Invega

General characteristics. Structure:

Active agent: Paliperidon – 3 mg.

Excipients: A macrogoal 200K - 81,43 mg, a macrogoal 7000K - 73,70 of mg, sodium chloride – 30 mg, povidone (K29-32) – 10 mg, a gietilloz – 10,45 mg, stearic acid – 0,75 mg, butyl hydroxytoluene – 0,11 mg, ferrous oxide red – 1,0 mg, ferrous oxide yellow – 0,03 mg, a macrogoal of 3350 - 1,0 mg, cellulose acetate (398-10) – 44,55 mg, dye white (a gipromelloza, titanium dioxide, lactoses monohydrate, triacetin) – 33 mg, karnaubsky wax – 0,03 mg.

Active agent: Paliperidon – 6 mg.

Excipients: A macrogoal 200K - 78,45 mg, a macrogoal 7000K - 73,70 of mg, sodium chloride – 30 mg, povidone (K29-32) – 10 mg, a gietilloz – 10,45 mg, stearic acid – 0,75 mg, butyl hydroxytoluene – 0,11 mg, ferrous oxide red – 1,01 mg, a macrogoal of 3350 - 1,00 mg, cellulose acetate (398-10) – 44,55 mg, dye beige (a gipromelloza, titanium dioxide, polyethyleneglycol 400, ferrous oxide yellow, ferrous oxide red) – 18 mg, karnaubsky wax – 0,03 mg.

Active agent: Paliperidon – 9 mg.

Excipients: A macrogoal 200K - 75,45 mg, a macrogoal 7000K - 73,70 of mg, sodium chloride – 30 mg, povidone (K29-32) – 10 mg, a gietilloz – 10,45 mg, stearic acid – 0,75 mg, butyl hydroxytoluene – 0,11 mg, ferrous oxide black – 0,01 mg, ferrous oxide red – 1,00 mg, a macrogoal of 3350 - 1,00 mg, cellulose acetate (398-10) – 44,55 mg, dye pink (a gipromelloza, titanium dioxide, polyethyleneglycol 400, ferrous oxide red) – 15 mg, karnaubsky wax – 0,03 mg.

Active agent: Paliperidon – 12 mg.

Excipients: A macrogoal 200K - 72,43 mg, a macrogoal 7000K - 73,70 of mg, sodium chloride – 30 mg, povidone (K29-32) – 10 mg, a gietilloz – 10,45 mg, stearic acid – 0,75 mg, butyl hydroxytoluene – 0,11 mg, ferrous oxide red – 1,00 mg, ferrous oxide yellow – 0,03 mg, a macrogoal of 3350 - 1,00 mg, cellulose acetate (398-10) – 44,55 mg, dye dark yellow (a gipromelloza, titanium dioxide, polyethyleneglycol 400, ferrous oxide yellow) – 12 mg, karnaubsky wax – 0,03 mg. The text on tablets of all dosages is made by ink water-soluble black (the structure blackened: a gipromelloza, ferrous oxide black, the water purified isopropanol, propylene glycol).

Description.

White, light orange (the weak brownish shade is allowed), pink ( the grayish shade is allowed) or dark yellow (the grayish shade) (according to a dosage – 3, 6, 9 or 12 mg is allowed) tablets of a kapsulovidny form. Tablets have a text of "PAL 3", "PAL 6", "PAL 9" or "PAL 12" (according to a dosage – 3, 6, 9 or 12 mg).

Outlets can be visible or invisible at visual survey.

Pharmacological properties:

Pharmacodynamics.

Action mechanism.

Paliperidon – it is central the acting antagonist dopamine D2 receptors having also high antagonism concerning serotoninovy 5-HT2-retseptorov. Besides, палиперидон is an antagonist alfa1-and alfa2-adrenergic receptors and N1-of histamine receptors. Paliperidon has no affinity to cholinergic, muskarinovy, and also beta1-and to beta2-adrenergic receptors. Pharmacological activity (+) and (-) - enantiomer of a paliperidon is identical in the qualitative and quantitative relations.

Antipsychotic action is caused by blockade of D2-dofaminergichesky receptors of mesolimbic and mesocortical system. Causes smaller suppression of motor activity and to a lesser extent induces a katalepsy, than classical anti-psychotics (neuroleptics).

The balanced central antagonism to serotonin and dopamine can reduce tendency to extrapyramidal side effects and expand therapeutic influence of drug with coverage of negative and productive symptoms of schizophrenia.

Paliperidon exerts impact on structure of a dream: reduces stage of latency before backfilling, reduces number of awakenings after backfilling, increases the general duration of a dream, increases time of a dream and raises an index of quality of a dream. Has antiemetic effect, can cause increase in concentration of prolactin in a blood plasma.

Pharmacokinetics.

If it is not stipulated differently, the pharmacokinetic data presented in this section are based on the data obtained for adult patients. Pharmacokinetic characteristics of a paliperidon after intake are proportional to the accepted dose in the recommended therapeutic range (3–12 mg once a day).

Absorption.

After reception of one dose of drug concentration of a paliperidon steadily increased in plasma, and the maximum concentration (Cmax) was reached later 24 h. At most of patients equilibrium concentration of a paliperidon were reached after 4–5 days of administration of drug once a day. Paliperidon is an active metabolite of a risperidon. Features of release of active ingredient from the drug Invega® provided smaller fluctuations of the maximum and minimum concentration of a paliperidon, than those which are observed when using usual dosage forms (an index of fluctuations of concentration of 38% in comparison from 125% for usual dosage forms).

After reception of tablets of a paliperidon there is interconversion (+) and (-) enantiomer, and the ratio the area under a curve "concentration time" (AUC) of AUC (+) / AUC (-) in an equilibrium state makes about 1,6. Absolute bioavailability of a paliperidon after oral administration makes 28% (23%-33% at a confidence interval of 90%).

After a single dose of 15 mg of a paliperidon in the form of a tablet of the prolonged release together with greasy Cmax and AUC high-calorific food increased, on average by 42 and 46% respectively of rather same indicators at reception of a tablet on an empty stomach. In other research after a single dose of 12 mg of a paliperidon in the form of a tablet of the prolonged release together with greasy Cmax and AUC high-calorific food increased, on average by 60 and 54% respectively of rather same indicators at reception of a tablet on an empty stomach. Thus, existence or absence in a food stomach during reception of a paliperidon can change concentration of a paliperidon in a blood plasma.

Distribution.

Paliperidon is quickly distributed in fabrics and liquids of an organism. The seeming distribution volume – 487 l. Extent of linkng with proteins of plasma makes 74%. Paliperidon contacts preferential an alfa1-acid glycoprotein and albumine.

Biotransformation and elimination.

In 1 week after reception of one standard tablet containing 1 mg of a paliperidon, 59% of a dose were allocated with urine in not changed look; it demonstrates to what палиперидон is not exposed to intensive metabolism in a liver. About 80% of drug were revealed in urine and about 11% – in Calais. Four ways of metabolism of a paliperidon of in vivo, any of which does not cover more than 6,5% of a dose, are known: dealkylation, hydroxylation, dehydrogenation and splitting of a benzizoksazol. The researches in vitro showed that isoenzymes of CYP2D6 and CYP3A4 of P450 cytochrome can play a part in metabolism of a paliperidon, however proofs that they play a significant role in metabolism of a paliperidon of in vivo, it was not succeeded to receive. In spite of the fact that in the general population activity of an isoenzyme of CYP2D6 significantly varies, population pharmacokinetic researches did not reveal essential distinctions of the seeming clearance of a paliperidon at patients with active metabolism of substrates of an isoenzyme of CYP2D6 and at patients with weak metabolism of substrates of an isoenzyme of CYP2D6. The researches in vitro with use of microsomal drugs of heterological systems showed that isoenzymes of CYP1A2, CYP2A6, CYP2C9, CYP2C19 and CYP3A5 do not participate in metabolism of a paliperidon.

The final elimination half-life of a paliperidon makes about 23 h. The researches in vitro showed what палиперидон is substrate of the R-glycoprotein and in high concentration poorly inhibits it. These in vivo are absent, the clinical importance is unknown.

Special groups.

Patients with abnormal liver functions.

Paliperidon is not exposed to intensive metabolism in a liver. Patients with easy and moderate abnormal liver functions have no need to reduce a dose of a paliperidon. The research in which patients with a moderate abnormal liver function participated (a class "B" on classification of Chayld-Pyyu) showed that at these patients of concentration of an untied paliperidon in plasma were similar to those at healthy people. Use of the drug Invega® for patients with heavy abnormal liver functions was not studied.

Patients with renal failures.

The dose of a paliperidon needs to be reduced at patients with a moderate and heavy renal failure. Excretion of a paliperidon was studied at patients with different degree of a renal failure. It was established that elimination of a paliperidon decreased in process of reduction of clearance of creatinine. The general clearance of a paliperidon was reduced by 32% at patients with easy renal failures (clearance of creatinine from 50 to <80 ml/min.), for 64% at patients with moderate renal failures (clearance of creatinine from 30 to <50 ml/min.) and for 71% at patients with heavy renal failures (clearance of creatinine from 10 to <30 ml/min.). The average final elimination half-life of a paliperidon made 24, 40 and 51 h at patients with easy, moderate and heavy renal failures respectively; at people with normal function of kidneys (clearance of creatinine of ≥80 ml/min.) this indicator made 23 h.

Teenagers.

System impact of a paliperidon on teenagers was comparable with that at adults. Concentration of a paliperidon in a blood plasma at teenagers with body weight <is 23% higher than 51 kg, than teenagers with body weight have ≥51 kg that is not clinically significant. The age does not influence concentration of a paliperidon in plasma.

Elderly patients.

It is not recommended to change a dose of a paliperidon depending on age of the patient. Results of a pharmacokinetic research in which elderly patients at the age of 65 years participated and are more senior, showed that the seeming clearance of a paliperidon in an equilibrium state after administration of drug of Invega® in this group was 20% lower, than at adult patients at the age of 18–45 years. At the same time, after introduction of the amendment on age decrease in clearance of creatinine, the population analysis did not reveal influence of age of patients with schizophrenia on pharmacokinetics of a paliperidon.

Race.

Changes of doses for patients of various race are not required. The population pharmacokinetic analysis showed lack of racial distinctions in pharmacokinetics of a paliperidon at drug Invega® use. Distinctions in pharmacokinetics in researches on Japanese and Caucasians are not revealed.

Floor.

The recommended doses of a paliperidon are identical to men and women. The seeming clearance of a paliperidon after administration of drug at women is about 19% lower, than at men. This difference is caused generally by distinctions in bezzhirovy a component of body weight and clearance of creatinine between men and women as population researches, after introduction of the amendment on bezzhirovy to a component of body weight and clearance of creatinine, did not reveal clinically significant distinctions in pharmacokinetics of a paliperidon at the men and women accepting drug.

Smoking.

It is not recommended to change doses of a paliperidon at smokers. The researches in vitro with use of liver enzymes of the person showed that палиперидон not yavlyaetsyasubstraty CYP1A2 isoenzyme and therefore smoking should not influence pharmacokinetics of a paliperidon. According to results of the researches in vitro, population researches did not reveal distinctions in pharmacokinetics of a paliperidon between smokers and non-smoking people.

Indications to use:

Schizophrenia, including in an aggravation phase at adult patients. Prevention of exacerbations of schizophrenia at adults.

Treatment of schizophrenia at teenagers aged from 12 up to 17 years.

Therapy of schizoaffective disorders: as monotherapy or as a part of a combination therapy with antidepressants and/or mood stabilizers at adult patients.

Route of administration and doses:

Drug is intended for intake. Tablets should be swallowed entirely, washing down with liquid, they cannot be chewed, divided into parts or to crush.

Schizophrenia.

Adults (18 years are more senior).

The recommended dose at adults makes 6 mg once a day, in the morning, irrespective of meal. Gradual increase in an initial dose is not required. In some patients the therapeutic effect is caused by lower or higher doses within the recommended range of 3-12 mg once a day. The general tendency to strengthening of effect at use of high doses of drug is observed. If increase in a dose is necessary, it is recommended to raise a dose on 3 mg in bucketed days more than 5 days.

Teenagers (12-17 years).

The recommended dose at teenagers makes 3 mg once a day, in the morning, irrespective of meal. Gradual increase in an initial dose is not required. In some patients the therapeutic effect is caused by higher doses within the recommended range of 6-12 mg once a day. Increase in a dose is possible only after clinical revaluation, with increase of a dose on 3 mg in bucketed days more than 5 days.

Schizoaffective disorders.

Adults (18 years are more senior).

The recommended dose at adults makes 6 mg once a day, in the morning. Gradual increase in an initial dose is not required. In some patients the therapeutic effect is caused by lower or higher doses within the recommended range of 6-12 mg once a day. Increase in a dose if it is necessary, has to be carried out only after assessment of a clinical condition of the patient. If increase in a dose is necessary, it is recommended to raise a dose on 3 mg in bucketed days more than 4 days. The maintenance therapy at patients with schizoaffective disorders was not studied.

Patients with abnormal liver functions.

The dose decline is not required from patients with weak or average degree of abnormal liver functions. Use of Invega® for patients with heavy abnormal liver functions was not studied.

Patients with renal failures.

For patients with an easy renal failure (clearance of creatinine ≥ 50, but <80 ml/min.) the recommended initial dose makes 3 mg once a day. This dose can be increased to 6 mg after assessment of a condition of the patient and taking into account portability of drug once a day. For patients with a moderate or heavy renal failure (clearance of creatinine ≥10, but <50 ml/min.) the recommended dose of drug makes 3 mg once a day. Use of the drug Invega® for patients with clearance of creatinine <10 ml/min. was not studied in this connection, these patients are not recommended to appoint drug.

Elderly patients.

For elderly patients with normal function of kidneys (clearance of creatinine of ≥80 ml/min.) the same doses of drug, as for adult patients with normal function of kidneys are recommended. At the same time, at elderly patients function of kidneys can be reduced, and in this case the dose of drug should be selected according to function of kidneys at the specific patient (see the section "Patients with Renal Failures"). It is necessary to be careful at use of drug for elderly patients with dementia in connection with the increased risk of developing of a stroke. Efficiency and safety of the drug Invega® at patients are more senior than 65 years at schizoaffective disorders was not studied.

Children and teenagers.

Efficiency and safety of Invega® medicine for treatment of schizophrenia at children are younger than 12 years was not studied. Efficiency and safety of Invega® medicine for treatment of schizoaffective disorders at patients are younger than 18 years was not studied.

Special groups of patients.

It is not recommended to change a dose of a paliperidon depending on a sex, age and from that, the patient smokes or not.

Transfer of patients into treatment by other antipsychotic drugs is not present systematically collected data on transfer of patients from treatment paliperidony on treatment by other antipsychotic drugs Now. The pharmacodynamics and pharmacokinetics at different antipsychotic drugs is not identical and therefore doctors have to watch closely a condition of patients at their transfer from one antipsychotic drug into another.

Features of use:

Malignant antipsychotic syndrome.

It is known that antipsychotic drugs, including палиперидон, can cause the malignant antipsychotic syndrome (MAS) which is characterized by a hyperthermia, muscle tension, instability of function of the autonomic nervous system, consciousness oppression, and also increase in serum of concentration of a kreatinfosfokinaza. At patients with ZNS can arise also a myoglobinuria (рабдомиолиз) and an acute renal failure. At emergence at the patient of objective or subjective symptoms of ZNS it is necessary to cancel immediately all antipsychotic drugs, including палиперидон.

Late dyskinesia.

The drugs having properties of antagonists of dopamine receptors can cause late dyskinesia which is characterized by the rhythmic involuntary movements, preferential language and/or mimic muscles. At emergence at the patient of the objective or subjective symptoms indicating late dyskinesia it is necessary to consider expediency of cancellation of all antipsychotic drugs, including палиперидон.

Lengthening of an interval of QT.

As well as for other antipsychotic means, patients should be careful at purpose of the drug Invega® with cardiac arrhythmias in the anamnesis, inborn lengthening of an interval of QT and combined use with the drugs extending QT interval.

Hyperglycemia and diabetes mellitus.

At treatment the drug Invega® observed a hyperglycemia, a diabetes mellitus and an aggravation of already available diabetes mellitus. Establishment of interrelation between use of atypical antipsychotic drugs and disturbances of exchange of glucose is complicated by the increased risk of development of a diabetes mellitus in patients with schizophrenia and prevalence of a diabetes mellitus in the general population. Considering these factors, interrelation between use of atypical antipsychotic drugs and development of the side effects connected with a hyperglycemia it is established not completely. At patients with the established diagnosis of a diabetes mellitus it is necessary to control glucose level regularly. Patients with risk factors of development of a diabetes mellitus (for example, obesity, family history of diabetes) have to undergo control of level of glucose in blood on an empty stomach in an initiation of treatment and periodically during treatment. At all patients it is necessary to carry out clinical control on existence of symptoms of a hyperglycemia and diabetes mellitus. Patients at whom at treatment by atypical neuroleptics hyperglycemia symptoms develop have to undergo control of level of glucose in blood. In certain cases simtoma of a hyperglycemia disappeared at the termination of reception of atypical antipsychotic drugs, however for some patients it is required anti-diabetic treatments, despite the termination of reception of the suspected drug.

Increase in body weight.

At treatment atypical anti-psychotics observed significant increase in body weight. It is necessary to carry out control of body weight of patients.

Giperprolaktinemiya.

As well as other antagonists of D2 of dopamine receptors, палиперидон increases the level of prolactin and this increase remains during all administration of drug. Action of a paliperidon is comparable with that at a risperidon, drug of the prolactin having the greatest influence on level among other antipsychotic drugs. Giperprolaktinemiya, irrespective of an etiology, can suppress GNRG expression (a gonadotrophin - rileasing-hormone) a hypothalamus that leads to decrease in secretion of gonadotrophins a hypophysis. It, in turn, can suppress reproductive function, weakening a sexual steroidogenesis at women and at men. At the patients accepting drugs, increasing prolactin level the galactorrhoea, an amenorrhea, a gynecomastia and impotence were registered. The long giperprolaktinemiya associated with a hypogonadism can lead to decrease in density of a bone tissue at women and at men.

Researches on cultures of in vitro fabrics showed that about one third of cases of a breast cancer at people prolactin - is dependent. It should be considered at purpose of the drugs increasing prolactin level, to patients with the breast cancer revealed earlier. The clinical and epidemiological trials conducted so far did not show communication between reception of atypical antipsychotic drugs and obrazovaniyemopukholy at people. However the available data are too limited to draw final conclusions.

Orthostatic hypotension.

Paliperidon has the alpha blocking activity and therefore can cause orthostatic hypotension in some patients. Paliperidon it is necessary to apply with care at patients with cardiovascular diseases (for example, heart failure, a heart attack or ischemia of a myocardium, disturbance of conductivity of a cardiac muscle), cerebrovascular diseases, and also with the states promoting arterial hypotension (for example, dehydration, a hypovolemia and therapy by anti-hypertensive drugs).

Regulation of body temperature.

Such undesirable effect as disturbance of ability of an organism to regulate temperature is attributed to antipsychotic drugs. It is necessary to be careful at purpose of a paliperidon to patients with states which can promote increase in internal body temperature, to which the intensive exercise stress, organism dehydration, influence of high external temperatures or simultaneous use of drugs with anticholinergic activity belong.

Antiemetic effect.

In preclinical trials the antiemetic effect of a paliperidon was revealed. This effect, in case of its emergence at people, can mask objective and subjective symptoms of overdose of some drugs, and also such diseases as impassability of intestines, a syndrome to Reja and a tumor of a brain.

Priapism.

The drugs having alpha and adrenoceptor blocking effects can cause a priapism. In post-market researches of a paliperidon messages on development of a priapism were received.

Suicide attempts.

The possibility of suicide attempts is characteristic of mental diseases therefore therapy of patients with high risk has to be carried out under careful observation. In these cases the drug Invega® has to be prescribed in the minimum quantity of tablets for reduction of risk of overdose.

Leukopenia, neutropenia, agranulocytosis.

The leukopenia, neutropenia and agranulocytosis were noted at use of antipsychotic means, including at drug Invega® use. The agranulocytosis was noted very seldom during post-marketing observations. To patients, with clinically significant reduction of quantity of leukocytes in the anamnesis or drug - a dependent leukopenia / neutropenia is recommended carrying out an integrated analysis of blood within the first months of therapy, the treatment termination by the drug Invega® has to be considered at the first clinically significant reduction of quantity of leukocytes in the absence of other possible reasons. Patients with clinically significant neutropenia are recommended to be observed regarding temperature increase or emergence of symptoms of an infection and to begin treatment immediately, at emergence of such simtom. Patients with a severe form of a neutropenia (absolute quantity of neutrophils less 1×109/l) have to stop drug Invega® use until the quantity of leukocytes is not normalized.

Venous thromboembolism.

At use of antipsychotic drugs cases of a venous thromboembolism were noted. As the patients accepting antipsychotic drugs often have risk of development of a venous thromboembolism, all possible risk factors have to be revealed to and during treatment by the drug Invega® and the warning measures have to be taken.

Intraoperative Syndrome of a Flabby Iris (ISFI).

ISDR was observed during performing surgery concerning existence of a cataract at the patients receiving therapy by drugs of group of antagonists α1-адренорецепторов. ISDR increases risk of emergence of the complications connected with an organ of sight in time and after carrying out operational intervention. The doctor performing such operation has to be beforehand informed that the patient accepted or accepts the drugs having activity of antagonists α1-адренорецепторов now. The potential advantage of cancellation of therapy by antagonists α1-адренорецепторов before an operative measure is not established, and has to be estimated taking into account the risks connected with therapy cancellation by antipsychotic drugs.

Pregnancy and care of the child.

The patient has to notify the doctor on pregnancy or its planning during treatment by the drug Invega®. It is necessary to be careful at purpose of the drug Invega® to nursing mothers. (see the section "Use at Pregnancy and a Lactation").

Alcohol intake.

Patients have to avoid alcohol intake during treatment by the drug Invega®.

The conditions leading to reduction of finding of drug in a GIT.

The conditions leading to reduction of finding of drug in a GIT, for example, the diseases connected with chronic diarrhea can cause reduction of absorption of a paliperidon.

The tablets Invega® are made with use of technology of osmotic release of active ingredient at which osmotic pressure provides release of a paliperidon with a controlled speed. The system resembling a kapsulovidny tablet superficially consists of osmotically active three-layered kernel surrounded with an intermediate cover and a semipermeable membrane. The three-layered kernel consists of two medicinal layers containing medicinal substance and excipients and also of the pushing-out layer containing osmotically active components. On a dome from medicinal layers there are two outlets made by means of the laser. In digestive tract the color cover is quickly dissolved, water begins to arrive in a tablet through the semipermeable controlling membrane. The membrane controls water inflow level, and it, in turn, controls the level of release of medicinal substance.

Hydrophilic polymers of a kernel of a tablet absorb water and bulk up, turning into the gel containing палиперидон which then is pushed out through openings in a dome. Insoluble components of a tablet are brought out of an organism with a chair. Patients should not worry if they notice in Calais something similar to a tablet. Influence on driving of the car and work with mechanisms Paliperidon can break the activity demanding bystry mental reaction and also can have visual effects therefore patients should abstain from driving of the car and work with mechanisms until their individual sensitivity to a paliperidon is established.

Side effects:

The undesirable effects observed at patients are provided below. Frequency of undesirable effects was classified as follows: very frequent (≥10%), frequent (≥1% and <10%), infrequent (≥0,1% and <1%), rare (≥0,01% and <0,1%) and very rare (<0,01%).

Infections: frequent – upper respiratory tract infections, a nasopharyngitis; infrequent – infections of urinary tract, an acariasis, bronchitis, an inflammation of a hypodermic fatty tissue, cystitis, ear infections, flu, an onychomycosis, pneumonia, respiratory infections, sinusitis, tonsillitis.

Disturbances from immune system:

- infrequent – anaphylactic reaction, hypersensitivity.

Disturbances from hemopoietic and lymphatic system:

- infrequent – anemia, decrease in a hematocrit, a neutropenia, decrease in quantity of leukocytes;

- rare – thrombocytopenia; very rare – an agranulocytosis.

Disturbances from endocrine system:

- infrequent – a giperprolaktinemiya;

- very rare – inadequate secretion of antidiuretic hormone.

Disturbances from a metabolism and food:

- infrequent – increase in activity of a kreatinfosfokinaza, anorexia, a hyperglycemia;

- rare – a diabetes mellitus, a hypoglycemia, water intoxication;

- very rare – diabetic ketoacidosis.

Disturbances of mentality:

- frequent – sleeplessness (including initial and average sleeplessness), a mania;

- infrequent – "dreadful" dreams, sleep disorders, a depression.

Disturbances from a nervous system:

- very frequent – a headache;

- frequent - an akathisia, dystonia, a dysarthtia, increase in a muscle tone, parkinsonism, sedation, drowsiness, a tremor, hypersalivation;

- infrequent – cerebrovascular disturbances, postural dizziness, dyskinesia, spasms, a faint, disturbance of attention, a hypesthesia, a loss of consciousness, paresthesia, a psychomotor hyperactivity, late dyskinesia, a hypokinesia, an opisthotonos.

It is known that antipsychotic drugs, including палиперидон, can cause the malignant antipsychotic syndrome (MAS) which is characterized by a hyperthermia, muscular rigidity, instability of function of the autonomic nervous system, consciousness oppression, increase in activity of a kreatinfosfokinaza, a myoglobinuria, rabdomiolizy, an acute renal failure.

Disturbances from organs of sight:

- infrequent – conjunctivitis, a xerophthalmus, photophobia, dacryagogue;

- with an unknown frequency: syndrome of a flabby iris (intraoperative).

Disturbance from an acoustic organ and labririntny disturbances:

- infrequent – ear pain, вертиго, a ring in ears.

- Disturbances from cardiovascular system:

- infrequent – bradycardia, a heart consciousness, an atrioventricular block, disturbance of conductivity, change on an ECG, increase in an interval of QT, ischemia, blood "inflows", increase in arterial pressure, a lowering of arterial pressure;

- rare – fibrillation of auricles;

- very rare – a deep vein thrombosis, an embolism of a pulmonary artery.

Disturbances from digestive tract:

- frequent – nausea, diarrhea, a lock, discomfort in an upper part of a stomach, dyspepsia, the increased appetite;

- infrequent – a hyporexia, a lip inflammation, a dysphagy, an incontience a calla, impassability of a small bowel, a meteorism, a gastroenteritis, a paraglossa, a dentagra, a dysgeusia;

- very rare – pancreatitis, intestinal impassability.

Disturbances from a liver and biliary tract:

- very rare - jaundice.

Disturbances from respiratory system:

- infrequent – pain in pharyngeal and guttural area, a nose congestion, cough, an asthma, a hyperventilation of lungs, goose breathing;

- rare – an apnoea syndrome in a dream.

Disturbances from skeletal and muscular and connecting fabric:

- frequent – a mialgiya, skeletal muscular pain;

- infrequent – muscular spasms, a dorsodynia, an arthralgia, constraint in a joint, swelling of a joint, muscular weakness, neck pain.

Disturbances from skin and hypodermic fabrics:

- infrequent – rash, an itch, an acne, a xeroderma, eczema, an erythema, seborrheal dermatitis, decolouration of skin;

- rare – a Quincke's edema, an alopecia.

Disturbances from kidneys and urinary tract:

- infrequent – a dysuria, a pollakiuria, an urine incontience, an urination delay;

Disturbances from generative organs and a mammary gland:

- infrequent – decrease in a libido, an anorgazmiya, allocations from nipples, erectile dysfunction, a gynecomastia, changes of a menstrual cycle, discomfort in a breast, sexual dysfunction, vaginal allocations, disturbance of an ejaculation, a nagrubaniye of mammary glands;

- very rare – a priapism.

Influence on the course of pregnancy, puerperal and perinatal states:

- very rare – a syndrome of "cancellation" at newborns.

Others: frequent – increase in body weight;

- infrequent – decrease in body weight, a fever, a face edema, gait disturbance, hypostases (including generalized hypostases, peripheral hypostases, soft hypostases), increase in body temperature, fever, thirst, discomfort in a breast;

- very rare – a hypothermia.

Laboratory tests:

- infrequent – increase in activity gamma глутамилтрансферазы, increase in activity of enzymes of a liver, increase in activity of transaminases, increase in concentration of cholesterol in blood, increase in concentration of triglycerides in blood.

Table 1. The side effects registered at ≥2% of the adult patients with schizophrenia receiving the drug Invega® in clinical trials.

System of bodies / Side effects

From a nervous system:

- headache: 11% (3 mg once a day); 12% (6 mg once a day); 14% (9 mg once a day); 14% (12 mg once a day); 12% (placebo);

- dizziness: 6 % (3 mg once a day); 5% (6 mg once a day); 4% (9 mg once a day); 5% (12 mg once a day); 4% (placebo);

- extrapyramidal frustration: 5 % (3 mg once a day); 2% (6 mg once a day); 7% (9 mg once a day); 7% (12 mg once a day); 2% (placebo);

- drowsiness: 5 % (3 mg once a day); 3% (6 mg once a day); 7% (9 mg once a day); 5% (12 mg once a day); 3% (placebo);

- akathisia: 4 % (3 mg once a day); 3% (6 mg once a day); 8% (9 mg once a day); 10% (12 mg once a day); 4% (placebo);

- tremor: 3 % (3 mg once a day); 3% (6 mg once a day); 4% (9 mg once a day); 3% (12 mg once a day); 3% (placebo);

- hypertension: 2 % (3 mg once a day); 1% (6 mg once a day); 4% (9 mg once a day); 3% (12 mg once a day); 1% (placebo);

- dystonia: 1 % (3 mg once a day); 1% (6 mg once a day); 4% (9 mg once a day); 4% (12 mg once a day); 1% (placebo);

- sedation: 1 % (3 mg once a day); 5% (6 mg once a day); 3% (9 mg once a day); 6% (12 mg once a day); 4% (placebo);

- parkinsonism: 0 % (3 mg once a day); <1 % (6 mg once a day); 2% (9 mg once a day); 1% (12 mg once a day); 0% (placebo).

From organs of sight:

- okulogirny crises: 0 % (3 mg once a day); 0 % (6 mg of 1 times put); 2% (9 mg once a day); 0% (12 mg once a day); 0% (placebo).

From cardiovascular system:

- sinus tachycardia: 9 % (3 mg once a day); 4 % (6 mg once a day); 4% (9 mg once a day); 7 (12 mg once a day); 4% (placebo);

- tachycardia: 2 % (3 mg once a day); 7 % (6 mg once a day); 7% (9 mg once a day); 7% (12 mg once a day); 3% (placebo);

- blockade of legs of a bunch: 3 % (3 mg a day); 1 % (6 mg a day); 3% (9 mg a day); <1 % (12 mg a day); 2% (placebo);

- Gis atrioventricular: 2 % (3 mg once a day); 0% (6 mg once a day); 2% (9 mg once a day); 1% (12 mg once a day); 1% (placebo);

- blockade of 1 degree sinus arrhythmia: 2 % (3 mg once a day); 1% (6 mg once a day); 1% (9 mg once a day); <1% (12 mg once a day); 0% (placebo);

- orthostatic hypotension: 2 % (3 mg once a day); 1% (6 mg once a day); 2% (9 mg once a day); 4% (12 mg once a day); 1% (placebo).

Gastrointestinal disturbances:

 - vomiting: 2 % (3 mg once a day); 3% (6 mg once a day); 4% (9 mg once a day); 5% (12 mg once a day); 5% (placebo);

- dryness in a mouth:  2 % (3 mg once a day); 3% (6 mg once a day); 1% (9 mg once a day); 3% (12 mg once a day); 1% (placebo);

- pain in an upper part of a stomach hypersalivation:  0 % (3 mg once a day); <1% (6 mg once a day); 1% (9 mg once a day); 4% (12 mg once a day); <1% (placebo).

General disturbances:

- adynamy: 2 % (3 mg once a day); <1 % (6 mg once a day); 2% (9 mg once a day); 2% (12 mg once a day); 1% (placebo);

- exhaustion: 2 % (3 mg once a day); 1 % (6 mg once a day); 2% (9 mg once a day); 2% (12 mg once a day); 1% (placebo).

Table 2. The side effects registered at ≥2% of the teenagers (12-17 years) with schizophrenia receiving the drug Invega® in clinical trials. 

System of bodies / Side effects.

Disturbances from cardiovascular system:

- tachycardia: 0% (1,5 mg once a day); 6% (3 mg once a day); 9% (6 mg once a day); 6% (12 mg once a day); 0% (placebo);

Disturbances from organs of sight:

- illegibility of visual perception:  0% (1,5 mg once a day); 0% (3 mg once a day); 0% (6 mg once a day); 3% (12 mg once a day); 0% (placebo).

Gastrointestinal disturbances:

- dryness in a mouth: 0% (1,5 mg once a day); 0% (3 mg once a day); 0% (6 mg once a day); 3% (12 mg once a day); 2% (placebo);

- hypersalivation: 2 % (1,5 mg once a day); 6% (3 mg once a day); 2% (6 mg once a day); 0% (12 mg once a day); 0% (placebo);

- paraglossa: 0 % (1,5 mg once a day); 0% (3 mg once a day); 0% (6 mg once a day); 3% (12 mg once a day); 0% (placebo);

- vomiting: 0 % (1,5 mg once a day); 6% (3 mg once a day); 11% (6 mg once a day); 3% (12 mg once a day); 10% (placebo).

General disturbances:

- adynamy: 0 % (1,5 mg once a day); 0% (3 mg once a day); 2% (6 mg once a day); 3% (12 mg once a day); 0% (placebo);

- fatigue: 4 % (1,5 mg once a day); 0% (3 mg once a day); 2% (6 mg once a day); 3% (12 mg once a day); 0% (placebo).

Infections:

- nasopharyngitis: 4 % (1,5 mg once a day); 0% (3 mg once a day); 4% (6 mg once a day); 0% (12 mg once a day); 2% (placebo).

Laboratory tests:

- increase in body weight: 7 % (1,5 mg once a day); 6% (3 mg once a day); 2% (6 mg once a day); 3% (12 mg once a day); 0% (placebo).

Disturbance from a nervous system:

- akathisia: 4 % (3 mg once a day); 6% (6 mg once a day); 11% (9 mg once a day); 17% (12 mg once a day); 0% (placebo);

- dizziness: 2 % (3 mg once a day); 6% (6 mg once a day); 2% (9 mg once a day); 3% (12 mg once a day); 0% (placebo);

- extrapyramidal frustration: 4 % (3 mg once a day); 19% (6 mg once a day); 18% (9 mg once a day); 23% (12 mg once a day); 0% (placebo);

- headache: 9 % (3 mg once a day); 6% (6 mg once a day); 4% (9 mg once a day); 14% (12 mg once a day); 4% (placebo);

- lethargy: 0 % (3 mg once a day); 0% (6 mg once a day); 0% (9 mg once a day); 3% (12 mg once a day); 0% (placebo);

- drowsiness: 9 % (3 mg once a day); 13% (6 mg once a day); 20% (9 mg once a day); 26% (12 mg once a day); 4% (placebo);

- glossolysis: 0 % (3 mg once a day); 0% (6 mg once a day); 0% (9 mg once a day); 3% (12 mg once a day); 0% (placebo).

Disturbance of mentality: 

- alarm: 0 % (3 mg once a day); 0% (6 mg once a day); 2% (9 mg once a day); 9% (12 mg once a day); 4% (placebo).

Disturbances from generative organs and a mammary gland:

- amenorrhea: 0 % (3 mg once a day); 6% (6 mg once a day); 0% (9 mg once a day); 0% (12 mg once a day); 0% (placebo);

- galactorrhoea: 0 % (3 mg once a day); 0% (6 mg once a day); 4% (9 mg once a day); 0% (12 mg once a day); 0% (placebo);

- hypostasis of mammary glands: 0 % (3 mg once a day); 0% (6 mg once a day); 0% (9 mg once a day); 3% (12 mg once a day); 0% (placebo).

Disturbances from respiratory system:

- nasal bleeding: 0 % (3 mg once a day); 0% (6 mg once a day); 2% (9 mg once a day); 0% (12 mg once a day); 0% (placebo).

* Extrapyramidal frustration include: okulogirny crisis, muscular rigidity, skeletal and muscular rigidity, constraint in a nape, a wryneck, a lockjaw, a bradykinesia, a rigidity cogwheel, dyskinesia, dystonia, extrapyramidal frustration, a hypertension, a hypokinesia, involuntary muscular contractions, gait parkinsonism, parkinsonism, a tremor and concern. Drowsiness includes drowsiness sedation and a hypersomnia.

Sleeplessness includes sleeplessness and initial sleeplessness. Tachycardia includes tachycardia, sinus tachycardia, and increase in heart rate. The hypertension includes a hypertension and increase in blood pressure. The gynecomastia includes a gynecomastia and swelling of a breast.

Paliperidon is an active metabolite of a risperidon, however on a profile of release and pharmacokinetic characteristics the drug Invega® considerably differs from dosage forms of a risperidon for intake with immediate release. Side effects about which it was reported at use of a risperidon can be observed at use of a paliperidon.

Elderly patients.

In the clinical trials conducted with participation of elderly patients with schizophrenia, the profile of safety of drug was same, as well as for younger patients. The drug Invega® was not studied at sick patients with dementia. In researches with other antipsychotic drugs increase in risk of death and cerebrovascular disturbances were noted. At elderly patients with dementia the risk of developing of a stroke is increased.

Other recorded cases.

Extrapyramidal symptom.

In the conducted clinical trials there were no distinctions at reception of placebo, a dosage of 3 mg and dosages of 6 mg. Dozozavisimy extrapyramidal symptoms were recorded at reception of high doses of the drug Invega® (9 mg and 12 mg). At clinical trials of schizoaffective disorders, cases of an extrapyramidal syndrome were revealed at higher doses of the drug Invega®, than at reception of placebo at all groups of patients without explicit interrelation with dosages. Extrapyramidal frustration included the integrated analysis and the following symptoms: dyskinesia, dystonia, hyperkinesia, parkinsonism and tremor.

Increase in body weight.

In clinical trials at patients with schizophrenia, the ratio of cases of increase in body weight more than for 7% of constant body weight was compared. Approximately identical ratio was revealed at administration of drug of Инвега® 3 mg and 6 mg in comparison with placebo and higher probability of increase in body weight was revealed for the drug Инвега® 9 of mg and 12 mg in comparison with placebo. In clinical trials at patients with schizoaffective disorders, at higher percent of the patients accepting drug of Invega ® (5%), increase in body weight more than 7% in comparison with the patients accepting placebo (1%) was noted. In this research of 27 patients divided into 2 groups, increase in body weight more than 7% at reception of low doses of the drug Invega® (3 mg and 6 mg), made 3%, for patients accepting high doses of the drug Invega® (9 mg and 12 mg) - 7%, and 1% in group where patients accepted placebo.

Laboratory indicators.

In clinical trials at patients with schizophrenia increase in concentration of prolactin in serum, was noted at administration of drug of Invega® at 67% of patients. Side reactions which can assume increase in level of prolactin (for example, an amenorrhea, a galactorrhoea, a gynecomastia) were noted more than in 2% of cases. The maximum value of increase in concentration of prolactin in serum were noticed for the 15th day of treatment, and remained above usual level before the end of treatment.

Class effects.

At reception of antipsychotic drugs, the following by-effects increase in an interval of QT, ventricular arrhythmia (fibrillation of auricles, ventricular tachycardia) can meet, unexpected and inexplicable death, a cardiac standstill and ventricular tachycardia on the pirouette type At reception of antipsychotic drugs were revealed cases of a venous thromboembolism, including cases of an embolism of lungs and cases of a deep vein thrombosis.

Interaction with other medicines:

It is necessary to be careful at co-administration of the drug Invega® with the drugs extending QT interval.

Influence of a paliperidon on other drugs.

Paliperidon, most likely, does not participate in clinically significant pharmacokinetic interactions with drugs which are metabolized by isoenzymes of system of P450 cytochrome. The researches in vitro with use of microsomes of a liver of the person showed what палиперидон does not cause essential oppression of biotransformation of drugs which are metabolized by P450 cytochrome isoenzymes, including CYP1A4, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4 and CYP3A5. Proceeding from it, there are no bases to assume what палиперидон will inhibit clearance of drugs which are metabolized by the specified enzymes in clinically significant degree. In the researches in vitro палиперидон did not induce activity of isoenzymes of CYP1A2, CYP2C19 or CYP3A4.

In high concentration палиперидон is weak inhibitor of the R-glycoprotein. These in vivo are absent, the clinical importance is unknown.

Considering the fact that палиперидон affects preferential TsNS, it needs to be used with care in combinations with other drugs of the central action and with alcohol. Paliperidon can neutralize action of a levodopa and other agonists of dopamine. Owing to ability of a paliperidon to cause orthostatic hypotension there can be the additive effect when using drug along with other drugs causing orthostatic hypotension.

Pharmacokinetic interaction of a paliperidon and lithium a little possibly. Co-administration of the drug Invega® in a dosage of 12 mg once a day and tablets of sodium of a divalproyeks of the prolonged action (in a dosage of 500-2000 mg once a day) does not influence Valproatum pharmacokinetics. In clinical trials at the patients accepting a constant dose of Valproatum, concentration of Valproatum in a blood plasma did not differ from that for the patients accepting together with Valproatum the drug Invega® in a dosage of 3-15 mg.

Ability of other drugs to influence on палиперидон. Paliperidon is not substrate of isoenzymes CYP1A2, CYP2A6, CYP2C9, CYP2C19 and CYP3A5. It demonstrates low probability of its interaction with inhibitors or inductors of the specified enzymes. The researches in vitro revealed the minimum participation of isoenzymes of CYP2D6 and CYP3A4 in metabolism of a paliperidon, at the same time, there are no proofs that these isoenzymes play a significant role in metabolism of a paliperidon of in vitro or in vivo. The researches in vitro showed what палиперидон is R-glycoprotein substrate.

Paliperidon restrictedly is metabolized by CYP2D6 isoenzyme (see the section "Pharmacokinetics"). In a research on adult volunteers of interaction of a paliperidon with paroksetiny, potential inhibitor of an isoenzyme CYP2D6, did not observe clinically significant change of pharmacokinetics of a paliperidon.

Combined use of a paliperidon from 200 mg of carbamazepine two times a day caused reduction of Cmax and AUC of a paliperidon approximately for 37%. This reduction is caused by increase in clearance of a paliperidon by 35% as a result of induction by carbamazepine of renal R-of a glycoprotein. Small reduction of amount of the drug excreted in not changed look allows to assume that at combined use carbamazepine has insignificant influence on CYP metabolism or bioavailability of a paliperidon. At purpose of carbamazepine the dose of a paliperidon has to be overpriced and increased if necessary. And, on the contrary, at carbamazepine cancellation the dose of a paliperidon has to be overpriced and reduced if necessary.

Paliperidon, being a cation at physiological values рН, is excreted preferential in an invariable look by kidneys; at the same time about a half of excretion falls to the share of filtering and about a half – on a share of active secretion. Use of a paliperidon along with Trimethoprimum which, as we know, inhibits active renal transport of cationic drugs did not influence pharmacokinetics of a paliperidon.

At co-administration of the drug Invega® in a dosage of 12 mg once a day and tablets of sodium of a divalproyeks of the prolonged action (2 tablets on 500 mg once a day) increase in Cmax and AUC of a paliperidon by 50% was observed. It is necessary to consider the possibility of reduction of a dose of the drug Invega® at co-administration with Valproatum on the basis of clinical assessment of the patient.

Simultaneous use of a paliperidon and risperidon was not a subject of scientific research. Paliperidon is an active metabolite of a risperidon and therefore at simultaneous use of a paliperidon and risperidon increase in levels of a paliperidon in blood is possible.

Contraindications:

It is contraindicated to patients with hypersensitivity to a paliperidon, a risperidon, and also to any auxiliary ingredient of drug.

With care.

Convulsive states in the anamnesis and the diseases reducing a threshold of convulsive readiness As well as other anti-psychotics палиперидон should be applied with care at the patients having the convulsive attacks or other diseases reducing a threshold of convulsive readiness in the anamnesis.

Dysphagy and narrowing of a gleam of digestive tract (possibility of obstruction). The tablets Invega® are not deformed and almost do not change the form in digestive tract and therefore patients should not appoint them with strong narrowing of a gleam of a gastro intestinal path (pathological or iatrogenic), and also to patients who suffer from a dysphagy or it is difficult for them to swallow of tablets. There are rare messages on the symptoms of obstruction of digestive tract connected with intake of non-deformable dosage forms with controlled release of active substance. Paliperidon treats too such dosage forms and therefore only those patients who can swallow of tablets entirely can appoint him.

Elderly patients with dementia. Efficiency and safety of a paliperidon did not estimate at elderly patients with dementia. Meta-analysis of 17 placebos - controlled researches showed that at the elderly patients with dementia receiving atypical antipsychotic drugs, such as рисперидон, арипипразол, olanzapine and кветиапин, was observed higher death rate in comparison with the patients receiving placebo. Placebo-controlled researches in which elderly patients with dementia participated showed the increased frequency of cerebrovascular undesirable effects (strokes and the tranzitorny ischemic attacks), including from the death, at the patients receiving some atypical antipsychotic drugs including рисперидон, арипипразол and olanzapine in comparison with patients who received placebo.

Parkinson's disease and dementia with Levi's little bodies. Doctors have to weigh attentively possible risks and potential advantage at purpose of antipsychotic drugs, including палиперидон, to the patients having Parkinson's disease or dementia with Levi's little bodies as at such patients the risk of development of a malignant antipsychotic syndrome or hypersensitivity to antipsychotic drugs can be increased. Manifestations of this hypersensitivity include, in addition to extrapyramidal symptoms, confusion of consciousness, a prituplennost of reactions iposturalny hypotension with frequent falling.

 

Overdose:

In general, objective and subjective symptoms of overdose of a paliperidon represent the strengthened pharmacological effects of this medicine, i.e. drowsiness and sedation, tachycardia and arterial hypotension, lengthening of an interval of QT and extrapyramidal symptoms. Bidirectional tachycardia and fibrillation of ventricles was observed at overdose by a peroral paliperidon. At acute overdose it is necessary to consider a possibility of toxic effect of several drugs. At assessment of therapeutic needs of the patient and efficiency of stopping of overdose it is necessary to remember that Invega® is drug with the prolonged release of active ingredient. The specific antidote of a paliperidon does not exist. It is necessary to carry out the standard supporting measures. It is necessary to provide and maintain good passability of respiratory tracts, and also adequate oxygenation and ventilation. It is necessary to organize at once monitoring of cardiovascular activity (ECG monitoring for the purpose of detection of possible arrhythmias). Arterial hypotension and kollaptoidny states are stopped intravenous administration of plasma substituting solutions and/or sympathomimetic means. In certain situations the gastric lavage (after an intubation if the patient is in unconsciousness), administration of absorbent carbon and purgatives is shown. At emergence of heavy extrapyramidal symptoms it is necessary to enter m-holinoblokatory. Observation of a condition of the patient and monitoring of the main physiological functions need to be continued before full elimination of effects of overdose.

Storage conditions:

To store at a temperature from 15 to 30 °C. To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Tablets of the prolonged action, coated, 3, 6, 9 and 12 mg. On 7 tablets, coated, in the blister from the aluminum and polyvinylchloride laminated by polychlorotrifluoroethylene. On 4 or 8 blisters together with the instruction on a medical use in a cardboard pack. On 30 tablets, coated, in bottles from polyethylene of high density, with the cover protecting from accidental opening by children. On one bottle together with the instruction on a medical use in a cardboard pack. Existence of control of the first opening in the form of stickers/stickers is possible (with one or from 2 parties of a cardboard pack).