Kseplion suspension for intramuscularly intravenous prolonged action. 150mg 1,5ml syringe with needles 1,5ml N1
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Active ingredients
Paliperidone
Release form
Suspension
Composition
Active ingredient: 100 mg of paliperidone in 1 ml of suspension (equivalent to 156 mg of paliperidone palmitate). Auxiliary substances: polysorbate 20, macrogol 4000 (polyethylene glycol 4000), citric acid monohydrate, sodium hydrogen phosphate, sodium dihydrogen phosphate monohydrate, sodium hydroxide, water for injections.
Pharmacological effect
Mechanism of action Paliperidone palmitate is hydrolyzed to paliperidone. The latter is a centrally active antagonist of predominantly serotonin 5-HT2A receptors, as well as dopamine D2 receptors, adrenergic α1 and α2 receptors, and H1-histamine receptors. Paliperidone does not bind to cholinergic m-receptors and to adrenergic β1 and β2 receptors. The pharmacological activity of (+) and (-) enantiomers of paliperidone is quantitatively and qualitatively the same. It is assumed that the therapeutic efficacy of the drug in schizophrenia is due to the combined blockade of D2 and 5-HT2A receptors.
Pharmacokinetics
Absorption and distribution Due to the extremely low solubility in water of paliperidone palmitate, after i / m administration, it slowly dissolves and is absorbed into the systemic circulation. After a single intramuscular injection, the concentration of paliperidone in the blood plasma slowly increases, reaching a maximum after 13-14 days (median) after administration to the deltoid muscle and 13-17 days after administration to the gluteus muscle. The release of the substance is detected as early as day 1 and persists for at least 126 days. The release characteristics of the active component and the dosage regimen of the drug Xeplion ensure the long-term maintenance of the therapeutic concentration. After a single dose of 25-150 mg to the deltoid muscle, the maximum concentration (Cmax) is on average 28% higher than after the gluteal muscle. At the beginning of therapy, the introduction of the drug into the deltoid muscle helps to quickly reach the therapeutic concentration of paliperidone (150 mg on day 1 and 100 mg on day 8) than the introduction to the gluteal muscle. After repeated injections, the difference in effects is less obvious. The average ratio of the maximum and equilibrium concentrations of paliperidone after the administration of 4 injections of the drug Cseplion at a dose of 100 mg in the gluteus muscle was 1.8, and after the injection into the deltoid muscle - 2.2.At doses of paliperidone 25-150 mg, the area under the concentration-time curve (AUC) of paliperidone changed in proportion to the dose, and Cmax at doses of more than 50 mg increased to a lesser extent than proportional to the dose. mg ranged from 25 to 49 days. After the administration of the (-) - enantiomer, paliperidone is partially converted into (+) - enantiomer, and the ratio of AUC (+) - and (-) - enantiomers is approximately 1.6-1.8. In the population analysis, the apparent volume of distribution of paliperid equal to 391 l; paliperidone binds to plasma proteins by 74%. Metabolism and excretion A week after a single oral dose of 1 mg of the drug 14C-paliperidone with immediate release of the active component in the urine, 59% of the administered dose is excreted unchanged; this indicates the absence of a significant metabolism of the drug in the liver. Approximately 80% of the administered radioactivity was detected in the urine and 11% in the feces. There are 4 known ways to metabolize the drug in vivo, but none of them causes metabolism of more than 6.5% of the administered dose: dealkylation, hydroxylation, dehydrogenization, cleavage of the benzisoxazole group. Although in vitro studies suggest a certain role of CYP2D6 and CYP3A4 isoenzymes in paliperidone metabolism, there is no evidence of the significant role of these isoenzymes in paliperidone metabolism in vivo. Population pharmacokinetic analysis did not reveal a noticeable difference in clearance of paliperidone after oral administration of the drug in people with an active and weak CYP2D6 metabolism. Studies using human liver microsomes in vitro have shown that paliperidone does not significantly inhibit the metabolism of drugs by isoenzymes CYP1A2, CYP2A6, CYP2D6, CYP2E1, CYP3A4 and CYP3A5. P-glycoprotein inhibitor. There is no relevant data in vivo, and the clinical significance of this information is unclear. In general, the concentration of paliperidone in the blood plasma during the exercise period after i / m administration of the drug Xseplion lay in the same range as after taking the paliperidone prolonged action orally with the release of the active component doses between 6 and 12 mg. The paliperidone loading scheme used maintains the concentration in this range even at the end of the inter-dose interval (8th and 36th day).Individual differences in the pharmacokinetics of paliperidone after administration of the drug Cseplion in different patients were less than after oral paliperidone administration of prolonged action. Due to the difference in the nature of the change in the median concentration of paliperidone in the blood plasma when using two drugs, caution should be exercised when directly comparing their pharmacokinetics. Particular categories of patients Disruption of liver function. Paliperidone does not undergo substantial metabolism in the liver. Although the use of the drug Xeplion in patients with mild or moderately impaired liver function has not been studied, with such violations of the liver function, dose adjustment is not required. In the study, the use of paliperidone orally in patients with moderate hepatic impairment (Child-Pugh class B) concentration of free paliperidone in plasma was the same as in healthy volunteers. In patients with severe hepatic impairment, paliperidone has not been studied. Renal impairment. For patients with impaired mild renal function, the dose of paliperidone should be reduced; Kseplion is not recommended for use in patients with impaired renal function of moderate severity and severe. The distribution of paliperidone after a single oral dose of a paliperidone tablet with a prolonged action of 3 mg was studied in patients with varying degrees of renal dysfunction. With a decrease in creatinine clearance (CK), paliperidone excretion was weakened: in cases of impaired renal function of mild severity (CK 50-80 ml / min) - by 32%, with moderate severity (CK 30-50 ml / min) - by 64%, with severe (CK 10-30 ml / min) - by 71%, resulting in AUC0-∞ increased compared with healthy volunteers, respectively, 1.5, 2.6 and 4.8 times. Based on a small amount of data on the use of the drug Xeplion in patients with impaired renal function of mild severity and from the results of pharmacokinetics simulation, the recommended loading dose of paliperidone for such patients is 75 mg on the 1st and 8th day; thereafter, 50 mg is injected every month (every 4 weeks). Older patients. Age itself is not a factor requiring dose adjustment. However, such a correction may be required due to an age-related decrease in QA.Rasa. A population pharmacokinetic analysis of the results of the study of paliperidone for oral administration did not reveal differences in the pharmacokinetics of paliperidone after administration of the drug by people of different races. Paul.No clinically significant differences in paliperidone pharmacokinetics in men and women were found. The effect of smoking on the pharmacokinetics of the drug. According to studies using human liver microsomes in vitro, paliperidone is not a substrate of CYP1A2, so smoking should not affect the pharmacokinetics of paliperidone. In accordance with these in vitro data, population pharmacokinetic analysis did not reveal differences in paliperidone pharmacokinetics in smokers and non-smokers.
Indications
Treatment of schizophrenia and prevention of recurrence of schizophrenia.
Contraindications
Hypersensitivity to paliperidone or any component of the drug Xeplion. Since paliperidone is an active metabolite of risperidone, Xeplion is contraindicated in patients with a known hypersensitivity to risperidone. With caution, orthostatic hypotension, having active alpha-cos i counts is untod). Kseplion should be used with caution in patients with cardiovascular diseases (for example, heart failure, heart attack or myocardial ischemia, cardiac conduction disorders), cerebral circulation disorders or conditions that predispose to lower blood pressure (for example, dehydration, decrease in circulating blood, use of hypotensive drugs). Convulsions As with other antipsychotics, Cseplion should be used with caution in patients who have convulsions or other diseases Considerations in which the convulsive threshold may decrease. Body temperature regulation With the use of antipsychotics, the deterioration of the body’s ability to lower body temperature is associated. It is recommended that caution be taken in prescribing Xeplion to patients who may be exposed to increases in body temperature, for example, strong physical exertion, high ambient temperature, effects of drugs with the activity of m-anticholinergics, atazhe dehydration. Interval Q-TK As in the case of other antipsychotics, should be about Patients with a history of arrhythmia or congenital lengthening of the QT interval, or taking drugs that prolong the QT interval, should use caution when prescribing a drug Kseplion. Taking into account the effect of paliperidone on the central nervous system (CNS), use different Kleplion in combination with other drugs and body products using different medications and body products. with alcohol.Paliperidone may weaken the effect of levodopa and dopamine agonists. Care should be taken when administering Xeplion to elderly patients with dementia, patients with Parkinson's disease, or Levi's calves with dementia.
Precautionary measures
It should be used with caution in the following cases: - in patients with cardiovascular diseases (for example, heart failure, heart attack or myocardial ischemia, impaired cardiac conduction), cerebral circulation disorders or conditions that predispose to lower blood pressure (for example, dehydration, decrease in the volume of circulating blood, the use of antihypertensive drugs); - in patients with a history of seizures or other conditions in which the seizure threshold may decrease - in patients who may be exposed to increases in body temperature, for example, heavy physical exertion, high ambient temperature, exposure to drugs with m-cholinolytic activity, as well as dehydration; - in patients with a history of arrhythmia or congenital lengthening of the QT interval , or taking drugs that extend the QT interval; - when used in combination with other drugs acting on the CNS, and alcohol. Paliperidone may reduce the effect of levodopa and dopamine agonists; - in patients with dementia, patients with Parkinson's disease or dementia with Levi bodies; - in patients with possible prolactin-dependent tumors. - in patients with impaired hepatic or renal function.
Use during pregnancy and lactation
Pregnancy The safety of the drug Kseplion IM or paliperidone orally during pregnancy in humans has not been established. With the use of high doses of paliperidone, a small increase in fetal mortality in animals was observed per os. Kseplion did not affect the course of gestation in rats upon i / m administration, but its high doses were toxic to pregnant females. Doses of paliperidone when administered and the drug Xeplion with the / m introduction, which create concentrations in excess of the maximum therapeutic dose in humans, respectively, 20-22 times and 6 times, did not affect the offspring of laboratory animals. Xeplion can be used during pregnancy only if the intended benefit to the mother outweighs the potential risk to the fetus.The effect of Cseplion on labor and delivery in humans is unknown. If a woman took antipsychotic drugs (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 feeding disorders. Breastfeeding In studies of the use of paliperidone in animals and risperidone in humans, excretion of paliperidone in breast milk has been found. Therefore, women receiving Xeplion should not breastfeed.
Dosage and administration
In patients who have never taken paliperidone orally or risperidone orally or parenterally, it is recommended to test paliperidone or risperidone orally for 2-7 days before starting treatment with Cseplion. week (both injections in the deltoid muscle). A dose of 75 mg is recommended monthly; The dose may be increased or decreased in the range of 25-150 mg, depending on the individual tolerance and / or effectiveness. After the second dose, subsequent injections can be given to the deltoid or flaccid muscle. The maintenance dose can be adjusted monthly. This should take into account the long-term release of the active ingredient from paliperidone palmitate, since the effect of changing doses can be fully manifested only after a few months. Dose Skip Avoiding skipping doses. The second loading dose of paliperidone is recommended to be administered after 1 week after the first dose. If this is not possible, then it can be entered 2 days earlier or later. Similarly, it is recommended to inject the third and subsequent doses monthly, but if this is not possible, then an injection can be given 7 days earlier or later. Dose admission (from 1 month to 6 weeks). After the start of treatment, it is recommended to inject the drug Xeplion monthly. If less than 6 weeks have passed since the last injection, then you should as soon as possible enter the next dose equal to the previous one. After that, administer the preparation monthly. Dose missed (period from> 6 weeks to 6 months).If it has been more than 6 weeks since the last injection of the drug Xeplion, then resume treatment at a dose equal to the previous one, as follows: 1. Inject another dose as soon as possible into the deltoid muscle, 2. after 1 week, another (same) dose is administered into the deltoid muscle, 3. resume injections in the deltoid or gluteal muscle with an interval of 1 month. Dose skip (term> 6 months). If more than 6 months have passed since the last injection of the drug Xeplion, then the treatment is started anew, as described above, to begin treatment. The method of administration and dose of Xeplion is intended only for intramuscular administration. The drug is slowly injected deep into the mouth. Injections should be carried out only by a medical professional. The entire dose is administered at one time; It is not possible to administer a dose for several injections. You can not enter the drug in the blood vessels or subcutaneously. Avoid accidental contact with a blood vessel. To do this, before starting the injection, the piston syringe is pulled back to check for a needle in a large blood vessel. If blood flows into the syringe in this case, the needle and the syringe should be removed from the patient's muscle and utilized. The recommended needle size for administering the drug Xeplion into the deltoid muscle is determined by the patient's body weight. For patients with body weight ≥90 kg, a long needle with a gray case from the kit is recommended. For patients with body weight. For the administration of the drug Xeplion into the gluteal muscle, a long needle with a gray body from the set is recommended. Injections should be carried out in the upper outer quadrant of the buttocks. It is necessary to introduce the drug alternately into the right and left gluteal muscle. Simultaneous use of Paliperidone palmitate and paliperidone orally or risperidone orally or parenterally has not been studied. Since paliperidone is the main active metabolite of risperidone, the possibility of additive action of paliperidone when using these drugs at the same time as Xeplion should be taken into account. Patients with impaired liver function has not been studied in patients with impaired liver function. Based on the results of the study of paliperidone for oral administration, for patients with impaired hepatic function, or moderately severe dose adjustment is not required.The use of the drug Kseplion of patients with severely impaired liver function has not been studied. Patients with impaired renal function. The use of the drug Xseplion in patients with impaired renal function has not been systematically studied. Mild patients with impaired renal function of mild severity (creatinine clearance from ≥50 to <80ml / min), it is recommended to start the use of the drug Xeplion with a dose of 100 mg on the 1st day and 75 mg after 1 week (both injections into the deltoid muscle). After that, 50 mg is administered each month to the deltoid or gluteal muscle. Cseplion is not recommended for patients with impaired renal function or severe (creatinine clearance <50 ml / min). Older patients In general, for elderly patients with normal renal function, the same dose of Xeplion is recommended as for younger patients with normal renal function . In elderly patients, kidney function can be reduced, and the above recommendations for patients with impaired renal function are extended to such patients. Teenagers and children The safety and efficacy of using Xeplion in patients younger than 18 years has not been studied. Other special categories of patientsDose correction of Xeplion depending on gender, race sick and no smoking required.
Side effects
Most of the undesirable adverse reactions (LPR) were mild or moderate. The adverse reactions observed in patients are indicated below. The frequency of adverse reactions was classified as follows: very frequent (≥10%), frequent (≥1% and <10%), infrequent (≥0.1% and Infections: frequent - upper respiratory tract infections. Metabolic disorders: infrequent - loss of appetite, increase appetite. Psychiatric disorders: very frequent - insomnia; frequent - agitation, nightmares; infrequent - anxiety. Violations of the nervous system: very frequent - headache; frequent akathisia, dizziness, extrapyramidal symptoms, drowsiness, infrequent - convulsions, posturally dizziness, salivation, dysarthria, dyskinesia, dystonia, neuroleptic malignant syndrome, lethargy, oromandibular dystonia, parkinsonism, psychomotor hyperreactivity, syncope. Ophthalmic disorders: infrequent - oculogy crisis, involuntary eye movement, ocular disturbances, involuntary eye movement, ocular syndrome, involuntary movement of the eye, eye syndrome, and infrequent - vertigo.Violations of the cardiovascular system: frequent - increased blood pressure; infrequent - bradycardia, blokadanozhek bundle branch block, postural orthostatic tachycardia syndrome, tachycardia, ortostaticheskayagipotenziya.Zheludochno-intestinal disorders: frequent - pain in the upper abdomen, constipation, diarrhea, dry slizistoyobolochki mouth, nausea, toothache, vomiting; infrequent abdominal discomfort, hypersecretion of saliva, discomfort in the stomach. Disorders of the musculoskeletal system and connective tissue: frequent - pain in the limbs. Disorders of the skin: infrequent - generalized itching, rash. Disorders of the reproductive system and mammary glands: infrequent - amenorrhea, erectile dysfunction, galactorrhea, gynecomastia, irregular menstruation, sexual dysfunction. Other: frequent - asthenic disorders, weakness, local reactions (pain, itching, induration at the injection site), weight gain . Changes in laboratory parameters: infrequent - increase in the concentration of serum prolactin, cholesterol and glucose in the blood. Side effects of paliperidone for ingestion Below are the side effects registered with paliperidone for use: Immune system disorders: anaphylactic reaction; Nervous system disorders: large and small convulsive seizures, tremor; Violations of the cardiovascular system: atrioventricular block I degree, feeling of heartbeat, syn lactation arrhythmia, sinus tachycardia, lowering blood pressure, ischemia of the cardiac; Disorders of the musculoskeletal system and connective tissue: muscular rigidity; Disorders of the reproductive system and mammary glands: priapism, nipple discharge; Other: peripheral edema; Changes in instrumental parameters: Electrocardiogram (ECG) Changes; Risperidone Safety Information; Paliperidone is an active metabolite of risperidone. The nature of the release of the active substance and the pharmacokinetics of paliperidone after administration of the drug Xeplion significantly differ from ottakovyh after ingestion of drugs risperidone with immediate release of the active substance or risperidone for intramuscular administration of prolonged action.Information on the safety of oral risperidone and long-acting risperidone for injection, obtained in clinical studies and in the framework of post-marketing control of the use of drugs, is given in the instructions for the medical use of these drugs.
Overdose
Since Kseplion is intended for administration by health workers, the likelihood of an overdose for patients is small. Symptoms In general, the expected signs and symptoms correspond to an increase in the known pharmacological action of paliperidone, i.e. drowsiness, lethargy, tachycardia, lowering blood pressure, prolongation of the QT interval, extrapyramidal symptoms. Polyformal ventricular tachycardia such as pirouette and ventricular fibrillation have been observed with an overdose of oral paliperidone. In the case of acute overdose, the possibility of patients receiving several drugs should be considered. Treatment When assessing the need for treatment and recovery of patients, the prolonged release of the active substance and the long half-life of paliperidone should be considered. There is no specific antidote for paliperidone. General supportive measures should be implemented, and the airway is permeable, maintain adequate ventilation of the lungs, and saturate the blood with oxygen. It should immediately begin monitoring the function of the cardiovascular system, including continuous monitoring of the ECG to detect possible arrhythmias. In the event of a decrease in arterial blood pressure and circulatory collapse, appropriate measures should be taken, for example, intravenous administration of solutions and / or sympathomimetics. With the development of severe extrapyramidal symptoms, anticholinergic drugs are used. The patient’s condition should be carefully monitored until recovery.
Interaction with other drugs
Like other antipsychotics, paliperidone may increase the QT interval, so it should be carefully combined with other drugs that increase the QT interval, such as antiarrhythmic drugs (including quinidine, disopyramide, procainamide, amiodarone, sotalol), antihistamine drugs antipsychotic drugs (chlorpromazine, thioridazine); antibiotics (includinggatifloxacin, moxifloxacin), some drugs against malaria (including mefloquine). Since paliperidone palmitate is hydrolyzed to paliperidone, the results of studies of paliperidone for oral administration should be taken into account when evaluating the possibility of drug interaction. that paliperidone will exhibit a clinically significant pharmacokinetic interaction with drugs metabolized by cytochrome P450 isoenzymes. Studies using human liver microsomes in vitro showed that paliperidone does not significantly weaken the metabolism of the isoenzymes CYP1A2, CYP2A6, CYP2C8 / 9/10, CYP2D6, CYP2E1, CYP3A4 and CYP3A5. Therefore, it is not expected that paliperidone will clinically significantly reduce the clearance of drugs metabolized by these isoenzymes. It is also not expected that paliperidone will exhibit the properties of an inducer of isoenzymes, since in in vitro studies, paliperidone did not induce the activity of CYPA2, CYPC19 or CYP3A4 isoenzymes. High concentrations of piperidone are a weak inhibitor of P-glycoprotein. However, there is no data in vivo in this respect, and the clinical significance of this phenomenon is unknown. Considering the effect of paliperidone on the central nervous system, it is necessary to use caution Xseplion in combination with other drugs of central action and alcohol. Paliperidone may weaken the effect of levodopa and dopamine receptor agonists. Due to the ability of Cseplion to cause orthostatic hypotension, additive enhancement of this effect can be observed when using Ceplion with other drugs that have this ability. such as phenothiazines, butyrophenones, tricyclic derivatives, selective serotonin reuptake inhibitors, tramado , mefloquine, etc.) Simultaneous administration of oral paliperidone at a dosage of 12 mg once a day and sodium pills of prolonged action (at a dosage of 500-2000 mg once a day) does not affect the pharmacokinetics of valproate. The pharmacokinetic interaction between the drug Kseplion and lithium is unlikely.
special instructions
The use of the drug Xeplion in acute psychomotor agitation or in severe psychotic condition It is not recommended to use the drug Xeplion in acute psychomotor agitation or in severe psychotic condition when immediate control of symptoms is necessary. Interval QT. Care should be taken when using paliperidone in patients with known cardiovascular diseases or. history of the QT interval, as well as the combined use of drugs that can cause lengthening of the QT interval. Malignant neuroleptic syndrome When using neuroleptics, including paliperidone, the development of malignant neuroleptic syndrome (ZNS), characterized by increased body temperature, muscle rigidity, instability of the autonomic nervous system, impaired consciousness and an increase in serum creatine phosphokinase concentration. In addition, myoglobinuria (rhabdomyolysis) and acute renal failure may occur. When symptoms appear suggesting an NNS, all antipsychotics, including Xeeplion, are canceled. If symptoms of tardive dyskinesia appear, the possibility of withdrawing all neuroleptics should be considered, including Cseplion. previously tolerated oral forms of paliperidone or risperidone. In the event of hypersensitivity reactions Nost you must stop using the product Kseplion take the necessary supportive clinical measures and conduct monitoring of the patient until the disappearance simptomov.Giperglikemiya diabetPri and diabetes treatment drug Kseplion observed hyperglycemia, diabetes mellitus, and exacerbation of existing diabetes mellitus.Establishing the relationship between the use of atypical antipsychotics and 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 antipsychotic drugs and the development of side effects associated with hyperglycemia is not fully established. All patients should be clinically monitored for the presence of symptoms of hyperglycemia and diabetes mellitus (see “Side Effects” section). Weight gain During treatment with atypical antipsychotics, a significant increase in body weight was observed. Patients should be monitored for body weight. Hyperprolactinemia Tissue culture studies indicate that human breast growth can be stimulated by prolactin. Although a direct link with the use of antipsychotics has not yet been demonstrated in clinical and epidemiological studies, caution should be exercised when using paliperidone in patients with possible prolactin-dependent tumors. Orthostatic hypotension. Having alpha-adrenergic blocker activity, paliperidone may cause some patients orthostatic hypotension. Kseplion should be used with caution in patients with cardiovascular diseases (for example, heart failure, heart attack or myocardial ischemia, cardiac conduction disorders), cerebral circulation disorders or conditions that predispose to lower blood pressure (for example, dehydration, decrease in circulating blood volume, use antihypertensive drugs). Cramps Like other neuroleptics, Xeplion should be used with caution in patients with a history of seizures or other e conditions in which the convulsive threshold may decrease. Renal failure The concentration of paliperidone in plasma is increased in patients with impaired renal function. In patients with impaired mild renal function, dose adjustment is recommended. Cseplion is not recommended for patients with moderate to severe renal dysfunction (creatinine clearance 50 ml / min). Hepatic insufficiency The use of Cseplion in patients with severe hepatic dysfunction (Child-Pugh class C) has not been studied.Caution should be exercised when using paliperidone in such patients. Older patients with dementia Cross-analysis of research results showed an increased mortality rate of elderly patients with dementia who received atypical antipsychotics, including risperidone, aripiprazole, olanzapine and quetiapine compared with placebo. Among patients treated with risperidone and placebo, mortality was 4% and 3.1%, respectively. The use of the drug Xeplion in elderly patients with dementia has not been studied. Since paliperidone is the active metabolite of risperidone, the experience with risperidone should be taken into account. For elderly patients with dementia taking risperidone, there was an increased mortality in patients taking furosemide and risperidone compared with the group taking only risperidone and the group taking only furosemide. There is no established pathophysiological mechanisms explaining this observation. However, special care should be taken.