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Instructions / Instruction for use: Asenapine

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Latin name of substance Asenapine

Azenapinum (genus Azenapini)

Chemical name

(3aS, 12bS) -rel-5-chloro-2,3,3a, 12b-tetrahydro-2-methyl-1H-dibenz [2,3: 6,7] oxepino [4,5-c] pyrrole

Gross formula

C17H16ClNO

Pharmacological group:

Neuroleptics

The nosological classification (ICD-10)

F20 Schizophrenia: Schizophrenic Conditions; An exacerbation of schizophrenia; Schizophrenia; Chronic schizophrenia; Dementia praecox; Bleuler's disease; Psychotic discordant; Dementia early; The febrile form of schizophrenia; Chronic schizophrenic disorder; Psychosis of the schizophrenic type; Acute form of schizophrenia; Acute schizophrenic disorder; Cerebral Organic Insufficiency in Schizophrenia; Acute attack of schizophrenia; Schizophrenic psychosis; Acute schizophrenia; Sluggish schizophrenia; Sluggish schizophrenia with apathoabulic disorders; Acute stage of schizophrenia with agitation

F31 Bipolar affective disorder: Mood disorders bipolar; Affective bipolar psychosis; Manic-melancholic psychosis; Intermittent psychosis; Circular psychosis; Cyclophrenia; Bipolar disorders; Bipolar disorders; Bipolar psychosis; Affective insanity; Manic-depressive syndrome; Psycho Manic-Depressive; Depressive episode of bipolar disorder

CAS code

65576-45-6

Characteristics of the substance Asenapine

Atypical antipsychotic. White or almost white powder.

Pharmacology

Pharmacological action - antipsychotic.

Has a high affinity for numerous receptors, incl. to serotonin 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT5, 5-HT6 and 5-HT7 (dissociation constants Ki = 2.5, 4.0, 0.06; 0.16, 0.03, 1.6, 0.25 and 0.13 nM), dopamine D1, D2, D3 and D4 receptors (Ki = 1.4, 1.3, 0.42 and 1.1 nM), α1 and α2-adrenoreceptors (Ki = 1.2 nM), histamine H1 receptors (Ki = 1.0 nM), and moderate affinity for H2 receptors (Ki = 6.2 nM). Virtually does not interact with m-holinoretseptorami (Ki = 8128 nM for M1-holinoretseptorov). The antipsychotic effect is mediated, as thought, by the effect on D2 and 5-HT2A receptors. In vitro, asenapine acts as an antagonist of these receptors.

Pharmacokinetics

With sublingual use, asenapine is rapidly absorbed, Tmax is reached within 0.5-1.5 hours. After a single dose of 5 mg Cmax - about 4 ng / ml, absolute bioavailability is 35%. A two-fold increase in the dose (from 5 to 10 mg) twice a day leads to an increase in exposure by a factor of 1.7. Absolute bioavailability if swallowed is very small (<2% when taken orally in the form of tablets). Binding to plasma proteins - 95% (with albumin and alpha-1-acid glycoprotein). Rapidly distributed, Vd - approximately 20-25 l / kg. Equilibrium concentration is achieved within 3 days with daily intake 2 times a day. The main pathways of metabolism are glucuronization and oxidative metabolism involving cytochrome P450 isoenzymes (predominantly CYP1A2). T1 / 2 - about 24 hours. After taking a single dose of [14C] -magnified asenapine, about 90% of the dose is excreted (approximately 50% with urine, 40% with feces). About 50% of the substances circulating in the plasma were identified: the prevailing metabolite was asenapine-N + -glucuronide; among others - N-desmethylazenapine, N-desmethylazenapine N-carbamoyl glucuronide and unchanged asenapine (in smaller amounts).

Smoking. Population pharmacokinetic analysis showed that smoking (induces CYP1A2) does not affect the clearance of asenapine in smokers. A cross-sectional study involving healthy male smokers (N = 24) showed that a single administration of asenapine sublingually at the same time as smoking did not affect the pharmacokinetics of asenapine.

Food. A cross-sectional study with healthy men (N = 26) showed that eating just before sublingual use of asenapine reduced its exposure by 20%; at meals after 4 hours the exposure was reduced by 10%.

Water. Consumption of water after several (2-5) minutes after taking asenapine leads to a decrease in its exposure (do not eat and drink for 10 minutes after taking asenapine).

During the clinical trials of asenapine, the effect of water intake at different times (2, 5, 10 and 30 min) was studied after taking 10 mg of asenapine sublingually in 15 healthy men. It was found that the exposure of asenapine with water intake 10 minutes after asenapine was equivalent to that observed with water intake after 30 minutes, but after 2 minutes, it was reduced by 19%, after 5 minutes by 10%.

Pharmacokinetics in special clinical cases

Violation of the function of the liver. With a single admission of 5 mg of asenapine sublingually in patients with mild or moderate hepatic insufficiency (Child-Pugh A and B, N = 16), the exposure of asenapine was 12% higher than in people with normal liver function (n = 8); correction of the dose is not required. In patients with severe hepatic insufficiency (Child-Pugh C, N = 6), the exposure of asenapine was on average 7 times higher than in patients with normal liver function; Asenapine is not recommended for patients with severe hepatic insufficiency.

Impaired renal function. After a single administration of asenapine at a dose of 5 mg, its exposure was similar for different degrees of renal insufficiency (N = 24) and in healthy subjects (N = 8); correction of the dose is not required. The effect of renal dysfunction on the excretion of metabolites and the effect of dialysis on the pharmacokinetics of asenapine has not been investigated.

Elderly age. In elderly patients with psychosis (N = 96) over the age of 65 (65-85 years), the concentrations of asenapine were higher in comparison with those in young patients (an average of 30-40%), and the exposure in some cases was higher in 2 times. Population pharmacokinetic analysis showed a decrease in clearance with increasing age, suggesting an increase in exposure in the elderly by 30%.

Floor. Differences in pharmacokinetics in women and men were not observed.

Carcinogenicity, mutagenicity, effects on fertility

Carcinogenicity. In studies on mice of the CD-1 line, when injecting animals with asenapine, SC at doses providing plasma levels (AUC) 5 times higher than those expected in humans with the maximum dose (10 mg twice daily), the frequency of mice in females was increased the occurrence of malignant lymphomas. At doses equivalent to 1.5 MPH, this effect was not manifested. The significance of these results for man is unknown. There was no increase in the frequency of detection of other tumors in female mice. In male mice, there was no increase in the incidence of any neoplasms.

In studies in rats of the Sprague-Dawley line with the use of asenapine, SC in the doses creating plasma levels (AUC) 5 times higher than those expected in humans with the maximum dose, there was no evidence of a carcinogenic effect.

Mutagenicity. Asenapine did not exhibit genotoxicity in a number of in vitro and in vivo tests.

Impact on fertility. In studies on rats there was no effect on fertility with the administration of asenapine inside at doses up to 11 mg / kg twice daily (10 times higher than MPDH, in terms of mg / m2).

Clinical researches

Schizophrenia

The efficacy of asenapine in the treatment of schizophrenia in adults was evaluated in three randomized, double-blind, placebo-controlled, short-term (6-week) fixed-dose and active-controlled studies (haloperidol, risperidone, and olanzapine) in the exacerbation of schizophrenia.

Bipolar disorder

The efficacy of monotherapy with asenapine in the treatment of acute manic or mixed conditions associated with bipolar disorder (with or without psychotic affect) was confirmed in two 3-week, randomized, double-blind, placebo-controlled trials in adults and in active-controlled (olanzapine ) study.

The efficacy of asenapine as an adjunctive therapy for acute mania has been established in one 12-week, placebo-controlled trial (3 weeks) in adults to arrest a manic or mixed episode in patients with bipolar disorder (both with psychotic affects and without them) , partially responding to monotherapy with lithium or valproate after 2 weeks of treatment.

Application of Asenapine

Treatment of schizophrenia. Coping of an acute manic or mixed episode with bipolar affective disorder (monotherapy, as well as additional therapy in combination with lithium or valproate).

Contraindications

Hypersensitivity.

Restrictions on the use

Severe hepatic insufficiency, children's age (should be avoided in pediatric practice, since safety and efficacy in children are not defined).

Application in pregnancy and lactation

When pregnancy is possible, if the expected effect of therapy exceeds the potential risk to the fetus.

The action category for fetus by FDA is C.

In animal studies, asenapine caused an increase in postimplantation losses, a decrease in body weight and survival of the young at doses similar or smaller than the recommended clinical doses. In these studies, there was no increase in the frequency of structural anomalies in the background of asenapine.

Thus, asenapine did not exhibit teratogenic properties in studies of reproduction in rats and rabbits with iv administration at doses up to 1.5 mg / kg in rats and 0.44 mg / kg in rabbits. These doses are equivalent to 0,7 and 0,4 MRDCH (10 mg twice a day sublingually, in terms of mg / m2), respectively. Plasma levels of asenapine and AUC in rabbits at the highest test dose were 2 times higher than those observed in humans with the maximum recommended dose.

In a study in rats treated with asenapine IV in doses of 0.3; 0,9 and 1,5 mg / kg / day (0,15, 0,4 and 0,7 MRDCH) from the 6th day of pregnancy on the 21st day after birth, there was an increase in postimplantation losses and early death of calves for all doses, while a decrease in the subsequent survival rate and body weight of the young - at two higher doses. An increase in postimplantation loss, a decrease in body weight and survival of calves were also noted if pregnant rats received asenapine orally.

Nonteratogenic effects. When antipsychotic agents are exposed to the fetus in the third trimester of pregnancy, there is a risk of developing a newborn extrapyramidal disorder and / or withdrawal symptoms. There are reports of agitation, hypertension / hypotension, tremor, drowsiness, respiratory distress syndrome and feeding disorders in such newborns. These complications vary in severity: from self-limiting to requiring intensive maintenance therapy and prolonged hospitalization.

The effect of asenapine on delivery and delivery in humans is unknown.

Asenapine is excreted into the milk of rats during lactation. It is not known whether asenapine or its metabolites are excreted into human milk. For the duration of treatment, breastfeeding should be discontinued.

Side effects of the substance Asenapine

The most frequent adverse effects (≥5% and observed at least 2 times more often with taking asenapine versus placebo) in patients with exacerbation of schizophrenia were: akathisia, oral hypoesthesia, drowsiness. The safety profile of asenapine with maintenance therapy is similar to that in the treatment of exacerbation of schizophrenia.

The most frequent adverse effects (≥5% and observed at least twice as often with asenapine versus placebo) with monotherapy of acute manic or mixed episodes in bipolar affective disorder were: drowsiness, dizziness, extrapyramidal symptoms with the exception of akathisia, an increase body weight; when used as an additional therapy for bipolar disorder - drowsiness and oral hypoesthesia.

It should be borne in mind that the side effect data obtained in placebo-controlled studies can not be used to predict the incidence of side effects in routine medical practice, the status of patients and other factors may differ from those that prevailed in clinical trials. Also the frequency of occurrence of side effects listed in the tables may differ from that obtained by other clinical researchers, each drug test can be conducted with a different set of conditions. However, the figures given give the doctor an idea of the relative contribution of the substance itself and other factors (not related to drugs) to the development of side effects when using drugs in the population.

Schizophrenia

Table 1 shows the side effects observed in patients with schizophrenia who received suben- ginal sublingual aspenapine at a dose range of 5 to 10 mg twice daily (adverse effects were noted with a frequency of ≥2% and exceeded the placebo frequency) with short-term placebo- controlled premarketing trials (three 6-week fixed-dose trials and one with a flexible dose).

Interrupted treatment due to side effects 9% of patients treated with asenapine, and 10% - in the placebo group.

Of the side effects listed in Table 1, a dose-dependent effect was akathisia.

Table 1

Side effects observed with the therapy with asenapine in the treatment of patients with schizophrenia (results of placebo-controlled trials)

Body Systems / Side Effects Placebo (N=378), % Asenapine 5 mg 2 times a day (N=274), % Asenapine 10 mg 2 times a day (N=208), % Asenapine* 5 or 10 mg 2 times a day (N=572), %
Gastrointestinal disorders
Constipation 6 7 4 5
Dry mouth 1 3 1 2
Oral Hypesthesia 1 6 7 5
Hypersalivation 0 <1 4 2
Gastric discomfort 1 <1 3 2
Vomiting 5 4 7 5
Increased appetite <1 3 0 2
Are common
Fatigue 3 4 3 3
Irritability <1 2 1 2
Metabolic
Weight gain <1 2 2 3
Nervous System Disorders
Akathisia1 3 4 11 6
Dizziness 4 7 3 5
Extrapyramidal symptoms (excluding akathisia) 2 7 9 12 10
Drowsiness3 7 15 13 13
Mental disorders
Insomnia 13 16 15 15
Cardiovascular disorders
Hypertension 2 2 3 2
* - A study with flexible doses (N = 90)1 - Akathisia includes: akathisia and hyperkinesia.

2 - Extrapyramidal symptoms include: dystonia, movement of the eyeball, dyskinesia, tardive dyskinesia, muscle rigidity, parkinsonism, tremor, extrapyramidal disorders (except akathisia).

3 - Drowsiness includes: drowsiness, sedation, hypersomnia.

Bipolar disorder (monotherapy)

Below (Table 2) presents the results of short-term placebo-controlled trials (two 3-week flexible dose trials) in which patients with mania received sublingual at the dose of 5 or 10 mg twice daily.

Approximately 10% (38/379) of patients treated with asenapine discontinued treatment due to side effects, compared to 6% (12/203) who received placebo. The most frequent adverse effects associated with discontinuation of treatment (noted in at least 1% of patients and at least 2 times more often than with placebo) were anxiety (1.1%) and oral hypoesthesia (1.1%) , in comparison with placebo (0%).

Bipolar disorder (complementary therapy)

Table 2 also shows data from 12-week placebo-controlled trials (with efficacy evaluation at 3 weeks) in adult patients with mania who received sublingual at the dose of 5 or 10 mg twice daily as an additional therapy for lithium or valproate.

Approximately 16% (25/158) of patients discontinued treatment due to side effects, compared to 11% (18/166) who received placebo. The most common adverse effects associated with discontinuation of treatment (noted in at least 1% of patients and at least 2 times more often than with placebo) were depression (2.5%), thoughts of suicide (2.5% ), aggravation of mania (1.9%), insomnia (1.9%), depressive symptoms (1.3%).

Table 2 shows the side effects that occurred at a rate of ≥2% and exceeded the placebo frequency in patients with bipolar disorder who received asenapine either as monotherapy or as adjunctive therapy.

Table 2

Side effects observed with the therapy with asenapine in the treatment of patients with bipolar disorder (results of placebo-controlled trials)

Body Systems / Side Effects

Gastrointestinal disorders

Monotherapy Supplementary Therapy
Placebo (N=203), % Asenapine 5 or 10 mg twice daily (N=379), % Placebo (N=166), % Asenapine 5 or 10 mg twice daily (N=158), %
Constipation
Dry mouth 1 3 - -
Oral Hypesthesia 2 4 2 3
Hypersalivation <1 4 0 5
Gastric discomfort 2 3 - -
Vomiting 1 4 - -
Increased appetite
Are common 2 4 2 4
Fatigue - - <1 3
Irritability
Metabolic <1 5 0 3
Weight gain
Nervous System Disorders 1 3 - -
Akathisia1 <1 2 - -
Dizziness
Extrapyramidal symptoms (excluding akathisia) 2 2 4 - -
Drowsiness3 3 11 2 4
Mental disorders <1 3 - -
Insomnia 11 12 - -
Cardiovascular disorders 2 7 5 6
Hypertension 6 24 10 22
Body Systems / Side Effects
Gastrointestinal disorders 2 4 - -
Constipation 1 2 - -
Dry mouth 5 6 8 10
Oral Hypesthesia
Hypersalivation - - <1 3

* - Study with flexible doses.

1 - Extrapyramidal symptoms include: dystonia, blepharospasm, torticollis, dyskinesia, tardive dyskinesia, muscle rigidity, parkinsonism, gait disturbance, masked face, tremor (excluding akathisia).

2 - Drowsiness includes: drowsiness, sedation, hypersomnia.

Dystonia is a class-effect of antipsychotic drugs. Symptoms of dystonia, prolonged abnormal muscle contraction can be noted in sensitive patients during the first few days of treatment. An increased risk of acute dystonia is observed in men and young age groups.

Extrapyramidal symptoms. In the short-term placebo-controlled trials of asenapine in schizophrenia and bipolar mania, the SAS-scale Simpson-Angus was used to evaluate extrapyramidal symptoms, BAS - the Barnes Akathisia Scale, AIMS - the Abnormal Involuntary Movement Scale.

Other effects. Oral hypoesthesia and paresthesia can be observed immediately after taking asenapine and are usually resolved within 1 hour.

Deviations of laboratory indicators. In the short-term studies of asenapine in schizophrenia and bipolar mania, no clinically significant changes in the level of glucose, cholesterol and triglycerides, hepatic transaminases, prolactin (in comparison with the baseline values), and creatine phosphokinase were found.

Other side effects observed during the premarketing assessment of asenapine

With frequency ≥0,1% and <1% there were: tachycardia, transitional blockade of the bundle branch, anemia, violation of eye accommodation, oral hypoesthesia, glossodynia, edema of the tongue, hyponatremia, dysarthria; with a frequency <0.1% - thrombocytopenia, the reaction of idiosyncrasy to the drug.

Post-marketing experience

Pronounced hypersensitivity reactions, incl. swelling of the tongue and larynx (pharyngeal edema).

Interaction

The risk associated with the use of asenapine in combination with other drugs has not been thoroughly studied. Caution should be exercised while taking asenapine with other drugs acting on the central nervous system and alcohol. Since asenapine is an α 1 -adrenoreceptor antagonist, it can potentially cause hypotension, and also enhance the effect of certain antihypertensive agents.

Simultaneous use of asenapine with substrates of the isoenzyme CYP2D6. In vitro studies have shown that asenapine is a weak inhibitor of CYP2D6. After simultaneous administration of dextromethorphan (substrate CYP2D6) and asenapine, volunteers measured dextrorphan / dextromethorphan (DX / DM) as a marker of CYP2D6 activity. Evidence of the inhibition of CYP2D6 was a reduction in the DX / DM ratio to 0.43 with 5 mg twice a day for asenapine. In the same study, taking paroxetine 20 mg / day resulted in a decrease in the DX / DM ratio to 0.032. In a separate study, a simultaneous single dose of 75 mg of imipramine and a single dose of 5 mg of asenapine did not affect the plasma concentrations of the metabolite of desipramine (substrate CYP2D6). Thus, in vivo, asenapine appears to be a weaker inhibitor of CYP2D6. Simultaneous single administration of 20 mg paroxetine (substrate and inhibitor CYP2D6) during the intake of asenapine in 15 healthy men 5 mg twice daily led to an almost 2-fold increase in paroxetine exposure. Asenapine can enhance the inhibitory effect of paroxetine on its own metabolism.

Caution should be exercised in the joint use of asenapine with drugs that are substrates or inhibitors of CYP2D6.

When combined with valproic acid and lithium, asenapine does not affect their plasma concentrations.

Overdose

Symptoms: in premarketing clinical trials involving more than 3,350 patients and healthy people, 3 cases of acute overdose in patients were recorded. The highest dose of asenapine was 400 mg, noted adverse reactions included agitation and confusion.

Treatment: maintenance therapy, ensuring airway patency, adequate oxygenation and ventilation. In the case of hypotension and vascular collapse - intravenous fluid and / or sympathomimetics (epinephrine and dopamine should not be used, since beta-stimulation can aggravate hypotension in conditions of an asenapine-induced alpha blockade). In the case of severe extrapyramidal symptoms, anticholinergic drugs should be prescribed. The specific antidote is unknown.

Routes of administration

Sublingually.

Precautions for the substance Asenapine

Increased mortality in elderly patients with psychosis associated with dementia. In elderly patients with psychosis associated with dementia, in the treatment of antipsychotic drugs, the risk of death is increased. An analysis of 17 placebo-controlled trials (lasting 10 weeks) in patients taking atypical antipsychotics revealed a drug-related mortality risk that was 1.6-1.7 times greater than that in the placebo group. During a typical 10-week controlled study, the death rate associated with the drug was 4.5%, while in the placebo group, 2.6%. Although the causes of death were varied, most of the deaths seemed to be associated with either cardiovascular (cardiac failure, sudden death) or with infectious (pneumonia) complications. Observational studies show that, as with the use of atypical antipsychotic drugs, and when treated with traditional antipsychotic drugs, mortality can be increased. How much the increase in mortality in observational studies can be attributed to the action of antipsychotics, and how much to the status of the patients themselves remains unclear. Asenapine is not approved for the treatment of psychosis in patients with dementia.

Neuroleptic malignant syndrome. With the reception of antipsychotic drugs, incl. Asenapine, associated with the development of a potentially fatal symptom complex, the so-called. malignant neuroleptic syndrome (CNS), the clinical manifestations of which are hyperthermia, muscle rigidity, loss of consciousness, autonomic instability (lability of the pulse and blood pressure, tachycardia, sweating, heart rhythm disturbance). Additional signs may include: increased levels of creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.

In the case of the development of the NSA, immediate discontinuation of antipsychotic and other previously taken drugs, intensive symptomatic therapy, medical control is necessary.

Hypersensitivity reactions. In patients treated with asenapine, hypersensitivity reactions were observed, including anaphylaxis and angioedema. In some cases, these reactions were noted after taking the first dose. Hypersensitivity reactions included, in addition, hypotension, tachycardia, tongue edema, dyspnea, shortness of breath, rash.

Orthostatic hypotension, syncope, other hemodynamic effects. Asenapine can cause orthostatic hypotension and fainting in some patients, especially at the beginning of treatment, since it is an α 1 -adrenoreceptor antagonist. In short-term studies in schizophrenic patients who received therapeutic doses of asenapine (5 or 10 mg twice daily) syncope was recorded in 0.2% (1/572) compared with 0.3% (1/378) of patients receiving a placebo . In short-term studies of asenapine in bipolar mania, syncope was reported in 0.3% (1/379) of patients receiving therapeutic doses of asenapine (5 or 10 mg twice daily), compared with 0% (0/203) of patients receiving placebo. During premarketing clinical trials, incl. long-term, without comparison with placebo, syncope was recorded in 0.6% (11/1953) of patients treated with asenapine.

In clinical pharmacology studies, 4 healthy volunteers who received asenapine IV, orally or sublingually, developed hypotension, bradycardia, and sinus pauses. These symptoms resolved spontaneously in 3 cases, in the fourth - external cardiac massage was needed. The risk of hypotension, bradycardia and sinus pause may be higher in nonpsychiatric patients compared to those who are mentally ill, which may be more adapted to certain effects of psychotropic drugs.

Patients should be instructed about measures that help reduce the risk of orthostatic hypotension (for example, sitting on the edge of the bed for several minutes before rising in the morning, slowly rising from sitting). Precautions should be used with caution in the elderly, in patients with cardiovascular disease (myocardial infarction or ischemic heart disease, heart failure or conduction disorders), cerebrovascular diseases, with factors predisposing to the development of hypotension (dehydration, hypovolemia, hypotensive therapy). Care should be taken when treating patients receiving other drugs at the same time, which can cause hypotension, bradycardia, respiratory depression, or CNS. When hypotension occurs, a decrease in the dose of asenapine is necessary.

Leukopenia, neutropenia, agranulocytosis. In clinical trials and in the postmarketing period, cases of transient leukopenia / neutropenia associated with the use of antipsychotic drugs were reported, incl. asenapine. Agranulocytosis (including fatal) was reported in connection with the reception of other drugs of this class.

Potential risk factors for leukopenia / neutropenia are the previous low white blood cell count and drug-induced leukopenia / neutropenia in the anamnesis. In such patients, it is often necessary to carry out a complete blood test during the first few months of treatment and stop the treatment with asenapine at the first sign of a decrease in white blood cells in the absence of other causes.

Careful observation of neutropenic patients is necessary in order to detect fever and other symptoms of infection and to conduct timely therapy. In the case of severe neutropenia (absolute number of neutrophils <1000 / mm3), treatment with asenapine should be discontinued.

Elongation of the QT interval. A study on the effect of asenapine on the QT / QTc interval included patients with schizophrenia in a clinically stable state (N = 151) who received asenapine at doses of 5, 10, 15 and 20 mg twice daily, and a placebo group. The intake of asenapine in these doses was associated with an increase in the QTc interval from 2 to 5 ms compared with placebo. None of the patients receiving asenapine had an increase in QTc ≥60 ms compared with the baseline and QTc did not exceed 500 ms.

In the short-term clinical trials of asenapine, there have been no reports of the development of torsade de pointes or other adverse reactions associated with delayed repolarization of the ventricles.

The simultaneous use of asenapine and other drugs should be avoided with the known ability to prolong the QTc interval, including antihypertensives of class 1A (eg, quinidine, procainamide) or class 3 (eg, amiodarone, sotalol), antipsychotics (eg, ziprasidone, thioridazine), antibacterial agents (eg, gatifloxacin, moxifloxacin). It should also avoid the use of asenapine in patients with a history of cardiac arrhythmia and other factors that may increase the risk of torsade de pointes and / or sudden death due to the use of drugs prolonging the QTc interval - such as bradycardia, hypokalemia or hypomagnesemia, and presence of the syndrome of congenital elongated interval QT.

Hyperprolactinemia. Like other antagonists of D2-dopamine receptors, asenapine can increase the level of prolactin, especially with prolonged admission. When conducting premarketing trials of asenapine, no clinically significant changes in the level of prolactin were found in comparison with baseline values.

Epileptic seizures were observed in 0% and 0.3% of cases (0/572, 1/379) in the treatment with asenapine at a dose of 5 and 10 mg twice daily, respectively, compared with placebo - 0% (0/503, 0 / 203) in studies of asenapine in schizophrenia and bipolar mania. In the period of premarketing trials of asenapine, including long-term, without comparison with placebo, epileptic seizures were recorded in 0.3% (5/1953) of patients treated with asenapine. Like other antipsychotic drugs, asenapine should be administered with caution to patients with epileptic seizures in the history, and also in the presence of conditions predisposing to lower the threshold of convulsive readiness, for example, Alzheimer's disease. Factors that contribute to reducing the threshold of convulsive readiness, may prevail in patients older than 65 years.

The possibility of cognitive and motor disorders. The drowsiness that occurred in patients treated with asenapine was usually transient in nature and was noted with the greatest frequency during the first week of treatment. In the period of premarketing clinical trials, incl. long-term, without comparison with placebo, drowsiness was noted in 18% (358/1953) of patients treated with asenapine. In short-term placebo-controlled studies, drowsiness (including sedation) led to discontinuation of 0.6% (12/1953) patients.

During the period of treatment, care must be taken when driving vehicles and engaging in other activities that require an increased concentration of attention and speed of psychomotor reactions.

Regulation of body temperature. In the short-term placebo-controlled studies of asenapine in schizophrenia and acute bipolar disorder, the frequency of body temperature increase was low (≤1%) and comparable to placebo. In premarketing clinical trials, the incidence of this side effect (pyrexia and sensation of fever) was also ≤1%.

Dysphagia. Disturbance of esophageal motility and aspiration are associated with the use of antipsychotic drugs. Dysphagia was noted in 0.2% and 0% (1/572, 0/379) patients receiving therapeutic doses of asenapine (5-10 mg twice daily) compared with 0% (0/378, 0/203) patients , who received placebo, in the conduct of short-term studies of asenapine in schizophrenia and bipolar disorder, respectively. In the period of premarketing clinical trials, incl. long-term, without comparison with placebo, dysphagia was reported in 0.1% (2/1953) of patients treated with asenapine.

Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, particularly Alzheimer's disease. Asenapine is not indicated for the treatment of dementia associated with psychosis, and should not be used in patients at risk of aspiration pneumonia.

Elderly age. Clinical studies of asenapine in the treatment of schizophrenia and bipolar disorder did not include a sufficient number of patients aged 65 years and older. Of the approximately 2,250 patients enrolled in premarketing clinical trials, 1.1% (25) were 65 years of age or older. There are many factors that can influence the effect of asenapine in elderly patients, these patients should be closely monitored.

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