INVEGA

Active material: Paliperidone
When ATH: N05AX13
CCF: Antipsychotic drug (anxiolytic)
ICD-10 codes (testimony): F20, F21, F22, F23, F25, F29
When CSF: 02.01.02.03
Manufacturer: JOHNSON & JOHNSON LTD {Russia}

Pharmaceutical form, composition and packaging

Sustained-release tablets, coated white, kapsulovidnoy form, with an inscription “PAL 3”; outlets may be visible or invisible by visual inspection.

Excipients: macrogol 200K, macrogol 7000K, sodium chloride, povidone (K29-32), gietilloza, stearic acid, butylhydroksytoluol, iron oxide red, iron oxide yellow, macrogol 3350, cellulose acetate (398-10), dye white (gipromelloza, Titanium dioxide, lactose monohydrate, triacetine), carnauba wax.

7 PC. – blisters (4) – packs cardboard.
7 PC. – blisters (8) – packs cardboard.
30 PC. – plastic bottles (1) – packs cardboard.

Sustained-release tablets, coated light orange (It allowed a weak brownish tint), kapsulovidnoy form, with an inscription “PAL 6”; outlets may be visible or invisible by visual inspection.

Excipients: macrogol 200K, macrogol 7000K, sodium chloride, povidone (K29-32), gietilloza, stearic acid, butylhydroksytoluol, iron oxide red, macrogol 3350, cellulose acetate (398-10), beige coloring (gipromelloza, Titanium dioxide, polyethylene glycol 400, iron oxide yellow, iron oxide red), carnauba wax.

7 PC. – blisters (4) – packs cardboard.
7 PC. – blisters (8) – packs cardboard.
30 PC. – plastic bottles (1) – packs cardboard.

Sustained-release tablets, coated Pink colour (allowed grayish), kapsulovidnoy form, with an inscription “PAL 9”; outlets may be visible or invisible by visual inspection.

Excipients: macrogol 200K, macrogol 7000K, sodium chloride, povidone (K29-32), gietilloza, stearic acid, butylhydroksytoluol, iron oxide black, iron oxide red, macrogol 3350, cellulose acetate (398-10), pink dye (gipromelloza, Titanium dioxide, polyethylene glycol 400, iron oxide red), carnauba wax.

7 PC. – blisters (4) – packs cardboard.
7 PC. – blisters (8) – packs cardboard.
30 PC. – plastic bottles (1) – packs cardboard.

Sustained-release tablets, coated dark yellow (allowed grayish), kapsulovidnoy form, with an inscription “PAL 12”; outlets may be visible or invisible by visual inspection.

Excipients: macrogol 200K, macrogol 7000K, sodium chloride, povidone (K29-32), gietilloza, stearic acid, butylhydroksytoluol, iron oxide red, iron oxide yellow, macrogol 3350, cellulose acetate (398-10), dark yellow dye (gipromelloza, Titanium dioxide, polyethylene glycol 400, iron oxide yellow), carnauba wax.

7 PC. – blisters (4) – packs cardboard.
7 PC. – blisters (8) – packs cardboard.
30 PC. – plastic bottles (1) – packs cardboard.

The inscription on the tablets of doses produced water-soluble black ink (gipromelloza, iron oxide black, Purified water, isopropanol, propylene glycol).

Pharmacological action

Antipsychotics (anxiolytic). Paliperidone - antagonist dopaminovыh D₂-receptors of the central action, also has high antagonism against serotonin 5-HT₂-receptors. Besides, paliperidone yavlyaetsya antagonistom α₁– и a₂-adrenergic and histamine H₁-receptors. Paliperidone has no affinity for holinoretseptorami, muscarinic, and β₁– и b₂-adrenoceptor. Pharmacological Activity (+)- and (-)-enantiomers of paliperidone is the same qualitatively and quantitatively.

Antipsychotic effect due to blockade of dopamine D₂-receptors and the mesolimbic system Mesocortical. It causes minimal suppression of motor activity and to a lesser extent induces catalepsy, than classical antipsychotics (neuroleptics).

Balanced central serotonin antagonism and dopamine can reduce susceptibility to extrapyramidal side effects and enhance the therapeutic effects of the drug, including negative and positive symptoms of schizophrenia.

Paliperidone has an effect on sleep structure: reduces latency to sleep, reduces the number of awakenings after sleep, increases total sleep time, It increases during sleep and improves sleep quality index. It has antiemetic effect, It can cause an increase in the concentration of prolactin in plasma.

Pharmacokinetics

The pharmacokinetic characteristics of paliperidone after ingestion proportional to the dose in the recommended therapeutic range (3-12 mg 1 time / day).

Absorption

After a single dose of the drug in the plasma paliperidone concentration steadily increased, and C_max He achieved later 24 no. Features of release of drug substance from the formulation Invega^® provides less fluctuation of maximum and minimum concentrations of paliperidone, than, observed with conventional dosage forms.

After receiving tablets paliperidone is a mutual transformation (+)- and (-)-enantiomers, and the ratio of AUC(+)/AUC(-) at steady state is about 1.6. The absolute bioavailability of paliperidone after oral administration of 28%.

After a single dose 15 mg paliperidone in the form of sustained release tablets with high-calorie oily food C_max and AUC increased, average, on 42-60% and 46-54% respectively, relative to the same parameters when taking the tablets on an empty stomach. Thus, the presence or absence of food in the stomach during reception can vary the concentration of paliperidone in plasma paliperidone.

Distribution

In most patients, C_ss paliperidone is achieved after 4-5 day dosing 1 time / day.

Paliperidone is rapidly distributed in tissues and body fluids. In Кажущийся_d – 487 l.

Plasma protein binding is 74%. Paliperidone binds preferentially to α₁-acid glycoprotein and albumin.

Metabolism and excretion

There are four ways in vivo metabolism of paliperidone, none of which covers more than 6.5% dose: dealkylation, hydroxylation, dehydrogenation and benzisoxazole splitting. Studies in vitro have shown, that CYP2D6 and CYP3A4 isoenzymes may play a role in the metabolism of paliperidone, However, evidence, they play an important role in the metabolism of paliperidone in vivo, failed to obtain. Despite, that in the general population, the rate of metabolism of CYP2D6 substrates varies considerably, population pharmacokinetic studies did not reveal significant differences apparent clearance of paliperidone after administration between fast and slow metabolizers CYP2D6 substrates. Studies in vitro using microsomal preparations of heterologous systems demonstrated, that CYP1A2 isoenzymes, CYP2A6, CYP2C9, CYP2C19 and CYP3A5 are not involved in the metabolism of paliperidone.

Through 1 one week after receiving the standard tablets, contained 1 mg paliperidone, 59% the dose is excreted in the urine as unchanged; this indicates, that paliperidone is not subjected to intensive metabolism in the liver. About 80% the active substance was found in urine and about 11% – Calais. The final T_1/2 paliperidone is about 23 no.

Pharmacokinetics in special clinical situations

In patients with impaired hepatic function it is not necessary to reduce the dose of paliperidone, since the latter is not subjected to intensive metabolism in the liver. Research, which involved patients with moderate hepatic impairment (Class B for Child-Pugh), found, that these patients the concentration of free plasma paliperidone were similar to those in healthy individuals.

Use of the drug Invega^® in patients with severe hepatic impairment has not been studied.

In patients with moderate and severe renal impairment the dose should be reduced paliperidone. Excretion of paliperidone was studied in patients with varying degrees of renal impairment. It was found, that the elimination of paliperidone decreased with decreasing QC. Total clearance of paliperidone was reduced by 32% in patients with mild renal impairment (KK from 50 to <80 ml / min), on 64% in patients with moderate renal impairment (KK from 30 to <50 ml / min) and 71% in patients with severely impaired renal function (KK from 10 to <30 ml / min). Average final T_1/2 paliperidone was 24, 40 and 51 hours in patients with mild, moderate and severe renal impairment, respectively,; in people with normal kidney function (QC ≥80 ml / min) the figure was 23 no.

It is not recommended to change the dose of paliperidone, depending on the age of the patient. The results of pharmacokinetic studies, which included elderly patients (age 65 and older, n=26) shown, that the apparent clearance of paliperidone in the steady state after taking the drug Invega^® in this group was 20% below, than in adults (18-45 Years, n=28). At the same time, after adjusting for age-related decline QC, population analysis showed no effect of age on the pharmacokinetics of schizophrenia paliperidone.

There is no need to change the dose of paliperidone, depending on the patient's race. Population analysis showed no effect of race on the pharmacokinetics of paliperidone after administration.

The recommended dose of paliperidone are the same for men and women. The apparent clearance of paliperidone after administration in women about 19% below, than men. This difference is mainly due to differences in lean body mass and CK between men and women, as population studies, after adjusting for lean body mass and QC, revealed no clinically relevant differences in the pharmacokinetics of paliperidone in men and women, taking the drug.

It is not recommended to change the dose of paliperidone in smokers. In vitro studies using human liver enzymes showed, that paliperidone is not a substrate of CYP1A2, and therefore smoking should not affect the pharmacokinetics of paliperidone. In accordance with the results of in vitro studies, population studies found no differences in the pharmacokinetics of paliperidone between smokers and nonsmokers.

Testimony

- Schizophrenia (incl. exacerbation);

- Prevention of exacerbations of schizophrenia.

Dosage regimen

The drug is intended for oral use. The recommended dose is 6 mg 1 time / day in the morning with or without food. The gradual increase of the initial dose is required. In some patients, the therapeutic effect causing lower or higher doses within the recommended range 3-12 mg 1 time / day. If necessary, increase the dose recommended to increase the dose by 3 mg / day at intervals more 5 d. The tablets should be swallowed whole, with some liquid, they can not chew, divided into pieces or grind.

To patients with mild renal impairment (CC ≥ 50 ml / min, but <80 ml / min) The recommended starting dose is 3 mg 1 time / day. This dose can be increased to 6 mg 1 time / day after assessing the patient's condition and subject tolerability. To Patients with moderate or severe renal impairment (CC ≥ 10 ml / min, but < 50 ml / min) The recommended dose is 3 mg 1 time / day. Use of the drug Invega^® in Patients with CC < 10 ml / min It has not been studied, and the drug is not recommended for these patients.

Patients with impaired liver function or moderate does not require dose reduction. Use of the drug Invega^® in patients with severely impaired hepatic function It has not been studied.

To elderly patients with normal renal function (QC ≥80 ml / min) recommended same dose, as for adults with normal renal function. At the same time, elderly patients renal function may be reduced, in this case, the dose should be selected according to the function of kidneys in an individual patient.

It is not recommended to change the dose of paliperidone according to sex, age and smoking habit.

Side effect

The most common side effects: headache, tachycardia, akathisia, sinus tachycardia, extrapyramidal symptoms, drowsiness, dizziness, sedation, tremor, arterial hypertension, dystonia, orthostatic hypotension, dry mouth.

Dose-dependent side effects: weight gain, headache, hyperptyalism, vomiting, dyskinesia, akathisia, dystonia, extrapyramidal symptoms, arterial hypertension, parkinsonizm.

The frequency of side effects listed below: Often (≥ 10 %), often (≥1 % and < 10 %), sometimes (≥0.1 % and <1 %), rarely (≥ 0.01 % and < 0.1 %) and very rare (< 0.01 %).

From the central and peripheral nervous system: very often - headache; often – akathisia, dizziness, dystonia, extrapyramidal symptoms, parkinsonizm, sedation, drowsiness, tremor; sometimes - postural dizziness, dyskinesia, generalized epilepsy, fainting, nightmares.

On the part of the organ of vision: sometimes - the involuntary rotation of the eyeball.

Cardio-vascular system: often - hypertension, sinus tachycardia, tachycardia, AV block I degrees, bundle-branch block, orthostatic hypotension; inogda - bradycardia, heartbeat, sinus arrhythmia, gipotenziya, išemiâ, ECG changes.

From the digestive system: often - pain in the upper abdomen, dry mouth, hyperptyalism, vomiting.

On the part of the musculoskeletal system: sometimes - muscle rigidity.

Reproductive system: sometimes - amenorrhea, galactorrhea, discharge from the nipple, erectile dysfunction, gynecomastia, changes in menstrual cycle.

Laboratory findings: increase in serum prolactin.

Allergic reactions: sometimes - anaphylactic reaction.

Other: often - asthenic disorders; sometimes - increased appetite, peripheral edema, weight gain.

Contraindications

- Hypersensitivity to paliperidone, risperidone, and to any subsidiary of the drug ingredient.

Pregnancy and lactation

There is currently no data on the safety of paliperidone during pregnancy in women and its impact on fetal development. The drug should not be administered during pregnancy except in cases of extreme necessity from a clinical point of view,. Influence of paliperidone generic activities on women unknown.

The use of antipsychotic drugs in the III trimester of pregnancy is associated with reversible extrapyramidal symptoms in the newborn.

Paliperidone is excreted in breast milk, so the drug should not be prescribed during lactation.

Cautions

NMS

Known, Antipsychotic drugs, including as paliperidone, NMS can cause, which is characterized by hyperthermia, muscle stiffness, instability of the autonomic nervous system function, depression of consciousness, as well as an increase in serum concentrations of CK. Patients with NMS may also occur myoglobinuria (raʙdomioliz) and acute renal failure. If you have a patient objective or subjective symptoms of NMS should immediately cancel all antipsychotics, including as paliperidone.

Pozdnyaya dyskinesia

Preparations, having dopamine receptor antagonist properties, can cause tardive dyskinesia, which is characterized by rhythmical involuntary movements, mainly language and / or facial muscles. If you have a patient objective or subjective symptoms, indicating tardive dyskinesias, should consider the abolition of all antipsychotics, including as paliperidone.

QT prolongation

As with other antipsychotics, Caution should be exercised when administering the drug Invega^® patients with a history of cardiac arrhythmia, congenital QT prolongation, and joint use of drugs, prolonging the QT interval.

Giperglikemiâ

In clinical studies of paliperidone occasionally observed undesirable effects, associated with glucose metabolism. It is recommended to carry out appropriate monitoring in patients with diabetes, and in patients, with risk factors for diabetes.

Orthostatic hypotension

Paliperidone has an activity of alpha-blockers, and thus may cause some patients orthostatic hypotension. Paliperidone must be used with caution in patients with cardiovascular disease (eg, heart failure, myocardial infarction or ischemia, conduction disorder of the heart muscle), cerebrovascular diseases, and to the states, contributing to the development of arterial hypotension (eg, dehydration, hypovolemia, and treatment with antihypertensive medications).

Convulsions

Like other antipsychotics, Paliperidone should be used with caution in patients, with a history of seizures or other diseases, lowering the seizure threshold.

Possibility of gastrointestinal obstruction

Invega pills^® nearly not deformed and does not change its form in the gastrointestinal tract, therefore they should not be used in patients with a strong narrowing of the gastrointestinal tract (pathological or iatrogenic), and patients, who suffer from dysphagia or who find it difficult to swallow tablets. There are rare reports of symptoms of gastrointestinal obstruction, associated with oral dosage forms nondeformable controlled release of the active substance. Paliperidone also refers to such dosage forms, and so it can be prescribed only to patients, that can swallow the tablets whole.

Elderly patients with dementia

Paliperidone is not studied in elderly patients with dementia. However, placebo-controlled trials, which involved elderly patients with dementia, showed increased incidence of cerebrovascular adverse effects (stroke and transient ischemic attack), incl. Fatal, patients, Get some atypical antipsychotics, vklyuchavshimi risperidone, aripiprazole, and olanzapine, compared to patients, who received placebo.

Parkinson's disease and dementia with Lewy bodies

It is necessary to carefully assess the potential risks and potential benefits in the appointment of antipsychotic drugs, including as paliperidone, patients, suffering from Parkinson's disease or dementia with Lewy bodies, since such patients may increase the risk of NMS, or increased sensitivity to antipsychotics, manifestations of which include, in addition to extrapyramidal symptoms, confusion, blunted reactions and postural hypotension with frequent falls.

Priapism

Preparations, capable of blocking alpha-adrenergic effects, can cause priapism. In clinical trials of paliperidone were observed cases priapism, However paliperidone has said pharmacological activity, so the treatment can not completely exclude the risk of priapism.

The regulation of body temperature

Antipsychotics attributed this undesirable effect, as a violation of the body's ability to regulate temperature. Care should be taken when appointing paliperidone in patients with conditions, which can enhance the internal body temperature, which include intense exercise, the impact of high external temperatures, concurrent use of drugs with anticholinergic activity, or dehydration.

Antiemetic effect

In preclinical studies it was identified antiemetic effects of paliperidone. This effect, if it occurs in humans, may mask the objective and subjective symptoms of an overdose of some drugs, and such diseases, as a bowel obstruction, Reye's syndrome and brain tumor.

Translation patients on treatment with other antipsychotic drugs

There is currently no systematic data collected on the transfer of patients to the treatment for the treatment of paliperidone other antipsychotic drugs. Pharmacodynamics and pharmacokinetics in different antipsychotics are not the same, so doctors must carefully monitor patients during their transfer from one antipsychotic to another.

Invega pills^® produced using techniques osmotic release drug substance, at which the osmotic pressure provides release paliperidone at a controlled rate. System, It looks like a tablet kapsulovidnuyu, It consists of an osmotically active core three-layer, surrounded by an intermediate sheath and a semipermeable membrane. The three-layer core consists of two drug layers, containing the drug substance and excipients, and from push layer, containing osmotically active components. On the dome dosage layers are two outlets, made by laser. The GI color shell rapidly dissolves, the membrane impregnated with water. With the penetration of water into the tablet core tablet core hydrophilic polymers absorb water and swell, turning into a gel, soderzhashtiy paliperidone, which is then pushed through the hole in the tablet. Coated tablet, and insoluble components of the tablet core, excreted in the stool. Patients do not have to worry, If you noticed in the stool something like a pill.

Effects on ability to drive vehicles and management mechanisms

Paliperidone may interfere with the ability of the activities, requiring quick mental reaction, and cause visual effects, therefore, patients should refrain from driving and using machinery until, until you have established their individual sensitivity to the drug.

Overdose

Symptoms are enhanced pharmacological effects of the drug: drowsiness, sedation, tachycardia, hypotension, QT prolongation, and extrapyramidal symptoms. In acute overdose, the possibility must be considered toxic effect of several drugs.

Treatment: in assessing the necessity and effectiveness of cupping treatment of overdose should be considered, that Invega^® is a drug with sustained release of the active substance. Paliperidone specific antidote does not exist. It is necessary to implement the common supportive measures. It should provide and maintain a good airway, as well as adequate oxygenation and ventilation. You must immediately organize monitoring of cardiovascular activity (ECG monitoring to detect possible arrhythmias). Hypotension and kollaptoidnye state cropped on / in a fluid and / or sympathomimetic. In some situations shown gastric lavage (after intubation, if the patient is unconscious), administration of activated charcoal and laxatives. In the event of severe extrapyramidal symptoms, anticholinergic agents should be entered. Monitoring the condition of the patient and monitoring of vital physiological functions must continue to eliminate the effects of overdose.

Drug Interactions

Caution should be exercised with concomitant administration of Invega^® with drugs, prolonging the QT interval.

Influence on other drugs paliperidone

Paliperidone, probably, not enter into a clinically significant pharmacokinetic interaction with drugs, are metabolized by cytochrome P450 isozymes. In vitro studies using human liver microsomes revealed, that paliperidone does not substantially oppression biotransformation of drugs, metabolized with participation of cytochrome P450 isoenzymes, including CYP1A4, CYP2А6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4 и CYP3A5. Therefore there is no reason to suppose, paliperidone that will inhibit clinically significant degree clearance of drugs, are metabolized by these enzymes. Besides, paliperidone, probably, It does not induce enzymes.

At high concentrations of paliperidone is a weak inhibitor of P-glycoprotein. These in vivo absent, the clinical significance is unknown.

Given the fact, that paliperidone operates mainly on the CNS, it must be used with caution in combination with other centrally acting drugs and ethanol.

Paliperidone may neutralize the effect of levodopa and other dopamine agonists.

Because of the ability of paliperidone to cause orthostatic hypotension may occur an additive effect when using the drug in conjunction with other drugs, cause orthostatic hypotension.

The ability of other drugs affect paliperidone

Paliperidone is not a substrate of CYP1A2 isoenzymes, CYP2А6, CYP2С9, CYP2C19 and CYP3A5. This indicates a low probability of its interaction with inhibitors or inducers of these enzymes. In in vitro studies revealed minimal participation of isoenzymes CYP2D6 and CYP3A4 in the metabolism of paliperidone, at the same time, there is no evidence, These isoenzymes play a significant role in the metabolism of paliperidone in vitro or in vivo.

Studies in vitro have shown, that paliperidone is a substrate for P-glycoprotein.

Paliperidone is metabolized to a limited extent by the CYP2D6 isoenzyme.. In a study in adult volunteers interaction paliperidone with paroxetine, a potent inhibitor of CYP2D6, There were no clinically significant changes in the pharmacokinetics of paliperidone.

In a joint application with carbamazepine paliperidone (200 mg 2 times / day) observed a decrease in C_max and AUC values ​​of paliperidone about 37%. This reduction is due to an increase in the clearance of paliperidone 35% as a result of induction of renal carbamazepine P-glycoprotein. A slight decrease in the number of drug, excreted unchanged in the, suggests, that the combined use of carbamazepine has only a negligible effect on the CYP-mediated metabolism or bioavailability of paliperidone. In the appointment of carbamazepine may be necessary to increase the dose of paliperidone. And vice versa, the abolition of carbamazepine may be necessary to decrease the dose of paliperidone.

Paliperidone, are cationic at physiological pH, excreted largely unchanged by the kidneys; with about half of excretion accounted for about half of the filter and - the share of active secretion. The use of paliperidone simultaneously with trimethoprim, which, as it is known, The inhibitory activity of renal cationic transport agents, It had no effect on the pharmacokinetics of paliperidone.

Concomitant use of risperidone and paliperidone It has not been the subject of scientific research. Paliperidone is an active metabolite of risperidone, and therefore the simultaneous use of paliperidone and risperidone may increase the concentration of paliperidone in plasma.

Conditions of supply of pharmacies

The drug is released under the prescription.

Conditions and terms

The drug should be stored at a temperature of from 15 ° to 30 ° C.. Shelf life – 2 year.