Composition, form of production and packaging
Tablets are sublingually round, from white to almost white, lyophilized, engraved "5" on one side.
1 tab.
Asenapine maleate 7.03 mg,
which corresponds to the content of asenapine 5 mg
[PRING] gelatin - 10 mg, mannitol - 7.5 mg.
10 pieces. - blisters (2) - packs of cardboard.
10 pieces. - blisters (6) - packs of cardboard.
10 pieces. - blisters (10) - packs of cardboard.
Tablets are sublingual round, from white to almost white, lyophilized, engraved "10" on one side.
1 tab.
Asenapine maleate 14.06 mg,
which corresponds to the content of asenapine 10 mg
[PRING] gelatin - 9.38 mg, mannitol - 7.03 mg.
10 pieces. - blisters (2) - packs of cardboard.
10 pieces. - blisters (6) - packs of cardboard.
10 pieces. - blisters (10) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2014.
PHARMACHOLOGIC EFFECT
Antipsychotic drug (antipsychotic). The mechanism of action of asenapine, as well as other drugs effective in the treatment of schizophrenia and bipolar disorder, is not fully understood. Given the nature of the interaction of asenapine with receptors, it is believed that the effectiveness is determined by the combined antagonistic effect on D 2 and 5-HT 2A receptors.
Asenapine has a high affinity for the serotonin receptors 5-HT 1A , 5-HT 1B , 5-HT 2A , 5-HT 2B , 5-HT 2C , 5-HT 5 , 5-HT 6 , 5-HT 7 , dopamine receptors D 2 , D 3 , D 4 and D 1 , adrenergic receptors? 1 and? 2 , histamine H 1 receptors and moderate affinity for histamine H 2 receptors. In vitro tests Asenapine exhibited antagonist properties to these receptors. Asenapine does not have a noticeable affinity for muscarinic cholinergic receptors.
PHARMACOKINETICS
Suction
After sublingual administration, asenapine is rapidly absorbed, and C max in plasma is observed after 0.5-1.5 hours. Absolute bioavailability of 5 mg asenapine in sublingual administration is 35%. Absolute bioavailability when ingested is low (<2%). Taking water after 2 or 5 minutes after using asenapine led to a decrease in the concentration of asenapine in the blood (by 19% and 10%, respectively). In this regard, within 10 minutes after taking asenapine should not drink or eat.
Increasing the dose from 5 to 10 mg 2 times / day leads to a nonlinear increase (1.7 times) of AUC and C max . A disproportionate increase in C max and AUC with increasing doses may be due to the restriction of absorption through the oral mucosa after sublingual administration.
Distribution
When taking the drug 2 times / day C ss is reached within 3 days. In general, the pharmacokinetics of asenapine in an equilibrium state is similar to that after a single administration of the drug.
Asenapine is rapidly distributed. V d is large (about 1700 L), which indicates active distribution into the extravascular space. Asenapine is efficiently (95%) associated with plasma proteins - albumin and a 1-acid glycoprotein.
Metabolism
Asenapine is extensively metabolized. The main pathways of the metabolism of asenapine are direct glucuronidation (under the action of the isoenzyme UGT1A4) and oxidation and demethylation mediated by isoenzymes of cytochrome P450 (mainly isoenzyme CYP1A2, and also isoenzymes 2D6 and 3A4). In an in vivo study, in people receiving labeled asenapine, predominantly asenapine N + -glucuronide was detected in the plasma, and other metabolites, including N-desmethylazenapine, N-desmethylazenapine N-carbamoylglucuronide, and unchanged asenapine were determined in a lower concentration. The activity of the drug is mainly determined by unchanged asenapine.
Asenapine is a weak inhibitor of the CYP2D6 isoenzyme. It does not induce induction of CYP1A2 or CYP3A4 isoenzymes in the culture of human hepatocytes.
The simultaneous use of asenapine with known inhibitors, inducers or substrates of these isoenzymes was studied in clinical studies of drug interactions.
Excretion
The clearance of asenapine is high and after intravenous administration is 52 l / h. Most of the dose of radioactively labeled asenapine is excreted by the kidneys (about 50%) and through the intestine (about 40%). Only a small part of the dose is excreted through the intestine (5-16%) in the form of unchanged asenapine. After the initial, faster phase of the distribution, T 1/2 of asenapine is approximately 24 hours.
Pharmacokinetics in specific patient groups
The pharmacokinetics of asenapine is similar in patients with a lung (class A in Child-Pugh) and moderate (class B in Child-Pugh), a violation of liver function and patients with normal liver function. In patients with severe liver function disorder (Child-Pugh class C), a 7-fold increase in the azepine AUC was observed.
The pharmacokinetics of asenapine after a single dose of 5 mg of asenapine was similar in patients with varying degrees of renal dysfunction and patients with normal renal function.
In elderly patients, the azepine AUC was approximately 30% higher than in older adults.
The pharmacokinetics of asenapine at a dose of 5 mg twice daily in adolescents aged 12 to 17 inclusive was similar to that of adults. In adolescents, increasing the dose from 5 to 10 mg twice daily did not result in an increase in AUC of asenapine.
With population pharmacokinetic analysis, no dependence of pharmacokinetics on sex was found.
In the population pharmacokinetic analysis, the race did not significantly affect the pharmacokinetics of asenapine.
In a population pharmacokinetic analysis, it was shown that smoking, which causes induction of the CYP 1A2 isoenzyme, does not affect the clearance of asenapine.In a special study, smoking with a single dose of 5 mg under the tongue did not affect the pharmacokinetics of asenapine.
INDICATIONS
Schizophrenia:
- for the arresting and supporting treatment of adult patients with schizophrenia.
Bipolar affective disorder:
- monotherapy: for the arresting treatment of manic or mixed episodes associated with bipolar affective disorder in adults;
- as an additional therapy with drugs of lithium or valproate for arresting manic or mixed episodes associated with bipolar affective disorder in adults.
DOSING MODE
Schizophrenia
Treatment with the drug Safris В® in adult patients should start with a dose of 5 mg 2 times / day. The recommended dose of the drug Saffris В® is 5-10 mg 2 times / day (daily dose of 10-20 mg).
In the course of short-term controlled clinical trials, no additional clinical effect was seen when taking the drug at a dose of 10 mg 2 times / day (daily dose of 20 mg) compared with a dose of 5 mg 2 times / day (daily dose of 10 mg).
Patients should be periodically examined to determine the need for maintenance therapy.
Bipolar affective disorder
The recommended initial dose of the drug Safris В® in adults with monotherapy is 10 mg 2 times / day (daily dose of 20 mg). Taking into account the clinical effectiveness, the dose can be reduced to 5 mg 2 times / day (daily dose of 10 mg). With combined therapy, the recommended initial dose is 5 mg 2 times / day (daily dose of 10 mg). Given the clinical response and tolerability, the dose can be increased to 10 mg 2 times / day (daily dose of 20 mg).
Based on the available evidence, one can not answer the question of how long a patient with bipolar affective disorder should take the drug Safris В® . In general, patients who responded to treatment are advised to continue taking Saffis В® after the phase of therapy.
Application rules
The tablet should be removed from the blister just before taking. Hands should be dry. Do not squeeze the pill through the blister. The blister should not be cut or torn. It is necessary to pull the colored tip of the foil and carefully take out the tablet. Do not break the tablet.
For optimal absorption, put the tablet under the tongue until it is completely dissolved. The tablet dissolves in saliva for a few seconds. The tablet can not be chewed and not swallowed. After taking the pill, do not eat or drink for 10 minutes.
When combined treatment with other drugs, the drug Safris В® should be taken last.
The effectiveness and safety of the drug in children under the age of 18 years has not been studied. There are only limited data on the safety of the drug Saffis В® in adolescents.
The drug Safris В® should be used with caution in elderly patients . Data on the safety and efficacy of the drug in patients aged 65 years and older are limited.
Correction of the dose in patients with impaired renal function is not required.
Correction of the dose in patients with mild and moderate impairment of liver function is not required. In patients with severe hepatic impairment (Child-Pugh class C) , a 7-fold increase in the azepine AUC was observed, therefore it is not recommended to prescribe the drug SaffisВ® to such patients.
SIDE EFFECT
The most common adverse reaction observed with the treatment with asenapine was drowsiness. The undesirable reactions observed during clinical and post-marketing studies related to the treatment with asenapine are presented in the table below and classified according to organ and organ system lesions and the frequency of their occurrence; very often (? 1/10), often (? 1/100 - <1/10), infrequently (? 1/1 000 - <1/100) and rarely (? 1/10 000 - <1/1 000) , is unknown (the frequency can not be estimated from the available data).
In each frequency group, adverse reactions are distributed in order of severity. The incidence of adverse reactions in post-marketing studies can not be determined, since reports of adverse reactions were spontaneous. Consequently, the frequency of such undesirable reactions is classified as "unknown".
Very often Often Seldom Seldom Unknown
On the part of the blood and lymphatic system
neutropenia
From the immune system
allergic reactions, severe hypersensitivity reactions, incl. anaphylactic / anaphylactoid reactions, angioedema, tongue edema and pharyngeal edema (laryngeal edema)
From the side of metabolism and nutrition
increase in body weight; increased appetite hyperglycemia
From the side of the psyche
anxiety
From the nervous system
drowsiness akathisia *; Parkinsonism *; dizziness; dystonia *; dysgeusia; dyskinesia *; sedation of dysarthria; fainting; extrapyramidal disorders; convulsive attacks * ZNS
From the side of the organ of vision
disruption of accommodation
From the side of the cardiovascular system
sinus bradycardia; blockade of the bundle of the bundle *; prolongation of QT interval on ECG; orthostatic hypotension; hypotension
From the respiratory system
pulmonary embolism
From the digestive system
hypoesthesia of the oral cavity; increased ALT activity paresthesia of the oral cavity; glossodynia; swelling of the tongue; dysphagia damage to the oral mucosa (inflammation, the formation of ulcers and blisters), hypersalivation
From the musculoskeletal system
Musculoskeletal stiffness rhabdomyolysis
On the part of the reproductive system
sexual dysfunction; amenorrhea of ​​gynecomastia; galactorrhea
General disorders
fatigue
* Akathisia includes such preferred terms Med-DRA (medical dictionary for regulatory activity) as akathisia and hyperkinesia.
Parkinsonism includes such preferred terms Med-DRA as parkinsonism, tremor, muscular hypertension, Parkinsonian resting tremor, gait disorder, rigidity of the "cogwheel" type, masklike face (Parkinson's face), pathological glabellar reflex and muscle rigidity;
* Dystonia includes such preferred terms Med-DRA as dystonia, convulsions of the eye, torticollis and blepharospasm.
* Dyskinesia includes such preferred terms Med-DRA as dyskinesia and tardive dyskinesia.
* Seizures include such preferred terms Med-DRA as seizures, epilepsy and partial seizures.
* The bundle branch blockade includes such preferred terms Med-DRA as blockade of the left bundle branch, blockade of the right bundle bundle, blockade of the bundle branch line.
Extrapyramidal symptoms (EPS)
In clinical trials, the incidence of extrapyramidal symptoms in the group treated with asenapine was higher than in the placebo group (15.4% and 11.0%, respectively).
In the short-term (6 weeks) clinical trials, the dependence of the incidence of akathisia on dose in patients with schizophrenia who received asenapine was found. The tendency to an increase in the frequency of parkinsonism with increasing doses of the drug was noted.
Orthostatic hypotension
The incidence of orthostatic hypotension in elderly patients who participated in the combined 2 and 3 phases of clinical trials was 4.1% compared to 0.3% of the total population of patients participating in these studies.
Weight gain
In short-term and long-term clinical trials in patients with schizophrenia and bipolar mania, the body weight when treated with asenapine increased by an average of 0.8 kg. The proportion of patients with clinically significant weight gain (? 7% of baseline weight) in short-term studies of patients with schizophrenia was 5.3% in the group treated with asenapine, compared with 2.3% in the placebo group. The proportion of patients with clinically significant weight gain (? 7% of baseline weight) in short-term studies of patients with bipolar mania was 6.5% in the group treated with asenapine compared with 0.6% in the placebo group.
Other side effects
Asenapine has anesthetic properties. Hypescension and paresthesia of the oral cavity can occur immediately after taking the drug and usually take place within 1 hour.
Change in the activity of liver enzymes in the blood
Transient asymptomatic elevation of liver transaminase activity (ALT and ACT) was observed frequently, especially at the beginning of therapy.
CONTRAINDICATIONS
- Children under 18 years of age (effectiveness and safety not studied);
- lactation period (lactation);
- hypersensitivity to asenapine or any other component of the drug.
PREGNANCY AND LACTATION
There are no sufficient data on the use of the drug Saffris В® in pregnant women. Safris В® is not recommended for use in pregnancy, except when the potential benefit to the patient significantly exceeds the possible risk to the fetus.
Information on the excretion of asenapine or its metabolites with breast milk is not available in women. In studies on rats, asenapine was excreted with milk during lactation. Women receiving Saffrys В® are not recommended breast-feeding.
In experimental animal studies, asenapine had no teratogenic effect. In these studies, signs of toxicity were found for the female and embryo.
APPLICATION FOR FUNCTIONS OF THE LIVER
Correction of the dose in patients with impaired renal function is not required.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
Correction of the dose in patients with mild and moderate impairment of liver function is not required. In patients with severe hepatic impairment (Child-Pugh class C) , a 7-fold increase in the azepine AUC was observed, therefore it is not recommended to prescribe the drug SaffisВ® to such patients.
APPLICATION FOR CHILDREN
Contraindicated use of the drug for children under the age of 18 years.
APPLICATION IN ELDERLY PATIENTS
The drug Safris В® should be used with caution in elderly patients . Data on the safety and efficacy of the drug in patients aged 65 years and older are limited.
SPECIAL INSTRUCTIONS
Elderly patients with psychosis on a background of dementia
In elderly patients with psychosis against the background of dementia in the treatment with antipsychotic drugs, the risk of death is increased. The drug Safris В® is not recommended for the treatment of patients with psychosis against the background of dementia.
Malignant neuroleptic syndrome
In the treatment with antipsychotic drugs, including the preparation Safris В® , cases of development of the NSH characterized by hyperthermia, rigidity of muscles, instability of the autonomic nervous system, impaired consciousness and increased serum creatinophosphinase level have been described.
Additional manifestations may be myoglobinuria (rhabdomyolysis) and acute renal failure.
If symptoms of NSA appear, the drug Saphris В® should be discontinued.
Convulsive seizures
When treatment with the drug Safris В® sometimes developed convulsive seizures. Therefore, Safris В® should be used with caution in patients with convulsive conditions in the anamnesis or conditions associated with seizures.
Suicide attempts
In psychotic illnesses and bipolar disorder, suicidal attempts can be observed, therefore treatment of patients with high risk of suicide should be conducted under strict supervision.
Orthostatic hypotension
The drug Safris В® can cause orthostatic hypotension and fainting, especially at the beginning of treatment, what probably reflects it? 1- adrenergic blocking properties.The use of the drug Saffrys В® sometimes had syncope. Elderly patients are particularly at risk of developing orthostatic hypotension. Safris В® should be used with caution in elderly patients and patients with cardiovascular diseases (eg, heart failure, myocardial infarction or myocardial ischemia and conduction disorders), cerebrovascular disease or conditions that predispose to the development of hypotension (eg, dehydration and hypovolemia).
Late dyskinesia
Dopamine receptor antagonists cause the development of tardive dyskinesia, characterized by rhythmic involuntary movements of mainly the tongue and / or face. In the treatment with the drug Safris В®, sometimes there were cases of late dyskinesia.
The occurrence of extrapyramidal symptoms is a risk factor for the development of tardive dyskinesia. When symptoms of tardive dyskinesia appear, treatment should be considered.
Hyperprolactinemia
In some patients taking the drug Safris В® , there was an increase in the concentration of prolactin. There were individual cases of adverse events associated with an increase in the concentration of prolactin in the blood.
Changing the QT interval
Probably, treatment with asenapine is not accompanied by a clinically significant lengthening of the QT interval. However, caution should be exercised when administering the drug Safris В® in patients with cardiovascular disease or a family history of the elongated QT interval, and concomitant therapy with other drugs to enhance the duration of QT interval.
Hyperglycemia and diabetes mellitus
during treatment with asenapine were sometimes observed hyperglycemia and exacerbation of existing diabetes history.
Establishing a connection between taking atypical antipsychotics and glucose metabolism disorder is complicated because of the increased risk of diabetes in patients with schizophrenia or bipolar disorder and the increasing incidence of diabetes mellitus in the general population.
Recommended regular clinical follow-up of patients with diabetes and patients with risk factors for developing this disease.
Dysphagia is
the treatment of antipsychotic-described cases of esophageal dysmotility and aspiration. Dysphagia sometimes develop in patients receiving the drug Safris В® .
Violation of thermoregulation
Treatment of antipsychotic drugs may involve a breach of thermoregulation. In applying asenapine clinically significant changes thermoregulation not develop. Appropriate assistance should be provided in the appointment of the drug Safris В®patients who may get into the situation, contributing to increase in body temperature, for example, performing physical exercise, the effect of heat, dehydration or receiving concomitant drugs with m-anticholinergic activity.
Patients with severe hepatic dysfunction
in patients with severe hepatic impairment (class C Child-Pugh) indicated 7-fold increase in the concentration of asenapine. In connection with this drug is not recommended Safris В® such patients.
Impact on the ability to drive vehicles and manage mechanisms
The influence of the drug Safris В® on the ability to drive and use sophisticated techniques have not been studied. Asenapine may cause somnolence and sedation. Therefore, patients should not drive a car and machinery until they are certain that the drug Safris В® has no adverse effects on them.
OVERDOSE
In clinical studies, asenapine was observed a few cases of overdose. The calculated doses were 15 to 400 mg. In most cases, it was unclear whether the patients took asenapine sublingual.
Undesired symptoms associated with drug intake, included agitation and confusion, akathisia, orofacial dystonia, sedation and asymptomatic ECG changes (bradycardia, supraventricular arrhythmias, slow intraventricular conduction).
Specific information on the treatmentasenapine no overdose. Antidote to asenapine did not exist. It is necessary to consider the possibility of an overdose as a result of receiving multiple drugs. It is necessary to control the function of the cardiovascular system in order to diagnose possible arrhythmias. In case of overdose shows maintenance therapy, adequate oxygenation and ventilation of the respiratory tract and symptomatic treatment. By reducing the blood pressure and collapse adequate measures are needed, in particular in / to the introduction of liquid and / or sympathomimetic drugs (adrenaline and dopamine should not be introduced, since the stimulation of? -adrenoceptor may further reduce blood pressure during blockade? -adrenoceptor under the action of the drug Safris В®). In the presence of severe extrapyramidal symptoms prescribed m-anticholinergic agent. The patient should be monitored closely until his condition is not normal.
DRUG INTERACTION
Asenapine has an effect on the CNS, however, be careful when applying it in combination with other medications central action. Patients should be cautioned that while taking the drug Safris В® should avoid alcohol.
The effect of other drugs on the pharmacokinetics of the drug Safris В®
Asenapine derived mainly by direct glyukuronirovaniya under isoenzyme UGT1A4 and oxidative metabolism by cytochrome P450 isozymes action (mainly isoenzyme CYP1A2).
It was studied the possible effect of inhibitors and inducers more of these isoenzymes in the pharmacokinetics of asenapine, namely fluvoxamine (an inhibitor of isozyme CYP1A2), paroxetine (an inhibitor of isozyme CYP2D6), imipramine (an inhibitor of isozyme CYP1A2 / 2C19 / 3A4), cimetidine (an inhibitor of isozyme CYP3A4 / 2D6 / 1A2), carbamazepine (inductor isozymes CYP3A4 / 1A2) and valproate (UGT enzyme inhibitor). Except fluvoxamine, clinically significant changes in the pharmacokinetics of asenapine was not detected while the use of the above drugs. The simultaneous use of fluvoxamine in a dose of 25 mg of 2 times / day with asenapine 5 mg 1 time / day resulted in an increase of asenapine AUC values by 29% .We can expect that the full therapeutic dose of fluvoxamine, will cause a more pronounced increase in asenapine plasma concentrations. In the application of asenapine in combination with fluvoxamine should be careful.
The possible effect of the drug Safris В® on the pharmacokinetics of other drugs
Due to the fact that asenapine has? 1 adrenoblokiruyuschee properties and can cause orthostatic hypotension, drug Safris В® can enhance the effects of some antihypertensive drugs.
In vitro studies indicate that asenapine has a weak inhibitory effect on the isoenzyme CYP2D6. Clinical studies of drug interactions in which examined the effects of inhibition of CYP2D6 isozyme asenapine, showed the following results:
1. The ratio was measured dextrorphan / dextromethorphan as a marker isoenzyme CYP2D6 activity following simultaneous administration of dextromethorphan and asenapine in healthy volunteers. The use of asenapine in a dose of 5 mg of 2 times / day resulted in a reduction of the ratio to 0.43, indicating that inhibition of isozyme CYP2D6. In the same study in the treatment of paroxetine at 20 mg / day, the ratio decreased to 0.032.
2. In a separate study simultaneous single dose of 75 mg and imipramine 5 mg asenapine no effect on the concentration of the metabolite desipramine (substrate isozyme CYP2D6).
3. Simultaneous single dose of 20 mg paroxetine (CYP2D6 isozyme substrate and inhibitor) during use of asenapine in a dose of 5 mg of 2 times / day in healthy male volunteers resulted in almost two-fold increase in AUC of paroxetine.
In vivo asenapine may have only a weak inhibitory effect on the isoenzyme CYP2D6. However, asenapine may enhance the inhibitory effects of paroxetine on its own metabolism.
Consequently, the drug Safris В® should be used with caution in combination with drugs that are substrates or inhibitors isozyme CYP2D6.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The preparation should be stored in a dry place, protected from light, reach of children at a temperature of from 2 В° to 30 В° C. Shelf life - 3 years.
