Safris

General characteristics. Structure:

Active ingredient: 7,03 mg or 14,06 mg of an azenapin of a maleate (5 mg of an azenapin or 10 mg of an azenapin are equivalent).

Excipients: gelatin, Mannitolum.

Pharmacological properties:

Pharmacodynamics. The mechanism of action of an azenapin, as well as other drugs, effective at treatment of schizophrenia and bipolar disorder, is found out not completely. Considering the nature of interaction of an azenapin with receptors, believe that efficiency is defined by the combined antagonistic impact on D2 and 5-HT2A receptors. Interaction with other receptors, for example, serotoninovy 5-HT1A, 5-HT1B, 5-HT2C, 5-HT6, 5-HT7, D3 and α2-адренорецепторами, can also influence clinical action of an azenapin.

Pharmacokinetics. Absorption. After sublingual reception азенапин it is quickly soaked up, and the maximum concentration (Cmax) in plasma is observed in 0,5-1,5 h. Absolute bioavailability of an azenapin of 5 mg at sublingual use makes 35%. Absolute bioavailability at intake low (<2%). Reception of water in 2 or 5 minutes after use of an azenapin led to decrease in concentration of an azenapin in blood (for 19% and 10% respectively). In this regard within 10 min. after reception of an azenapin it is not necessary to drink or eat food.

Distribution. Azenapin is quickly distributed. The volume of distribution big (about 1700 l) that indicates active distribution in extravasated space. Azenapin effectively (for 95%) contacts proteins of plasma – albumine and α1-кислым a glycoprotein.

Metabolism. Azenapin is intensively metabolized. The main ways of metabolism of an azenapin are a direct glyukuronirovaniye (under the influence of UGT1A4 isoenzyme) both the oxidation and demethylation mediated by P450 cytochrome isoenzymes (generally CYP1A2 isoenzyme, and also isoenzymes 2D6 and ZA4). In the research in vivo at the people receiving marked азенапин in plasma other metabolites, including N-desmetilazenapin, N-desmetilazenapina N-karbamoilglyukuronid, and not changed азенапин were defined preferential азенапин by N+ glucuronide, and also in smaller concentration. Activity of drug is defined preferential not changed azenapiny.

Azenapin is a weak inhibitor of an isoenzyme CYP2D6. It does not cause induction of isoenzymes of CYP1A2 or CYP3A4 in culture of human hepatocytes.

Simultaneous use of an azenapin with the known inhibitors, inductors or substrates of these isoenzymes is studied in clinical trials of interactions of medicines (see the section "Interaction of Medicines").

Removal. The clearance of an azenapin high and after intravenous administration makes 52 l/h. The most part of a dose it is radioactive a marked azenapin it is removed by kidneys (about 50%) and through intestines (about 40%). Only a small part of a dose is removed through intestines (5-16%) in the form of not changed azenapin. After initial more bystry phase of distribution the elimination half-life of an azenapin makes about 24 h.

Linearity of pharmacokinetics. Increase in a dose from 5 to 10 mg (by 1,7 times) under a curve "concentration – time" (AUC) and Cmax twice a day leads the areas to nonlinear increase. Disproportionate increase in Cmax and AUC at increase in a dose can be a consequence of restriction of absorption through a mucous membrane of an oral cavity after sublingual reception.

At administration of drug twice a day the equilibrium state is reached within 3 days. In general the pharmacokinetics of an azenapin in an equilibrium state is similar to that after a single dose of drug.

Pharmacokinetics at special groups of patients.
- patients with an abnormal liver function. The pharmacokinetics of an azenapin is similar at patients to a lung (a class A on Chayld-Pyyu) and moderated (a class B on Chayld-Pyyu) an abnormal liver function and patients to normal function of a liver. At patients with a heavy abnormal liver function (a class C on Chayld-Pyyu) 7-fold increase in AUC of an azenapin was observed (see the section "Route of Administration and Doses").
- patients with a renal failure. After a single dose of 5 mg of an azenapin patients had a similar pharmacokinetics of an azenapin with various degree of a renal failure and patients with normal function of kidneys.
- elderly patients. At elderly patients of AUC the azenapina was about 30% higher, than at adults of younger age.
- teenagers. In a dose of 5 mg twice a day teenagers aged from 12 up to 17 years inclusive had a similar pharmacokinetics of an azenapin to that at adults. Teenagers have an increase in a dose from 5 to 10 mg twice a day did not lead to increase in AUC of an azenapin.
- sex. In the population pharmacokinetic analysis dependence of pharmacokinetics on a floor was not revealed.
- race. In the population pharmacokinetic analysis race had no significant effect on pharmacokinetics of an azenapin.
- smoking. In the population pharmacokinetic analysis it was shown that smoking which causes induction of an isoenzyme of CYP1A2 does not exert impact on clearance of an azenapin. In a special research smoking against the background of a single dose of 5 mg under language did not influence pharmacokinetics of an azenapin.

Indications to use:

Schizophrenia: the drug Safris® is shown for the stopping and supporting treatment of adult patients with schizophrenia.

Bipolar affective disorder: monotherapy: the drug Safris® is shown for the stopping treatment of the maniacal or mixed episodes connected with bipolar affective disorder at adults.

Additional therapy: the drug Safris® is shown as additional therapy with drugs of lithium or Valproatum for stopping of the maniacal or mixed episodes connected with bipolar affective disorder at adults.

Route of administration and doses:

Standard doses at treatment of adult patients. Schizophrenia. Treatment it is necessary to begin with the drug Safris® with a dose 5 mg two times a day. The recommended dose of the drug Safris® makes 5-10 mg two times a day (a daily dose of 10-20 mg).

During short-term controlled clinical trials the additional clinical effect at administration of drug in a dose of 10 mg was not shown two times a day (a daily dose of 20 mg) in comparison with a dose of 5 mg two times a day (a daily dose of 10 mg). Patients should be inspected periodically for the purpose of definition of need of a maintenance therapy.

Bipolar affective disorder. The recommended initial dose of the drug Safris® at monotherapy makes 10 mg two times a day (a daily dose of 20 mg). Taking into account clinical performance the dose can be lowered to 5 mg two times a day (a daily dose of 10 mg). At a combination therapy the recommended initial dose makes 5 mg two times a day (a daily dose of 10 mg). Taking into account the clinical answer and portability the dose can be increased to 10 mg two times a day (a daily dose of 20 mg).

On the basis of the available evidential data it is impossible to answer a question as long the patient with bipolar affective disorder has to accept the drug Safris®. In general the patients who answered treatment are recommended to continue administration of drug of Safris® and after stopping therapy phase.

The way a primeneniya:tabletka should be taken from the blister just before reception. Hands have to be dry. Do not squeeze out a tablet via the blister. The blister should not be cut or torn. It is necessary to pull for a color tip of a foil and to carefully take out a tablet. Not to break a tablet.

For optimum absorption to put a tablet under language before its full dissolution. The tablet is dissolved in saliva within several seconds. Not to chew and not to swallow of a tablet. After reception of a tablet is not and not to drink within 10 minutes.

At the combined treatment with other drugs the drug Safris® should be accepted the last.

Use for special groups of patients.
- children: efficiency and safety of use of drug for children are younger than 18 years is not studied. There are only limited data on safety of use of the drug Safris® for teenagers (see the section "Pharmacokinetics").
- elderly patients: the drug Safris® should be used with care at elderly patients. Data on safety and efficiency of use of drug for patients at the age of 65 years are also more senior are limited (see the Section "Pharmacokinetics").
- patients with a renal failure: dose adjustment with a renal failure is not required from patients.
- patients with an abnormal liver function: dose adjustment with an easy and moderate abnormal liver function is not required from patients. At patients with a heavy abnormal liver function (a class C on Chayld-Pyyu) 7-fold increase in AUC of an azenapin therefore such patients are not recommended to appoint the drug Safris® was observed (see the Section "Pharmacokinetics").

Features of use:

Influence on ability to drive the car and to use a difficult technique. Influence of the drug Safris® on ability to drive the car and to use a difficult technique were not studied. Azenapin can cause drowsiness and sedation. In this regard patients should not drive the car and mechanisms until they are sure that the drug Safris® has no undesirable effect on them.

Use at pregnancy and during breastfeeding. there are no residual data on use of the drug Safris® for pregnant women. Azenapin had no teratogenic effect in animal experiments. In these researches toxicity signs for a female and an embryo were revealed.

Newborns whose mothers accepted antipsychotic means in the third trimester of pregnancy are in risk group of development of extrapyramidal symptoms and/or a withdrawal after the delivery. Messages on development of agitation, an arterial hypertension and hypotonia, a tremor, drowsiness, respiratory a distress syndrome and disturbances of food at these newborns are received.

These complications vary on severity and duration. In certain cases they are self-stopped, in other cases demand carrying out an intensive care and extension of term of hospitalization.

The drug Safris® is not recommended to be used at pregnancy unless the potential advantage for the patient considerably exceeds possible risk for a fruit.

With breast milk women have no data on removal of an azenapin or its metabolites. In researches on rats азенапин it was allocated with milk at a lactation. Feeding is not recommended to the women accepting Safris® by a breast.

Side effects:

Drowsiness was the most frequent undesirable reaction (HP) observed at treatment azenapiny.
The undesirable reactions observed during the clinical and post-market researches, connected with treatment azenapiny are given in the table below and classified by defeats of bodies and systems of bodies and frequency of their emergence; very often (≤1/10), it is frequent (≤1/100 – <1/10), infrequently (≤1/1000 – <1/100) and is rare (≤1/10 000 – <1/1 000), it is unknown (frequency cannot be estimated on the basis of the available data).
In each group on the frequency of HP are distributed as decrease in gravity. Frequency of emergence of undesirable reactions in post-market researches cannot be determined as messages on HP were spontaneous. Therefore, frequency such are qualified by HP as it "is unknown".

Bodies and systems of bodies	Very frequent	Frequent	Infrequent	Rare	It is unknown
Disturbances from blood and lymphatic system				neutropenia
Disturbances from immune system					allergic reactions
Disturbances from a metabolism and food		increase in body weight; increase in appetite	hyperglycemia
Disturbances of mentality	alarm
Disturbances from a nervous system	drowsiness	akathisia *; parkinsonism *; dizziness; dystonia * dysgeusia dyskinesia *; sedation	dysarthtia; syncope ekstrapiramidpy disturbances; convulsive attacks *	zlokachsstvenny antipsychotic syndrome
Disturbances from an organ of sight				accommodation disturbance
Disturbances from heart			sinus bradycardia; blockade of a leg of a ventriculonector *; lengthening of an interval of QT on the electrocardiogram
Disturbances from vessels			orthostatic hypotension; hypotension
Disturbances from respiratory system, bodies of a difficult cell and a mediastinum				pulmonary embolism
Disturbances from digestive tract		oral cavity gipssteziya	oral cavity paresthesia; glossodynia; paraglossa; dysphagy
Disturbances from outside baking of biliary tract		increase in activity of alaninaminotranspherase
Disturbances from skeletno myshemny and connecting fabric		to rigidnoyet muscles		рабдомиолиз
Pregnancy, after the patrimonial period and perinatal states					withdrawal at newborns
Disturbances from generative organs and mammary glands			sexual dysfunction; amenorrhea	Gynecomastia, galactorrhoea
The general frustration and disturbances in the place in maintaining		fatigue

* The akathisia includes such preferable terms of Med-DRA (the medical dictionary for normative and legal activity) as an akathisia and a hyperkinesia.
* Parkinsonism includes such preferable terms of Med-DRA as parkinsonism, a tremor, a muscular hypertension, a parkinsonichesky tremor of rest, gait disturbance, rigidity as "cogwheel", the maskopodobny person (Parkinson's face), a pathological glabellar reflex and muscular rigidity;
* Dystonia includes such preferable terms of Med-DRA as dystonia, oculogyric spasms, a wryneck and a nictitating spasm.
* Dyskinesia includes such preferable terms of Med-DRA as dyskinesia and late dyskinesia.
* Attacks include such preferable terms of Med-DRA as spasms, epilepsy and partial attacks.
* Blockade of a leg of a ventriculonector includes such preferable terms of Med-DRA as blockade of the left leg of a ventriculonector, blockade of the right leg of a ventriculonector, blockade of a leg of a ventriculonector.

- extrapyramidal symptoms (EPS). During short-term (6 weeks) clinical trials dependence of frequency of an akathisia on a dose at the patients with schizophrenia receiving азенапин was revealed. The tendency to increase in frequency of parkinsonism at increase in doses of drug is noted.
- increase in body weight. In short-term and long clinical trials at patients with schizophrenia and a bipolar mania body weight at treatment azenapiny increased on average by 0,8 kg. The share of patients with clinically significant increase in body weight (≥7% of weight of initial) in short-term researches of patients with schizophrenia made 5,3% in group of the patients accepting азенапин in comparison with 2,3% in group of placebo.

The share of patients with clinically significant increase in body weight (≥7% of weight of initial) in short-term researches of patients with a bipolar mania made 6,5% in group of the patients accepting азенапин in comparison with 0,6% in group of placebo.

- other side effects. Azenapin has anestetichesky properties. The hypesthesia and paresthesia of an oral cavity can directly arise after administration of drug and usually pass within 1 hour.
- post-market researches. The patients accepting азенапин have messages on serious reactions of hypersensitivity, including anaphylactic/anaphylactoid reactions, such as a paraglossa and swelled drinks. The patients accepting азенапин have messages on injuries of a mucous membrane of an oral cavity including an inflammation, formation of ulcers and blisters. Local anestetichesky properties of an azenapin need to be considered as a possible alternative etiological factor of development of symptoms from a stomatopharynx.
- change of activity of enzymes of a liver in blood. Tranzitorny asymptomatic increase in activity of transaminases of a liver, alaninaminotranspherase (ALT) and aspartate aminotransferase (ACT) were observed often, especially at the beginning of therapy.

Interaction with other medicines:

Azenapin has effect on the central nervous system (CNS) (see the section "Side effect") therefore it is necessary to be careful at its use in a combination with other drugs of the central action. Patients need to be warned that at administration of drug of Safris® it is necessary to avoid alcohol intake.

Influence of other drugs on drug Safris® pharmacokinetics. Azenapin is brought generally by a direct glyukuronirovaniye under the influence of an isoenzyme of UGT1A4 and oxidizing metabolism under the influence of P450 cytochrome isoenzymes (generally CYP1A2 isoenzyme). In this regard possible effects of inhibitors and inductors of these isoenzymes on pharmacokinetics of an azenapin were studied (see the table below). Except for a fluvoksamin (powerful inhibitor of an isoenzyme CYP1A2) of clinically significant changes of pharmacokinetics of an azenapin at simultaneous use with the studied drugs it was not revealed.

Drug (alleged influence on CYP450/UGT isoenzymes)	Scheme of use		Effect on pharmacokinetics of an azenapin		Recommendations
	Drug	Azenapin	Cmax	AUC0-∞
Fluvoksamin (CYP1A2 isoenzyme inhibitor)	25 mg twice a day 8 days	5 mg once	+13%	+29%	At simultaneous use to be careful *
Paroksetin (CYP2D6 isoenzyme inhibitor)	20 mg/days within 9 days	5 mg once	- 13%	- 9%	Dose adjustment of an azenapin is not required (see also "Possible influence of an azenapin on pharmacokinetics of other drugs")
Imipraminum (inhibitor of isoenzymes of C YP1A2/2C19/3 A4)	75 mg once	5 mg once	+17%	+10%	Dose adjustment of an azenapin is not required
Cimetidinum (inhibitor of isoenzymes CYP3A4/2D6/1A2)	800 mg twice a day within 8 days	5 mg once	- 13%	+1%	Dose adjustment of an azenapin is not required
Carbamazepine (inductor of isoenzymes CYP3A4/1A2)	200 mg twice a day within 4 days 400 mg twice a day within 15 days	5 mg once	- 16%	- 16%	Dose adjustment of an azenapin is not required
Valproic acid (UGT isoenzyme inhibitor)	500 mg twice a day within 9 days	5 mg once	2%	- 1%	Dose adjustment of an azenapin is not required

* in a full therapeutic dose флувоксамин can cause more expressed increase in concentration of an azenapin in plasma.

Possible influence of the drug Safris® on pharmacokinetics of other drugs. Because азенапин has α1-адреноблокирующим properties and it is capable to cause orthostatic hypotension (see the section "Special Instructions"), the drug Safris® can strengthen effects of some hypotensive drugs.

The researches in vitro demonstrate to what азенапин has a weak inhibiting effect on CYP2D6 isoenzyme. Clinical trials of interaction of medicines in which effects of inhibition azenapiny CYP2D6 isoenzyme were studied showed the following results:
– The ratio декстрорфан / dextromethorphan as a marker of activity of an isoenzyme of CYP2D6 after simultaneous administration of dextromethorphan and an azenapin at healthy volunteers was measured. Use of an azenapin in a dose of 5 mg twice a day led to decrease in this ratio to 0,43 that indicated CYP2D6 isoenzyme inhibition. In the same research at treatment paroksetiny in a dose of 20 mg/days the specified ratio decreased to 0,032.
– In a separate research the concomitant single dose of 75 mg of Imipraminum and 5 mg of an azenapin did not exert impact on concentration of a metabolite of desipramine (CYP2D6 isoenzyme substrate).
– The concomitant single dose of 20 mg of a paroksetin (substrate and inhibitor of an isoenzyme CYP2D6) during use of an azenapin in a dose of 5 mg twice a day at male healthy volunteers led almost to 2-fold increase in AUC of a paroksetin.

In vivo азенапин can have only a weak inhibiting effect on CYP2D6 isoenzyme. However азенапин can strengthen the inhibiting effects of a paroksetin on own metabolism.

Therefore, the drug Safris® should be used with care in a combination with the drugs which are substrates or inhibitors of an isoenzyme CYP2D6.

Contraindications:

- hypersensitivity to an azenapin or any other component of drug;
- children's age up to 18 years (efficiency and safety are not studied);
- feeding period breast.

With care:
- elderly patients with psychosis against the background of dementia. At elderly patients with psychosis against the background of dementia at treatment antipsychotic means increased risk of death. The drug Safris® is not recommended for treatment of patients with psychosis against the background of dementia.
- malignant antipsychotic syndrome. At treatment antipsychotic means, including the drug Safris®, described cases of development of the malignant antipsychotic syndrome which is characterized by a hyperthermia, muscle tension, instability of the autonomic nervous system, disturbance of consciousness and increase in level of a kreatinfosfokinaza in blood serum.

Can be additional manifestations a myoglobinuria (рабдомиолиз) and an acute renal failure. At emergence of symptoms of a malignant antipsychotic syndrome administration of drug of Safris® needs to be stopped.
- convulsive attacks. At treatment by the drug Safris® convulsive attacks sometimes developed. Therefore the drug Safris® should be used with care at patients with convulsive states in the anamnesis or the states connected with spasms.
- suicide attempts. At psychotic diseases and bipolar disorder suicide attempts therefore treatment of patients with high risk of a suicide should be carried out under strict observation can be observed.
- orthostatic hypotension. The drug Safris® can cause orthostatic hypotension and a syncope, especially in an initiation of treatment that perhaps reflects it α1-адреноблокирующие properties. At use of the drug Safris® faints were sometimes observed. Patients of advanced age are especially subject to risk of development of orthostatic hypotension. The drug Safris® should be used with care at elderly patients and patients with cardiovascular diseases (for example, heart failure, a heart attack or ischemia of a myocardium and disturbances of conductivity), a cerebrovascular disease or states which contribute to development of hypotonia (for example, dehydration and a hypovolemia).
- late dyskinesia. Antagonists of dopamine receptors cause development of the late dyskinesia which is characterized by the rhythmical involuntary movements generally of language and/or persons. At treatment by the drug Safris® cases of late dyskinesia sometimes developed. Emergence of extrapyramidal symptoms is risk factor of development of late dyskinesia. At emergence of symptoms of late dyskinesia it is necessary to consider a question of treatment cancellation.
- giperprolaktinemiya. At some patients accepting the drug Safris® increase in concentration of prolactin was noted. Separate cases of the undesirable phenomena connected with increase in concentration of prolactin in blood were observed.
- change of an interval of QT. Possibly, treatment azenapiny is not followed by clinically significant lengthening of an interval of QT. However, it is necessary to be careful at purpose of the drug Safris® at patients with cardiovascular diseases or in the presence in the family anamnesis of the extended interval of QT and at other drugs increasing QT interval duration accompanying therapy.
- hyperglycemia and diabetes mellitus. During treatment azenapiny the hyperglycemia and exacerbations of the diabetes existing in the anamnesis were sometimes observed. Establishment of communication between reception of atypical antipsychotic means and disturbance of metabolism of glucose is complicated owing to the increased risk of development of a diabetes mellitus in patients with schizophrenia or bipolar disorder, and the increasing number of cases of development of a diabetes mellitus in the general population. Regular clinical observation of patients with a diabetes mellitus and patients with risk factors of development of this disease is recommended.

Dysphagy. At treatment antipsychotic drugs described cases of disturbance of motility of a gullet and aspiration. The dysphagy sometimes developed at the patients receiving the drug Safris®.

Thermal control disturbance. Treatment by antipsychotic means can be followed by thermal control disturbance. At use of an azenapin clinically significant changes of thermal control did not develop. Appropriate assistance has to be given at purpose of the drug Safris® to patients who can get into the situations promoting fervescence, for example, performance of physical exercises, influence of high temperature, dehydration or reception of the accompanying medicines with m-holinoblokiruyushchey by activity.

Patients with a heavy abnormal liver function. At patients with a heavy abnormal liver function (a class C on Chayld-Pyyu) 7-fold increase in concentration of an azenapin was noted. In this regard such patients are not recommended to appoint the drug Safris®.

Overdose:

In clinical trials of an azenapin several cases of overdose were observed. Calculated doses made from 15 to 400 mg. In most cases remained not clear whether patients азенапин under language accepted. The undesirable phenomena connected with administration of drug included agitation and confusion of consciousness, an akathisia, orofatsialny dystonia, sedation and asymptomatic changes on an ECG (bradycardia, supraventricular premature ventricular contraction, delay of intra ventricular conductivity).

There is no specific information on overdose treatment azenapiny. The antidote to an azenapin does not exist. It is necessary to consider a possibility of overdose as a result of reception of several drugs. It is necessary to control function of cardiovascular system for the purpose of diagnosis of possible arrhythmias. At overdose the maintenance therapy, adequate oxygenation and ventilation of respiratory tracts and a symptomatic treatment are shown. At a lowering of arterial pressure and a collapse adequate measures, in particular intravenous administration of liquid and/or sympathomimetic drugs are necessary (adrenaline and dopamine should not be entered as stimulation of β-adrenoceptors can promote a further lowering of arterial pressure at blockade of α-adrenoceptors under the influence of the drug Safris®). In the presence of heavy extrapyramidal symptoms appoint means m-holinoblokiruyushchiye. The patient has to be under careful observation while its state is not normalized.

Storage conditions:

To store in the dry place protected from light at a temperature from 2 to 30 °C. To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Tablets hypoglossal 5 mg, 10 mg. On 10 tablets in PVC/PA / the aluminum blister. On 2, 6 or 10 blisters together with the application instruction in a cardboard pack.