Expiration date: 03/2025
Structure and Composition:
The tablets of the prolonged action covered with a cover. 1 tablet contains:
paliperidone 3, 6, 9 or 12 mg
Excipients: Macrogol Macrogol 7000K 200K Sodium chloride Povidone (K29-32) gietilloza stearic acid butylhydroxytoluene iron oxide red iron oxide yellow Macrogol 3350 Cellulose acetate (398-10) dye white (hypromellose, titanium dioxide, lactose monohydrate, triacetin) carnauba wax
in blister 7 pcs. In the paper cartons of 4 or 8 blisters or vial PE 30 pcs. In the paper cartons 1 bottle.
The tablets of the prolonged action covered with a cover. 1 tablet contains:
Description pharmaceutical form:
White, light orange (may be faint brownish tint), pink (allowed grayish hue) or dark yellow (may be grayish hue) (respectively, the dosage - 3, 6, 9, or 12 mg) tablets kapsulovidnoy form. The tablets have the inscription «PAL 3», «PAL 6», «PAL 9» or «PAL 12" (or dose - 3, 6, 9, or 12 mg). The outlets may be visible or invisible by visual inspection.
Pharmacokinetics:
The pharmacokinetic characteristics of paliperidone after ingestion are proportional to the dose in the recommended therapeutic range (3-12 mg 1 time per day).
Absorption. After receiving one dose of paliperidone plasma levels steadily increased and the Cmax was reached after 24 hours. The majority of patients achieved steady-state concentrations of paliperidone after 4-5 days of dosing one time per day.
Properties of the release of the drug substance provided Invegi lower Cmax and Cmin fluctuations than those observed with conventional dosage forms.
After receiving tablets paliperidone interconversion occurs (+) and (-) enantiomers, and the ratio of AUC (+) / AUC (-) in a steady state of about 1.6. The absolute bioavailability after oral administration of paliperidone is 28%.
After a single dose of paliperidone 15 mg in the form of sustained release tablets with high-calorie oily food Cmax and AUC increased, on average, at 42-60 and 46-54%, respectively, relative to the same parameters in the fasted tablet. Thus, the presence or absence of food in the stomach during reception may change paliperidone plasma concentration of paliperidone.
Distribution. Paliperidone is rapidly distributed in tissues and body fluids. The apparent distribution volume - 487 l. The degree of plasma protein binding is 74%. Paliperidone binds preferentially to alpha 1-acid glycoprotein and albumin.
Biotransformation and elimination. After 1 week after administration of one standard tablet of 1 mg paliperidone contained 59% of the dose is excreted in the urine as unchanged it indicates that paliperidone is not subjected to intensive metabolism in the liver. About 80% of the drug was found in urine and about 11% - in the feces. There are four ways of paliperidone metabolism in vivo, none of which covers more than 6.5% of the dose: dealkylation, hydroxylation, dehydrogenation and decomposition benzisoxazole. Studies in vitro have shown that CYP2D6 and CYP3A4 isoenzymes of cytochrome P450 may play a role in the metabolism of paliperidone, but the evidence that they play a significant role in the metabolism of paliperidone in vivo, could not be obtained. Despite the fact that in the general population CYP2D6 substrates metabolic rate varies considerably, population pharmacokinetic studies did not reveal any significant differences apparent clearance of paliperidone after administration of the drug between the fast and slow metabolisers CYP2D6 substrates. Studies in vitro using microsomal preparations of heterologous systems showed that the isozymes CYP1A2, CYP2A6, CYP2C9, CYP2C19 and CYP3A5 are not involved in the metabolism of paliperidone.
The final T1 / 2 paliperidone is about 23 hours.
Special groups
Patients with impaired hepatic function. In patients with impaired hepatic function there is no need to reduce the dose of paliperidone, as the latter is not subjected to intensive metabolism in the liver. The study, which involved patients with moderate hepatic impairment (Class "B" on the Child-Pugh classification), has shown that in these patients the concentration of free plasma paliperidone were similar to those of healthy people. Application of medication Invega in patients with severe hepatic impairment has not been studied.
Patients with impaired renal function. The dose of paliperidone should be reduced in patients with moderate and severe renal impairment. Excretion of paliperidone was studied in patients with varying degrees of renal impairment. It has been found that the elimination of paliperidone decreased with decreasing Cl creatinine. Total clearance of paliperidone was reduced by 32% in patients with mild renal impairment (Cl creatinine - from 50 to <80 ml / min), 64% - in patients with moderate renal impairment (Cl creatinine - from 30 to <50 ml / min) and 71% - in patients with severe renal impairment (Cl creatinine - <30 ml / min). Average final T1 / 2 of paliperidone in patients with mild, moderate and severe renal impairment amounted to 24, 40 and 51 h, respectively, in humans with normal renal function (creatinine Cl - & ge80 ml / min), the figure was 23 hours.
Elderly patients. It is not recommended to change the dose of paliperidone according to the age of the patient. The results of pharmacokinetic studies involving elderly patients (age - 65 years and older, n = 26) showed that the apparent clearance of paliperidone in the steady state after receiving Invegi in this group was 20% lower than in adults (18-45 s, n = 28). However, after adjustment for age-related decline Cl creatinine, population analysis showed no effect of age on the pharmacokinetics in patients with schizophrenia paliperidone.
Children and adolescents. The safety and efficacy of paliperidone in patients younger than 18 years have not been studied.
Race. No need to change the dose of paliperidone, depending on the patient's racial identity. Population analysis showed no effect of race on the pharmacokinetics of paliperidone after administration of the drug.
Floor. The recommended dose of paliperidone are the same for men and women. Apparent clearance of paliperidone after dosing female approximately 19% lower than in men. This difference is mainly due to differences in lean body mass and creatinine Cl between men and women, as population studies, after adjusting for lean body mass and Cl creatinine revealed no clinically relevant differences in the pharmacokinetics of paliperidone in men and women who took the drug .
Smoking. Do not change the dose of paliperidone in smokers. in vitro studies using human liver enzymes have shown that paliperidone is not a substrate of CYP1A2, smoking and so should not affect the pharmacokinetics of paliperidone. In accordance with the results of in vitro studies, population studies have found no differences in the pharmacokinetics of paliperidone between smokers and nonsmokers.
Description of the pharmacological actions:
Mechanism of action. Paliperidone - is a centrally acting antagonist of dopamine D2-receptor, which also has a high antagonism against serotonin 5-HT2 receptors. Furthermore, paliperidone antagonist is alpha 1 and alpha 2 adrenergic receptors and histamine H1-receptor. Paliperidone has no affinity for cholinergic, muscarinic and beta1- and beta2-adrenergic receptors. The pharmacological activity of (+) - and (-) - paliperidone enantiomers is the same qualitatively and quantitatively.
Antipsychotic effect due to blockade of dopamine D2-receptors and mesolimbic system Mesocortical. It causes minimal suppression of motor activity and to a lesser extent induces catalepsy than classic antipsychotics (neuroleptics).
Balanced central antagonism of serotonin and dopamine may reduce the propensity for extrapyramidal side effects and enhance the therapeutic effects of the drug with negative coverage and productive symptoms of schizophrenia.
Paliperidone affects the sleep pattern: reduced latency to sleep and number of awakenings after sleep, increased total sleep time, sleep time, increases and improves sleep quality index. It has antiemetic effect may cause an increase in the concentration of prolactin in plasma.
Indications:
- schizophrenia, including in the acute phase
- prevention of relapse of schizophrenia.
Contraindications:
Hypersensitivity to paliperidone, risperidone, and any additional ingredients of the drug.
Carefully
Spasmodic state history and diseases that reduce the seizure threshold. 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 gastrointestinal tract (the possibility of obstruction). Invega pills are not deformed, and almost do not change their shape in the gastrointestinal tract, and therefore should not be administered to patients with a strong narrowing of the lumen of the gastrointestinal tract (pathologic or iatrogenic), as well as patients who suffer from dysphagia or who have difficulty swallowing pills. There are rare reports of gastrointestinal obstruction symptoms associated with oral dosage forms nondeformable controlled release of the active substance. Paliperidone also relates to such dosage forms, and so it can be prescribed only to patients who can swallow the tablets whole.
Elderly patients with dementia. Efficacy and safety of paliperidone were not evaluated in elderly patients with dementia.
A meta-analysis of 17 placebo-controlled studies showed that elderly patients with dementia treated with atypical antipsychotics such as risperidone, aripiprazole, olanzapine, and quetiapine, there was a higher mortality rate compared with patients receiving placebo.
Placebo-controlled trials, involving elderly patients with dementia have shown an increased incidence of cerebrovascular adverse events (cerebrovascular accidents and transient ischemic attack), including: fatal, in patients treated with some atypical antipsychotics (including risperidone, olanzapine and aripiprazole), compared with patients who received placebo.
In Parkinson's disease and dementia with Lewy bodies. Physicians should carefully weigh the risks and the potential benefit in the appointment of antipsychotic drugs, including paliperidone, patients suffering from Parkinson's disease or dementia with Lewy bodies, since these patients may be increased risk of developing neuroleptic malignant syndrome or increased sensitivity to antipsychotics. Manifestation of this increased sensitivity include, in addition to extrapyramidal symptoms, confusion, dullness reactions and postural hypotension with frequent falls.
Application of pregnancy and breastfeeding:
There is currently no data on the safety of paliperidone for pregnant women and fetal development. The drug should not be given to pregnant women except in cases where it is absolutely necessary from a clinical point of view. Influence of paliperidone on the generic activities of women is not known.
The use of antipsychotics during the last trimester of pregnancy is associated with reversible extrapyramidal symptoms in the newborn.
Lactation. Paliperidone passes into breast milk, therefore the drug should not be administered during lactation.
Side effect:
The most common adverse effects of paliperidone in clinical trials were headache, tachycardia, akathisia, sinus tachycardia, extrapyramidal symptoms, somnolence, dizziness, sedation, tremor, hypertension, dystonia, orthostatic hypotension, and dry mouth.
For a dose-dependent adverse effects include weight gain, headache, salivation, vomiting, dyskinesia, akathisia, dystonia, extrapyramidal symptoms, hypertension and Parkinsonism.
The following are the adverse effects observed in patients with frequency and is classified as follows: very common - & ge10% often - & ge1% and <10% of rare - & ge0,1% and <1% of rare - & ge0,01% and <0.1 % and very rarely - <0.01%.
Immune system: rarely - anaphylactic reaction.
Metabolic disorders: rarely - increased appetite.
Psychiatric disorders: uncommon - "terrible" dream.
Disorders of the nervous system: very often - headache often - akathisia, dizziness, dystonia, extrapyramidal symptoms, hypertension, parkinsonism, sedation, somnolence, tremor rare - postural dizziness, dyskinesia, grand mal seizures, syncope.
Eye disorders: rarely - involuntary rotation of the eyeball.
Violations of the cardiovascular system: often - tachycardia (including sinus), AV blockade degree I, bundle branch block blockade, orthostatic hypotension rarely - bradycardia, palpitations, sinus arrhythmia, hypotension, ischemia.
Gastrointestinal disorders: often - pain in the upper abdomen, dry mouth, hypersalivation, vomiting.
Violations of the musculoskeletal system and connective tissue disorders: rarely - muscle rigidity.
Violations of the reproductive system and mammary glands: rarely - amenorrhea, galactorrhea, nipple discharge, erectile dysfunction, gynaecomastia, menstrual cycle changes.
Other: often - asthenic disorders rarely - peripheral edema, ECG changes, increased body mass index.
Lab tests: increased serum prolactin.
Drug Interactions:
Caution must be exercised with concomitant administration of paliperidone with drugs that prolong the interval QT.
Influence on other drugs paliperidone
Paliperidone is likely not involved in clinically significant pharmacokinetic interactions with drugs that are metabolized by cytochrome P450 isoenzymes system. in vitro studies using human liver microsomes showed that paliperidone does not substantially oppression bioconversion of drugs that are metabolized by cytochrome P450 isoenzymes, including CYP1A4, CYP2A6, CYP2S8 / 9/10, CYP2D6, CYP2E1, CYP3A4 and CYP3A5. Therefore there is no reason to suppose that paliperidone is inhibited in a clinically significant degree the clearance of drugs that are metabolized by these enzymes. Furthermore, paliperidone likely does not induce enzymes.
At high concentrations of paliperidone is a weak inhibitor of P-glycoprotein. In vivo data are not available, the 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 and central action of alcohol. Paliperidone may neutralize the effect of levodopa and other dopamine agonists.
Due to the ability of paliperidone to cause orthostatic hypotension may occur when using the additive effect of the drug concurrently with other drugs that cause orthostatic hypotension.
The influence of other drugs on paliperidone
Paliperidone is not a substrate isozymes CYP1A2, CYP2A6, CYP2C9, CYP2C19 and CYP3A5. This indicates a low probability of its interaction with inhibitors or inducers of these enzymes. in vitro studies showed minimal involvement isoenzymes CYP2D6 and CYP3A4 in the metabolism of paliperidone, however, no evidence that these isozymes play a significant role in the metabolism of paliperidone in vitro or in vivo.
Studies in vitro have shown that paliperidone is a P-glycoprotein substrate.
Paliperidone partially metabolized by CYP2D6 (see. "Pharmacokinetics"). In a study of adult volunteers paliperidone interaction with paroxetine, a potent inhibitor of CYP2D6, no clinically significant changes in the pharmacokinetics of paliperidone.
The combined use of paliperidone with carbamazepine 200 mg 2 times a day caused a decrease in Cmax and AUC of paliperidone by about 37%. This reduction in clearance of paliperidone due to an increase of 35% as a result of induction of renal carbamazepine P-glycoprotein. A slight decrease in the amount of the drug excreted in unchanged form, which suggests that the combined use of carbamazepine has only a negligible effect on the CYP-conditioned metabolism or bioavailability of paliperidone. In the appointment of carbamazepine dose of paliperidone should be reassessed and increased if necessary. Conversely, when the cancellation of carbamazepine dose of paliperidone should be reassessed and reduced if necessary.
Paliperidone is a cationic at physiological pH values, primarily excreted unchanged by the kidneys with about half excretion accounts for filtering share and about half - in the proportion of active secretion. The use of paliperidone simultaneously with trimethoprim, which is known to inhibit active renal cation transport drugs had no effect on the pharmacokinetics of paliperidone.
Simultaneous use of risperidone and paliperidone were not the subject of scientific research. Paliperidone is an active metabolite of risperidone and therefore the simultaneous use of paliperidone and risperidone, paliperidone may increase blood levels.
Dosage and administration:
Inside, in the morning, regardless of the meal, swallowing whole, with some liquid, without chewing, not divided into parts, not grinding. The recommended dose is 6 mg once a day. A gradual increase in the initial dose is not required. In some patients, the therapeutic effect of causing a lower or higher dose within the recommended range of 3-12 mg 1 time per day. If necessary to increase the dose, it is recommended to increase the dose of 3 mg per day with an interval of 5 days.
Patients with impaired hepatic function. Patients with mild to moderate hepatic dysfunction dose reduction is required. Use of the drug in patients with severe hepatic impairment has not been studied.
Patients with impaired renal function. For patients with mild renal impairment (Cl creatinine - & ge50, but <80 ml / min) the recommended starting dose is 1 mg 3 times a day. This dose can be increased up to 6 mg 1 time per day. Changing the dose if indicated follows the patient assessment and taking into account the individual tolerance of the drug.
For patients with moderate or severe renal impairment (Cl creatinine - & ge10, but <50 ml / min) the recommended dose is 1 mg 3 times a day.
The use of Invega in patients with Cl creatinine <10 ml / min has not been studied, and therefore is not recommended for the preparation of this category of patients.
Elderly patients. For older patients with normal renal function (Cl creatinine - & ge80 ml / min) recommended the same dose as that for adult patients with normal renal function. However, elderly patients renal function can be reduced in this case, the dose should be selected according to the function of kidneys in an individual patient (cm. "Patients with impaired renal function" section).
Special groups of patients. Do not change the dose of paliperidone according to gender, age, and whether the patient smokes or not.
Transfer of patients to treatment with other antipsychotic drugs. Currently there are no systematically collected data on the transfer of patients to the treatment of paliperidone in the treatment of other antipsychotic drugs. Pharmacodynamics and pharmacokinetics in different antipsychotics are not the same, and so doctors must carefully monitor patients during their transfer from one antipsychotic to another.
Overdose:
Symptoms: In general, objective and subjective symptoms of overdose of paliperidone are enhanced pharmacological effects of the drug, ie, drowsiness and sedation, tachycardia and hypotension, QT prolongation, and extrapyramidal symptoms. In acute overdosage the possibility must be considered toxic effect of several drugs.
Treatment: in assessing the therapeutic needs of the patient and the efficiency of the relief of an overdose should be remembered that Invega is a drug with sustained release of the drug substance. Paliperidone specific antidote does not exist. common supportive measures should be implemented. It is necessary to ensure and maintain a good airway and adequate oxygenation and ventilation. You must immediately organize the monitoring of cardiovascular activity (ECG monitoring to detect possible arrhythmias). Hypotension and cropped kollaptoidnye state / in the introduction of fluids and / or sympathomimetic agents. In certain situations shown gastric lavage (after intubation, if the patient is unconscious) administering the activated carbon and laxatives. In the event of severe extrapyramidal symptoms anticholinergic preparations must be entered. Monitoring the condition of the patient and monitoring of vital physiological functions must continue to eliminate the effects of overdose.
Special instructions:
Neuroleptic malignant syndrome. It is known that antipsychotics, including paliperidone may cause neuroleptic malignant syndrome (NMS), characterized by hyperthermia, muscle rigidity, instability function of the autonomic nervous system, depression of consciousness, as well as an increase in serum creatine phosphokinase concentrations. Patients with NMS may also occur myoglobinuria (rhabdomyolysis) and acute renal failure. In the event the patient is objective or subjective symptoms of NMS should be abolished immediately all antipsychotics, including paliperidone.
Tardive Dyskinesia. Preparations having properties dopamine receptor antagonists can cause tardive dyskinesia, characterized by involuntary rhythmic movements mainly language and / or facial muscles. In the event of a patient objective or subjective symptoms suggestive of tardive dyskinesia, it is necessary to consider the feasibility of abolishing all antipsychotics, including paliperidone.
Lengthening of the QT interval. As with other antipsychotics, caution should be exercised in the appointment of paliperidone in patients with cardiac arrhythmias in the history of congenital prolongation of the QT interval, and a joint application with drugs that prolong the QT interval.
Hyperglycemia. 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 mellitus, and in patients with risk factors for diabetes mellitus (see. "Side effects").
Orthostatic hypotension. Paliperidone has an activity of alpha-blockers and may therefore cause some patients orthostatic hypotension. Paliperidone must be used with caution in patients with cardiovascular disease patients (eg heart failure, myocardial infarction or ischemia, conduction abnormalities of the heart muscle), cerebrovascular disease, and in conditions conducive to hypotension (eg dehydration, hypovolemia, and treatment with antihypertensive medications).
The regulation of body temperature. Antipsychotics attributed this undesirable effect, as a violation of the body's ability to regulate temperature. Caution should be exercised in the appointment of paliperidone in patients with conditions that may enhance the core body temperature, which include intense physical activity, the impact of high external temperatures, the simultaneous use of drugs with anticholinergic activity, or dehydration.
Antiemetic effect. In preclinical studies were identified antiemetic effect of paliperidone. This effect, if it occurs in humans, may 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 tumor.
Priapism. Drugs capable of blocking alpha-adrenergic effects may cause priapism. cases of priapism have been observed in clinical trials of paliperidone, paliperidone has however specified pharmacological activity, and so the treatment can not completely exclude the risk of priapism.
Invega Tablets are manufactured using technology osmotic drug substance release in which the osmotic pressure provides release paliperidone at a controlled rate. The system resembles kapsulovidnuyu tablet consists of a three-layered osmotically active core surrounded by an intermediate cladding and a semipermeable membrane. The three-layer core consists of two drug layers comprising the drug substance and excipients, as well as push layer containing osmotically active components. On the dome of the drug layers, there are two outlet holes made by laser. In the digestive tract colored shell dissolves quickly and the membrane is impregnated with water. With the penetration of water into the tablet core tablet core hydrophilic polymers absorb water and swell, becoming a gel containing paliperidone, which is then pushed through the hole in the tablet. Sheath tablets and insoluble components of the tablet core, excreted in the stool. Patients should not have to worry, if you noticed in the stool something like a tablet.
Effects on driving and using machinery. Paliperidone may interfere with activities requiring quick mental reactions, therefore patients should refrain from driving and using machinery until such time as there is no set of individual sensitivity to paliperidone.
