old woman presenting with flecainide induced syncope due to torsades de pointes (TP) ventricular tachycardia. Before TP onset, the QTc interval reached 680 ms without changes in QRS duration. None of the usual triggers were found. Prolongation of QT under flecaïnide is exceptional and the occurrence of TP without concurrent triggers has not been reported in the literature.
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.