Prolongación del tiempo QT
Eventos adversos de medicamentos
|Dolor de cabeza|
Variantes ✨Para la evaluación computacionalmente intensiva de las variantes, elija la suscripción estándar paga.
Explicaciones de las sustancias para pacientes.
No existen advertencias adicionales para la combinación de asenapina y tranilcipromina. Consulte también la información especializada pertinente.
Los cambios informados en la exposición corresponden a los cambios en la curva de concentración plasmática-tiempo [ AUC ]. No esperamos ningún cambio en la exposición a asenapina, cuando se combina con tranilcipromina (100%). No esperamos ningún cambio en la exposición a tranilcipromina, cuando se combina con asenapina (100%).
Los parámetros farmacocinéticos de la población media se utilizan como punto de partida para calcular los cambios individuales en la exposición debidos a las interacciones.
La asenapina tiene una baja biodisponibilidad oral [ F ] del 100 %, por lo que el nivel plasmático máximo [Cmax] tiende a cambiar fuertemente con una interacción. La vida media terminal [ t12 ] es de 24 horas y se alcanzan niveles plasmáticos constantes [ Css ] después de aproximadamente 96 horas. La unión a proteínas [ Pb ] es moderadamente fuerte al 100 % y el volumen de distribución [ Vd ] es muy grande a 1700 litros. El metabolismo tiene lugar principalmente a través de CYP1A2 y el transporte activo tiene lugar especialmente a través de UGT1A4.
La tranilcipromina tiene una biodisponibilidad oral media [ F ] del 100 %, por lo que los niveles plasmáticos máximos [Cmax] tienden a cambiar con una interacción. La vida media terminal [ t12 ] es relativamente corta a las 2.5 horas y los niveles plasmáticos constantes [ Css ] se alcanzan rápidamente. Se desconoce la unión a proteínas [ Pb ]. El metabolismo no tiene lugar a través de los citocromos comunes.
|Efectos serotoninérgicos a||3||Ø||+++|
Recomendación: El riesgo de un síndrome serotoninérgico aumenta, pero sin una respuesta exacta a las preguntas sobre los síntomas cognitivos, vegetativos y neuromusculares no podemos hacer recomendaciones de acción.
Clasificación: La tranilcipromina aumenta considerablemente la actividad serotoninérgica. Según nuestro conocimiento, la asenapina no aumenta la actividad serotoninérgica.
|Kiesel & Durán b||2||+||+|
Recomendación: Como precaución, se debe prestar atención a los síntomas anticolinérgicos, especialmente después de aumentar la dosis y en dosis en el rango terapéutico superior.
Clasificación: La Asenapina y tranilcipromina solo tienen un efecto leve sobre el sistema anticolinérgico. El riesgo de síndrome anticolinérgico con este medicamento es relativamente bajo si la dosis se encuentra en el rango habitual.
Prolongación del tiempo QT
La asenapina puede aumentar potencialmente el tiempo QT, pero no tenemos conocimiento de arritmias del tipo torsades de pointes. No conocemos ningún potencial de prolongación del intervalo QT de la tranilcipromina.
Efectos adversos generales
|Efectos secundarios||∑ frecuencia||ase||tra|
|Dolor de cabeza||30.1 %||n.a.||30.1|
|Aumento de peso||11.5 %||11.5||n.a.|
|Visión borrosa||10.1 %||n.a.||10.1|
Acatisia (9.5%): asenapina
Síndrome neuroléptico maligno: asenapina
Hiperglucemia (8.4%): asenapina
Suicida (2.5%): tranilcipromina, asenapina
Hipotensión ortostática (1.5%): asenapina
Edema periférico: tranilcipromina
Crisis hipertensiva: tranilcipromina
Pérdida de apetito: tranilcipromina
Disfunción eréctil: tranilcipromina
Reacción de hipersensibilidad: asenapina
Con base en sus respuestas e información científica, evaluamos el riesgo individual de efectos secundarios adversos. Estas recomendaciones están destinadas a asesorar a los profesionales y no sustituyen la consulta con un médico. En la versión de prueba restringida (alfa), el riesgo de todas las sustancias aún no se ha evaluado de manera concluyente.
Abstract: Excessive stimulation of serotonin 5HT1A receptors causes a syndrome of serotonin excess that consists of shivering, muscle rigidity, salivation, confusion, agitation and hyperthermia. The most common cause of this syndrome is an interaction between a monoamine oxidase inhibitor (MAOI) and a specific serotonin reuptake inhibitor. Venlafaxine is a new antidepressant agent that inhibits the reuptake of serotonin and norepinephrine. We report a venlafaxine-MAOI interaction that resulted in the serotonin syndrome in a 23-y-old male who was taking tranylcypromine for depression. He had been well until the morning of presentation when he took 1/2 tab of venlafaxine. Within 2 h he became confused with jerking movements of his extremities, tremors and rigidity. He was brought directly to a hospital where he was found to be agitated and confused with shivering, myoclonic jerks, rigidity, salivation and diaphoresis. His pupils were 7 mm and sluggishly reactive to light. Vital signs were: blood pressure 120/67 mm Hg, heart rate 127/min, respiratory rate 28/min, and temperature 97 F. After 180 mg of diazepam i.v. he remained tremulous with muscle rigidity and clenched jaws. He was intubated for airway protection and because of hypoventilation, and was paralyzed to control muscle rigidity. His subsequent course was remarkable for non-immune thrombocytopenia which resolved. The patient's maximal temperature was 101.2 F and his CPK remained < 500 units/L with no other evidence of rhabdomyolysis. His mental status normalized and he was transferred to a psychiatry ward. This patient survived without sequelae due to the aggressive sedation and neuromuscular paralysis.
Abstract: A number of novel serotonergic antidepressants have been introduced to clinical practice over the last decade. These medications are felt to be safe alternatives to the traditional tricyclic antidepressants and monoamine oxidase inhibitors, particularly in the overdose setting. Serious adverse reactions and drug interactions have been appreciated and fatalities have been reported. We describe the development of the serotonin syndrome in a 60 year old female on chronic tranylcypromine treatment following the inadvertent ingestion of a single dose of venlafaxine. Manifestations included and altered mental status that progressed to hyperthermia and coma. She recovered quickly and without complications. Health care providers and poison specialists need to be aware that this potentially serious syndrome can be precipitated by a single dose of a serotonin reuptake inhibitor in patients being treated with a monoamine oxidase inhibitor.
Abstract: No Abstract available
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: It has been over 50 years since a review has focused exclusively on the monoamine oxidase (MAO) inhibitor tranylcypromine (TCP). A new review has therefore been conducted for TCP in two parts which are written to be read preferably in close conjunction: part I - pharmacodynamics, pharmacokinetics, drug interactions, toxicology; and part II - clinical studies with meta-analysis of controlled studies in depression, practice of TCP treatment, place in therapy. The irreversible and nonselective MAO-A/B inhibitor TCP has been confirmed as an efficacious and safe antidepressant drug. For the first time, a meta-analysis of controlled clinical trials in depression demonstrated that TCP is superior to placebo (pooled logOR=0.509, 95%CI=0.026 to 0.993, 4 studies) and equal to other antidepressants (pooled logOR=0.208, 95%CI=-0.128 to 0.544, 10 studies). In treatment resistant depression (TRD) after tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs), TCP was superior to placebo (logOR=2.826, 95%CI=1.494 to 4.158, one study) and non-established antidepressants (pooled logOR=1.976, 95%CI=0.907 to 3.045, 4 studies), and was equal to other MAO inhibitors and an antidepressant combination (pooled logOR=-0.366, 95%CI=-0.869 to 0.137, 4 studies). Controlled studies revealed that TCP might provide a special advantage in the treatment of atypical depression, which was supported by a recent PET study of MAO-A activity in brain. However, TCP treatment remains beset with the need for a mandatory tyramine-restricted diet and is therefore limited to use as a third-line antidepressant according to recent treatment algorithms and guidelines for depression treatment. On the other hand, the effort needed to maintain a tyramine-restricted diet may have been overestimated in the perception of both doctors and patients, which may have led to relative underuse of TCP. Interaction with serotonergic drugs bears the risk of severe serotonin toxicity (SST) and combination with indirect sympathomimetic drugs may result in hypertensive crisis which both adds to the risks of TCP. At the same time, TCP has low to no risks of central anticholinergic, sedative, cardiac conduction, body weight, hemostatic effects, or pharmacokinetic drug interactions. Neuroprotection by MAO inhibitors due to reduced oxidative stress is becoming increasingly studied. Taken together, TCP is being increasingly recognized as an important option in systematic treatment approaches for patients suffering from severe courses of depression, such as TRD and atypical depression, by offering a MAO-related pathophysiological rationale.
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.