Safris® (Saphris®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceAsenapineAsenapine
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  • Safris®
    pills n / az. 
    Organon, N.V.     Netherlands
    • Dosage form: & nbspsublingual tablets
    Composition:

    1 tablet of the hyoid contains active substance Asenapine maleate 7.03 mg or 14.06 mg (equivalent to 5 mg of asenapine or 10 mg of asenapine).

    Excipients: gelatin 10.0 mg or 9.38 mg, mannitol 7.50 mg or 7.03 mg.
    Description:

    Round from white to almost white color lyophilized tablets with engraving 5 or 10 on the one hand.

    Pharmacotherapeutic group:Antipsychotic agent (antipsychotic)
    ATX: & nbsp

    N.05.A.H.05   Asenapine

    Pharmacodynamics:

    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 D2 and 5-HT2A receptors. Asenapine has a high affinity for the serotonin receptors 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT5, 5-HT6, 5-HT7, dopamine receptors D2, D3, D4 and D1, adrenoreceptors α1 and α2, histamine H1 receptors and moderate affinity for histamine H2 receptors.

    In the tests in vitro Asenapine exhibited antagonist properties to these receptors. Asenapine does not possess a noticeable affinity for muscarinic cholinergic receptors.

    Pharmacokinetics:

    Suction

    After sublingual admission asenapine quickly absorbed, and the maximum concentration (CmAx) in plasma is observed after 0.5-1.5 hours. Absolute bioavailability of 5 mg asenapine for sublingual use is 35%. Absolute bioavailability with oral administration is low (<2%). Taking water after 2 or 5 minutes after using asenapine leads 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.

    Distribution

    Asenapine is rapidly distributed. The distribution volume is large (approximately 1700 liters), which indicates an active distribution in the extravascular space. Asenapine effectively (95%) binds to plasma proteins, including albumin and α1-acid glycoprotein.

    Metabolism

    Asenapine is extensively metabolized. The main routes of metabolism of asenapine are direct glucuronidation (under the action of the isoenzyme UGT1A4), as well as oxidation and demethylation mediated by cytochrome isoenzymes P450 (mainly isoenzyme CYP1A2 and, to a certain extent, isoenzymes 2D6 and 4). In the study in vivo in people who received labeled asenapine, plasma was predominantly asenapine N+-glucuronide, as well as in a lesser concentration, other metabolites, including N-desmethylazenapine, N-desmethylazenapine N-carbamoyl-glucuronide, and unchanged asenapine. The activity of the drug is mainly determined by unchanged asenapine. Asenapine is a weak isoenzyme inhibitor CYP2D6. It does not induce induction of isoenzymes CYP1A2 or CYP3A4 in the culture of human hepatocytes. The simultaneous use of asenapine with known inhibitors, inducers or substrates of these isoenzymes has been studied in clinical studies of drug interactions (see "Interaction with Other Drugs").

    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 distribution, the half-life of asenapine is approximately 24 hours.

    Linearity of pharmacokinetics

    Increasing the dose from 5 to 10 mg twice a day results in a nonlinear increase (1.7 times) of the area under the "concentration-time" curve (AUC) and Cmax. The disproportionate increase in CmOh and AUC with an increase in the dose may be due to the restriction of absorption through the mucosa of the oral cavity after sublingual administration.

    When taking the drug twice a day, the equilibrium state 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.

    Pharmacokinetics in specific patient groups

    Patients with impaired hepatic function

    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 is observed AUC asenapine (see section "Method of administration and dose").

    Patients with impaired renal function

    The pharmacokinetics of asenapine after single dose of 5 mg is similar in patients with different degrees disorders of kidney function and patients with normal kidney function.

    Elderly patients

    In elderly patients, the aUC of asenapine is approximately 30% higher than in older adults.

    Teens

    The pharmacokinetics of asenapine at a dose of 5 mg twice daily in adolescents aged 12 to 17 inclusive is similar to that of adults.In adolescents, increasing the dose from 5 to 10 mg twice daily does not increase the aUC of asenapine.

    Gender identity

    With population pharmacokinetic analysis, no dependence of pharmacokinetics on sex was found.

    Race

    In the population pharmacokinetic analysis, the race did not significantly affect the pharmacokinetics of asenapine.

    Smoking

    In a population pharmacokinetic analysis, it was shown that smoking, which causes induction of the CYP1A2 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:

    The drug Safris ® is indicated for opaque and supporting treatment for adults patients with schizophrenia.

    Bipolar affective disorder:

    Monotherapy: The drug Safris® is indicated for the treatment of manic or mixed episodes associated with bipolar affective disorder in adults.

    Additional therapy: The drug Saffis® is indicated as an additional therapy with preparations of lithium or valproate for cupping manic or mixed episodes associated with bipolar affective disorder in adults.

    Contraindications:

    - hypersensitivity to asenapine or any other component of the drug;

    - Children under 18 years of age (effectiveness and safety not studied);

    - the period of breastfeeding.

    Carefully:

    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 ® 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 Saphris®, cases of development of malignant neuroleptic syndrome characterized by hyperthermia, rigidity of muscles, instability of the autonomic nervous system, impaired consciousness and increased serum creatinophosphinase level were described. Additional manifestations may be myoglobinuria (rhabdomyolysis) and acute renal failure.When symptoms of a malignant neuroleptic syndrome appear, the use of Saffis® should be stopped.

    Convulsive seizures

    In the treatment with the drug Saffrys®, convulsive seizures sometimes developed. therefore The drug Safris® should be used with caution in patients with convulsive conditions in the anamnesis or conditions associated with seizures.

    Suicide attempts

    In psychotic, diseases and bipolar disorder can be observed suicidal attempts, so treatment of patients at high risk of suicide should to conduct under strict supervision.

    Orthostatic hypotension

    The drug Safris® can cause orthostatic hypotension and fainting, especially at the beginning of treatment, which probably reflects it αl-adrenoblocking properties. When The use of the drug Saffrys® sometimes had syncope. Patients elderly age are particularly at risk of developing orthostatic hypotension. The drug Safris® should be used with caution in the elderly patients and patients with cardiovascular diseases (for example, heart failure, infarction (or myocardial ischemia and conduction disorders), cerebrovascular disease or conditions that predispose to the development of hypotension (for example, dehydration and hypovolemia).

    Late dyskinesia

    Antagonists of dopamine receptors cause the development of tardive dyskinesia, characterized by rhythmic involuntary movements in the main language and / or face. In the treatment with drug Safris®, sometimes cases of tardive dyskinesia developed. 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 Saffrys®, 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.

    Change of the interval OT

    Probably, the treatment with asenapine is not accompanied by a clinically significant lengthening of the interval QT. However, caution should be exercised when prescribing Saffrys® patients with cardiovascular diseases or if they have a family history of an elongated interval QT and with concomitant therapy with other drugs that increase the duration of the interval QT.

    Hyperglycemia and diabetes mellitus

    During treatment with asenapine, hyperglycemia and exacerbations of the existing history of diabetes were sometimes observed. The establishment of a link between the administration of atypical antipsychotics and impaired glucose metabolism is complicated by the increased risk of developing diabetes in patients with schizophrenia or bipolar disorder and the increasing incidence of diabetes in the general population. It is recommended to regularly monitor patients with diabetes mellitus and patients with risk factors for this disease.

    Dysphagia

    When treating with antipsychotic drugs, cases of abnormal esophageal motility and aspiration are described. Dysphagia sometimes developed in patients who received the drug Safris®.

    Violation of thermoregulation

    Treatment with antipsychotic drugs can be accompanied by a violation of thermoregulation. With the use of asenapine, clinically significant changes in thermoregulation did not develop. Appropriate care should be provided with the appointment of the drug Saffrys® to patients who can get into situations that increase body temperature, for example, doing physical exercises,exposure to high temperature, dehydration, or taking concomitant medications with m-cholinoblocking activity.

    Patients with severe impairment Functions liver
    In patients with severe liver function disorder (Child-Pugh class C), a 7-fold increase in the concentration of asenapine was noted. In this regard, it is not recommended to prescribe the drug Saffrys® to such patients.
    Pregnancy and lactation:

    There are no sufficient data on the use of the drug Saffrys in pregnant women. Asenapine did not have teratogenic effects in animal experiments. In these studies, signs of toxicity were found for the female and embryo.

    Newborns whose mothers took antipsychotic drugs in the third trimester of pregnancy are at risk of developing extrapyramidal symptoms and / or withdrawal after delivery. There have been reports of the development of agitation, arterial hypertension and hypotension, tremor, drowsiness, respiratory distress syndrome, and malnutrition in these newborns.

    These complications vary in severity and duration. In some cases, they are self-sustaining, in other cases require intensive therapy and prolongation of hospitalization.

    The drug Saffis® 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 Saffris® are not recommended breast-feeding.

    Dosing and Administration:

    Standard doses for the treatment of adult patients

    Schizophrenia


    Treatment with drug Safris ® should be started with a dose of 5 mg twice a day. The recommended dose of Saffis ® is 5-10 mg twice a 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 twice a day (daily dose of 20 mg) compared with a dose of 5 mg twice daily (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 Saffis® with monotherapy is 10 mg twice a day (daily dose of 20 mg). Given the clinical effectiveness, the dose can be reduced to 5 mg twice a day (daily dose of 10 mg).With combined therapy, the recommended initial dose is 5 mg twice daily (daily dose of 10 mg). Given the clinical response and tolerability, the dose can be increased to 10 mg twice daily (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 Saffis®. In general, patients who responded to treatment are advised to continue taking Saffis® after the phase of therapy.

    Mode of application

    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, place 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 ® should be taken last.

    Use in special patient groups

    Children

    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 ® in adolescents (see section Pharmacokinetics).

    Elderly patients

    The drug Safris ® should be used with caution in elderly patients. Data on the safety and efficacy of the drug in patients age 65 and older are limited (see Section Pharmacokinetics).

    Patients with impaired renal function

    Correction of the dose in patients with impaired renal function is not required.

    Patients with impaired hepatic function

    Correction of the dose in patients with mild and moderate impairment of liver function is not required. In patients with severe impairment of liver function (Child-Pugh class C), a 7-fold increase was observed AUC Asenapine, therefore it is not recommended to prescribe the drug Saffrys® to such patients (see Section Pharmacokinetics).

    Side effects:

    The most common undesirable reaction (IIP), observed with the treatment of asenapine, is drowsiness. The adverse reactions observed during clinical and post-marketing studies associated with the treatment with asenapine,are presented in the table below and are classified but lesions of organs and systems of organs 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 group HP are distributed in frequency and in order of decreasing severity. Frequency of occurrence of undesirable reactions in post-marketing studies can not be determined, since the reports on HP were spontaneous. Consequently, the frequency of such HP qualify as "unknown".

    Organs and organ systems

    Very Frequent

    Frequent

    Infrequent

    Rare

    Unknown

    Violations of the blood and lymphatic system




    Neutropenia


    Immune system disorders





    Allergic reactions, severe hypersensitivity reactions, including anaphylactic / anaphylactoid reactions, angioedema, tongue edema and pharyngeal edema (laryngeal edema)

    Disorders from the metabolism and nutrition


    Increased body weight, increased appetite

    Hyperglycaemia



    Disorders of the psyche

    Anxiety





    Disturbances from the nervous system

    Drowsiness

    Akathisia *, parkinsonism *, dizziness, dystonia *, dysgeusia, dyskinesia *, sedation

    Dysarthria, fainting, extrapyramidal disorders, convulsive seizures *

    Malignant neuroleptic syndrome


    Visual impairment




    Violation of accommodation


    Heart Disease



    Sinus bradycardia, bundle branch blockade *, prolongation of QT interval on electrocardiogram



    Vascular disorders



    Orthostatic hypotension, hypotension



    Disturbances from the respiratory system, chest and mediastinal organs




    Pulmonary embolism


    Disorders from the gastrointestinal tract


    Hypesesia of the oral cavity

    Paresthesia of the mouth, glossodynia, edema of the tongue, dysphagia


    Damage to the oral mucosa (inflammation, the formation of ulcers and blisters), hypersalivation

    Disturbances from the liver and bile ducts


    Increased activity of alanine aminotransferase




    Disturbances from musculoskeletal and connective tissue


    Rigidity of muscles


    Rhabdomyolysis


    Pregnancy, the postpartum period and perinatal conditions





    The syndrome of cancellation in newborns

    Violations of the genitals and mammary glands



    Sexual dysfunction, amenorrhea

    Gynecomastia, galactorrhea


    General disorders and disorders at the site of administration


    Fatigue




    * Akathisia includes such preferred terms Med-DRA (medical dictionary for regulatory activity) as akathisia and hyperkinesia.

    Parkinsonism includes such preferred terms Med-DRA Parkinsonism, tremor, muscle hypertension, Parkinsonian tremor trembling, gait disturbance, rigidity as a "cogwheel" type, masklike face (Parkinson's face), pathological glabellar reflex and muscle rigidity;

    * Dystonia includes such preferred terms Med-DRA as a dystonia, convulsions of a look, torticollis and blepharospasm.

    * Dyskinesia includes such preferred terms Med-DRA as dyskinesia and tardive dyskinesia.

    * Seizures include such preferred terms Med-DRA like seizures, epilepsy and partial seizures.

    * The bundle bundle blockade includes such preferred terms Med-DRA as a blockade of the left branch of the bundle, a blockade of the right bundle of the bundle, a blockade of the bundle of the bundle.

    Extrapyramidal symptoms (EPS)

    In clinical trials, the incidence of extrapyramidal of the symptoms in the group of patients treated with asenapine was higher than in the placebo group (15.4% and 11.0 % respectively).

    In the short-term (6 weeks) clinical studies, the dependence of the incidence of akathisia on the dose was revealed in patients with schizophrenia who received asenapine. 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 with 0.3 % relative to the general population of patients participating in these studies.

    Weight gain

    In short-term and long-term clinical trials in patients with schizophrenia and bipolar mania body weight in the treatment with asenapine increased by an average of 0.8 kg. The proportion of patients with a clinically significant increase in body weight (> 7% of baseline body weight) in short-term studies of patients with schizophrenia was 5.3 % in the group of patients taking asenapine, compared with 2.3% in the placebo group. The proportion of patients with clinically significant weight gain (> 7% of initial weight) in the short-term studies of patients with bipolar mania was 6.5% in the group of patients taking asenapine, but 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 increase in the activity of liver transaminases, alanine aminotransferase (ALT) and aspartate aminotransferase (ACT) were observed frequently, especially at the beginning of therapy.

    Overdose:

    In clinical studies of asenapine, several cases of overdose have been observed. Estimated doses were from 15 to 400 mg. In most cases, it remains unclear whether the patients asenapine under the tongue. Undesirable effects associated with including agitation and confusion, akathisia, orofacial dystonia, sedation and asymptomatic changes on the ECG (bradycardia, supraventricular extrasystole, slowing of intraventricular conduction). Specific There is no information on the treatment of an overdose with asenapine. There is no antidote to asenapine. It is necessary to consider the possibility of an overdose as a result of taking several drugs.It is necessary to monitor the function of the cardiovascular system with the aim of diagnosis of possible arrhythmias. Overdose shows supportive therapy, adequate oxygenation and ventilation of the respiratory tract, and symptomatic treatment. With a reduction in blood pressure and collapse, adequate measures are needed, in particular intravenous fluid administration and / or sympathomimetic drugs (epinephrine and dopamine should not be given, as stimulation of β-adrenoreceptors can further reduce blood pressure when blocking α-adrenergic receptors under the effect of the drug Safris®). In the presence of severe extrapyramidal symptoms, m-cholinoblocking agents are prescribed. The patient must be carefully monitored until his condition is normalized.

    Interaction:

    Asenapine exerts an effect on the central nervous system (CNS) (see section "Side effect"), so caution should be exercised when it is used in combination with other drugs of central action. Patients should be warned that alcohol should be avoided when taking Saffis®.

    The effect of other drugs on the pharmacokinetics of the drug Saffrys®

    Asenapine is excreted mainly by direct glucuronation under the action of an isoenzyme UGTIA4 and oxidative metabolism under the action of cytochrome P450 isoenzymes (mainly isoenzyme CYP1A2). The possible effect of inhibitors and inducers of several of these isoenzymes on the pharmacokinetics of asenapine, namely fluvoxamine (an isoenzyme inhibitor CYP1A2), paroxetine (inhibitor of isoenzyme CYP2D6), imipramine (inhibitor of isoenzymes CYP1A2 / 2C19 / 3 A4), cimetidine (inhibitor of isoenzymes CYP3A4/2D6/1A2), carbamazepine (inducer of isoenzymes CYP3A4/1A2) and valproate (an enzyme inhibitor UGT). With the exception of fluvoxamine, clinically significant changes in the pharmacokinetics of asenapine when used concomitantly with the above agents were not detected. Simultaneous application of fluvoxamine at a dose of 25 mg twice daily with aspenin at a dose of 5 mg once a day led to an increase in the value AUC of asenapine by 29%. It can be expected that a full therapeutic dose of fluvoxamine will cause a more pronounced increase in the concentration of asenapine in the blood plasma.Care should be taken when using asenapine in combination with fluvoxamine.

    The possible effect of the drug Safris® on the pharmacokinetics of other drugs

    Due to asenapine possesses αl-adrenoblocking properties and is able to cause orthostatic hypotension (see section "Special instructions"), the drug Safris ® can enhance the effects of certain antihypertensive drugs.

    Research in vitro evidence that asenapine has a weak inhibitory effect on the isoenzyme CYP2D6. Clinical studies of the interaction of drugs, in which the effects of inhibition of azenapine isoenzyme CYP2D6, demonstrated the following results:

    - The dextrorphan / dextromethorphan ratio was measured as a marker of isoenzyme activity CYP2D6 after the simultaneous administration of dextromethorphan and asenapine in healthy volunteers. The use of asenapine at a dose of 5 mg twice daily led to a decrease in this ratio to 0.43, indicating inhibition of the isoenzyme CYP2D6. In the same study, when paroxetine was treated at a dose of 20 mg / day, this ratio was reduced to 0.032.

    - In a separate study, simultaneous single administration of 75 mg of imipramine and 5 mg of asenapine does not affect the concentration of the metabolite of desipramine (isoenzyme substrate CYP2D6).

    - Simultaneous single administration of 20 mg of paroxetine (substrate and inhibitor of isoenzyme CYP2D6) during the administration of asenapine at a dose of 5 mg twice daily in healthy male volunteers resulted in an almost 2-fold increase AUC paroxetine.

    In vivo Asenapine can exert only a weak inhibitory effect on the isoenzyme CYP2D6. but asenapine can enhance the inhibitory effects of paroxetine on their own metabolism.

    Therefore, the drug Safris® should be used with caution in combination with preparations that are substrates or inhibitors of the isoenzyme CYP2D6.

    Effect on the ability to drive transp. cf. and fur:

    The effect of the drug Safris® on the ability to drive a car and use sophisticated technology has not been studied. Asenapine can cause drowsiness and sedation. In this regard, patients should not drive the car and mechanisms until they are sure that the drug Safris® does not have an undesirable effect on them.

    Form release / dosage:Tablets sublingual 5 mg, 10 mg.
    Packaging:

    For 10 tablets in PVC / PA / aluminum blister. For 2, 6 or 10 blisters together with instructions for use in a cardboard box.

    Storage conditions:

    Store in a dry place protected from light at a temperature of 2 to 30 ° C.

    Keep out of the reach of children.

    Shelf life:

    3 years

    Do not use after the expiry date printed on the package.

    Terms of leave from pharmacies:On prescription
    Registration number:LP-001526
    Date of registration:21.02.2012
    The owner of the registration certificate:Organon, N.V.Organon, N.V. Netherlands
    Manufacturer: & nbsp
    ORGANON, N.V. Netherlands
    Representation: & nbspMSD Pharmaceuticals Ltd.MSD Pharmaceuticals Ltd.
    Information update date: & nbsp27.05.2013
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