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 asenapine and sertindole. 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 asenapine, when combined with sertindole (100%). We did not detect any change in exposure to sertindole. We currently cannot estimate the influence of asenapine.
The pharmacokinetic parameters of the average population are used as the starting point for calculating the individual changes in exposure due to the interactions.
Asenapine has a low oral bioavailability [ F ] of 2%, which is why the maximum plasma level [Cmax] tends to change strongly with an interaction. The terminal half-life [ t12 ] is 24 hours and constant plasma levels [ Css ] are reached after approximately 96 hours. The protein binding [ Pb ] is moderately strong at 95% and the volume of distribution [ Vd ] is very large at 1700 liters. The metabolism mainly takes place via CYP1A2 and the active transport takes place in particular via UGT1A4.
Sertindole has a mean oral bioavailability [ F ] of 75%, which is why the maximum plasma levels [Cmax] tend to change with an interaction. The terminal half-life [ t12 ] is rather long at 72 hours and constant plasma levels [ Css ] are only reached after more than 288 hours. The protein binding [ Pb ] is very strong at 99.5%. The metabolism takes place via CYP2D6 and CYP3A4, among others.
|Serotonergic Effects a||0||Ø||Ø|
Rating: According to our knowledge, neither asenapine nor sertindole increase serotonergic activity.
|Kiesel & Durán b||1||+||Ø|
Recommendation: As a precaution, attention should be paid to anticholinergic symptoms, especially after increasing the dose and at doses in the upper therapeutic range.
Rating: Asenapine only has a mild effect on the anticholinergic system. The risk of anticholinergic syndrome with this medication is rather low if the dosage is in the usual range. According to our knowledge, sertindole does not increase anticholinergic activity.
QT time prolongation
Rating: In combination, asenapine and sertindole can potentially trigger ventricular arrhythmias of the torsades de pointes type.
General adverse effects
|Side effects||∑ frequency||ase||ser|
|Nasal congestion||26.7 %||n.a.||26.7|
|Abnormal ejaculation||15.6 %||n.a.||15.6|
|Weight gain||12.4 %||11.5||+|
|Orthostatic hypotension||2.5 %||1.5||+|
Neuroleptic malignant syndrome: asenapine
Peripheral edema: sertindole
Hypersensitivity reaction: asenapine
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: The effect of erythromycin on the pharmacokinetic disposition of oral sertindole, a new antipsychotic compound, was investigated. Ten subjects who completed the study received a single 4-mg dose of sertindole without or with concomitant erythromycin 250 mg taken orally 4 times daily. Coadministration of sertindole and erythromycin led to a 33% decrease (P < 0.05) in mean (+/- SD) time to reach maximum plasma concentration (tmax) value and a 15% elevation (P < 0.05) in the mean maximum plasma concentration (Cmax) value of sertindole. The mean area under the concentration-time curve (AUC) value of sertindole did not change significantly in the presence of erythromycin (alone: 159 +/- 111 ng.hr/mL, in combination: 179 +/- 144 ng.hr/mL, P > 0.05). The presence of erythromycin also significantly increased the dehydrosertindole Cmax and AUC means by 16% and 21%, respectively, possibly due to inhibition of the CYP3A metabolic isozyme responsible for the elimination of this metabolite. The rate of absorption of sertindole and the rate of appearance of dehydrosertindole in the systemic circulation after a 4-mg sertindole single dose were slightly enhanced by concomitant dosing of erythromycin. In conclusion, there is a small but noticeable effect of erythromycin on the pharmacokinetic disposition of sertindole. The effects are believed to have little clinical significance.
Abstract: Recently, antipsychotic medications of the novel or atypical classes have received increased attention because of concerns with respect to potential lengthening of the QT interval, yet the currently available and commonly prescribed conventional antipsychotics are significantly more cardiotoxic, particularly agents in the butyrophenone and phenothiazine classes. Lengthening of the QT interval can be associated with a fatal paroxysmal ventricular arrhythmia known as torsades de pointes. The specific duration of the QT interval at which the risk of an adverse cardiac event is greatest, is not established. There is not only significant variation in the applied definition of an abnormal interval, but the maximal QT interval in healthy volunteers is greater than the currently accepted standards. The QT interval is influenced by normal physiological and pathologic factors, but the mechanisms remain unclear. Using recombinant technology, haloperidol and sertindole have been demonstrated to be high-affinity antagonists of a human cardiac potassium channel encoded by the human ether-a-go-go-related gene. Pimozide, however, has been shown to act principally through calcium channel antagonism, and chlorpromazine may affect sodium channels. Nevertheless, it is possible that these effects are significant only in the presence of predisposing factors, either genetic or acquired. Despite proven efficacy in clinical trials and subsequent supervised use in Europe, a number of recently developed antipsychotic medications are not available to patients in North America. Yet, conventional antipsychotic medications that would not be approved by current safety standards continue to be widely used.
Abstract: (1) The first-line drug for the treatment of schizophrenic disorders is a neuroleptic such as haloperidol. Amisulpride may be preferable when haloperidol causes unacceptable neurological reactions. Overall, the risk-benefit balance of more recent, so-called atypical neuroleptics is no better. (2) Sertindole, a neuroleptic, was first marketed in 1996 in several European countries before being withdrawn two years later because of numerous cardiac adverse effects. It has once again been approved and should soon be available on the French market. (3) Two comparative double-blind trials suggest that a daily sertindole dose of 24 mg is about as effective as 10 mg of haloperidol. Sertindole was no more effective than risperidone in a trial comparing these two drugs. (4) Like other 'atypical' neuroleptics, sertindole has few short-term neurological adverse effects (extrapyramidal syndrome) at the doses used in clinical trials. However, it causes weight gain. Sertindole also has alpha blocking properties, which can cause postural hypotension and reduce ejaculate volume; it also has atropinic effects (constipation, dry mouth, etc.). (5) Sertindole provokes a dose-dependent increase in the QT interval more frequently than haloperidol in comparative trials, and apparently more frequently than other 'atypical' neuroleptics such as risperidone and olanzapine. Sertindole has been suspected of increasing cardiovascular mortality but this has not been established. (6) Sertindole is metabolised by cytochrome P450 isoenzymes CYP 2D6 and CYP 3A4, hence a high risk of pharmacokinetic interactions. (7) In practice, when haloperidol has to be withdrawn because of adverse effects, especially neurological reactions, it is better to continue to resort to amisulpride, for example, with close monitoring of adverse effects, rather than expose patients to the potential dangers of sertindole.
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: INTRODUCTION: Despite the progress in antipsychotic treatment, modern antipsychotic medication is still associated with side effects, reduced compliance, drug discontinuation and insufficient effects on negative and cognitive symptoms. Sertindole is an antipsychotic compound, with high affinity for dopamine D(2), serotonin 5-HT(2A), 5-HT(2C) and α(1)-adrenergic receptors, which has been reintroduced in the market after extended re-evaluation of its safety and risk-benefit profile. AREAS COVERED: Sertindole's pharmacological profile, pharmacokinetics, neuophysiological properties, efficacy on positive, negative and cognitive symptoms and safety issues are covered in this article, based on a literature review from 1990 to 2012. EXPERT OPINION: Based on five double-blind, randomized, placebo-, haloperidol- or risperidone-controlled studies in patients with schizophrenia, sertindole shows a comparable efficacy with haloperidol and risperidone on positive symptoms, while the effect on negative symptoms seems to be superior. Sertindole is generally well tolerated, but is associated with a dose-related QTc interval prolongation (+22 ms). Risk factors for drug-induced arrhythmia, such as cardiac diseases, congenital long QT syndrome, prolongated QTc at baseline, etc. and drug interactions should be considered before prescribing sertindole. To minimize cardiovascular risk, regular ECG recording is required. Sertindole can be an important second-line option for the treatment of schizophrenia for patients intolerant to at least one other antipsychotic. Further comparison with other SGAs and investigations on subgroups (e.g., children, elderly, first-episode, treatment-refractory patients, etc.) are still needed for a precise understanding of the therapeutic benefits and its role in schizophrenia therapy.
Abstract: Nowadays, new schizophrenia treatments are more ambitious than ever, aiming not only to improve psychotic symptoms, but also quality of life and social reinsertion. Our objective is to briefly but critically review the diagnosis of schizophrenia, the atypical antipsychotics sertindole's pharmacology, safety and status, and mainly evaluate the effects of sertindole compared with other second generation antipsychotics for people with schizophrenia and schizophrenia-like psychosis. In vitro studies showed that sertindole exerts a potent antagonism at serotonin 5-HT2A, 5-HT2C, dopamine D2, and αl adrenergic receptors. Sertindole offers an alternative treatment option for refractory patients given its good EPS profile, favorable metabolic profile, and comparable efficacy to risperidone. Due to cardiovascular safety concerns, sertindole is available as a second-line choice for patients intolerant to other antipsychotic agents. Further clinical studies, mainly comparisons with other second-generation antipsychotic agents, are needed to define the role of sertindole in the treatment of schizophrenia.
Abstract: No Abstract available
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.