Allongement du temps QT
Événements indésirables médicamenteux
|Gain de poids|
Variantes ✨Pour une évaluation intensive des variantes par ordinateur, veuillez choisir l'abonnement standard payant.
Explications concernant les substances pour les patients
Nous n'avons pas de mise en garde supplémentaire concernant l'association de asénapine et de palonosétron. Veuillez également consulter les informations pertinentes des spécialistes.
Les changements d'exposition rapportés correspondent aux changements de la courbe concentration-temps plasmatique [ AUC ]. Nous ne prévoyons aucun changement dans l'exposition à la asénapine, lorsqu'il est associé à la palonosétron (100%). Nous n'avons détecté aucun changement dans l'exposition à la palonosétron. Nous ne pouvons actuellement pas estimer l'influence de la asénapine.
Les paramètres pharmacocinétiques de la population moyenne sont utilisés comme point de départ pour calculer les changements individuels d'exposition dus aux interactions.
La asénapine a une faible biodisponibilité orale [ F ] de 100 %, c'est pourquoi la concentration plasmatique maximale [Cmax] a tendance à changer fortement avec une interaction. La demi-vie terminale [ t12 ] est de 24 heures et des taux plasmatiques constants [ Css ] sont atteints après environ 96 heures. La liaison aux protéines [ Pb ] est modérément forte à 95% et le volume de distribution [ Vd ] est très grand à 1700 litres. Le métabolisme se fait principalement via CYP1A2 et le transport actif s'effectue notamment via UGT1A4.
La palonosétron a une biodisponibilité orale élevée [ F ] de 100 %, c'est pourquoi la concentration plasmatique maximale [Cmax] a tendance à peu changer au cours d'une interaction. La demi-vie terminale [ t12 ] est assez longue (jusqu'à 45 heures) et des taux plasmatiques constants [ Css ] ne sont atteints qu'après plus de 180 heures. La liaison aux protéines [ Pb ] est plutôt faible à 62%. Environ 20 % d'une dose administrée sont excrétés sous forme inchangée par les reins et cette proportion est rarement modifiée par les interactions. Le métabolisme a lieu via CYP1A2, CYP2D6 et CYP3A4, entre autres.
|Effets sérotoninergiques a||1||Ø||+|
Recommandations: Par mesure de précaution, les symptômes de surstimulation sérotoninergique doivent être pris en compte, en particulier après l'augmentation de la dose et à un niveau compris dans le spectre thérapeutique supérieure.
Note: La palonosétron a un effet léger sur le système sérotoninergique. Le risque de syndrome sérotoninergique peut être classé comme faible avec ce médicament si la posologie est dans la fourchette habituelle. À notre connaissance, la asénapine n'augmente pas l'activité sérotoninergique.
|Kiesel & Durán b||1||+||Ø|
Recommandation: Par mesure de précaution, une attention particulière doit être portée aux symptômes anticholinergiques, en particulier après augmentation de la dose et à de celles situées dans la marge thérapeutique supérieure.
Notation: La asénapine n'a qu'un effet modéré sur le système anticholinergique. Le risque de syndrome anticholinergique avec ce médicament est plutôt faible si la dosage est respecté. À notre connaissance, la palonosétron n'augmente pas l'activité anticholinergique.
Allongement du temps QT
Note: En association, la asénapine et la palonosétron peuvent potentiellement déclencher des arythmies ventriculaires de type torsades de pointes.
Effets indésirables généraux
|Effets secondaires||∑ fréquence||asé||pal|
|Gain de poids||11.5 %||11.5||n.a.|
|Mal de crâne||9.0 %||n.a.||9.0|
|Hypotension orthostatique||1.5 %||1.5||n.a.|
Crise d'épilepsie: palonosétron, asénapine
Syndrome malin des neuroleptiques: asénapine
Réaction d'hypersensibilité: palonosétron, asénapine
Sur la base de vos réponses et des informations scientifiques, nous évaluons le risque individuel d'effets secondaires indésirables. Ces recommandations sont destinées à conseiller les professionnels et ne se substituent pas à la consultation d'un médecin. Dans la version d'essai (alpha), le risque de toutes les substances n'a pas encore été évalué de manière concluante.
Abstract: Palonosetron (Aloxi(R), Onicit(R)) is a potent, single stereoisomeric 5-HT(3) receptor antagonist developed to prevent chemotherapy-induced nausea and vomiting. The pharmacokinetics and metabolic disposition of a single intravenous [(14)C]-palonosetron (10 microg/kg, 0.8 microCi/kg) bolus dose were evaluated in six healthy volunteers (three males, three females) using serial blood, plasma, urine and fecal samples obtained over 10 days. The safety, tolerability and cardiac effects were assessed. Radiolabeled metabolic characterization revealed that unchanged palonosetron accounted for 71.9% of the total radioactivity in plasma over 96 h, with an extensive distribution volume (8.34 l/kg) and mean plasma elimination half-life of 37 h. Approximately 83% of the dose was recovered in urine ( approximately 40% as unchanged drug, with 50% metabolized; M9 and M4 were the major metabolites) and 3.4% in feces. Hydrolysis of urine samples suggests that the metabolites are not beta-glucuronide or sulfate conjugates of the parent drug or metabolites. The blood to plasma concentration ratio of the total radioactivity was 1.2, on average, indicating little selective partitioning in erythrocytes. Palonosetron was generally well tolerated; headache was the most frequently reported adverse event. Electrocardiograms and 72 h Holter monitoring revealed no clinically significant changes. Palonosetron circulates in plasma mainly as the parent drug. Renal elimination is the primary excretion route, with parent drug and metabolites M9 and M4 accounting for the majority of palonosetron disposition. These results indicate that both renal and hepatic routes are involved in the elimination of palonosetron from the body.
Abstract: An assessment of the effects of asenapine on QTc interval in patients with schizophrenia revealed a discrepancy between the results obtained by two different methods: an intersection-union test (IUT) (as recommended in the International Conference on Harmonisation E14 guidance) and an exposure-response (E-R) analysis. Simulations were performed in order to understand and reconcile this discrepancy. Although estimates of the time-matched, placebo-corrected mean change in QTc from baseline (ddQTc) at peak plasma concentrations from the E-R analysis ranged from 2 to 5 ms per dose level, the IUT applied to simulated data from the E-R model yielded maximum ddQTc estimates of 7-10 ms for the various doses of asenapine. These results indicate that the IUT can produce biased estimates that may induce a high false-positive rate in individual thorough QTc trials. In such cases, simulations from an E-R model can aid in reconciling the results from the two methods and may support the use of E-R results as a basis for labeling.
Abstract: The metabolism and excretion of asenapine [(3aRS,12bRS)-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]-oxepino [4,5-c]pyrrole (2Z)-2-butenedioate (1:1)] were studied after sublingual administration of [(14)C]-asenapine to healthy male volunteers. Mean total excretion on the basis of the percent recovery of the total radioactive dose was ∼90%, with ∼50% appearing in urine and ∼40% excreted in feces; asenapine itself was detected only in feces. Metabolic profiles were determined in plasma, urine, and feces using high-performance liquid chromatography with radioactivity detection. Approximately 50% of drug-related material in human plasma was identified or quantified. The remaining circulating radioactivity corresponded to at least 15 very polar, minor peaks (mostly phase II products). Overall, >70% of circulating radioactivity was associated with conjugated metabolites. Major metabolic routes were direct glucuronidation and N-demethylation. The principal circulating metabolite was asenapine N(+)-glucuronide; other circulating metabolites were N-desmethylasenapine-N-carbamoyl-glucuronide, N-desmethylasenapine, and asenapine 11-O-sulfate. In addition to the parent compound, asenapine, the principal excretory metabolite was asenapine N(+)-glucuronide. Other excretory metabolites were N-desmethylasenapine-N-carbamoylglucuronide, 11-hydroxyasenapine followed by conjugation, 10,11-dihydroxy-N-desmethylasenapine, 10,11-dihydroxyasenapine followed by conjugation (several combinations of these routes were found) and N-formylasenapine in combination with several hydroxylations, and most probably asenapine N-oxide in combination with 10,11-hydroxylations followed by conjugations. In conclusion, asenapine was extensively and rapidly metabolized, resulting in several regio-isomeric hydroxylated and conjugated metabolites.
Abstract: BACKGROUND AND OBJECTIVE: The effects of hepatic or renal impairment on the pharmacokinetics of atypical antipsychotics are not well understood. Drug exposure may increase in patients with hepatic disease, owing to a reduction of certain metabolic enzymes. The objective of the present study was to study the effects of hepatic or renal impairment on the pharmacokinetics of asenapine and its N-desmethyl and N⁺-glucuronide metabolites. METHODS: Two clinical studies were performed to assess exposure to asenapine, desmethylasenapine and asenapine N⁺-glucuronide in subjects with hepatic or renal impairment. Pharmacokinetic parameters were determined from plasma concentration-time data, using standard noncompartmental methods. The pharmacokinetic variables that were studied included the maximum plasma concentration (C(max)) and the time to reach the maximum plasma concentration (t(max)). Eligible subjects, from inpatient and outpatient clinics, were aged ≥18 years with a body mass index of ≥18 kg/m² and ≤32 kg/m². Sublingual asenapine (Saphris®) was administered as a single 5 mg dose. RESULTS: Thirty subjects participated in the hepatic impairment study (normal hepatic function, n = 8; mild hepatic impairment [Child-Pugh class A], n = 8; moderate hepatic impairment [Child-Pugh class B], n = 8; severe hepatic impairment [Child-Pugh class C], n = 6). Thirty-three subjects were enrolled in the renal impairment study (normal renal function, n = 9; mild renal impairment, n = 8; moderate renal impairment, n = 8; severe renal impairment, n = 8). Asenapine and N-desmethylasenapine exposures were unaltered in subjects with mild or moderate hepatic impairment, compared with healthy controls. Severe hepatic impairment was associated with increased area under the plasma concentration-time curve from time zero to infinity (AUC(∞)) values for total asenapine, N-desmethylasenapine and asenapine N⁺-glucuronide (5-, 3-, and 2-fold, respectively), with slight increases in the C(max) of asenapine but 3- and 2-fold decreases in the C(max) values for N-desmethylasenapine and asenapine N⁺-glucuronide, respectively, compared with healthy controls. The mean AUC(∞) of unbound asenapine was more than 7-fold higher in subjects with severe hepatic impairment than in healthy controls. Mild renal impairment was associated with slight elevations in the AUC(∞) of asenapine compared with healthy controls; alterations observed with moderate and severe renal impairment were marginal. N-desmethylasenapine exposure was only slightly altered by renal impairment. No correlations were observed between exposure and creatinine clearance. CONCLUSION: Severe hepatic impairment (Child-Pugh class C) was associated with pronounced increases in asenapine exposure, but significant increases were not seen with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, or with any degree of renal impairment. Asenapine is not recommended in patients with severe hepatic impairment; no dose adjustment is needed in patients with mild or moderate hepatic impairment, or in patients with renal impairment.
Abstract: BACKGROUND: Palonosetron is a recently introduced 5-hydroxytryptamine-3 (5-HT3) receptor antagonist useful for postoperative nausea and vomiting prophylaxis. However, 5-HT3 receptor antagonists increase the corrected QT (QTc) interval in patients who undergo general anesthesia. This retrospective study was performed to evaluate whether palonosetron would induce a QTc prolongation in patients undergoing general anesthesia with sevoflurane. METHODS: We reviewed a database of 81 patients who underwent general anesthesia with sevoflurane. We divided the records into palonosetron (n = 41) and control (n = 40) groups according to the use of intraoperative palonosetron, and analyzed the electrocardiographic data before anesthesia and 30, 60, 90, and 120 min after skin incision. Changes in the QTc interval from baseline, mean blood pressure, heart rate, body temperature, and sevoflurane concentrations at each time point were compared between the two groups. RESULTS: The QTc intervals at skin incision, and 30, 60, 90, and 120 min after the skin incision during general anesthesia were significantly longer than those at baseline in the two groups (P < 0.001). The changes in the QTc intervals were not different between the two groups (P = 0.41). However, six patients in the palonosetron group showed a QTc interval > 500 ms 30 min after skin incision, whereas no patient did in the control group (P = 0.01). No significant differences were observed between the two groups in mean blood pressure, body temperature, heart rate, or sevoflurane concentrations. CONCLUSIONS: Palonosetron may induce QTc prolongation during the early general anesthesia period with sevoflurane.
Abstract: No Abstract available
Abstract: PURPOSE: The use of serotonin type 3 (5-HT3) receptor antagonists (RAs) in the prevention of nausea and vomiting caused by emetogenic chemotherapy is part of a comprehensive management strategy for patients undergoing chemotherapy. Electrocardiographic effects have been reported in patients after intravenous administration of 5-HT3 RAs. The present study investigated the electrocardiogram (ECG) profile of the 5-HT3 RA palonosetron following International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) E14 Guidelines. METHODS: A total of 221 healthy subjects (101 females, 120 males) were randomized in this phase I, double-blind, double-dummy, parallel group study and assigned to one of five treatments: placebo, palonosetron (0.25, 0.75, or 2.25 mg), or moxifloxacin (400 mg). ECGs were recorded for 24 h pre-dosing until 48 h post-dose. The primary endpoint was the placebo time-matched and baseline-subtracted individual QTc interval prolongation (ΔΔQTcI). RESULTS: The QTc interval was not prolonged after administration of palonosetron (ΔΔQTcI upper confidence interval was <10 ms for all time points in all palonosetron treatment groups). Assay sensitivity was confirmed with the expected change in the QTc interval after administration of the positive control moxifloxacin. CONCLUSIONS: Palonosetron, even at supratherapeutic doses, has no effect on cardiac repolarization as measured by the QTc interval in a validated controlled clinical trial.
Abstract: Asenapine is one of the newer atypical antipsychotics on the market. It is a sublingually administered drug that is indicated for the treatment of both schizophrenia and bipolar disorder, and is considered to be safe and well tolerated. Herein, we report a 71-year-old female with a history of bipolar disorder who had ventricular trigemini and experienced a large increase in her QTc interval after starting treatment with asenapine. These changes ceased following withdrawal of asenapine. In this case report, we discuss the importance of cardiac monitoring when switching antipsychotics, even to those that are considered to have low cardiac risk.
Abstract: BACKGROUND: Anticholinergic drugs put elderly patients at a higher risk for falls, cognitive decline, and delirium as well as peripheral adverse reactions like dry mouth or constipation. Prescribers are often unaware of the drug-based anticholinergic burden (ACB) of their patients. This study aimed to develop an anticholinergic burden score for drugs licensed in Germany to be used by clinicians at prescribing level. METHODS: A systematic literature search in pubmed assessed previously published ACB tools. Quantitative grading scores were extracted, reduced to drugs available in Germany, and reevaluated by expert discussion. Drugs were scored as having no, weak, moderate, or strong anticholinergic effects. Further drugs were identified in clinical routine and included as well. RESULTS: The literature search identified 692 different drugs, with 548 drugs available in Germany. After exclusion of drugs due to no systemic effect or scoring of drug combinations (n = 67) and evaluation of 26 additional identified drugs in clinical routine, 504 drugs were scored. Of those, 356 drugs were categorised as having no, 104 drugs were scored as weak, 18 as moderate and 29 as having strong anticholinergic effects. CONCLUSIONS: The newly created ACB score for drugs authorized in Germany can be used in daily clinical practice to reduce potentially inappropriate medications for elderly patients. Further clinical studies investigating its effect on reducing anticholinergic side effects are necessary for validation.
Abstract: A highly selective and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay has been described for the determination of asenapine (ASE) in presence of its inactive metabolites-desmethyl asenapine (DMA) and asenapine--glucuronide (ASG). ASE, and ASE 13C-d3, used as internal standard (IS), were extracted from 300 µL human plasma by a simple and precise liquid-liquid extraction procedure using methyl-butyl ether. Baseline separation of ASE from its inactive metabolites was achieved on Chromolith Performance RP(100 mm × 4.6 mm) column using acetonitrile-5.0 mM ammonium acetate-10% formic acid (90:10:0.1, v/v/v) within 4.5 min. Quantitation of ASE was done on a triple quadrupole mass spectrometer equipped with electrospray ionization in the positive mode. The protonated precursor to product ion transitions monitored for ASE and ASE 13C-d3 were286.1 → 166.0 and290.0 → 166.1, respectively. The limit of detection (LOD) and limit of quantitation (LOQ) of the method were 0.0025 ng/mL and 0.050 ng/mL respectively in a linear concentration range of 0.050-20.0 ng/mL for ASE. The intra-batch and inter-batch precision (% CV) and mean relative recovery across quality control levels were ≤ 5.8% and 87.3%, respectively. Matrix effect, evaluated as IS-normalized matrix factor, ranged from 1.03 to 1.05. The stability of ASE under different storage conditions was ascertained in presence of the metabolites. The developed method is much simpler, matrix free, rapid and economical compared to the existing methods. The method was successfully used for a bioequivalence study of asenapine in healthy Indian subjects for the first time.