Verlängerung der QT-Zeit
Varianten ✨Für die rechenintensive Bewertung der Varianten bitte das kostenpflichtige Standard Abonnement wählen.
Eklärungen für Patienten zu den Wirkstoffen
Für die Kombination von Orphenadrin und Asenapin liegen uns keine zusätzlichen Warnhinweise vor. Bitte konsultieren Sie zusätzlich die jeweiligen Fachinformationen.
Die genannten Expositionsveränderungen beziehen sich jeweils auf Veränderungen der Plasmakonzentrations-Zeit-Kurve [ AUC ]. Für Orphenadrin erwarten wir keine Veränderung der Exposition, wenn eine Kombination mit Asenapin (100%) erfolgt. Für Asenapin erwarten wir keine Veränderung der Exposition, wenn eine Kombination mit Orphenadrin (100%) erfolgt.
Für die Berechnung der individuellen Expositionsveränderungen durch die Wechselwirkungen werden als Ausgangsbasis die pharmakokinetischen Parameter der durchschnittlichen Population verwendet.
Orphenadrin hat eine hohe orale Bioverfügbarkeit [ F ] von 90%, weshalb die maximalen Plasmaspiegel [ Cmax ] sich bei einer Interaktion tendentiell wenig verändern. Die terminale Halbwertszeit [ t12 ] beträgt 16.5 Stunden und konstante Plasmaspiegel [ Css ] werden ungefähr nach 66 Stunden erreicht. Die Proteinbindung [ Pb ] ist mit 95% mässig stark. Die Metabolisierung findet vor allem über CYP3A4 statt.
Asenapin hat eine tiefe orale Bioverfügbarkeit [ F ] von 2%, weshalb die maximalen Plasmaspiegel [ Cmax ] sich bei einer Interaktion tendentiell stark verändern. Die terminale Halbwertszeit [ t12 ] beträgt 24 Stunden und konstante Plasmaspiegel [ Css ] werden ungefähr nach 96 Stunden erreicht. Die Proteinbindung [ Pb ] ist mit 95% mässig stark und das Verteilungsvolumen [ Vd ] ist mit 1700 Liter sehr gross. Die Metabolisierung findet vor allem über CYP1A2 statt und der aktive Transport erfolgt insbesondere über UGT1A4.
|Serotonerge Effekte a||0||Ø||Ø|
Bewertung: Gemäss unseren Erkenntnissen erhöhen weder Orphenadrin noch Asenapin die serotonerge Aktivität.
|Kiesel & Durán b||4||+++||+|
Empfehlung: Das Risiko für anticholinerge Nebenwirkungen wie Verschwommensehen, Verwirrtheit und Tremor ist unter dieser Therapie erhöht. Nach Möglichkeit sollte die Therapie umgestellt werden oder der Patient engmaschig auf weitere Symptome wie z.B. Obstipation, Mydriasis und verminderte Vigilanz monitorisiert werden.
Bewertung: Gemeinsam erhöhen Orphenadrin (stark) und Asenapin (mild) die anticholinerge Aktivität.
Verlängerung der QT-Zeit
Asenapin kann potentiell die QT-Zeit verlängern, aber Arrhythmien vom Typ Torsades de pointes sind uns nicht bekannt. Für Orphenadrin ist uns kein QT-Zeit verlängerndes Potential bekannt.
|Orthostatische Hypotonie||1.5 %||n.a.||1.5|
Verschwommenes Sehen: Orphenadrin
Malignes neuroleptisches Syndrom: Asenapin
Überempfindlichkeitsreaktion: Orphenadrin, Asenapin
Basierend auf Ihren
Abstract: Plasma concentrations of orphenadrine were measured by a specific gas chromatographic method in 5 healthy male volunteers after a single oral dose of orphenadrine hydrochloride 100mg. The single dose pharmacokinetic profile of orphenadrine was evaluated from these data. The elimination half-life ranged from 13.2-20.1h after the commercial tablet formulation. Plasma concentrations, determined in volunteers and patients under different conditions of repeated oral administration of the same formulation of orphenadrine hydrochloride exceeded the theoretical values, predicted from the single dose pharmacokinetics, by a factor 2 to 3. The elimination half-lives after discontinuation of treatment showed a 2 to 3-fold increase over the single dose values. This demonstrates a clear discrepancy between the multiple and single dose pharmacokinetics of orphenadrine. Experiments in dogs suggested competition for biotransformation between orphenadrine and its metabolite N-demethylorphenadrine. Product inhibition of this type could explain the observed discrepancy.
Abstract: Expression and inhibition of cytochrome P450 (CYP) isozymes capable of forming an orphenadrine metabolite complex were studied in microsomes of untreated and inducer-treated male and female rats. High levels of complex-forming isozymes were found in microsomes of untreated male as compared to female rats. Treatment of male rats with several P450 inducers did not considerably increase the extent of in vitro complex formation. In female rats, however, phenobarbital or dexamethasone treatments led to pronounced induction. The isozyme specificity of complex formation was investigated by several approaches including: 1. inhibition by orphenadrine of isozyme-specific P450 activities, such as hydroxylation of testosterone, O-dealkylation of pentoxy-and ethoxyresorufin and complex formation with triacetyloleandomycin (TAO), 2. inhibition of orphenadrine complex formation by metyrapone, TAO, and cimetidine, and 3. correlation of complex levels with immunochemically, enzymatically, or spectroscopically determined amounts of P450 isozymes. Our data suggest that CYP2C11, a CYP3A isozyme and an unidentified P450 species are involved in complex formation with orphenadrine, but exclude the involvement of CYP1A1/2 and CYP2B1/2. The capability of CYP2C11 to form a metabolite complex with orphenadrine is strongly suggested for the following reasons: 1. Efficient inhibition of testosterone 2 alpha- and 16 alpha-hydroxylation by complex formation with orphenadrine in microsomes of untreated male rats, 2. high expression of orphenadrine-complexing isozymes in untreated male compared to female rats, 3. specific inhibition of in vitro complex formation by cimetidine, 4. suppression of complex-forming isozymes by 3-methylcholanthrene and beta-naphthoflavone, and 5. concomitant induction of complex-forming isozymes, immunodetectable CYP2C11, and testosterone 2 alpha-hydroxylase by stanozolol. That at least one, but not all, CYP3A isozymes is involved in complex formation is concluded from inhibition experiments with TAO that show that orphenadrine complexation can be significantly inhibited in microsomes of dexamethasone-treated, but not in microsomes of untreated rats. Furthermore, complex formation with TAO is not inhibited by orphenadrine in microsomes of phenobarbital (PB)-treated rats. In PB-treated female rats, a further unidentified complex-forming isozyme can be detected that is not inhibited by complex formation with TAO.
Abstract: OBJECTIVE: To assess the potential of anticholinergic drugs as a cause of non-degenerative mild cognitive impairment in elderly people. DESIGN: Longitudinal cohort study. SETTING: 63 randomly selected general practices in the Montpellier region of southern France. PARTICIPANTS: 372 people aged > 60 years without dementia at recruitment. MAIN OUTCOME MEASURES: Anticholinergic burden from drug use, cognitive examination, and neurological assessment. RESULTS: 9.2% of subjects continuously used anticholinergic drugs during the year before cognitive assessment. Compared with non-users, they had poorer performance on reaction time, attention, delayed non-verbal memory, narrative recall, visuospatial construction, and language tasks but not on tasks of reasoning, immediate and delayed recall of wordlists, and implicit memory. Eighty per cent of the continuous users were classified as having mild cognitive impairment compared with 35% of non-users, and anticholinergic drug use was a strong predictor of mild cognitive impairment (odds ratio 5.12, P = 0.001). No difference was found between users and non-users in risk of developing dementia at follow-up after eight years. CONCLUSIONS: Elderly people taking anticholinergic drugs had significant deficits in cognitive functioning and were highly likely to be classified as mildly cognitively impaired, although not at increased risk for dementia. Doctors should assess current use of anticholinergic drugs in elderly people with mild cognitive impairment before considering administration of acetylcholinesterase inhibitors.
Abstract: Anticholinergic Drug Scale (ADS) scores were previously associated with serum anticholinergic activity (SAA) in a pilot study. To replicate these results, the association between ADS scores and SAA was determined using simple linear regression in subjects from a study of delirium in 201 long-term care facility residents who were not included in the pilot study. Simple and multiple linear regression models were then used to determine whether the ADS could be modified to more effectively predict SAA in all 297 subjects. In the replication analysis, ADS scores were significantly associated with SAA (R2 = .0947, P < .0001). In the modification analysis, each model significantly predicted SAA, including ADS scores (R2 = .0741, P < .0001). The modifications examined did not appear useful in optimizing the ADS. This study replicated findings on the association of the ADS with SAA. Future work will determine whether the ADS is clinically useful for preventing anticholinergic adverse effects.
Abstract: OBJECTIVES: To examine the longitudinal relationship between cumulative exposure to anticholinergic medications and memory and executive function in older men. DESIGN: Prospective cohort study. SETTING: A Department of Veterans Affairs primary care clinic. PARTICIPANTS: Five hundred forty-four community-dwelling men aged 65 and older with diagnosed hypertension. MEASUREMENTS: The outcomes were measured using the Hopkins Verbal Recall Test (HVRT) for short-term memory and the instrumental activity of daily living (IADL) scale for executive function at baseline and during follow-up. Anticholinergic medication use was ascertained using participants' primary care visit records and quantified as total anticholinergic burden using a clinician-rated anticholinergic score. RESULTS: Cumulative exposure to anticholinergic medications over the preceding 12 months was associated with poorer performance on the HVRT and IADLs. On average, a 1-unit increase in the total anticholinergic burden per 3 months was associated with a 0.32-point (95% confidence interval (CI)= 0.05-0.58) and 0.10-point (95% CI=0.04-0.17) decrease in the HVRT and IADLs, respectively, independent of other potential risk factors for cognitive impairment, including age, education, cognitive and physical function, comorbidities, and severity of hypertension. The association was attenuated but remained statistically significant with memory (0.29, 95% CI=0.01-0.56) and executive function (0.08, 95% CI=0.02-0.15) after further adjustment for concomitant non-anticholinergic medications. CONCLUSION: Cumulative anticholinergic exposure across multiple medications over 1 year may negatively affect verbal memory and executive function in older men. Prescription of drugs with anticholinergic effects in older persons deserves continued attention to avoid deleterious adverse effects.
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: 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.