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 tolterodine and asenapine. Please also consult the relevant specialist information.
The reported changes in exposure correspond to the changes in the plasma concentration-time curve [ AUC ]. We did not detect any change in exposure to tolterodine. We currently cannot estimate the influence of asenapine. We do not expect any change in exposure for asenapine, when combined with tolterodine (100%).
The pharmacokinetic parameters of the average population are used as the starting point for calculating the individual changes in exposure due to the interactions.
Tolterodine has a low oral bioavailability [ F ] of 17%, which is why the maximum plasma level [Cmax] tends to change strongly with an interaction. The terminal half-life [ t12 ] is rather short at 6 hours and constant plasma levels [ Css ] are reached quickly. The protein binding [ Pb ] is 96.3% strong and the volume of distribution [ Vd ] is very large at 88 liters, which is why, with a mean hepatic extraction rate of 0.51, both liver blood flow [Q] and a change in protein binding [Pb] are relevant. The metabolism takes place via CYP2D6 and CYP3A4, among others.
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.
|Serotonergic Effects a||0||Ø||Ø|
Rating: According to our knowledge, neither tolterodine nor asenapine increase serotonergic activity.
|Kiesel & Durán b||4||+++||+|
Recommendation: The risk of anticholinergic side effects such as blurred vision, confusion and tremor is increased with this therapy. If possible, the therapy should be switched or the patient should be closely monitored for other symptoms, such as constipation, mydriasis and reduced vigilance.
Rating: Together, tolterodine (strong) and asenapine (mild) increase anticholinergic activity.
QT time prolongation
Rating: In combination, tolterodine and asenapine can potentially trigger ventricular arrhythmias of the torsades de pointes type.
General adverse effects
|Side effects||∑ frequency||tol||ase|
|Weight gain||11.5 %||n.a.||11.5|
|Abdominal pain||4.0 %||4.0||n.a.|
|Orthostatic hypotension||1.5 %||n.a.||1.5|
Neuroleptic malignant syndrome: asenapine
Angioedema: tolterodine, asenapine
Hypersensitivity reaction: tolterodine, 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 aim of this study was to determine the pharmacokinetics, pharmacodynamics, and safety of tolterodine following single oral and intravenous doses in healthy volunteers. A secondary aim was to identify major urinary metabolites and determine mass balance. Single oral doses of 0.2, 0.4, 0.8, 1.6, 3.2, 6.4, and 12.8 mg of tolterodine (as the tartrate salt) were given to 17 healthy male volunteers. Two intravenous doses (0.64 and 1.28 mg) were administered to 8 of the volunteers and mass balance was studied after a single oral dose of 5 mg (14C)-tolterodine in 6 subjects. Tolterodine was rapidly absorbed following oral administration (time to peak serum concentration 0.9 +/- 0.4 h). The absolute bioavailability was highly variable, ranging from 10 to 70%. The volume of distribution at steady-state ranged from 0.9 to 1.6 l/kg and systemic clearance ranged from 0.23 to 0.52 l/h/kg, which resulted in a terminal half-life of 2-3 h. Tolterodine exhibited high first-pass metabolism and 2 hepatic metabolic pathways were identified: oxidation and dealkylation. Independent of route of administration, < 1% of the parent compound was excreted unchanged in urine. Five metabolites were structurally identified in urine. Following oral administration of (14C)-tolterodine, the excretion of radioactivity into urine and feces was 77 +/- 4.0% and 17 +/- 3.5%, respectively. Tolterodine decreased stimulated salivation after 3.2 mg, increased heart rate after 6.4 mg, and nearpoint of vision after 12.8 mg. Six of 8 subjects reported micturition difficulties after a dose of 12.8 mg. The lack of a direct relationship between tolterodine serum concentrations and effects on stimulated salivation suggested the presence of pharmacologically active metabolite(s).
Abstract: The aim of this study was to determine in vitro protein binding of tolterodine and its 5-hydroxymethyl (5-HM) and N-dealkylated metabolites in serum from humans and several animal species at concentrations similar to those obtained in clinical and preclinical studies. Binding of tolterodine and the two metabolites to human serum albumin and alpha1-acid glycoprotein (AAG) was also assessed, as was binding of tolterodine to red blood cells. Ex vivo protein binding of tolterodine and 5-HM was determined in serum samples from healthy volunteers treated with oral tolterodine 4 mg twice daily for 8 days. Tolterodine exhibited high protein binding in human serum; the unbound fraction (f(u)) was 3.7%. The unbound fraction of tolterodine in cat and dog serum (1.5 and 2.1%, respectively) was lower compared with human serum; f(u) was higher in the other species investigated (rat, 22%; mouse, 16-17%; rabbit, 39%). The unbound fraction of 5-HM was much higher in serum from humans (36%) and all animal species investigated (mouse, 72%; rabbit, 68%; cat, 32%; dog, 45%). Binding of N-dealkylated tolterodine to proteins in human serum was intermediate (f(u) 14%). AAG was the major binding protein for tolterodine and 5-HM, and the degree of binding increased with increasing concentration of the protein. The association constant of 5-HM for AAG was lower than that of tolterodine (1.3 x 10(5) M(-1) versus 2.1 x 10(6) M(-1)). The blood:plasma tolterodine concentration ratio was 0.6 in both humans and dog; thus, a minor fraction of tolterodine was present in red blood cells compared with plasma (0.18 and 0.36, respectively). In the mouse, tolterodine was equally present in blood and plasma. In ex vivo samples, f(u) values for tolterodine (pH adjusted) varied between 1.6 and 4.9% (mean 2.8%), which could be explained by differences in AAG concentrations. There was good correlation between observed f(u) values for tolterodine and those predicted on the basis of AAG levels. Similar findings were observed for 5-HM.
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: The objective of our study was to determine the QTc effects of tolterodine. A crossover-design thorough QT study of recommended (2 mg twice daily) and supratherapeutic (4 mg twice daily) doses of tolterodine, moxifloxacin (400 mg once daily), and placebo was performed. Electrocardiograms (ECGs) and pharmacokinetic samples were obtained on days 1-4; time-matched baseline ECGs were taken on day 0. Mean placebo-subtracted change from baseline Fridericia-corrected QT (QTcF) during peak drug exposure on day 4 was the primary end point. Mean QTcF prolongation of moxifloxacin was 8.9 ms (machine-read) and 19.3 ms (manual-read). At recommended and supratherapeutic tolterodine doses, mean QTcF prolongation was 1.2 and 5.6 ms (machine-read), respectively, and 5.0 and 11.8 ms (manual-read), respectively. The QTc effect of tolterodine was lower than moxifloxacin. No subject receiving tolterodine exceeded the clinically relevant thresholds of 500 ms absolute QTc or 60 ms change from baseline. In conclusion, tolterodine does not have a clinically significant effect on QT interval.
Abstract: No Abstract available
Abstract: The objective of this study was to measure the anticholinergic activity (AA) of medications commonly used by older adults. A radioreceptor assay was used to investigate the AA of 107 medications. Six clinically relevant concentrations were assessed for each medication. Rodent forebrain and striatum homogenate was used with tritiated quinuclidinyl benzilate. Drug-free serum was added to medication and atropine standard-curve samples. For medications that showed detectable AA, average steady-state peak plasma and serum concentrations (C(max)) in older adults were used to estimate relationships between in vitro dose and AA. All results are reported in pmol/mL of atropine equivalents. At typical doses administered to older adults, amitriptyline, atropine, clozapine, dicyclomine, doxepin, L-hyoscyamine, thioridazine, and tolterodine demonstrated AA exceeding 15 pmol/mL. Chlorpromazine, diphenhydramine, nortriptyline, olanzapine, oxybutynin, and paroxetine had AA values of 5 to 15 pmol/mL. Citalopram, escitalopram, fluoxetine, lithium, mirtazapine, quetiapine, ranitidine, and temazepam had values less than 5 pmol/mL. Amoxicillin, celecoxib, cephalexin, diazepam, digoxin, diphenoxylate, donepezil, duloxetine, fentanyl, furosemide, hydrocodone, lansoprazole, levofloxacin, metformin, phenytoin, propoxyphene, and topiramate demonstrated AA only at the highest concentrations tested (patients with above-average C(max) values, who receive higher doses, or are frail may show AA). The remainder of the medications investigated did not demonstrate any AA at the concentrations examined. Psychotropic medications were particularly likely to demonstrate AA. Each of the drug classifications investigated (e.g., antipsychotic, cardiovascular) had at least one medication that demonstrated AA at therapeutic doses. Clinicians can use this information when choosing between equally efficacious medications, as well as in assessing overall anticholinergic burden.
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: This review highlights the design and development of fesoterodine (Toviaz) as a prodrug of 5-hydroxymethyl tolterodine (5-HMT), which is also the active metabolite of tolterodine, for the treatment of overactive bladder (OAB). Tolterodine and 5-HMT are both potent antimuscarinic agents. A prodrug approach was necessary for systemic bioavailability of 5-HMT after oral administration. Fesoterodine was selected amongst a series of ester analogues of 5-HMT to develop an advanced OAB treatment with an optimum biopharmaceutics profile, while maintaining a pharmacological link to tolterodine. While tolterodine and 5-HMT have similar antimuscarinic activity, the logD value, a determinant of lipophilicity and permeability across biological interfaces such as the gut wall and blood-brain barrier, is considerably lower for 5-HMT (0.74) versus tolterodine (1.83). In contrast to the cytochrome P450 (CYP) 2D6-mediated metabolism of tolterodine, 5-HMT formation from fesoterodine occurs via ubiquitous nonspecific esterases. Consequently, treatment with fesoterodine results in consistent, genotype-independent exposure to a singular active moiety (5-HMT); treatment with tolterodine results in CYP2D6 genotype-dependent exposure to varying proportions of two active moieties (5-HMT and tolterodine). At least partially due to the avoidance of variations in pharmacokinetic exposures observed with tolterodine, it was possible to develop fesoterodine with the flexibility of two efficacious and well-tolerated dosage regimens of 4 and 8 mg daily.
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/AIMS: The nature and extent of adverse cognitive effects due to the prescription of anticholinergic drugs in older people with and without dementia is unclear. METHODS: We calculated the anticholinergic load (ACL) of medications taken by participants of the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of ageing, a cohort of 211 Alzheimer's disease (AD) patients, 133 mild cognitive impairment (MCI) patients and 768 healthy controls (HC) all aged over 60 years. The association between ACL and cognitive function was examined for each diagnostic group (HC, MCI, AD). RESULTS: A high ACL within the HC group was associated with significantly slower response speeds for the Stroop color and incongruent trials. No other significant relationships between ACL and cognition were noted. CONCLUSION: In this large cohort, prescribed anticholinergic drugs appeared to have modest effects upon psychomotor speed and executive function, but not on other areas of cognition in healthy older adults.
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: The objective of this analysis was to explore exposure-response modeling of data from a thorough QT (TQT) study of tolterodine in CYP2D6 extensive (EMs) and poor metabolizers (PMs). Crossover treatments of the TQT study included the recommended (2 mg twice daily) and supratherapeutic (4 mg twice daily) doses of tolterodine, moxifloxacin (400 mg once daily), and placebo. The concentration-response relationships for the QTc effects of moxifloxacin and tolterodine were described using a linear model with baseline effect, placebo effect, and a drug effect. The mixed effects modeling approach, using the first order conditional estimation method, was implemented in NONMEM. Simulated data from 250 trial replicates were used for limited predictive check and to describe the expected extreme responders in this study, under the derived model and point estimates. Modeling results for tolterodine showed linear concentrationdependent increases in QTc interval, with no difference in slopes between EMs and PMs. Modelpredicted QTc prolongations for tolterodine and moxifloxacin were consistent with their respective observed mean results. No subjects were predicted to have increases of > 60 milliseconds (ms); the predicted incidence of borderline QTc increases (> 30 and ≤ 60 ms) remained low at the supratherapeutic tolterodine dose in both PMs (9.1%) and EMs (3.9%). In conclusions, this analysis supports our clinical experience that tolterodine does not have a clinically significant effect on QT interval.
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.