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Instruction for use: Invega

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Dosage form: tablets

Active substance: Paliperidone*

ATX

N05AX13 Paliperidone

Pharmacological group:

Neuroleptics

The nosological classification (ICD-10)

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

F25 Schizoaffective disorders: Schizoaffective disorders; Schizoaffective psychosis; Schizoaffective disorder

Composition

Tablets of prolonged action, covered with a coating.

active substance:

paliperidone 3 mg

auxiliary substances: Macrogol 200K - 81.43 mg; macrogol 7000K - 73.7 mg; sodium chloride - 30 mg; Povidone (K29-32) - 10 mg; hyetylose - 10.45 mg; stearic acid - 0.75 mg; butylhydroxytoluene - 0.11 mg; iron oxide red - 1 mg; iron oxide yellow - 0.03 mg; macrogol 3350 - 1 mg; cellulose acetate (398-10) - 44.55 mg; dye white (hypromellose, titanium dioxide, lactose monohydrate, triacetin) - 33 mg; carnauba wax - 0.03 mg

Tablets of prolonged action, covered with a coating.

active substance:

paliperidone 6 mg

auxiliary substances: Macrogol 200K - 78.45 mg; macrogol 7000K - 73.7 mg; sodium chloride - 30 mg; Povidone (K29-32) - 10 mg; hyetylose - 10.45 mg; stearic acid - 0.75 mg; butylhydroxytoluene - 0.11 mg; iron oxide red - 1.01 mg; macrogol 3350 - 1 mg; cellulose acetate (398-10) - 44.55 mg; dye beige (hypromellose, titanium dioxide, polyethylene glycol 400, iron oxide yellow, iron oxide red) - 18 mg; carnauba wax - 0.03 mg

Tablets of prolonged action, covered with a coating.

active substance:

paliperidone 9 mg

auxiliary substances: Macrogol 200K - 75.45 mg; macrogol 7000K - 73.7 mg; sodium chloride - 30 mg; Povidone (K29-32) - 10 mg; hyetylose - 10.45 mg; stearic acid - 0.75 mg; butylhydroxytoluene - 0.11 mg; iron oxide black - 0.01 mg; iron oxide red - 1 mg; macrogol 3350 - 1 mg; cellulose acetate (398-10) - 44.55 mg; dye pink (hypromellose, titanium dioxide, polyethylene glycol 400, iron oxide red) - 15 mg; carnauba wax - 0.03 mg

Tablets of prolonged action, covered with a coating.

Pharmacodynamics

Mechanism of action

Paliperidone is a centrally acting antagonist of dopamine D2 receptors, which also has a high antagonism for serotonin 5-HT2 receptors. In addition, paliperidone is an antagonist of α1 and α2-adrenergic receptors and H1-histamine receptors. Paliperidone does not have affinity for cholinergic, muscarinic, and β1- and β2-adrenergic receptors. The pharmacological activity of the (+) and (-) - enantiomers of paliperidone is the same in qualitative and quantitative terms.

The antipsychotic effect is due to the blockade of D2-dopaminergic receptors of the mesolimbic and mesocortical system. It causes less inhibition of motor activity and to a lesser degree induces catalepsy than classical antipsychotics (antipsychotics).

A balanced central antagonism to serotonin and dopamine can reduce the propensity to extrapyramidal side effects and expand the therapeutic effect of the drug to include negative and productive symptoms of schizophrenia.

Paliperidone has an effect on the structure of sleep: reduces the latent period before falling asleep, reduces the number of awakenings after falling asleep, increases the total duration of sleep, prolongs sleep time, and increases the index of sleep quality. Has antiemetic effect, can cause an increase in the concentration of prolactin in the blood plasma.

Pharmacokinetics

Unless otherwise specified, the pharmacokinetic data presented in this section are based on data obtained for adult patients. The pharmacokinetic characteristics of paliperidone after ingestion are proportional to the dose taken in the recommended therapeutic range (3-12 mg once a day).

Absorption

After taking one dose of the drug, the concentration of paliperidone in the plasma increased steadily, and Cmax was reached after 24 hours. In most patients, equilibrium concentrations of paliperidone were achieved after 4-5 days of taking the drug 1 time per day. Paliperidone is an active metabolite of risperidone. Features of the release of the active ingredient from Invega® provided smaller fluctuations in the maximum and minimum concentrations of paliperidone than those observed with conventional dosage forms (concentration fluctuation index 38% compared to 125% for conventional dosage forms).

After taking the tablets of paliperidone, the (+) and (-) enantiomers are mutually converted, and the ratio of AUC-AUC (+) / AUC (-) - in the equilibrium state is about 1.6. The absolute bioavailability of paliperidone after oral administration is 28% (23-33% with a confidence interval of 90%). After a single administration, 15 mg of paliperidone in the form of a sustained release tablet together with fatty high-calorie food Cmax and AUC increased by an average of 42 and 46%, respectively, relative to the same indices when taking the fasting tablet. In another study, after a single dose of 12 mg of paliperidone in the form of a sustained release tablet together with fatty high-calorie food, Cmax and AUC increased by an average of 60% and 54%, respectively, relative to the same indices when taking the fasting tablet. Thus, the presence or absence of food during the reception of paliperidone may alter the concentration of paliperidone in the blood plasma.

Distribution

Paliperidone is quickly distributed in tissues and body fluids. Apparent Vd - 487 liters. The degree of binding to plasma proteins is 74%. Paliperidone binds primarily to the α1-acid glycoprotein and albumin.

Biotransformation and elimination

After 1 week after taking one standard tablet containing 1 mg of paliperidone, 59% of the dose was excreted unchanged in the urine; this indicates that paliperidone does not undergo intensive metabolism in the liver. About 80% of the drug was found in urine and about 11% in feces. There are four ways of metabolizing paliperidone in vivo, none of which covers more than 6.5% of the dose: dealkylation, hydroxylation, dehydrogenation, and cleavage of benzisoxazole. In vitro studies have shown that cytochrome P450 CYP2D6 and CYP3A4 isoenzymes may play a role in the metabolism of paliperidone, but evidence that they play a significant role in the metabolism of paliperidone in vivo has not been obtained. Although the activity of the CYP2D6 isoenzyme varies significantly in the general population, population pharmacokinetic studies have not revealed significant differences in the apparent clearance of paliperidone in patients with active metabolism of CYP2D6 isoenzyme substrates and in patients with a weak metabolism of CYP2D6 isoenzyme substrates. In vitro studies using microsomal preparations of heterologous systems have shown that the isoenzymes CYP1A2, CYP2A6, CYP2C9, CYP2C19 and CYP3A5 are not involved in the metabolism of paliperidone.

The final T1 / 2 paliperidone is about 23 hours.

In vitro studies have shown that paliperidone is a substrate of P-glycoprotein and weakly inhibits it at high concentrations. In vivo data are not available, clinical significance is unknown.

Special Groups

Patients with impaired hepatic function. Paliperidone does not undergo intensive metabolism in the liver. In patients with mild and moderate impairment of liver function, there is no need to reduce the dose of paliperidone. A study in which patients with moderate impaired hepatic function (class B Child-Pugh classification) participated showed that in these patients the concentrations of unbound plasma paliperidone were similar to those in healthy people. The use of Invega® in patients with severe impairment of liver function has not been studied.

Patients with impaired renal function. The dose of paliperidone should be reduced in patients with moderate and severe renal dysfunction. Paliperidone excretion was studied in patients with varying degrees of renal dysfunction. It was found that the elimination of paliperidone decreased as the clearance of creatinine decreased. The total clearance of paliperidone was reduced by 32% in patients with mild renal impairment (Cl creatinine from 50 to <80 mL / min), by 64% in patients with moderate renal impairment (Cl creatinine 30 to <50 mL / min) and 71% in patients with severe impaired renal function (Cl creatinine 10 to <30 mL / min). The mean final T1 / 2 paliperidone was 24, 40 and 51 h in patients with mild, moderate and severe renal dysfunction, respectively; in people with normal renal function (Cl creatinine> 80 ml / min), this value was 23 hours.

Teenagers. The systemic effect of paliperidone on adolescents was comparable to that of adults. The concentration of paliperidone in blood plasma in adolescents with a body weight <51 kg is 23% higher than in adolescents with a body weight of ≥51 kg, which is clinically insignificant. Age does not affect the concentration of paliperidone in plasma.

Elderly patients. It is not recommended to change the dose of paliperidone depending on the age of the patient. Results of a pharmacokinetic study in which elderly patients aged 65 years and older participated, showed that the apparent clearance of paliperidone in the equilibrium state after taking Invega® in this group was 20% lower than in adult patients aged 18-45 years. However, after making an adjustment to the age-related decline in creatinine clearance, population analysis did not reveal the effect of the age of schizophrenic patients on the pharmacokinetics of paliperidone.

Race affiliation. Dosage adjustment for patients of different race is not required. Population pharmacokinetic analysis showed no racial differences in the pharmacokinetics of paliperidone when using Invega®. There were no differences in pharmacokinetics in studies of Japanese and Caucasoids.

Floor. The recommended doses of paliperidone are the same for men and women. The apparent clearance of paliperidone after taking the drug in women is about 19% lower than that of men. This difference is mainly due to differences in the fat-free body weight and creatinine clearance between men and women, since population studies, after adjusting for the non-fat component of body weight and creatinine clearance, did not reveal clinically significant differences in the pharmacokinetics of paliperidone in men and women taking the drug.

Smoking. It is not recommended to change the doses of paliperidone in smokers. in vitro studies using human liver enzymes have shown that paliperidone is not a substrate of isoenzyme CYP1A2, and therefore smoking should not affect the pharmacokinetics of paliperidone. According to the results of in vitro studies, population studies have not revealed differences in the pharmacokinetics of paliperidone between smokers and non-smokers.

Indications of the Invega

schizophrenia, incl. in the phase of exacerbation in adult patients;

prevention of exacerbations of schizophrenia in adults;

treatment of schizophrenia in adolescents aged 12 to 17 years;

treatment of schizoaffective disorder: as monotherapy or in combination therapy with antidepressants and / or mood stabilizers in adult patients.

Contraindications

Contraindicated in patients with hypersensitivity to paliperidone, risperidone, as well as any auxiliary ingredient of the drug.

With caution: convulsive conditions in the anamnesis and diseases that reduce the threshold of convulsive readiness. Like other antipsychotics, paliperidone should be used with caution in patients with a history of seizures or other conditions that reduce the seizure threshold.

Dysphagia and narrowing of the lumen of the digestive tract (the possibility of obstruction). Invega® tablets do not deform and almost do not change their shape in the digestive tract, and therefore they should not be prescribed to patients with severe narrowing of the lumen of the gastrointestinal tract (pathological or iatrogenic), as well as to patients who suffer from dysphagia or who are difficult to swallow tablets. There are rare reports of symptoms of GI tract obstruction associated with ingestion of non-deformable dosage forms with controlled release of the active substance. Paliperidone also refers to such dosage forms, and therefore it can be prescribed only to those patients who can swallow tablets whole.

Elderly patients with dementia. The efficacy and safety of paliperidone was not assessed in elderly patients with dementia. A meta-analysis of 17 placebo-controlled trials showed that elderly patients with dementia who received atypical antipsychotics such as risperidone, aripiprazole, olanzapine, and quetiapine had a higher mortality rate compared to patients receiving placebo. Placebo-controlled trials involving elderly patients with dementia demonstrated an increased incidence of cerebrovascular unwanted effects (strokes and transient ischemic attacks), including fatal, in patients treated with some atypical antipsychotics, which included risperidone, aripiprazole, and olanzapine, compared with patients who received placebo.

Parkinson's disease and dementia with Levy bodies. Doctors should carefully weigh the possible risks and potential benefits of prescribing antipsychotics, including paliperidone, to patients with Parkinson's disease or dementia with Levy bodies, since such patients may have increased risk of developing neuroleptic malignant syndrome (CNS) or increased sensitivity to antipsychotics. Manifestations of this hypersensitivity include, in addition to extrapyramidal symptoms, confusion, dull reactions and postural hypotension with frequent falls.

Application in pregnancy and lactation

At present, there is no data on the safety of paliperidone for pregnant women and intrauterine fetal development. The drug can be used in pregnant women only in case of emergency, when the potential benefit to the mother exceeds the possible risk to the fetus. The effect of paliperidone on the generic activity of women is unknown. In the case of a woman taking antipsychotic medications (including paliperidone) in the third trimester of pregnancy, newborns are at risk of extrapyramidal disorders and / or withdrawal syndrome of varying severity. These symptoms may include agitation, hypertension, hypotension, tremor, drowsiness, respiratory disorders, and breast-feeding disorders. Therefore, it is necessary to carry out special monitoring of newborns. If it is necessary to interrupt treatment during pregnancy, then gradually reduce the dose.

Paliperidone in clinically significant doses penetrates into breast milk; therefore, the drug should not be administered during lactation.

Side effects

The undesirable effects observed in patients are listed below. The incidence of adverse effects was classified as follows: very often (≥10%); often (≥1 and <10%); infrequently (≥0.1 and <1%); rarely (≥0.01 and <0.1%) and very rarely (<0.01%).

Infections: often - infections of the upper respiratory tract, nasopharyngitis; infrequently - urinary tract infections, acrodermatitis, bronchitis, inflammation of subcutaneous fat, cystitis, ear infections, influenza, onychomycosis, pneumonia, respiratory infections, sinusitis, tonsillitis.

From the immune system: infrequently - anaphylactic reaction, hypersensitivity.

From the hematopoietic and lymphatic system: infrequently - anemia, a decrease in hematocrit, neutropenia, a decrease in the number of leukocytes; rarely - thrombocytopenia; very rarely - agranulocytosis.

From the endocrine system: infrequently - giperprolaktinemiya; very rarely - inadequate secretion of ADH.

From the side of metabolism and nutrition: infrequently - increased activity of CK, anorexia, hyperglycemia; rarely - diabetes, hypoglycemia, water intoxication; very rarely diabetic ketoacidosis.

Disorders of the psyche: often - insomnia (including initial and average insomnia), mania; infrequently - nightmarish dreams, sleep disturbances, depression.

From the nervous system: very often - headache; often - akathisia, dystonia, dysarthria, increased muscle tone, parkinsonism, sedative effect, drowsiness, tremor, salivation; infrequently - cerebrovascular disorders, postural dizziness, dyskinesia, convulsions, fainting, attention disturbance, hypoesthesia, loss of consciousness, paresthesia, psychomotor hyperactivity, tardive dyskinesia, hypokinesia, opisthotonus.

It is known that antipsychotic drugs, including paliperidone, can cause CNS, which is characterized by hyperthermia, muscle rigidity, autonomic nervous system instability, depression of consciousness, increased activity of CK, myoglobinuria, rhabdomyolysis, acute renal insufficiency.

On the part of the organs of vision: infrequently - conjunctivitis, dry eyes, photophobia, lacrimation; with an unknown frequency - a syndrome of flabby iris (intraoperative).

From the side of the hearing organ and labyrinthine disorders: infrequently - pain in the ears, vertigo, ringing in the ears.

On the part of the CVS: infrequent - bradycardia, palpitations, AV blockade, conduction disturbance, ECG changes, QT interval increase, ischemia, high blood pressure, increased blood pressure, lowering blood pressure; rarely - atrial fibrillation; very rarely - deep vein thrombosis, pulmonary embolism.

From the gastrointestinal tract: often - nausea, diarrhea, constipation, discomfort in the upper abdomen, dyspepsia, increased appetite; infrequent - decreased appetite, inflammation of the lips, dysphagia, stool incontinence, small intestine obstruction, flatulence, gastroenteritis, edema of the tongue, toothache, dysgeusia; very rarely - pancreatitis, intestinal obstruction.

From the liver and biliary tract: very rarely - jaundice.

On the part of the respiratory system: infrequently - pain in the pharyngeal region, nasal congestion, cough, shortness of breath, hyperventilation of the lungs, wheezing; rarely - sleep apnea syndrome.

From the musculoskeletal and connective tissue: often - myalgia, musculoskeletal pain; infrequently - muscle spasms, back pain, arthralgia, joint stiffness, swelling of the joint, muscle weakness, neck pain.

From the skin and subcutaneous tissues: infrequently - rash, itching, acne, dry skin, eczema, erythema, seborrheic dermatitis, discoloration of the skin; rarely - Quincke's edema, alopecia.

From the side of the kidneys and urinary tract: infrequently - dysuria, pollakiuria, urinary incontinence, urinary retention.

From the genitals and the breast: infrequently - decreased libido, anorgasmia, discharge from the nipples, erectile dysfunction, gynecomastia, changes in the menstrual cycle, sexual dysfunction, vaginal discharge, ejaculation, breast engorgement; very rarely - priapism.

Influence on the course of pregnancy, postpartum and perinatal conditions: very rarely - withdrawal syndrome in newborns.

Others: often - weight gain; infrequently - weight loss, chills, edema of the face, gait disturbance, edema (including generalized, peripheral, soft), increased body temperature, fever, thirst; very rarely - hypothermia.

Laboratory Tests: infrequently, an increase in GGT activity, an increase in the activity of liver enzymes, an increase in the activity of transaminases, an increase in the concentration of cholesterol in the blood, an increase in the concentration of triglycerides in the blood. Information on dose-related side effects is given in Tables 1 and 2.

Table 1

Adverse events reported in ≥2% of adult schizophrenic patients receiving Invega® in clinical trials

System of organs / side effects 3 mg 1 per a day, % 6 mg 1 per a day, % 9 ěmg1 per a day, % 12 mg 1 per a day, % Placebo, %
From the nervous system
headache 11 12 14 14 12
dizziness 6 5 4 5 4
extrapyramidal disorders * 5 2 7 7 2
drowsiness 5 3 7 5 3
akathisia 4 3 8 10 4
tremor 3 3 4 3 3
hypertension 2 1 4 3 1
dystonia 1 1 4 4 1
sedative effect 1 5 3 6 4
parkinsonism 0 <1 2 1 0
From the side of the organs of sight
oculogic crises 0 0 2 0 0
On the part of the CAS
sinus tachycardia 9 4 4 7 4
tachycardia 2 7 7 7 3
block bundle of the bundle 3 1 3 <1 2
AV blockade of the I degree 2 0 2 1 1
sinus arrhythmia 2 1 1 <1 0
orthostatic hypotension 2 1 2 4 1
Gastrointestinal disorders
vomiting 2 3 4 5 5
dry mouth 2 3 1 3 1
pain in the upper abdomen 1 3 2 2 1
hypersalivation 0 <1 1 4 <1
Common violations
asthenia 2 <1 2 2 1
fatigue 2 1 2 2 1
Table 2Adverse events reported in ≥2% of adolescents 12-17 years with schizophrenia receiving Invega®, in clinical trials
System of organs / side effects 1,5 mg 1 per a day, % 3 mg 1 per a day, % 6 mg 1 per a day, % 12 mg 1 per a day, % Placebo, %
On the part of the CAS
tachycardia 0 6 9 6 0
From the side of the organs of sight
blurred vision 0 0 0 3 0
Gastrointestinal disorders
dry mouth 0 0 0 3 2
hypersalivation 2 6 2 0 0
swelling of the tongue 0 0 0 3 0
vomiting 0 6 11 3 10
Common violations
asthenia 0 0 2 3 0
fatigue 4 0 2 3 0
Infections
nasopharyngitis 4 0 4 0 2
Laboratory Tests
weight gain 7 6 2 3 0
From the nervous system
akathisia 4 6 11 17 0
dizziness 2 6 2 3 0
extrapyramidal disorders * 4 19 18 23 0
headache 9 6 4 14 4
lethargy 0 0 0 3 0
drowsiness 9 13 20 26 4
paralysis of the tongue 0 0 03 0
Mental disturbance
anxiety 0 0 2 9 4
From the genitals and breast
amenorrhea 0 6 0 0 0
galactorrhea 0 0 4 0 0
swelling of the mammary glands 0 0 0 3 0
From the respiratory system
nose bleed 0 0 2 0 0

* Extrapyramidal disorders include: oculogic crisis, muscle rigidity, musculoskeletal rigidity, stiffness in the occiput, torticollis, trismus, bradykinesia, cogwheel, dyskinesia, dystonia, extrapyramidal disorders, hypertension, hypokinesia, involuntary muscular contractions, parkinsonism gait, parkinsonism, tremor and anxiety. Drowsiness includes drowsiness sedation and hypersomnia. Insomnia includes insomnia and initial insomnia. Tachycardia includes tachycardia, sinus tachycardia, and an increase in heart rate. Hypertension includes hypertension and increased blood pressure. Gynecomastia includes gynecomastia and swelling of the breast.

Paliperidone is an active metabolite of risperidone, however, according to the release profile and pharmacokinetic characteristics, the preparation of Invega significantly differs from the dosage forms of risperidone for oral administration with immediate release. Side effects reported with risperidone may be observed with paliperidone.

Elderly patients. In clinical trials conducted with elderly patients with schizophrenia, the drug safety profile was the same as for younger patients. Invega® was not studied in patients with dementia. In studies with other antipsychotic drugs, an increased risk of death and cerebrovascular disorders was noted. In elderly patients with dementia, the risk of a stroke increases.

Other reported cases

Extrapyramidal symptom. In the clinical studies conducted, there was no difference in taking placebo, a dosage of 3 mg and a dosage of 6 mg. Dose-dependent extrapyramidal symptoms were documented by taking high doses of Invega® (9 and 12 mg). In clinical trials of schizoaffective disorders, cases of extrapyramidal syndrome were detected at all doses of Invega ® in all patient groups without an explicit relationship with dosages.

Extrapyramidal disorders included the following symptoms: dyskinesia, dystonia, hyperkinesia, parkinsonism and tremor.

Weight gain. In clinical studies in patients with schizophrenia, the ratio of cases of body weight increase of more than 7% of the constant body weight was compared. Approximately the same ratio was found with Invega® 3 and 6 mg in comparison with placebo and a higher probability of weight gain was found for Invega® 9 and 12 mg in comparison with placebo.

In clinical studies of patients with schizoaffective disorders, a higher percentage of patients taking Invega® (5%) experienced a weight gain of more than 7% compared to patients taking placebo (1%). In this study, 27 patients were divided into 2 groups, an increase in body weight of more than 7% when taking low doses of Invega® (3 and 6 mg) was 3% for patients taking high doses of Invega® (9 and 12 mg) - 7% and 1% in the group where patients took placebo.

Laboratory indicators. In clinical studies of patients with schizophrenia, an increase in serum prolactin concentration was noted with the ingestion of Invega® in 67% of patients. Adverse reactions that may suggest an increase in the level of prolactin (eg amenorrhea, galactorrhea, gynecomastia) have been reported in more than 2% of cases. The maximum increase in prolactin concentration in the serum was observed on the 15th day of treatment, and remained above the usual level until the end of treatment.

Class effects. When taking antipsychotics, the following side effects can occur: increased QT interval, ventricular arrhythmia (atrial fibrillation, ventricular tachycardia), unexpected and unexplained death, cardiac arrest and ventricular tachycardia of the pirouette type. When receiving antipsychotic drugs, cases of venous thromboembolism, including cases of pulmonary embolism and deep vein thrombosis, were identified.

Interaction

Care should be taken when concomitantly administering Invega® with drugs that extend the QT interval.

Effect of paliperidone on other drugs

Paliperidone, most likely, does not participate in clinically significant pharmacokinetic interactions with drugs that are metabolized by isoenzymes of the cytochrome P450 system. In vitro studies using human liver microsomes have shown that paliperidone does not significantly inhibit the bioconversion of drugs that are metabolized by cytochrome P450 isoenzymes, including CYP1A4, CYP2A6, CYP2C8 / 9/10, CYP2D6, CYP2E1, CYP3A4 and CYP3A5. Based on this, there is no reason to assume that paliperidone will inhibit clinically significant clearance of drugs that are metabolized by these enzymes. In studies in vitro, paliperidone did not induce the activity of isoenzymes CYP1A2, CYP2C19 or CYP3A4.

In high concentrations, paliperidone is a weak inhibitor of P-glycoprotein. In vivo data are not available, clinical significance is unknown.

Given the fact that paliperidone acts primarily on the central nervous system, it must be used with caution in combination with other drugs of central action and alcohol.

Paliperidone can neutralize the effects of levodopa and other dopamine agonists. Due to the ability of paliperidone to cause orthostatic hypotension, there can be an additive effect when using the drug simultaneously with other drugs that cause orthostatic hypotension.

The pharmacokinetic interaction between paliperidone and lithium is unlikely.

Simultaneous administration of Invega® in a dosage of 12 mg once a day and sodium divalproex tablets of prolonged action (at a dosage of 500-2000 mg once a day) does not affect the pharmacokinetics of valproate. In clinical studies in patients taking a constant dose of valproate, the concentration of valproate in the blood plasma did not differ from that for patients taking the drug Invega® with a dose of 3-15 mg with valproate.

The ability of other drugs to affect paliperidone

Paliperidone is not a substrate for the isoenzymes CYP1A2, CYP2A6, CYP2C9, CYP2C19 and CYP3A5. This indicates a low probability of its interaction with inhibitors or inducers of these enzymes. In vitro studies have revealed minimal participation of CYP2D6 and CYP3A4 isoenzymes in the metabolism of paliperidone, however, there is no evidence that these isozymes play a significant role in the metabolism of paliperidone in vitro or in vivo. In vitro studies have shown that paliperidone is a substrate of P-glycoprotein. Paliperidone is boundedly metabolized by the CYP2D6 isoenzyme (see "Pharmacokinetics"). In a study in adult volunteers of the interaction of paliperidone with paroxetine, a potential inhibitor of the isoenzyme CYP2D6, there was no clinically significant change in the pharmacokinetics of paliperidone.

The combined use of paliperidone with 200 mg of carbamazepine 2 times a day caused a decrease in Cmax and AUC of paliperidone by about 37%. This decrease is caused by an increase in clearance of paliperidone by 35% as a result of induction of renal P-glycoprotein by carbamazepine. A slight decrease in the amount of the drug excreted unchanged suggests that, when combined, carbamazepine has little effect on the CYP-mediated metabolism or bioavailability of paliperidone. When prescribing carbamazepine, the dose of paliperidone should be overestimated and increased if necessary. Conversely, with the withdrawal of carbamazepine, the dose of paliperidone should be overestimated and reduced if necessary.

Paliperidone, which is a cation at physiological pH values, is excreted mainly unchanged in kidneys; while about half of the excretion falls on the share of filtration and about half - on the share of active secretion. The use of paliperidone concomitantly with trimethoprim, which is known to inhibit the active renal transport of cationic preparations, did not affect the pharmacokinetics of paliperidone.

With simultaneous administration of Invega® in a dosage of 12 mg once a day and sodium divalproex tablets of prolonged action (2 tablets at 500 mg once a day), an increase in Cmax and AUC of paliperidone by 50% was observed. It should be considered the possibility of reducing the dose of Invega® with simultaneous administration with valproate on the basis of clinical evaluation of the patient.

The simultaneous use of paliperidone and risperidone was not the subject of scientific research. Paliperidone is an active metabolite of risperidone, and therefore, with the simultaneous use of paliperidone and risperidone, it is possible to increase the levels of paliperidone in the blood.

Dosing and Administration

Inside, the tablets should be swallowed whole, squeezed with liquid, they can not be chewed, divided into parts or chopped.

Schizophrenia

Adults (over 18 years). The recommended dose in adults is 6 mg once a day, in the morning, regardless of food intake. A gradual increase in the initial dose is not required. In some patients, the therapeutic effect causes lower or higher doses within the recommended range of 3-12 mg once daily. There is a general tendency to increase the effect when using large doses of the drug. In case the dose increase is necessary, it is recommended to increase the dose by 3 mg per day at intervals of more than 5 days.

Teenagers (12-17 years old). The recommended dose for adolescents is 3 mg 1 time per day, in the morning, regardless of food intake. A gradual increase in the initial dose is not required. In some patients, the therapeutic effect causes higher doses within the recommended range of 6-12 mg once a day. The dose increase is possible only after a clinical reassessment, with an increase in the dose of 3 mg per day at intervals of more than 5 days.

Schizoaffective disorder

Adults (over 18 years). The recommended dose for adults is 6 mg once a day, in the morning. A gradual increase in the initial dose is not required. In some patients, the therapeutic effect causes lower or higher doses within the recommended range of 6-12 mg once daily. An increase in the dose, if necessary, should be performed only after an assessment of the patient's clinical condition. In case the dose increase is necessary, it is recommended to increase the dose by 3 mg / day at intervals of more than 4 days. Supportive therapy in patients with schizoaffective disorders has not been studied.

Patients with impaired hepatic function. In patients with mild to moderate liver function, no dose reduction is required. The use of Invega® in patients with severe impairment of liver function has not been studied.

Patients with impaired renal function. For patients with mild renal impairment (Cl creatinine ≥50, but <80 mL / min), the recommended initial dose is 3 mg 1 time per day. This dose can be increased to 6 mg once a day after assessing the patient's condition and taking into account the tolerability of the drug. For patients with moderate or severe renal dysfunction (Cl creatinine ≥10, but <50 mL / min), the recommended dose is 3 mg 1 time per day. The use of Invega® in patients with Cl creatinine <10 ml / min has not been studied, and therefore it is not recommended to prescribe the drug to these patients.

Elderly patients. For elderly patients with normal renal function (Cl creatinine ≥80 ml / min), the same doses are recommended as for adult patients with normal renal function. However, in elderly patients, kidney function can be reduced, and in this case the dose of the drug should be selected according to the function of the kidney in a particular patient (see "Patients with impaired renal function"). Caution should be exercised when using the drug in elderly patients with dementia due to an increased risk of stroke. The efficacy and safety of Invega® in patients over 65 years of age with schizoaffective disorders has not been studied.

Children and teenagers. The efficacy and safety of Invega® medicinal product for the treatment of schizophrenia in children younger than 12 years has not been studied. The efficacy and safety of Invega® medicinal product for the treatment of schizoaffective disorders in patients younger than 18 years of age has not been studied.

Special patient groups

It is not recommended to change the dose of paliperidone depending on sex, age and whether the patient smokes or not.

Transfer of patients to treatment with other antipsychotic drugs

At present, there is no systematically collected data on the transfer of patients from paliperidone treatment to treatment with other antipsychotic drugs. Pharmacodynamics and pharmacokinetics in different antipsychotics are not the same, and therefore doctors should closely monitor the condition of patients when transferring them from one antipsychotic to another.

Overdose

Symptoms: In general, the objective and subjective symptoms of paliperidone overdose are the enhanced pharmacological effects of this drug, i.e. drowsiness and sedation, tachycardia and arterial hypotension, prolongation of the QT interval and extrapyramidal symptoms. Bi-directional tachycardia and ventricular fibrillation were observed with an overdose of oral paliperidone. In case of acute overdose, it is necessary to consider the possibility of toxic effects of several drugs.

When assessing the therapeutic needs of the patient and the effectiveness of overdose management, it must be remembered that Invega® is a drug with a sustained release of the active ingredient.

Treatment: it is necessary to implement generally accepted supportive measures. It is necessary to ensure and maintain good airway patency, as well as adequate oxygenation and ventilation. It is necessary to immediately monitor cardiovascular activity (ECG monitoring in order to identify possible arrhythmias). Arterial hypotension and collapoid states are stopped iv by the introduction of plasma-substituting solutions and / or sympathomimetic agents. In certain situations, gastric lavage is shown (after intubation, if the patient is unconscious), the introduction of activated charcoal and laxatives. If severe extrapyramidal symptoms occur, m-holinoblockers should be administered. Monitoring of the patient's condition and monitoring of basic physiological functions must be continued until the consequences of overdose are completely eliminated. There is no specific antidote for paliperidone.

Special instructions

ZNS. It is known that antipsychotic drugs, including paliperidone, can cause CNS, which is characterized by hyperthermia, rigidity of muscles, instability of autonomic nervous system function, depression of consciousness, as well as increase in serum concentrations of CK. In patients with ZNS, myoglobinuria (rhabdomyolysis) and acute renal failure may also occur. If a patient develops objective or subjective symptoms of the NSA, all antipsychotics, including paliperidone, should be immediately discontinued.

Late dyskinesia. Drugs that have the properties of dopamine receptor antagonists can cause tardive dyskinesia, which is characterized by rhythmic involuntary movements, predominantly of the tongue and / or facial musculature. If the patient has objective or subjective symptoms that indicate tardive dyskinesia, it is necessary to consider the feasibility of the abolition of all antipsychotics, including paliperidone.

Elongation of the QT interval. As with other antipsychotics, caution should be exercised in prescribing Inveg® to patients with a history of cardiac arrhythmias, congenital QT interval elongation, and joint use with QT-prolonging drugs.

Hyperglycemia and diabetes mellitus. In the treatment with Invega ®, hyperglycemia, diabetes mellitus and exacerbation of already existing diabetes mellitus were observed. Establishing the relationship between the use of atypical antipsychotics and impaired glucose metabolism is complicated by an increased risk of developing diabetes in patients with schizophrenia and the prevalence of diabetes in the general population. Given these factors, the relationship between the use of atypical antipsychotics and the development of side effects associated with hyperglycemia has not been fully established. Patients with established diagnosis of diabetes should regularly monitor glucose levels. Patients with risk factors for developing diabetes (eg obesity, family history of diabetes) should undergo fasting blood glucose control at the beginning of treatment and periodically during treatment. In all patients, it is necessary to conduct clinical monitoring for the presence of symptoms of hyperglycemia and diabetes mellitus. Patients who have atypical antipsychotics develop symptoms of hyperglycemia should undergo glucose control in the blood. In some cases, symptoms of hyperglycemia disappeared with discontinuation of atypical antipsychotics, but some patients require antidiabetic treatment, despite discontinuation of the drug.

Weight gain. In the treatment with atypical antipsychotics, a significant increase in body weight was observed. It is necessary to monitor the body weight of patients.

Hyperprolactinemia. Like other antagonists of D2-dopamine receptors, paliperidone raises the level of prolactin, and this increase persists throughout the administration of the drug. The action of paliperidone is comparable to that of risperidone, the drug with the greatest effect on prolactin levels among other antipsychotics. Hyperprolactinaemia, regardless of etiology, can suppress the expression of GnRH hypotolamus, which leads to a decrease in the secretion of gonadotropins by the pituitary gland. This, in turn, can suppress reproductive function, weakening sexual steroidogenesis in women and men. In patients taking drugs that increase the level of prolactin, galactorrhea, amenorrhea, gynecomastia and impotence were recorded. Prolonged hyperprolactinaemia associated with hypogonadism can lead to a decrease in bone density in women and men.

Studies on tissue cultures in vitro have shown that approximately one third of breast cancer cases in humans are prolactin-dependent. This should be taken into account in the appointment of drugs that increase the level of prolactin, in patients with previously identified breast cancer. Clinical and epidemiological studies conducted to date have not shown a link between the use of atypical antipsychotics and the formation of tumors in humans. However, the available data are too limited to draw definitive conclusions.

Orthostatic hypotension. Paliperidone has α-blocking activity, and therefore can cause orthostatic hypotension in some patients. Paliperidone should be used with caution in patients with cardiovascular diseases (for example, heart failure, myocardial infarction or ischemia, cardiac muscle conduction disorders), cerebrovascular diseases, as well as with states conducive to arterial hypotension (eg, dehydration, hypovolemia and antihypertensive therapy).

Regulation of body temperature. Antipsychotic drugs attribute such an undesirable effect as a violation of the body's ability to regulate temperature. Caution should be exercised in appointing paliperidone to patients with conditions that can contribute to an increase in body internal temperature, including intensive physical activity, dehydration, exposure to high external temperatures, or simultaneous use of drugs with anticholinergic activity.

Antiemetic effect. In pre-clinical studies, antiemetic effect of paliperidone was detected. This effect, if it occurs in humans, can mask the objective and subjective symptoms of an overdose of certain drugs, as well as diseases such as intestinal obstruction, Reye's syndrome and brain tumors.

Priapism. Drugs that have α-adrenergic blocking effects can cause priapism. Post-marketing studies of paliperidone have been reported on the development of priapism.

Suicide attempts. The possibility of suicidal attempts is characteristic of mental illness, so the therapy of high-risk patients should be carefully monitored. In these cases, the preparation of Invega® should be prescribed in the minimum amount of tablets to reduce the risk of overdose.

Leukopenia, neutropenia, agranulocytosis. Leukopenia, neutropenia, and agranulocytosis were noted with the use of antipsychotics, incl. when using the drug Invega. Agranulocytosis was observed very rarely during postmarketing observations. Patients with a clinically significant reduction in the number of leukocytes in the history or drug-dependent leukopenia / neutropenia recommended a complete blood test during the first months of therapy; the cessation of treatment with Invega® should be considered at the first clinically significant decrease in the number of white blood cells in the absence of other possible causes. Patients with clinically significant neutropenia are advised to be observed for fever or symptom onset of infection and begin treatment immediately if such symptoms occur. Patients with severe neutropenia (absolute neutrophil counts less than 1 · 109 / L) should stop using Invega® until the white blood cell count is normalized.

Venous thromboembolism. When using antipsychotic drugs, cases of venous thromboembolism were noted. Since patients taking antipsychotics often have a risk of developing venous thromboembolism, all possible risk factors should be identified before and during treatment with Invega® and precautionary measures are taken.

Intraoperative syndrome of sagging iris (ISDR). ISDR was observed during the operative intervention for the presence of cataract in patients receiving therapy with the group of α 1 -adrenoreceptor antagonists. The ISDR increases the risk of complications associated with the organ of vision, during and after the operation. The physician conducting such an operation should be informed in advance that the patient has or is currently taking drugs that have α 1 -adrenoreceptor antagonist activity. The potential benefit of the abolition of α1-adrenergic antagonists before surgery is not established, and should be evaluated taking into account the risks associated with the abolition of antipsychotic medications.

Pregnancy and childcare. The patient should notify his doctor about pregnancy or its planning during treatment with Invega®. Caution should be exercised when prescribing Invega® to nursing mothers (see "Application for Pregnancy and Breastfeeding").

Alcohol consumption. Patients should avoid alcohol during treatment with Invega®.

Conditions leading to a decrease in the location of the drug in the digestive tract. Conditions that lead to a decrease in the location of the drug in the digestive tract, for example, diseases associated with chronic diarrhea, can cause a decrease in absorption of paliperidone.

Invega® tablets are manufactured using the osmotic release technology of the active substance, in which the osmotic pressure releases paliperidone at a controlled rate. The system, outwardly resembling a capsular tablet, consists of an osmotically active three-layer core surrounded by an intermediate membrane and a semipermeable membrane. The three-layered core consists of two medicinal layers containing the drug substance and auxiliary substances, as well as an ejecting layer containing osmotically active components. On the dome on the side of medicinal layers there are two outlets made with a laser. In the gastrointestinal tract, the colored membrane dissolves rapidly, water begins to enter the tablet through a semipermeable control membrane. The membrane controls the level of water intake, which in turn controls the level of release of the drug substance.

The hydrophilic polymers of the tablet core absorb water and swell, turning into a gel containing paliperidone, which is then ejected through the holes in the dome. Insoluble tablet components are excreted from the body with a stool. Patients should not worry if they notice something like a pill in the stool.

Influence on driving and working with machinery. Paliperidone may interfere with activities requiring a rapid mental reaction, and may also have visual effects, so patients should refrain from driving the car and working with the mechanisms until their individual sensitivity to paliperidone is established.

Release form

The tablets of the prolonged action covered with a cover, 3 mg, 6 mg, 9 mg and 12 mg.

By 7 tab. in a blister of aluminum and PVC, laminated with polychlorotrifluoroethylene. For 4 or 8 blisters in a cardboard box.

For 30 tablets. in a vial of HDPE, with a lid protecting against accidental opening by children. On 1 fl. in a cardboard box.

It is possible to have the first opening control in the form of a sticker / sticker (one or two sides of a cardboard bundle).

Conditions of leave from pharmacies

On prescription.

Storage conditions of the drug Invega

At a temperature of 15-30 ° C.

Keep out of the reach of children.

Shelf life of the drug Invega

2 years.

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

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