Instruction for use: Xeplion

Dosage form: suspension for intramuscular administration of the prolonged action

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

Composition

Suspension for intramuscular administration of prolonged action 1 ml

active substance:

paliperidone 100 mg

(equivalent to 156 mg of paliperidone palmitate)

auxiliary substances: polysorbate 20 - 12 mg; Macrogol 4000 (polyethylene glycol 4000) - 30 mg; citric acid monohydrate - 5 mg; sodium hydrophosphate - 5 mg; sodium dihydrogen phosphate monohydrate - 2.5 mg; sodium hydroxide - 2.84 mg; water for injection - up to 1 ml

Description of dosage form

White or almost white suspension, free from foreign inclusions.

Pharmachologic effect

The pharmacological action is neuroleptic.

Pharmacodynamics

Mechanism of action

Paliperidone palmitate hydrolyzes to paliperidone. The latter is a central active antagonist of predominantly serotonin 5-HT2A receptors, as well as dopamine D2 receptors, adrenergic α1 and α2 receptors, and histamine H1 receptors. Paliperidone does not bind to cholinergic m-receptors and to adrenergic β1 and β2 receptors. 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

Suction and distribution

Due to the extremely low solubility in water of paliperidone, palmitate is slowly dissolved after the / m administration and absorbed into the systemic bloodstream. After a single intravenous injection, the concentration of paliperidone in the blood plasma increases slowly, 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 the first day and remains at least 126 days. The release characteristics of the active ingredient and the dosage regimen of the Xseplion drug ensure a sustained maintenance of the therapeutic concentration. After a single dose of 25-150 mg in the deltoid muscle Cmax, on average, 28% more than after the introduction of the gluteus muscle. At the beginning of the therapy, the introduction of the drug into the deltoid muscle helps to reach the therapeutic concentration of paliperidone (150 mg on day 1 and 100 mg on day 8) faster than the introduction to the gluteus muscle. After multiple injections, the difference in effect is less obvious. The average ratio of Cmax and Css of paliperidone after the administration of 4 injections of the drug Xeplion at a dose of 100 mg in the gluteus muscle was 1.8, and after the introduction into the deltoid muscle - 2.2. At doses of paliperidone 25-150 mg, the AUC of paliperidone changed in proportion to the dose, and Cmax at doses greater than 50 mg increased to a lesser extent than proportionally to the dose.

Median T1 / 2 paliperidone after the administration of the drug Xeplion in doses of 25-150 mg ranged from 25-49 days.

In studies in vitro, paliperidone showed the properties of the P-glycoprotein substrate, and in high concentrations - the properties of a weak inhibitor of P-glycoprotein. There is no corresponding data in vivo, and the clinical significance of this information is unclear.

In general, the concentration of paliperidone in blood plasma during the period of loading after the IM administration of the drug Xeplion was in the same range as after the administration of paliperidone prolonged action orally in 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 (day 8 and day 36). Individual differences in the pharmacokinetics of paliperidone after administration of Xeplion in different patients were less than after oral administration of paliperidone. Because of the difference in the nature of the median change in the concentration of paliperidone in blood plasma when using these drugs, caution should be exercised in direct comparison of their pharmacokinetics.

Special categories of patients

Violation of the function of the liver. Paliperidone does not undergo significant metabolism in the liver. Although the use of the drug Xeplion in patients with impaired liver function of mild or moderate severity has not been studied, with such violations of the liver, dose adjustment is not required. In the study, the use of paliperidone orally in patients with impaired liver function of moderate severity (Child-Pugh class B), the concentration of free paliperidone in blood plasma was the same as in healthy volunteers. In patients with impaired liver function of a serious degree, the use of paliperidone has not been studied.

Impaired renal function. For patients with impaired renal function of mild severity, the dose of paliperidone should be reduced; Xeplion is not recommended for patients with impaired renal function of moderate severity and severity. The distribution of paliperidone after single ingestion of a paliperidone tablet with prolonged action of 3 mg in patients with varying degrees of impaired renal function was studied. With the decrease in Cl creatinine, the excretion of paliperidone was weakened: when the renal function of mild severity was impaired (Cl creatinine 50-80 ml / min) by 32%, at an average severity (Cl creatinine 30-50 ml / min) by 64% severe (Cl creatinine 10-30 ml / min) - by 71%, resulting in AUC0-∞ increased in comparison with healthy volunteers, respectively, in 1.5, 2.6 and 4.8 times. Based on a small amount of data on the use of Xeplion in patients with impaired renal function of mild severity and the results of pharmacokinetics modeling, the recommended loading dose of paliperidone for such patients is 75 mg on the 1 st and 8 th day; after that monthly (every 4 weeks) 50 mg are administered.

Elderly patients. Age in itself is not a factor requiring dose adjustment. However, such correction may be required due to an age-related decrease in Cl creatinine.

Race. Population pharmacokinetic analysis of the results of paliperidone for oral administration revealed no difference in the pharmacokinetics of paliperidone after taking the drug by people of different races.

Floor. Clinically significant differences in the pharmacokinetics of paliperidone in men and women were not 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. According to these in vitro data, population pharmacokinetic analysis did not reveal differences in the pharmacokinetics of paliperidone in smokers and non-smokers.

Indications of the drug Xeplion

Treatment of schizophrenia and prevention of recurrence of schizophrenia.

Contraindications

hypersensitivity to paliperidone or any component of the drug;

patients with a known hypersensitivity to risperidone (because paliperidone is an active metabolite of risperidone).

Carefully

Orthostatic hypotension. Possessing the activity of α-adrenoblocker, paliperidone in some patients can cause orthostatic hypotension. Xenopion should be used with caution in patients with cardiovascular diseases (for example, heart failure, myocardial infarction or ischemia, cardiac conduction disorder), cerebral circulation disorders or conditions predisposing to lowering blood pressure (eg dehydration, reduction of bcc, use of antihypertensive drugs).

Convulsions. Like other antipsychotics, Xeplion should be used with caution in patients who have a history of seizures or other conditions in which the convulsive threshold may be reduced.

Regulation of body temperature. With the use of neuroleptics attributed to the deterioration of the body's ability to lower body temperature. It is advisable to use caution when prescribing Xeplion to patients who may be exposed to the effects of increasing body temperature, such as strong physical activity, high ambient temperature, exposure to drugs with m-cholinolytics activity, and dehydration.

QT interval. As with other antipsychotics, caution should be exercised in prescribing Xeplion to patients who have a history of arrhythmia or congenital prolongation of the QT interval, or who take drugs that extend the QT interval.

Given the action of paliperidone on the central nervous system, caution should be used with Xeplion in combination with other drugs acting on the central nervous system and alcohol. Paliperidone can reduce the effect of levodopa and dopamine agonists.

Caution should be exercised when prescribing Xeplion to elderly patients with dementia, patients with Parkinson's disease or dementia with Levy bodies (see "Special instructions").

Application in pregnancy and lactation

The safety of the use of the drug Xeplion IM or paliperidone orally during pregnancy in humans is not established. When high doses of paliperidone were administered orally, there was a slight increase in fetal mortality in animals. Xeplion with the IM introduction did not affect the course of pregnancy in rats, but high doses of it were toxic to pregnant females. The doses of paliperidone when taken orally and the drug Xeplion with the IM introduction, which create concentrations exceeding the maximum therapeutic dose in humans, respectively, by 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 exceeds the potential risk to the fetus. The effect of the drug Xeplion on labor and birth in humans is unknown.

In the case of a woman taking antipsychotics (including paliperidone) in the third trimester of pregnancy, newborns have a 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.

In studies of the use of paliperidone in animals and risperidone in humans, paliperidone was excreted in breast milk. Therefore, women who receive Xeplion should not breast-feed their children.

Side effects

Most unwanted adverse reactions were mild or moderate.

The undesirable reactions observed in patients are listed below. The frequency of undesired reactions 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; infrequently - acrodermatitis, bronchitis, inflammation of subcutaneous fat, ear infections, eye infections, influenza, onychomycosis, pneumonia, respiratory tract infections, sinusitis, subcutaneous abscess, tonsillitis, urinary tract infections.

From the immune system: infrequently - hypersensitivity.

From the blood and lymphatic system: infrequently - neutropenia, a decrease in the number of white blood cells; rarely - thrombocytopenia; very rarely - agranulocytosis.

From the endocrine system: rarely - inadequate secretion of ADH.

Metabolic disorders: often - weight gain; infrequently - anorexia, hyperglycemia, decreased appetite, increased appetite, weight loss, polydipsia, diabetes mellitus; rarely - hypoglycemia; very rarely - diabetic ketoacidosis, water intoxication.

Mental disorders: very often - insomnia, agitation; often - nightmares, anxiety; infrequently - depression, sleep disturbance, mania.

From the nervous system: very often - headache; often - akathisia, dizziness, extrapyramidal symptoms, drowsiness, Parkinsonism (including akinesia, bradykinesia, rigidity as a cogwheel, drooling, extrapyramidal symptoms, deflection of the glabellar reflex, muscle rigidity, stiffness in muscles, musculoskeletal stiffness); infringement of coordination, cerebrovascular disorders, convulsions (including epileptic convulsions), distraction of attention, postural dizziness, dysarthria, dyskinesia (including athetosis, chorea, choreoathetosis, movement disturbance, muscle contractions, clonic convulsions); dystonia (including blepharospasm, neck spasm, emprostotonus, facial spasm, laryngospasm, involuntary muscle contractions, myotonia, eyeball movements, opisthotonus, oropharyngeal spasm, pleurototonus, sardonic smile, tetany, paralysis of the tongue, spasm of the tongue, rivosheya, convulsive clenching of the jaw), hypoesthesia, paresthesia, psychomotor hyperactivity, syncope, severe dyskinesia, tremor.

Ophthalmic disorders: infrequent - dry eyes, increased lacrimation, ocular hyperemia, involuntary movement of the eyeball, blurred vision.

From the organ of hearing and balance: infrequently - vertigo, pain in the ear.

From the CVS: often - increased blood pressure; infrequently - AV blockade, bradycardia, conduction disturbance, ECG disturbances, QT interval prolongation on ECG, palpitation, postural orthostatic tachycardia syndrome, sinus arrhythmia, tachycardia, atrial fibrillation, orthostatic hypotension; rarely - deep vein thrombosis; very rarely - pulmonary embolism.

On the part of the respiratory system: infrequently - cough, dyspnoea, epistaxis, nasal congestion, pain in the pharyngeal region, obstruction of the respiratory tract, wheezing, obstruction of the lungs; very rarely - sleep apnea syndrome.

Gastrointestinal disorders: often - pain in the upper abdomen, constipation, diarrhea, dryness of the oral mucosa, nausea, toothache, vomiting, abdominal discomfort; infrequently - dyspepsia, dysphagia, fecal incontinence, flatulence, gastroenteritis, edema of the tongue, dysgeusia; rarely - pancreatitis.

From the hepatobiliary system: very rarely - jaundice.

From the osteomuscular system and connective tissue: often - pain in the limbs, musculoskeletal pain; infrequently - arthralgia, back pain, joint stiffness, swelling of the joints, muscle spasms, pain in the neck.

From the skin: infrequently - acne, dry skin, eczema, erythema, hyperkeratosis, urticaria, pruritus, rash, alopecia; rarely - angioedema.

From the urinary system: infrequently - dysuria, pollakiuria, urinary incontinence; rarely - urinary retention.

On the part of the reproductive system and mammary glands: infrequently - amenorrhea, galactorrhea, gynecomastia, sexual dysfunction, ejaculation disorders, erectile dysfunction, vaginal discharge; very rarely - priapism.

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

Other: often - asthenic disorders, weakness, local reactions (pain, itching, compaction at the injection site); infrequent - discomfort in the chest, chills, swelling of the face, gait disturbance, tightness at the injection site, edema (including generalized edema, peripheral edema, mild edema), thirst, increased body temperature; rarely - hypothermia, abscess at the injection site, inflammation of the subcutaneous tissue at the injection site, hematoma at the injection site; very rarely - a cyst at the injection site, necrosis at the injection site, an ulcer at the injection site.

Changes in laboratory parameters: infrequently - an increase in the activity of GGT, liver enzymes, transaminases, cholesterol concentration in the blood, triglyceride concentration in the blood, hyperglycemia.

Interaction

Paliperidone may increase the QT interval, so it should be carefully combined with other drugs that increase the QT interval: antiarrhythmic drugs, incl. quinidine, procainamide, amiodarone, sotalol; antipsychotic drugs (chlorpromazine, thioridazine), antibiotics, incl. gatifloxacin, moxifloxacin.

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.

The ability of the drug Xeplion to influence other drugs

It is not expected that paliperidone will exhibit clinically significant pharmacokinetic interaction with drugs metabolized by isoenzymes of the cytochrome P450 system. Studies using human liver microsomes in vitro have shown that paliperidone does not significantly weaken the metabolism of substances with 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 isoenzyme inducer, in studies in vitro, paliperidone did not induce the activity of isoenzymes CYPA2, CYPC19 or CYP3A4.

Paliperidone in high concentrations is a weak inhibitor of P-glycoprotein. However, there is no dta in vivo in this regard, and the clinical significance of this phenomenon is not known.

Given the action of paliperidone on the central nervous system, caution should be used with Xeplion in combination with other drugs of central action and alcohol.

Paliperidone may lessen the effect of levodopa and dopamine receptor agonists.

Due to the ability of the Xeplion preparation to cause orthostatic hypotension, an additive enhancement of this effect can be observed when using Xeplion together with other drugs possessing this ability.

Simultaneous administration of oral paliperidone 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.

Pharmacokinetic interaction between the drug Xseplion and lithium is unlikely.

The ability of other drugs to affect Xeplion

Paliperidone is not a substrate for the isoenzymes CYP1A2, CYP2A6, CYP2C9, CYP2C19 and CYP3A5. This suggests a weak probability of interaction with the inhibitors and inducers of these isoenzymes. Although in vitro studies show the possibility of minimal participation of CYP2D6 and CYP3A4 in the metabolism of paliperidone, there is currently no evidence that these enzymes can play a significant role in the metabolism of paliperidone in vitro or in vivo. In vitro studies indicate that paliperidone is a substrate of P-glycoprotein.

Paliperidone is metabolized to a limited extent by the CYP2D6 isoenzyme. In a study of the interaction of paliperidone for oral administration with an active inhibitor of CYP2D6 paroxetine in healthy volunteers, there was no clinically significant change in the pharmacokinetics of paliperidone.

Receiving paliperidone with a sustained release of the active ingredient (1 time per day) orally simultaneously with carbamazepine (200 mg twice daily) resulted in a decrease in the mean Cmax and AUC of paliperidone by about 37%. This decrease is largely due to an increase in renal clearance of paliperidone by 35%, probably due to the activation of renal P-glycoprotein carbamazepine. When you start using carbamazepine, the dose of Xeplion should be reviewed and, if necessary, increased. Conversely, with the withdrawal of carbamazepine, the dose of Xeplion should be reviewed and, if necessary, reduced.

Paliperidone at physiological pH values is a cation and is basically excreted unchanged through the kidneys - half by filtration, and half by active secretion. The simultaneous use of trimethoprim, which inhibits the active cation transport system in the kidneys, did not affect the pharmacokinetics of paliperidone.

With the simultaneous administration of oral paliperidone prolonged action in a dosage of 12 mg 1 time per day and tablets of prolonged action of sodium divalproex 2 table. 500 mg once a day there was an increase in Cmax and AUC of paliperidone by 50%, probably as a result of increased absorption of the drug by oral administration. Since there was no significant effect on overall clearance, no clinically significant interaction between sodium divalproex, sustained-release tablets, and Xseplion is expected. It should be considered the possibility of reducing the dose of Xseplion while concomitant administration with valproate on the basis of clinical evaluation of the patient. Studies of interaction with the drug Xeplion was not conducted.

The pharmacokinetic interaction of lithium and paliperidone is unlikely.

The use of Xeplion together with risperidone

The use of Xeplion together with risperidone has not been studied. Since paliperidone is an active metabolite of risperidone, the simultaneous use of the drug Xeplion and risperidone should take into account an increase in the concentration of paliperidone in the blood plasma.

Dosing and Administration

Only for the IM introduction.

In patients who never took paliperidone orally or risperidone orally or parenterally, it is recommended that the tolerance of paliperidone or risperidone be checked orally for 2-7 days before starting treatment with Xseplion.

It is recommended to start treatment with Xeplion with a dose of 150 mg on the first day and 100 mg after 1 week (both injections into the deltoid muscle). A maintenance dose of 75 mg once a month is recommended; the effect can be observed from taking larger or smaller doses in the range of 25-150 mg, depending on individual tolerability and / or efficacy. After the second dose, subsequent supporting injections can be performed in the deltoid or gluteal muscles.

The maintenance dose can be adjusted monthly. In this case, the long-term release of the active ingredient from paliperidone palmitate should be taken into account. the effect of dose changes may fully manifest only after a few months.

Dose skip

Avoidance of skipping doses. The second loading dose of paliperidone is recommended to be administered 1 week after the first dose. If this is not possible, you can enter it 2 days earlier or later. Similarly, the third and subsequent doses are recommended to be administered monthly, but if this is not possible, the injection can be done 7 days earlier or later.

If the second injection of Xeplion was not made on time (1 week ± 2 days), it is recommended that the treatment resume depending on the time that has elapsed since the day of the first injection.

Passing the second initial dose (less than 4 weeks). If less than 4 weeks have elapsed since the first injection, the patient should be given a second injection at a dose of 100 mg in the deltoid muscle as soon as possible. The third injection of the drug Xseplion in a dose of 75 mg should be done in the deltoid or gluteal muscles 5 weeks after the first injection (not including the time of the second injection). In the future, a monthly injection rate of 25 to 150 mg per deltoid or gluteal muscle should be followed, depending on individual tolerability and / or efficacy.

Passage of the second initial dose (term from 4 to 7 weeks). If from the day of the first injection of the drug Xeplion passed from 4 to 7 weeks, the treatment is renewed by the introduction of two injections in a dosage of 100 mg as follows: the first injection into the deltoid muscle is done as soon as possible; after 1 week, make a second injection in the deltoid muscle, then continue the monthly injection of the deltoid or gluteal muscles at a dose of 25 to 150 mg, depending on individual tolerability and / or efficacy.

Pass the second initial dose (more than 7 weeks). If more than 7 weeks have elapsed since the first injection of Xeplion, treatment is also initiated, as in the case of initiation of Xeplion treatment.

Supervision of the maintenance dose (duration from 1 month to 6 weeks). After the start of treatment, it is recommended to inject Xeplion every month. If less than 6 weeks have passed since the last injection, the next dose equal to the previous one should be administered as soon as possible. After this, administer the drug every month.

Passage maintenance dose (the period from 6 weeks to 6 months). If more than 6 weeks have elapsed since the last injection of Kseplion, the following is recommended:

- for patients stabilized with a dose of 25 mg to 100 mg:

1) inject the drug into the deltoid muscle as soon as possible at the dose at which the patient's condition stabilized before the injection was missed;

2) the next injection into the deltoid muscle (the same dose) is done in a week on the 8th day;

3) Next, the monthly injection course in the deltoid or gluteus muscle is resumed at a dose of 25 to 150 mg, depending on individual tolerability and / or efficacy;

- for patients stabilized with a dose of 150 mg:

1) as soon as possible, administer a dose of 100 mg to the deltoid muscle;

2) after 1 week, another dose of 100 mg (8th day) is injected into the deltoid muscle;

3) Next, the monthly injection course in the deltoid or gluteal muscles is renewed at a dose of 25 to 150 mg, depending on individual tolerability and / or efficacy.

Maintenance dose skipping (duration> 6 months). If more than 6 months have elapsed since the last injection of Xeplion, the treatment starts anew, as described above - to start treatment /

Method of administration

The drug is slowly injected deep into the muscle. Injections should be performed only by a medical professional. The whole dose is administered at a time; Do not administer the dose for several injections. Do not administer the drug into the vessels or sc. Avoid accidental ingestion in a blood vessel. For this, before the injection of the drug, the syringe plunger is pulled back to check for the needle entering the large blood vessel. In the event that blood is drawn into the syringe, the needle and syringe must be removed from the patient's muscle and disposed of.

The recommended size of the needle to guide the drug Xeplion in the deltoid muscle is determined by the patient's body weight. For patients weighing ≥90 kg, a long needle with a gray body from the kit is recommended. For patients with a body weight <90 kg, a short needle with a blue body from the kit is recommended. It should be alternately injected into the right and left deltoid muscles.

For the introduction of the drug Xeplion in the gluteus muscle is recommended a long needle with a gray body from the kit. Injections should be performed in the upper outer quadrant of the buttock. It should be alternately injected into the right and left gluteal muscles.

The 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 should be taken into account when using these drugs simultaneously with the Xeplion drug.

Special patient groups

Patients with impaired liver function. The use of Xeplion in patients with impaired liver function has not been studied. Based on the results of paliperidone for oral examination, correction of the dose is not required for patients with a mild or moderate degree of liver function disorder. The use of Xeplion in patients with impaired hepatic function was not studied.

Patients with impaired renal function. The use of Xeplion in patients with impaired renal function has not been systematically studied. In patients with impaired renal function of mild severity (Cl creatinine from ≥50 to <80 ml / min), it is recommended to start using Xseplion from a dose of 100 mg on day 1 and 75 mg in 1 week (both injections into the deltoid muscle) . After that, injections in a dose of 50 mg into the deltoid or gluteus muscles are injected after 1 month, and then the dose is changed from 25 to 100 mg, depending on individual tolerance and / or efficacy.

Xeplion is not recommended for patients with impaired renal function of moderate or severe degree (Cl creatinine <50 ml / min).

Elderly 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 these recommendations are extended to the above recommendations for patients with impaired renal function.

Teenagers and children. The safety and effectiveness of the use of Xeplion in patients younger than 18 years of age has not been studied.

Other special categories of patients. Correction of the dose of Xeplion depending on sex, race of patients and smoking is not required.

Translation from other neuroleptics

Data on the transfer of patients with schizophrenia from other antipsychotics to Xeplion or its use at the same time as other neuroleptics were not systematically collected. For patients who have never taken oral paliperidone or oral or injectable risperidone, tolerability with oral paliperidone or oral risperidone should be investigated before starting treatment with Xseplion. At the beginning of treatment with Xeplion, previously used antipsychotics may be canceled. Xeplion should be administered as described above. If the patient receives an injectable antipsychotic antipsychotic, Xeplion treatment is started immediately with a maintenance dose at the time of the next scheduled injection. The treatment with Xeplion should be continued 1 time per month. The initial dose in the first week of treatment is not required.

In patients who have been stabilized with different doses of the drug Rispeplet Konsta®, a suspension for long-acting IM administration, Css of the active substance can reach similar values during maintenance therapy with Xeplion 1 time per month according to the scheme indicated in the table.

Table

Cancellation of the previous antipsychotic should be carried out in accordance with the instructions for medical use. If Xeplion is withdrawn, prolonged release of the active ingredient should be considered. As in the case of other neuroleptics, the need to continue the use of prophylaxis for the development of extrapyramidal disorders should be periodically evaluated.

Composition of the preparation

The kit includes: pre-filled syringe with the drug, 2 needles for IM injections (in the deltoid and gluteus muscles) - a long needle with a gray body and a short needle with a blue casing.

Instructions for use of the preparation kit

The syringe is intended for single administration only.

Intensively shake the syringe for 10 seconds to obtain a uniform suspension.

2. Select the appropriate needle.

For the introduction into the deltoid muscle of patients weighing <90 kg, use a short needle (with a blue body), and patients with a body weight ≥90 kg - a long needle (with a gray body).

To insert into the gluteus muscle use a long needle (with a gray body).

Holding the syringe vertically, remove the rubber cap from it by gently rotating it clockwise.

4. Half open the safe needle package, grasp the needle cap through the package and insert the syringe into the luer needle cap by gently rotating clockwise.

Remove the cap from the needle by pulling it along the needle. Do not rotate the cap; this can loosen the needle connection with the syringe.

Route the syringe with a needle upwards and squeeze out air from the syringe, slightly pressing the piston.

7. Enter the entire contents of the syringe into the selected muscle (deltoid or gluteal). Do not administer the drug into a blood vessel or pen.

After completion of the injection, bring the needle protection to the working position large (see Figure 7) or the index finger (see figure 8) with a finger or pressing the syringe against a hard surface (see Figure 9). Needle protection must lock with a click. A syringe with a needle should be destroyed as it should be.

Overdose

Since Xeplion is intended for administration by health workers, the likelihood of its overdose is small.

Symptoms: In general, the expected signs and symptoms correspond to the enhancement of the known pharmacological action of paliperidone, i.e. drowsiness, retardation, tachycardia, decreased blood pressure, prolongation of the QT interval, extrapyramidal symptoms. Polyformal ventricular tachycardia of the "pirouette" type and ventricular fibrillation were noted during an overdose of oral paliperidone. In the case of acute overdose, consideration should be given to the possibility of obtaining several drugs by patients.

Treatment: when assessing the need for treatment and recovery of patients should take into account the long-term release of the active substance and large T1 / 2 paliperidone. There is no specific antidote for paliperidone. General support measures should be implemented, the airway patency should be ensured and maintained, sufficient ventilation of the lungs and oxygen saturation of the blood. Immediately begin monitoring the function of the CAS, including continuous monitoring of the ECG to detect possible arrhythmia. In the case of a reduction in blood pressure and circulatory collapse, appropriate measures should be taken, for example, intravenous administration of solutions and / or sympathomimetics. When developing severe extrapyramidal symptoms, anticholinergic drugs are used. The patient's condition should be carefully monitored before recovery.

Special instructions

Malignant neuroleptic syndrome

With the use of neuroleptics, incl. paliperidone, the development of malignant neuroleptic syndrome (CNS), characterized by hyperthermia, muscle rigidity, instability of the autonomic nervous system, impaired consciousness and increased serum creatinophosphinase concentration. In addition, myoglobinuria (rhabdomyolysis) and acute renal failure may occur. When there are symptoms suggestive of the NSA, all neuroleptics, including Xeplion, are canceled.

Late dyskinesia

The use of drugs that have the properties of dopamine receptor antagonists is accompanied by the development of tardive dyskinesia, characterized by rhythmic, involuntary movements, mainly of the tongue and / or facial muscles. When symptoms of tardive dyskinesia should be considered, the possibility of reversing all antipsychotics, including Xeplion, should be considered.

Hyperglycemia and diabetes mellitus

When treating the drug Xseplion, hyperglycemia, diabetes mellitus and exacerbation of 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 mellitus 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. In all patients, it is necessary to conduct clinical monitoring for the presence of symptoms of hyperglycemia and diabetes mellitus (see "Side effects").

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.

Elderly patients with dementia

Cross-sectional analysis of the results of studies showed an increased mortality of elderly patients with dementia who received atypical antipsychotics, incl. 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 Xeplion in elderly patients with dementia has not been studied. Since paliperidone is an active metabolite of risperidone, the experience with risperidone should be considered. 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 furosemide-only group. There are no pathophysiological mechanisms that explain this observation. Nevertheless, special care should be taken when prescribing the drug in such cases. There was no increase in mortality in patients taking other diuretics simultaneously with risperidone. Regardless of treatment, dehydration is a common risk factor for mortality and should be carefully monitored in elderly patients with dementia.

Disorders of cerebral circulation

In placebo-controlled studies, an increased incidence of cerebral circulatory disorders (transient and stroke) was detected, including. with fatal outcome, in elderly patients with dementia, who received some atypical antipsychotics, incl. risperidone, aripiprazole and olanzapine, compared with placebo.

Leukopenia, neutropenia, agranulocytosis

Leukopenia, neutropenia, and agranulocytosis were noted with the use of antipsychotics, incl. when using the drug Xeplion. Agranulocytosis was very rare 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; discontinuation of Xeplion treatment 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 should be observed for fever or symptom onset and should begin treatment immediately if symptoms occur. Patients with severe neutropenia (absolute neutrophil counts less than 1 · 109 / L) should stop using Xeplion until the number of white blood cells 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 Xseplion and preventive measures should be taken.

Parkinson's disease and dementia with Levi bodies

The physician should compare the risks and benefits of using antipsychotics, including Xeplion, in patients with Parkinson's disease or dementia with Levy bodies. in both these categories of patients, the risk of developing the NSA and the risk of hypersensitivity to neuroleptics may be increased. Manifestations of hypersensitivity can include confusion, blunting of pain sensitivity, unstable posture with frequent falls, and extrapyramidal symptoms.

Priapism

There are data on the ability of drugs that have the properties of α-adrenoblockers to cause priapism. Priapism is registered in the post-marketing control of paliperidone.

Antiemetic action

In preclinical studies of paliperidone, an antiemetic effect was found. The appearance of this effect in a patient may mask the signs and symptoms of an overdose of certain drugs or, for example, conditions such as bowel obstruction, Reye's syndrome or a brain tumor.

Introduction

With the IM introduction, care should be taken to avoid accidental ingestion of the drug into the blood vessel.

Influence on the ability to drive a car or perform work that requires an increased speed of physical and mental reactions. Xeplion can disrupt the performance of actions requiring concentration of attention and speed of psychomotor reactions, and can affect vision. Therefore, patients should be advised not to drive vehicles and moving mechanisms until their individual sensitivity is established.

Release form

Suspension for intramuscular administration of prolonged action, 100 mg / 1 ml. By 0.25, 0.5, 0.75, 1 or 1.5 ml of the preparation in a syringe from the cyclolefin copolymer. The kit includes 2 needles for intravenous injections (in the deltoid and gluteal muscles). A pre-filled syringe with the drug and 2 needles in a plastic pallet covered with PE film is placed in a cardboard box.

Conditions of leave from pharmacies

On prescription.

Storage conditions of the drug Xeplion

At a temperature not exceeding 30 ° C.

Keep out of the reach of children.

Shelf life of the drug Xeplion

2 years.

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