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 phenelzine. 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 phenelzine (100%). We do not expect any change in exposure for phenelzine, when combined with asenapine (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.
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.
The bioavailability of phenelzine is unknown. The terminal half-life [ t12 ] is 11.6 hours and constant plasma levels [ Css ] are reached after approximately 46.4 hours. Protein binding [ Pb ] is not known. The metabolism does not take place via the common cytochromes.
|Serotonergic Effects a||3||Ø||+++|
Recommendation: The risk of a serotonergic syndrome is increased, but without an exact answers to the cognitive, vegative and neuromuscular symptom questions we cannot make any recommendations for action.
Rating: Phenelzine greatly increases serotonergic activity. According to our knowledge, asenapine does not increase serotonergic activity.
|Kiesel & Durán b||2||+||+|
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 and phenelzine only have 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.
QT time prolongation
Asenapine can potentially increase QT time, but we do not know about torsades de pointes arrhythmias. We do not know of any QT-prolonging potential for phenelzine.
General adverse effects
|Side effects||∑ frequency||ase||phe|
|Weight gain||12.4 %||11.5||+|
|Orthostatic hypotension||2.5 %||1.5||+|
|Abdominal pain||1.0 %||n.a.||+|
Seizure: phenelzine, asenapine
Neuroleptic malignant syndrome: asenapine
Abnormal ejaculation: phenelzine
Erectile dysfunction: phenelzine
Orgasm disorder: phenelzine
Hypertensive crisis: phenelzine
Liver failure: phenelzine
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: OBJECTIVE: To report a serious drug interaction possibly occurring with the monoamine oxidase inhibitor phenelzine and the selective serotonin reuptake inhibitor sertraline. CASE SUMMARY: A 61-year-old woman with treatment-refractory major depressive disorder was being treated unsuccessfully with lithium, phenelzine, thioridazine, and doxepin. Sertaline 100 mg/d was added to the patient's therapy. Within three hours of ingesting the first dose, the patient experienced a dramatic increase in her temperature, pulse, and respirations along with labile blood pressure, and symptoms of rigidity, diaphoresis, shivering, and decreased sensorium. The patient was transported to the emergency room and treated with diazepam 10 mg iv, followed by midazolam 10 mg iv for control of rigidity. She was also intubated. The patient then experienced precipitous falls in her blood pressure and respiratory rate. Ice packs combined with a cooling blanket and dantrolene 80 mg iv were administered to control fever and rigidity, respectively. She had an initial working diagnosis of neuroleptic malignant syndrome, which was later changed to serotonin syndrome. Dantrolene was continued for 72 hours at which time the patient was extubated and transferred to a psychiatric unit. CONCLUSIONS: Selective serotonin reuptake inhibitor antidepressants should not be combined with monoamine oxidase inhibitor antidepressants because of the risk of serotonin syndrome.
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: 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: A 27-year-old Caucasian female with a history of depression was admitted to our local hospital with vague events that occurred a day before. This included an episode of dysarthria, and unsteadiness, followed by feeling generally unwell. Two weeks prior to presentation she was commenced on phenelzine. During clinical assessment she suddenly deteriorated with a dramatic fall in her conscious level. Moreover, she became hyperthermic, tachycardic, and diaphoretic, and developed increased tone in all muscles and ocular clonus. Rectal diazepam was administered but failed to control the symptoms. Consequently, she was transferred to the intensive care unit for intubation and muscle relaxants were commenced. She responded well and recovered next day without complications. Her symptoms and signs were consistent with the serotonin syndrome with phenelzine being the likely cause. To the best of our knowledge, this is the first reported case to associate the condition with phenelzine alone at therapeutic dose.
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.