Prolongación del tiempo QT
Eventos adversos de medicamentos
|Dolor de cabeza|
Variantes ✨Para la evaluación computacionalmente intensiva de las variantes, elija la suscripción estándar paga.
Explicaciones de las sustancias para pacientes.
No existen advertencias adicionales para la combinación de abarelix y ranolazina. Consulte también la información especializada pertinente.
Los cambios informados en la exposición corresponden a los cambios en la curva de concentración plasmática-tiempo [ AUC ]. No esperamos ningún cambio en la exposición a abarelix, cuando se combina con ranolazina (100%). No esperamos ningún cambio en la exposición a ranolazina, cuando se combina con abarelix (100%).
Los parámetros farmacocinéticos de la población media se utilizan como punto de partida para calcular los cambios individuales en la exposición debidos a las interacciones.
Se desconoce la biodisponibilidad de la abarelix. La vida media terminal [ t12 ] es relativamente extensa a las 316.8 horas y los niveles plasmáticos constantes [ Css ] sólo se alcanzan después de más de 1267.2 horas. La unión a proteínas [ Pb ] es 100 % fuerte. Actualmente, se sigue trabajando en el metabolismo por citocromos.
La ranolazina tiene una biodisponibilidad oral media [ F ] del 100 %, por lo que los niveles plasmáticos máximos [Cmax] tienden a cambiar con una interacción. La vida media terminal [ t12 ] es relativamente corta a las 1.65 horas y los niveles plasmáticos constantes [ Css ] se alcanzan rápidamente. La unión a proteínas [ Pb ] es relativamente débil al 100 % y el volumen de distribución [ Vd ] es muy grande a 133 litros, Dado que la sustancia tiene una tasa de extracción hepática baja de 0,9, el desplazamiento de la unión a proteínas [Pb] en el contexto de una interacción puede conducir a una mayor exposición. El metabolismo tiene lugar a través de CYP2D6 y CYP3A4, entre otros y el transporte activo tiene lugar especialmente a través de PGP.
|Efectos serotoninérgicos a||0||Ø||Ø|
Clasificación: Según nuestro conocimiento, ni la abarelix ni la ranolazina aumentan la actividad serotoninérgica.
|Kiesel & Durán b||0||Ø||Ø|
Clasificación: Según nuestro conocimiento, ni la abarelix ni la ranolazina aumentan la actividad anticolinérgica.
Prolongación del tiempo QT
Clasificación: En combinación, la abarelix y la ranolazina pueden desencadenar potencialmente arritmias ventriculares del tipo torsades de pointes.
Efectos adversos generales
|Efectos secundarios||∑ frecuencia||aba||ran|
|Dolor de cabeza||5.5 %||n.a.||5.5|
Con base en sus respuestas e información científica, evaluamos el riesgo individual de efectos secundarios adversos. Estas recomendaciones están destinadas a asesorar a los profesionales y no sustituyen la consulta con un médico. En la versión de prueba restringida (alfa), el riesgo de todas las sustancias aún no se ha evaluado de manera concluyente.
Abstract: The metabolism of ranolazine (RS-43285) or (+)N-(2,6-dimethylphenyl)-4[2-hydroxy-3-(2-methoxyphenoxy)-propyl]-1- piperazine acetamide dihydrochloride was investigated in man using plasma samples obtained from four different clinical studies. The metabolite profiles following single and multiple doses of 342 mg instant release (IR) ranolazine, following multiple doses of 1000 mg sustained release (SR) ranolazine and following dosing with both ranolazine (IR) and a potentially co-administered drug, diltiazem, were compared. Metabolism of ranolazine in man was shown by LC/MS analysis to be extensive with up to seven primary routes of metabolism identified. N-dealkylation by hydrolysis at the piperazine ring produced three metabolites whilst O-demethylation and O-dearylation at the methoxyphenoxy moiety produced a further two compounds. Additionally, hydrolysis of the amide group formed one other species. Oxygenation at various points in the molecule produced a further four metabolites. Direct conjugation of ranolazine with glucuronic acid and with an uncharacterized adduct were also identified as a route of elimination. Ten other biotransformation products were formed as a result of multiple metabolic steps. Conjugation was also associated with the desmethyl metabolite (glucuronide and unidentified conjugates) of hydroxylated ranolazine. In a previous publication (Journal of Chromatography, 1995, accepted for publication) semi-quantitative analyses of pooled plasma from the study where ranolazine was dosed at 1000 mg twice daily showed that of the twelve metabolites studied only four accounted for AUC's in excess of 10% of the ranolazine AUC.
Abstract: Ranolazine is a novel compound under development as an antianginal agent. The multiple-dose pharmacokinetics of extended-release ranolazine and 3 major metabolites was investigated in healthy subjects (N = 8) and subjects with mild to severe renal impairment (N = 21). The ranolazine AUC(0-12) (area under the concentration-time curve between 0 and 12 hours after dosing) geometric mean ratio versus healthy subjects at steady state was 1.72 (90% confidence interval [CI], 1.07-2.76) in subjects with mild impairment, 1.80 (90% CI, 1.13-2.89) in those with moderate impairment, and 1.97 (90% CI, 1.23-3.16) in those with severe renal impairment. Creatinine clearance was negatively correlated with AUC(0-12) and the maximum observed concentration for ranolazine and the O-dearylated metabolite (P < .05 for all variables), as well as the N-dealkylated metabolite (P < .001), but not for the O-demethylated metabolite. Less than 7% of the administered dose was excreted unchanged in all groups, indicating that factors other than reduced glomerular filtration rate contributed to the increase in ranolazine concentrations in renal impairment. No serious adverse events were observed in the study.
Abstract: Ranolazine is a compound that is approved by the US FDA for the treatment of chronic angina pectoris in combination with amlodipine, beta-adrenoceptor antagonists or nitrates, in patients who have not achieved an adequate response with other anti-anginals. The anti-anginal effect of ranolazine does not depend on changes in heart rate or blood pressure. It acts through different pharmacological mechanisms where inhibition of the late inward sodium current (reducing calcium overload and thereby left ventricular diastolic tension) is one plausible mechanism of reduced oxygen consumption. Initial studies used an oral solution or an immediate-release (IR) capsule, but subsequently an extended-release (ER) formulation was developed to allow for twice-daily administration with maintained efficacy. Following administration of an oral solution or IR capsule, peak plasma concentrations (C(max)) are observed within 1 hour. After administration of radiolabelled ranolazine, 73% of the dose was excreted in urine, and unchanged ranolazine accounted for <5% of radioactivity in both urine and faeces. The absolute bioavailability ranges from 35% to 50%. Food has no effect on rate or extent of absorption from the ER formulation. Ranolazine protein binding is about 61-64% over the therapeutic concentration range. Volume of distribution at steady state ranges from 85 to 180 L. Ranolazine is extensively metabolised by cytochrome P450 (CYP) 3A enzymes and, to a lesser extent, by CYP2D6, with approximately 5% excreted renally unchanged. Elimination half-life of ranolazine is 1.4-1.9 hours but is apparently prolonged, on average, to 7 hours for the ER formulation as a result of extended absorption (flip-flop kinetics). Elimination occurs through parallel linear and saturable elimination pathways, where the saturable pathway is related to CYP2D6, which is partly inhibited by ranolazine. Oral plasma clearance diminishes with dose from, on average, 45 L/h at 500 mg twice daily to 33 L/h at 1000 mg twice daily. The departure from dose proportionality for this dose range is modest, with increases in steady-state C(max) and area under plasma concentration-time curve (AUC) from 0 to 12 hours of 2.5- and 2.7-fold, respectively. Ranolazine pharmacokinetics are unaffected by sex, congestive heart failure and diabetes mellitus. AUC increases up to 2-fold with advancing degree of renal impairment. Ranolazine is a weak inhibitor of CYP3A, and increases AUC and C(max) for simvastatin, its metabolites and HMG-CoA reductase inhibitor activity <2-fold. Digoxin AUC is increased 40-60% by ranolazine through P-glycoprotein inhibition. Ranolazine AUC is increased by CYP3A inhibitors ranging from 1.5-fold for diltiazem 180 mg once daily to 3.9-fold for ketoconazole 200 mg twice daily. Verapamil increases ranolazine exposure approximately 2-fold. CYP2D6 inhibition has a negligible effect on ranolazine exposure.
Abstract: (1) Betablockers such as atenolol are the first-line symptomatic treatment for stable angina. Calcium channel blockers such as verapamil and amlodipine are second-line alternatives; (2) Ranolazine is now authorized for symptomatic adjuvant treatment of angina in patients who are poorly controlled by a betablocker and/or a calcium channel blocker. Its mechanism of action is poorly understood; (3) In two randomised double-blind trials in respectively 565 and 823 patients treated for 7 and 12 weeks, ranolazine (500 mg to 1000 mg twice a day), added to ongoing amlodipine therapy only provided a limited benefit, preventing less than one angina attack per week; (4) Comparative trials failed to show whether ranolazine has a clear-cut impact on mortality; (5) Ranolazine prolongs the QT interval in a dose-dependent manner and thus exposes patients to the risk of torsades de pointes. It is also associated with gastrointestinal disorders (constipation, nausea, vomiting) and dizziness; (6) Ranolazine is metabolised by the cytochrome P450 isoenzymes CYP 3A4 and CYP 2D6 and is also a P-glycoprotein substrate. There is therefore a high risk of pharmacokinetic interactions. There is also a risk of pharmacodynamic interactions with drugs that prolong the QT interval; (7) In practice, the efficacy of ranolazine in the prevention of angina attacks does not outweigh the risk of severe adverse effects.
Abstract: AIMS: Clinical utility of QTc prolongation as a predictor for sudden cardiac death (SCD) has not been definitely established. Ranolazine causes modest QTc prolongation, yet it shows antiarrhythmic properties. We aimed to determine the association between prolonged QTc and risk of SCD, and the effect of ranolazine on this relationship. METHODS AND RESULTS: The relationship between baseline QTc and SCD was studied in 6492 patients with non-ST elevation acute coronary syndrome (NSTEACS) randomized to placebo or ranolazine in the MERLIN-TIMI 36 trial. In the placebo group, an abnormal QTc interval (≥450 ms in men, ≥470 ms in women) was associated with a two-fold increased risk of SCD (hazard ratio, HR, 2.3, P = 0.005) after adjustment for other risk factors (age ≥75 years, NYHA class III/IV, high TIMI risk score, ventricular tachycardia ≥8 beats, digitalis, and antiarrhythmics). In the ranolazine group, the association between abnormal QTc and SCD was similar to placebo, but not significant (HR 1.8, P = 0.074). There was no significant difference between placebo and ranolazine in the risk for SCD in patients with abnormal QTc (HR 0.78, P = 0.48). When QTc was used as a continuous variable, for every 10 ms increase in QTc, hazard rate for SCD increased significantly by 8% (P = 0.007) in the placebo group, and only by 2.9% (P = 0.412; P for interaction=0.25) in the ranolazine group. CONCLUSION: In NSTEACS patients treated with placebo, prolonged QTc was a significant independent predictor for SCD. Ranolazine, compared with placebo, was not associated with increased risk for SCD in patients with prolonged QTc.
Abstract: A case of unstable angina developed slow junctional rhythm with QTc prolongation and transient Torsades de pointes following simultaneous use of Ivabradine, Diltiazem and Ranolazine. Effect of Diltiazem on hepatic isoenzyme CYP 3A could be responsible. Such a combination should be avoided.