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 nicardipine 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 nicardipine, when combined with abarelix (100%). We do not expect any change in exposure for abarelix, when combined with nicardipine (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.
Nicardipine has a low oral bioavailability [ F ] of 35%, which is why the maximum plasma level [Cmax] tends to change strongly with an interaction. The protein binding [ Pb ] is moderately strong at 95%. The metabolism takes place via CYP2C8 and CYP3A4, among others and the active transport takes place in particular via 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 nicardipine nor abarelix increase serotonergic activity.
|Kiesel & Durán b||0||Ø||Ø|
Rating: According to our knowledge, neither nicardipine nor abarelix increase anticholinergic activity.
QT time prolongation
Rating: In combination, nicardipine and abarelix can potentially trigger ventricular arrhythmias of the torsades de pointes type.
General adverse effects
|Side effects||∑ frequency||nic||aba|
|Peripheral edema||5.9 %||5.9||n.a.|
|Myocardial infarction||0.0 %||0.0||n.a.|
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: OBJECTIVES: To assess relative roles of the intestinal and hepatic stereoselective metabolism of nicardipine in an oral first-pass disposal with and without grapefruit juice intake. METHODS: The kinetic profiles of (+)- and (-)-nicardipine were studied in the six normal healthy male volunteers who received oral (40 mg) and intravenous (2 mg) racemic nicardipine, first with water and second with grapefruit juice. Both the enantiomers were determined by the stereoselective high-performance liquid chromatographic method, and hemodynamic parameters (arterial blood pressure, heart rate, and electrocardiogram) were assessed when each blood sample was taken. RESULTS: Grapefruit juice compared with water intake caused a significant (P < 0.05) increase in the mean oral (+)- and (-)-nicardipine bioavailability (Fobs) (48.6+/-5.0% and 105.6+/-7.8%) and dose-absorbed (Fabs) available fraction unmetabolized at the gut (Fg) (48.2+/-5.6% and 110.9+/-8.8%, respectively) with no significant change in the hepatic first-pass effect. However, all of the mean kinetic parameters of both the enantiomers after the intravenous dosing of racemic nicardipine did not differ between the grapefruit juice- and water-intake trial phases. The mean percentage changes in oral AUC (43.1+/-3.4% in [+]-nicardipine and 90.9 6.4% in [-]-nicardipine, or Fobs) and Fabs Fg by grapefruit juice tended to be greater for (-)-nicardipine than for (+)-nicardipine and the mean oral (+)/(-)-nicardipine AUC ratio was significantly reduced by grapefruit juice (from 2.25+/-0.37 to 1.75+/-0.28) (P < 0.05). Except for heart rates, which were greater with grapefruit juice (P < 0.05) at 1 and 2 h after the oral dose of nicardipine, the mean hemodynamic variables did not differ between the two trial phases. CONCLUSION: We conclude that the gut is the major presystemic disposal site of racemic nicardipine in humans. Grapefruit juice appears to affect this metabolic disposal of (-)-nicardipine to a somewhat greater extent compared with that of (+)-nicardipine, with an early postdose transient tachycardia after the oral dosing of racemic nicardipine.
Abstract: 1 The metabolism of metoprolol depends in part on the genetically determined activity of the CYP2D6 isoenzyme. In vitro studies have shown that nicardipine is a potent inhibitor of CYP2D6 activity. Since the combination of metoprolol and nicardipine is likely to be used for the treatment of hypertension, we examined the interaction between these two drugs at steady-state. 2 Fourteen healthy volunteers, seven extensive and seven poor metabolisers of dextromethorphan were studied in a double-blind, randomised cross-over four-period protocol. Subjects received nicardipine 50 mg every 12 h, metoprolol 100 mg every 12 h, a combination of both drugs and placebo during 5.5 days. Steady-state pharmacokinetics of nicardipine and metoprolol were analyzed. Beta-adrenoceptor blockade was assessed as the reduction of exercise-induced tachycardia. 3 During treatment with metoprolol, alone or in combination with nicardipine, its steady-state plasma concentrations were higher in subjects of the poor metaboliser phenotype than in extensive metabolisers. Beta-adrenoceptor blockade was also more pronounced in poor metabolisers than in extensive metabolisers of dextromethorphan during treatment with metoprolol alone or in combination with nicardipine (24.0 +/- 2.4% vs 17.1 +/- 3.5% and 24.1 +/- 2.5% vs 15.4 +/- 2.7% reduction in exercise trachycardia, respectively, P < 0.01 in each case). 4 Nicardipine produced a small increase in plasma metoprolol concentration in extensive metabolisers from 35.9 +/- 16.6 to 45.8 +/- 15.4 ng ml(-1) (P < 0.02), but had no significant effect in poor metabolisers. However, nicardipine did not alter the R/S metoprolol ratio in plasma 3 h after dosing, the plasma concentration of S-(-)-metoprolol 3 h after dosing or the beta-adrenoceptor blockade produced by metoprolol in subjects of both phenotypes. The partial metabolic clearance of metoprolol to alpha-hydroxy-metoprolol was not altered significantly in extensive metabolisers. Plasma nicardipine concentration and beta-adrenoceptor blocking effects did not differ between the phenotypes and were not influenced by metoprolol. We conclude that beta-adrenoceptor blockade during repeated dosing with metoprolol is more pronounced in poor than in extensive metaboliser subjects, that nicardipine decreases a CYP2D6-independent route of metoprolol elimination but does not increase beta-adrenoceptor blockade during repeated dosing with metoprolol.
Abstract: PURPOSE: The purpose of this study was to ascertain, in the context of an integrated health care delivery system, the association between a comprehensive list of drugs known to have potential QT liability and QT prolongation or shortening. METHODS: By using a self-controlled crossover study with 59 467 subjects, we ascertained intra-individual change in log-linear regression-corrected QT (QTcreg ) during the period between 1995 and mid-2008 for 90 drugs while adjusting for age, gender, race/ethnicity, comorbid conditions, number of electrocardiograms (ECGs), and time between pre-ECG and post-ECG. The proportion of users of each drug-developing incident long QT was also estimated. RESULTS: Two drugs (nicardipine and levalbuterol) had no statistically significant intra-individual QTcreg shortening effects, 10 drugs had no statistically significant prolonging effect, and 78 (87%) of the drugs had statistically significant intra-individual mean QTcreg lengthening effects, ranging from 7.6 ms for aripiprazole to 25.2 ms for amiodarone. Three drugs were associated with mean QTcreg prolongation of 20 ms or greater: amiodarone (antiarrhythmic), terfenadine (antihistaminic), and quinidine (antiarrhythmic); whereas 11 drugs were associated with mean QTcreg prolongation of 15 ms or greater but less than 20 ms: trimipramine (tricyclic antidepressant), clomipramine (tricyclic antidepressant), disopyramide (antiarrhythmic), chlorpromazine (antipsychotic), sotalol (beta blocker), itraconazole (antifungal), phenylpropanolamine (decongestant/anorectic), fenfluramine (appetite suppressant), midodrine (antihypotensive), digoxin (cardiac glycoside/antiarrhythmic), and procainamide (antiarrhythmic). CONCLUSIONS: QT prolonging effects were common and varied in strength. Our results lend support to past Food and Drug Administration regulatory actions and support the role for ongoing surveillance of drug-induced QT prolongation.