Verlängerung der QT-Zeit
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Eklärungen für Patienten zu den Wirkstoffen
Für die Kombination von Tizanidin 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 Tizanidin 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 Tizanidin (100%) erfolgt.
Für die Berechnung der individuellen Expositionsveränderungen durch die Wechselwirkungen werden als Ausgangsbasis die pharmakokinetischen Parameter der durchschnittlichen Population verwendet.
Tizanidin hat eine tiefe orale Bioverfügbarkeit [ F ] von 15%, weshalb die maximalen Plasmaspiegel [ Cmax ] sich bei einer Interaktion tendentiell stark verändern. Die terminale Halbwertszeit [ t12 ] ist mit 1.5 Stunden eher kurz und konstante Plasmaspiegel [ Css ] werden schnell erreicht. Das therapeutische Fenster ist eng und die Sicherheitsmarge daher klein. Schon kleine Expositionsänderungen können das Toxizitätsrisiko erhöhen. Die Proteinbindung [ Pb ] ist mit 30% sehr schwach und das Verteilungsvolumen [ Vd ] ist mit 160 Liter sehr gross, da die Substanz aber ein hohe hepatische Extraktionsrate von 0.82 besitzt sind nur Veränderung des Leberblutflusses [ Q ] relevant. Die Metabolisierung findet vor allem über CYP1A2 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 Tizanidin 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 Tizanidin (stark) und Asenapin (mild) die anticholinerge Aktivität.
Verlängerung der QT-Zeit
Bewertung: In Kombination können Tizanidin und Asenapin potentiell ventrikuläre Arrhythmien vom Typ Torsades de pointes auslösen.
|Orthostatische Hypotonie||1.5 %||n.a.||1.5|
Erhöhte Transaminasen: Tizanidin
Malignes neuroleptisches Syndrom: Asenapin
Basierend auf Ihren
Abstract: The pharmacokinetics of tizanidine, a new centrally acting muscle relaxant, have been studied in 18 normal male volunteers who received orally a single 5 mg dose, a single 20 mg dose, or repeated administration of 4 mg every 8 hr for 13 doses of [14C]tizanidine. Serial blood and breath samples and complete urine and feces were collected and analyzed for total radioactivity as well as intact tizanidine. Tizanidine was rapidly and almost completely absorbed from the gastrointestinal tract, although the estimated bioavailability was only 21% due to extensive first-pass metabolism. The pharmacokinetics of tizanidine appeared to be linear in the 0-20 mg dose range, as indicated by the dose-proportional blood levels of total radioactivity as well as of parent drug. Absorbed tizanidine was almost completely metabolized before excretion, the major excretory route being via the kidneys. The terminal half-lives of tizanidine and radioactivity were ca 3 hr and 61 hr, respectively, and 76%-77% of the administered radioactivity was recovered within 120 hr. Repeated administration of [14C]tizanidine resulted in no apparent change in pharmacokinetic characteristics. During the 4 mg q 8 hr regimen, blood levels of tizanidine reached steady state after only 2 or 3 doses, whereas those of total radioactivity approached steady state after approximately 4 days. The degree of accumulation of radioactivity, unlike that of parent drug, was inconsistent with the terminal half-life, but instead implied a shorter effective half-life of ca. 16 hr. It appears that the terminal phase of the blood radioactivity profile represents a metabolite that is reversibly bound to and slowly released from a specific tissue depot, and that this binding involves a finite amount of drug regardless of the dose. The oral administration of [14C]tizanidine prescribed in the present study was safe and well tolerated.
Abstract: Clinical trials with tizanidine when administered alone have shown that 5-chloro-4-(2-imidazolin-2-ylamino)-2,1,3-benzothiodiazole (tizanidine) is safe and effective for spasticity control. However, given its mechanism of action and requirement for titration, clinical experience suggests that tizanidine is likely to be used in combination with other antispastic agents with different mechanisms of action, such as baclofen. The objective of this study was to examine the pharmacokinetics of both tizanidine and baclofen under steady-state conditions when administered alone or concomitantly. This was a randomized, three-period, multiple-dose, Latin Square design study consisting of tizanidine HCl, 4 mg t.i.d. for seven consecutive doses; baclofen, 10 mg t.i.d. for seven consecutive doses; and both regimens simultaneously for seven consecutive doses. Drug administration was performed every 8 h, three times daily. Fifteen normal men served as study subjects. A priori, a clinically significant difference was set as 30%. Concentrations of tizanidine and baclofen were nearly identical during the single and concomitant dosing periods. All of the calculated steady-state pharmacokinetic parameter changes for baclofen, tizanidine, and its major metabolites were within the 30% criterion. Small differences in renal clearance were observed when the two drugs were coadministered, but these changes are unlikely to be clinically important. Thus, it is unlikely that coadministration of tizanidine and baclofen during dose-titration of the former will result in a pharmacokinetic interaction.
Abstract: OBJECTIVE: Our objective was to study the effect of fluvoxamine on the pharmacokinetics and pharmacodynamics of tizanidine, a centrally acting skeletal muscle relaxant. METHODS: In a double-blind, randomized, 2-phase crossover study, 10 healthy volunteers took 100 mg fluvoxamine or placebo orally once daily for 4 days. On day 4, each ingested a single 4-mg dose of tizanidine. Plasma concentrations of tizanidine and fluvoxamine and pharmacodynamic variables were measured. A caffeine test was performed on day 3 to examine the role of cytochrome P450 (CYP) 1A2 in tizanidine pharmacokinetics. RESULTS: On average, fluvoxamine increased the total area under the concentration-time curve [AUC(0- infinity )] of tizanidine 33-fold (range, 14-fold to 103-fold; P =.000002) and the peak plasma concentration 12-fold (range, 5-fold to 32-fold; P =.000001). The mean elimination half-life of tizanidine was prolonged from 1.5 to 4.3 hours (P =.00004) by fluvoxamine. The AUC(0- infinity ) of tizanidine and its increase by fluvoxamine correlated with the caffeine/paraxanthine ratio and its increase, respectively (P <.03). All pharmacodynamic variables revealed a significant difference between the fluvoxamine and placebo phases, eg, in the maximal effects on systolic blood pressure (-35 mm Hg, P =.000009), diastolic blood pressure (-20 mm Hg, P =.00002), heart rate (-4 beats/min, P =.007), Digit Symbol Substitution Test (P =.0003), subjective drug effect (P =.0000001), and drowsiness (P =.0002). In particular, the decrease in systolic blood pressure, to the level of 80 mm Hg or even less, was an alarming finding. CONCLUSIONS: Fluvoxamine seriously affects the pharmacokinetics of tizanidine and increases the intensity and duration of its effects. Inhibition of tizanidine-metabolizing enzyme(s), mainly CYP1A2, by fluvoxamine seems to explain the observed interaction. Because of the potentially hazardous consequences, the concomitant use of tizanidine with fluvoxamine, or other potent inhibitors of CYP1A2, should be avoided.
Abstract: BACKGROUND AND OBJECTIVE: Oral contraceptives (OCs) can inhibit drug metabolism, but their effect on various cytochrome P450 (CYP) enzymes and drugs can be different. Our objective was to study the effect of combined OCs, containing ethinyl estradiol (INN, ethinylestradiol) and gestodene, on CYP1A2 activity, as well as their interaction potential with tizanidine. METHODS: In a parallel-group study, 15 healthy women using OCs and 15 healthy women without OCs (control subjects) ingested a single dose of 4 mg tizanidine. Plasma and urine concentrations of tizanidine, as well as several of its metabolites (M-3, M-4, M-5, M-9, and M-10), and pharmacodynamic variables were measured until 24 hours after dosing. As a marker of CYP1A2 activity, an oral caffeine test was performed in both groups. RESULTS: The mean area under the plasma concentration-time curve from time 0 to infinity [AUC0-infinity] of tizanidine was 3.9 times greater (P<.001) and the mean peak plasma tizanidine concentration (Cmax) was 3.0 times higher (P<.001) in the OC users than in the control subjects. In 1 OC user the AUC0-infinity of tizanidine exceeded the mean AUC0-infinity of the control subjects by nearly 20 times. There were no significant differences in the elimination half-life or time to peak concentration in plasma of tizanidine between the groups. Tizanidine/metabolite ratios in plasma (M-3 and M-4) and urine (M-3, M-4, M-5, M-9, and M-10) were 2 to 10 times higher in the users of OCs than in the control subjects. In the OC group the excretion of unchanged tizanidine into urine was, on average, 3.8 times greater (P=.008) than in the control subjects. The plasma caffeine/paraxanthine ratio was 2.8 times higher (P<.001) in the OC users than in the control subjects. The caffeine/paraxanthine ratio correlated significantly with the AUC0-infinity and peak concentration of tizanidine in plasma, with its excretion into urine, and with, for example, the tizanidine/M-3 and tizanidine/M-4 area under the plasma concentration-time curve ratios. Both the systolic and diastolic blood pressures were lowered by tizanidine more in the OC users (-29+/- 10 mm Hg and -21+/- 8 mm Hg, respectively) than in the control subjects (-17+/- 9 mm Hg and -13+/- 5 mm Hg, respectively) (P < .01). CONCLUSIONS: OCs containing ethinyl estradiol and gestodene increase, to a clinically significant extent, the plasma concentrations and effects of tizanidine, probably mainly by inhibiting its CYP1A2-mediated presystemic metabolism. Care should be exercised when tizanidine is prescribed to OC users.
Abstract: OBJECTIVE: Rifampicin greatly reduces the plasma concentrations of many drugs. Our aim was to characterise the inducibility of cytochrome P450 (CYP) 1A2 by rifampicin, using tizanidine and caffeine as probe drugs for presystemic and systemic CYP1A2-mediated metabolism. METHODS: In a randomised, 2-phase crossover study, ten healthy volunteers were given a 5-day pretreatment with 600 mg rifampicin or placebo once daily. On day 6, a single 4-mg dose of tizanidine was administered orally. Plasma and urine concentrations of parent tizanidine and several of its metabolites (M-3, M-4, M-5, M-9, M-10) and pharmacodynamic variables were measured up to 24 h. A caffeine test was performed in both phases. RESULTS: Rifampicin moderately reduced the peak plasma concentration (by 51%; P = 0.002) and area under the plasma concentration-time curve [AUC(0-infinity)] (by 54%; P = 0.009) of parent tizanidine, and had no effect on its half-life. The tizanidine/M-3 and tizanidine/M-4 AUC(0-infinity) ratios were slightly (by 30%; P = 0.014; and by 38%; P = 0.007) decreased by rifampicin. Also, the excretion of metabolites M-3, M-4 and M-5 into urine was reduced (P < 0.005), but that of M-10 was increased (P = 0.008) by rifampicin. Rifampicin reduced the tizanidine/M-10 ratio (by 55%; P = 0.047) but had no significant effect on the other tizanidine/metabolite ratios in urine. The caffeine/paraxanthine ratio was reduced by 23% (P = 0.081) by rifampicin. The effect of rifampicin on the caffeine/paraxanthine ratio correlated significantly with the effect of rifampicin on, for example, the AUC(0-infinity) of tizanidine and the tizanidine/M-3 AUC(0-infinity) ratio. The pharmacodynamic effects of tizanidine were reduced by rifampicin. CONCLUSIONS: Rifampicin moderately decreases the plasma concentrations of tizanidine. The strong inducing effects of rifampicin on other CYP enzymes, e.g. CYP3A4, may have contributed to the findings, and the inducibility of CYP1A2-mediated presystemic (tizanidine) and systemic (tizanidine, caffeine) metabolism by rifampicin is weak at the most. Compared to CYP3A4 substrate drugs, substrates of CYP1A2 are much less susceptible to drug interactions caused by enzyme inducers of the rifampicin type.
Abstract: AIMS: Case reports suggest an interaction between rofecoxib and the CYP1A2 substrate tizanidine. Our objectives were to explore the extent and mechanism of this possible interaction and to determine the CYP1A2 inhibitory potency of rofecoxib. METHODS: In a randomized, double-blind, two-phase cross-over study, nine healthy subjects took 25 mg rofecoxib or placebo daily for 4 days and, on day 4, each ingested 4 mg tizanidine. Plasma concentrations and the urinary excretion of tizanidine, its metabolites (M) and rofecoxib, and pharmacodynamic variables were measured up to 24 h. On day 3, a caffeine test was performed to estimate CYP1A2 activity. RESULTS: Rofecoxib increased the area under the plasma concentration-time curve (AUC(0-infinity)) of tizanidine by 13.6-fold [95% confidence interval (CI) 8.0, 15.6; P < 0.001), peak plasma concentration (C(max)) by 6.1-fold (4.8, 7.3; P < 0.001) and elimination half-life (t(1/2)) from 1.6 to 3.0 h (P < 0.001). Consequently, rofecoxib markedly increased the blood pressure-lowering and sedative effects of tizanidine (P < 0.05). Rofecoxib increased several fold the tizanidine/M-3 and tizanidine/M-4 ratios in plasma and urine and the tizanidine/M-5, tizanidine/M-9 and tizanidine/M-10 ratios in urine (P < 0.05). In addition, it increased the plasma caffeine/paraxanthine ratio by 2.4-fold (95% CI 1.4, 3.4; P = 0.008) and this ratio correlated with the tizanidine/metabolite ratios. Finally, the AUC(0-25) of rofecoxib correlated with the placebo phase caffeine/paraxanthine ratio (r = 0.80, P = 0.01). CONCLUSIONS: Rofecoxib is a potent inhibitor of CYP1A2 and it greatly increases the plasma concentrations and adverse effects of tizanidine. The findings suggest that rofecoxib itself is also metabolized by CYP1A2, raising concerns about interactions between rofecoxib and other CYP1A2 substrate and inhibitor drugs.
Abstract: AIMS: Tizanidine, one of the few oral antispastic therapies approved for use in the USA, has a narrow therapeutic index that can often make optimal patient dosing difficult. We surveyed the published literature for data on potential tizanidine dose relationships to pharmacokinetics, drug safety and effectiveness, as well as to provide practical drug dosing advice. RESULTS: The number of primary studies that describe tizanidine dose proportionality relationships was somewhat limited, even when including studies that used doses above those currently recommended or data from drug-drug interaction studies that resulted in supra-therapeutic tizanidine concentrations. DISCUSSION AND CONCLUSIONS: There is substantial evidence to show that plasma tizanidine concentrations are linearly related to dose in healthy subjects and patients, although there is a high degree of intersubject variability. The most common adverse events and pharmacodynamic effects are related to plasma concentrations. The clinical implications of the large interpatient variability in plasma tizanidine concentrations and its narrow therapeutic index make it necessary to individualise patient therapy. Practical advice on tizanidine dosing and/or switching between formulations is provided.
Abstract: BACKGROUND: Adverse effects of anticholinergic medications may contribute to events such as falls, delirium, and cognitive impairment in older patients. To further assess this risk, we developed the Anticholinergic Risk Scale (ARS), a ranked categorical list of commonly prescribed medications with anticholinergic potential. The objective of this study was to determine if the ARS score could be used to predict the risk of anticholinergic adverse effects in a geriatric evaluation and management (GEM) cohort and in a primary care cohort. METHODS: Medical records of 132 GEM patients were reviewed retrospectively for medications included on the ARS and their resultant possible anticholinergic adverse effects. Prospectively, we enrolled 117 patients, 65 years or older, in primary care clinics; performed medication reconciliation; and asked about anticholinergic adverse effects. The relationship between the ARS score and the risk of anticholinergic adverse effects was assessed using Poisson regression analysis. RESULTS: Higher ARS scores were associated with increased risk of anticholinergic adverse effects in the GEM cohort (crude relative risk [RR], 1.5; 95% confidence interval [CI], 1.3-1.8) and in the primary care cohort (crude RR, 1.9; 95% CI, 1.5-2.4). After adjustment for age and the number of medications, higher ARS scores increased the risk of anticholinergic adverse effects in the GEM cohort (adjusted RR, 1.3; 95% CI, 1.1-1.6; c statistic, 0.74) and in the primary care cohort (adjusted RR, 1.9; 95% CI, 1.5-2.5; c statistic, 0.77). CONCLUSION: Higher ARS scores are associated with statistically significantly increased risk of anticholinergic adverse effects in older patients.
Abstract: The aim of this study was to determine whether mexiletine, a CYP1A2 inhibitor, altered the pharmacokinetics and pharmacodynamics of tizanidine. The pharmacokinetics of tizanidine were examined in an open-label study in 12 healthy participants after a single dose of tizanidine (2 mg) with and without mexiletine coadministration (50 mg, 3 times as a pretreatment for a day and 2 times on the study day). Compared with tizanidine alone, mexiletine coadministration increased the peak plasma concentration (1.8 +/- 0.8 vs 5.3 +/- 1.8 ng/mL), area under the curve (4.5 +/- 2.2 vs 15.4 +/- 6.5 ng x h/mL), and the half-life (1.3 +/- 0.2 vs 1.8 +/- 0.7 h) of tizanidine, respectively (P < .05). Reduction in systolic blood pressure (-10 +/- 8 vs -24 +/- 7 mm Hg) and diastolic blood pressure (-10 +/- 7 vs -18 +/- 8 mm Hg) after tizanidine administration was also significantly enhanced by coadministration of mexiletine (P < .01). Of the 15 patients treated with tizanidine and mexiletine, 4 suffered tizanidine-induced adverse effects such as drowsiness and dry mouth in the retrospective survey. Present results suggested that coadministration of mexiletine increased blood tizanidine concentrations and enhanced tizanidine pharmacodynamics in terms of reduction in blood pressure and adverse symptoms.
Abstract: Prolongation of the QT interval can predispose to a potentially fatal polymorphic ventricular tachycardia called torsades de pointes (TdP). Although usually self-limited, TdP may degenerate into ventricular fibrillation and cause sudden death. Some medications that cause QT prolongation and possible TdP are commonly used in general practice. This paper presents a case of sudden death that is likely from drug-induced TdP. It reviews the mechanisms, risk factors, offending agents, and management of drug-induced torsades de pointes.
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: Tizanidine (Zanaflex) is a centrally acting imidazoline muscle relaxant that is structurally similar to clonidine (α(2)-adrenergic agonist) but not to other myorelaxants such as baclofen or benzodiazepines. Interestingly, cardiac arrhythmias and QT interval prolongation have been reported with tizanidine. OBJECTIVE: To evaluate the effects of tizanidine on cardiac ventricular repolarization. METHODS: (1) Whole-cell patch-clamp experiments: HERG- or KCNQ1+KCNE1-transfected cells were exposed to tizanidine 0.1-100 µmol/L (n = 29 cells, total) to assess drug effect on the rapid (I(Kr)) and slow (I(Ks)) components of the delayed rectifier potassium current. (2) Langendorff retroperfusion experiments: isolated hearts from male Hartley guinea pigs (n = 6) were exposed to tizanidine 1 µmol/L to assess drug-induced prolongation of monophasic action potential duration measured at 90% repolarization (MAPD(90)). (3) In vivo wireless cardiac telemetry experiments: guinea pigs (n = 6) implanted with radio transmitters were injected a single intraperitoneal (ip) dose of tizanidine 0.25 mg/kg and 24 hours electrocardiography (ECG) recordings were made. RESULTS: (1) Patch-clamp experiments revealed an estimated IC(50) for tizanidine on I(Kr) above 100 µmol/L. Moreover, tizanidine 1 µmol/L had hardly any effect on I(Ks) (5.23% ± 4.54% inhibition, n = 5 cells). (2) While pacing the hearts at stimulation cycle lengths of 200 or 250 ms, tizanidine 1 µmol/L prolonged MAPD(90) by 8.22 ± 2.03 (6.7%) and 11.70 ± 3.08 ms (8.5%), respectively (both P < .05 vs baseline). (3) Tizanidine 0.25 mg/kg ip caused a maximal 11.93 ± 1.49 ms prolongation of corrected QT interval (QTc), 90 minutes after injection. CONCLUSION: Tizanidine prolongs the QT interval by blocking I(Kr). Patients could be at risk of cardiac proarrhythmia during impaired drug elimination, such as in case of CYP1A2 inhibition during drug interactions.
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: PURPOSE: Some macrolide and quinolone antibiotics (MQABs) are associated with QT prolongation and life-threatening torsade de pointes (TdP) arrhythmia. MQAB may also inhibit cytochrome P450 isoenzymes and thereby cause pharmacokinetic drug interactions (DDIs). There is limited data on the frequency and management of such risks in clinical practice. We aimed to quantify co-administration of MQAB with interacting drugs and associated adverse drug reactions. METHODS: We conducted an observational study within our pharmacoepidemiological database derived from electronic medical records of a tertiary care hospital. Among all users of MQAB associated with TdP, we determined the prevalence of additional QT-prolonging drugs and risk factors and identified contraindicated co-administrations of simvastatin, atorvastatin, or tizanidine. Electrocardiographic (ECG) monitoring and associated adverse events were validated in medical records. RESULTS: Among 3444 administered courses of clarithromycin, erythromycin, azithromycin, ciprofloxacin, levofloxacin, or moxifloxacin, there were 1332 (38.7 %) with concomitant use of additional QT-prolonging drugs. Among those, we identified seven cases of drug-related QT prolongation, but 49.1 % had no ECG monitoring. Of all MQAB users, 547 (15.9 %) had hypokalemia. Forty-four MQAB users had contraindicated co-administrations of simvastatin, atorvastatin, or tizanidine and three of those related adverse drug reactions. CONCLUSION: In the studied real-life setting, we found a considerable number of MQAB users with additional risk factors for TdP but no ECG monitoring. However, adverse drug reactions were rarely found, and costs vs. benefits of ECG monitoring have to be weighted. In contrast, avoidable risk factors and selected contraindicated pharmacokinetic interactions are clear targets for implementation as automated alerts in electronic prescribing systems.
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.