Xeplion - instructions for use, dose, side effects, contraindications

Active substancePaliperidonePaliperidone

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Invega®

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Johnson & Johnson, LLC Russia

Xseplion

suspension w / m

Johnson & Johnson, LLC Russia

Trevikta

suspension w / m

Johnson & Johnson, LLC Russia

Dosage form: & nbspsuspension for intramuscular administration of prolonged action

Composition:

Each pre-filled syringe contains:

Active substance: 100 mg of paliperidone in 1 ml of suspension (equivalent to 156 mg of paliperidone palmitate).

Excipients: 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:

White or almost white suspension, free from foreign inclusions.

Pharmacotherapeutic group:antipsychotic agent (antipsychotic)

ATX: & nbsp

N.05.A.X Other antipsychotics

N.05.A.X.13 Paliperidone

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 αl- and α2 receptors and H1-histamine 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 a combined blockade D2 and 5-HT2areceptors.

Pharmacokinetics:

Suction and distribution

Due to the extremely low solubility in water of paliperidone, palmitate is slowly dissolved after intramuscular injection and absorbed into the systemic bloodstream. After a single intramuscular 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 is retained for 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, the maximum concentration (C max) is 28% more than on the gluteus muscle.At the beginning of the treatment, the introduction of the drug into the deltoid muscle helps to reach the therapeutic concentration of paliperidone (150 mg on the first day and 100 mg on the 8th day) faster than the introduction to the gluteus muscle. After multiple injections, the difference in effect is less obvious. The average ratio of the maximum and equilibrium concentrations of paliperidone after the administration of 4 injections of Xeplion in a dose of 100 mg in the gluteal muscle was 1.8, and after the introduction into the deltoid muscle, 2.2. At doses of paliperidone 25-150 mg the area under the curve "concentration-time" (AUC) Paliperidone changed in proportion to the dose, and C_max at doses greater than 50 mg increased to a lesser extent than proportionally to the dose.

The median half-life of paliperidone after the administration of Xeplion in doses of 25-150 mg ranged from 25-49 days.

After administration of the preparation, the (-) - enantiomer of paliperidone is partially converted to the (+) - enantiomer, and the ratio AUC (+) - and (-) - enantiomers is about 1.6-1.8.

In population analysis, the apparent volume of distribution of paliperidone was 391 liters; paliperidone binds to blood plasma proteins by 74%.

Metabolism and excretion

For a week after a single oral intake of 1 mg of the drug ¹⁴C-paliperidone with immediate release of the active component with urine in unchanged form, 59% of the administered dose is withdrawn; this indicates a lack of significant metabolism of the drug in the liver. Approximately 80% of the introduced radioactivity was detected in urine and 11% in feces. There are 4 ways of metabolism of the drug in vivo, but none of them causes metabolism more than 6.5% of the administered dose: dealkylation, hydroxylation, dehydrogenation, elimination of the benzisoxazole group. Although research in vitro allow to assume a certain role of isoenzymes CYP2D6 and CYP3A4 in the metabolism of paliperidone, data on the significant role of these isoenzymes in the metabolism of paliperidone in vivo no. Population pharmacokinetic analysis revealed no significant difference in clearance of paliperidone after oral administration of the drug lpeople with active and weak metabolism CYP2D6. Studies using human liver microsomes in vitro showed that paliperidone does not substantially inhibit the metabolism of drugs by isoenzymes CYP1A2, CYP2A6, CYP2D6, CYP2E1, CYP3A4 and CYP3A5.

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

In general, the concentration of paliperidone in blood plasma during the period of loading after intramuscular injection of the Xseplion drug was in the same range as after the administration of oral delayed paliperidone with the release of the active ingredient at doses between 6 and 12 mg. The paliperidone loading scheme used maintains concentrations 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 Xseplion 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 two drugs are used, 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 Xseplion 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 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 a prolonged effect of 3 mg in patients with varying degrees of impaired renal function was studied. With the decrease in the clearance of creatinine (CC), the removal of paliperidone was weakened: when the renal function was mild (KK 50-80 ml / min) - by 32%, with an average severity (KK 30-50 ml / min) - 64% at a severe degree (CC 10-30 ml / min) - by 71%, resulting in AUC0-∞ increased compared with healthy volunteers, respectively, at 1.5, 2.6 and 4.8 times. Based on a small amount of data on the use of Xseplion in patients with impaired renal function of mild severity and from 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; then monthlyevery 4 weeks), 50 mg are administered.

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

Race. Population pharmacokinetic analysis of the study results paliperidone for oral administration did not reveal differences 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 CYP1A2, so smoking should not affect the pharmacokinetics of paliperidone.In accordance with these data in vitro, Population pharmacokinetic analysis did not reveal differences in the pharmacokinetics of paliperidone 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.

Because the paliperidone is an active metabolite of risperidone, Xenplion is contraindicated in patients with known hypersensitivity to risperidone.

Carefully:Caution should be used with Xseplion in the following cases (see "Special instructions" for more information):
- 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 (for example, dehydrationthe use of antihypertensive drugs).

- In patients who have a history of convulsions or other conditions in which the convulsive threshold may be reduced.

- In patients who can be exposed to the effects of increasing body temperature, for example, strong physical activity, high ambient temperature, effects of drugs with m-cholinolytics activity, and also dehydration.

- In patients who have a history of arrhythmia or congenital lengthening of the interval Q-T, or taking drugs that extend the interval Q-T.

- When used in combination with other drugs acting on the central nervous system and alcohol. Paliperidone can weaken the effect of levodopa and dopamine agonists.

- In patients with dementia, patients with Parkinson's disease or dementia with Levi bodies.

- Patients with possible prolactin-dependent tumors.

- In patients with impaired function liver or kidney.

Pregnancy and lactation:

Pregnancy

Safety of the use of the drug Xeplion intramuscularly or paliperidone orally during pregnancy in humans is not established. When application of high doses of paliperidone orally there was a slight increase in fetal mortality in animals. Xeplion, when administered intramuscularly, did not affect the course of pregnancy in rats, but its high doses were toxic to pregnant females.The doses of paliperidone when taken orally and the drug Xeplion when administered intramuscularly, which create concentrations exceeding the maximum therapeutic doses in humans by 20-22 times and 6 times, respectively, did not affect the offspring of laboratory animals. Xenplion 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.

If female was antipsychotic drugs (including paliperidone) in third trimester pregnancy, neonates 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.

Breast-feeding

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

Dosing and Administration:In patients who never took paliperidone by mouth or risperidone orally or parenterally, before starting treatment with Xseplion, it is recommended that the tolerability of paliperidoya or risperidone be checked orally for 2-7 days.

It is recommended to begin 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 25-150 mg, depending on individual tolerability and / or efficacy. After the second initial dose, subsequent supporting injections can be performed in the deltoid or gluteus muscle. The maintenance dose can be adjusted monthly. This should take into account the long-term release of the active ingredient from paliperidoya palmitate, since the effect of dose change 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, then you can enter it 4 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 Xplion was not done on time (one week ± 4 days), it is recommended to resume treatment depending on the time that has elapsed since the day of the first injection.

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

Pass the second initial dose (the period from 4 to 7 pedel). If from the day of the first injection of the Xeplion drug has passed from 4 to 7 weeks, the treatment is renewed by injecting two injections at 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

a monthly course of injections into the deltoid or gluteus muscle at a dose of 25 mg to 150 mg, depending on individual tolerability and / or efficacy.

Passing the second initial dose (more 7 weeks). If more than 7 weeks have elapsed since the first injection of Xeplion, treatment is started in the same way as in the case of initiation of Xeplion treatment.

Passing maintenance dose (period from 1 month to 6 weeks). After the start of treatment, it is recommended to inject Xseplion 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.

Supervision of the maintenance dose (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 stabilization of the condition has passed patient before admission;

2) The next injection in deltoid muscle (same dose) do in a week on the 8th day;

3) Then resume the monthly a course of injections into the deltoid or gluteus muscle at a dose of 25 mg up to 150 mg, depending on the individual tolerance and / or efficiency.

For patients, stabilized a dose of 150 mg:

1) Dose as soon as possible 100 mg in the deltoid muscle;

2) After 1 week, another dose of 100 mg (8th day) in deltoid muscle;

3) Then resume the monthly a course of injections into the deltoid or gluteus muscle at a dose of 25 mg up to 150 mg, depending on the individual tolerance and / or efficiency.

Maintenance dose skip (term > 6 months). If from the moment the last injection of the drugXeplion passed more than 6 months, then the treatment starts anew, as described above to begin treatment.

Mode of application

Xeplion is intended for intramuscular administration only. 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 subcutaneously. 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 enters the syringe, it is necessary to remove the needle and syringe from the patient's muscle and dispose of them.The recommended size of the needle for the administration of Xseplion to the deltoid muscle is determined by the patient's body weight. For patients with body weight ≥90 kg recommended long needle with a gray body from the kit. 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 muscle.

For the introduction of the drug Xseplion 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. You should alternately inject the drug into the right and left gluteus muscle. Because the paliperidone is the main active metabolite of risperidone, caution should be exercised while using the Xseplion and risperidone or the oral form of paliperidone for a long period of time. Data on the safety of simultaneous use of Xseplion and other antipsychotics are limited.

Patients with impaired hepatic function

The use of Xeplion in patients with impaired liver function has not been studied. Based on the results of the study of paliperidone for oral administration, correction of the dose is not required for patients with impaired liver function of mild or moderate severity.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 mild renal function (creatinine clearance from ≥ 50 to <80 mL / min) is recommended to begin application Kseplion preparation with a dose of 100 mg per 1 - th day and 75 mg after 1 week (both injection into the deltoid muscle). After that, after 1 month, inject a dose of 50 mg into the deltoid or gluteus muscle, and thenchange the dose from 25 mg to 100 mg, depending on individual tolerability and / or efficacy. Xeplia is not recommended for patients with impaired renal function of moderate or severe degree (creatinine clearance <50 ml / min).

Elderly patients

In general, for elderly patients with normal kidney function the same dose of Xeplioi is recommended as for younger patients with normal renal function. In elderly patients, kidney function can be reduced, and in such patients extend the above recommendations for patients with impaired renal function.

Teens and children

Security and efficiency application of the drug Xeplioi in patients under the age of 18 years 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 simultaneously with other antipsychotics 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 gradually eliminated. Xeplion should be administered as described in the section "Administration and dosage" above. If the patient receives an injectable antipsychotic antipsychotic, Xenplion treatment is started immediately with a maintenance dose at the time of the next scheduled injection.

The drug Xseplion should be continued once a month.The initial dose in the first week of treatment is not required.

In patients who have been stabilized with different doses of the preparation Rispeplet Konsta®, suspension for intramuscular administration of prolonged action, equilibrium concentrations of the active substance can reach similar values during maintenance therapy with Xseplion once a month according to the following scheme:

The last dose	Initial dose
Rispeplet Konsta®	Xseplion
25 mg every two weeks	50 mg once a month
37.5 mg every two weeks	75 mg once a month
50 mg every other week	100 mg once a month

Cancellation of the previous antipsychotic should be carried out in accordance with the instructions for medical use. With cancellation of the drug Xeplion should consider the long-term release of the active ingredient. 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.

Side effects:The most frequent adverse reactions reported in clinical trials were insomnia, headache, anxiety, upper respiratory tract infections,injection site reactions, parkinsonism, weight increase, akathisia, excitement, sedation, drowsiness, nausea, constipation, dizziness, musculoskeletal pain, tachycardia, tremors, abdominal pain, vomiting, diarrhea, fatigue, dystonia. Of these, sedation and snotty were dose-dependent. Most unwanted adverse reactions (NDP) were weak or moderate.

The undesirable reactions observed in patients are listed below. The frequency of unwanted reactions was classified as follows: Often (≥ 10 %),often (≥ 1 % and <10%), infrequently (≥ 0.1% and <1%), rarely (≥0.01% and <0.1%) and rarely (< 0,01 %).

Infections:

often - Urinary system infections, influenza, upper respiratory tract infections; infrequently -acarodermatitis, bronchitis, inflammation of subcutaneous fat, ear infections, eye infections, pneumonia, respiratory tract infections, sinusitis, subcutaneous abscess, tonsillitis, cystitis;

rarely - onychomycosis.

From the immune system:

infrequently hypersensitivity;

rarely - anaphylactic reactions.

Violations from the blood and lymphatic system:

infrequently - anemia, decrease hematocrit, an increase in the number eosinophils, a decrease in the number white blood cells;

rarely - thrombocytopenia, neuropathy, agranulocytosis.

Disorders from the endocrine system:

often hyperprolactinemia;

rarely - inadequate secretion of antidiuretic hormone;

with unknown frequency - glucose in urine.

Metabolic disorders:

often - hyperglycemia, decrease body weight, increased concentration triglycerides in blood plasma, weight gain;

infrequently - Hyperinsulinemia, anorexia, decreased appetite, increase in appetite, sugar diabetes, increased concentration cholesterol in the blood;

rarely - polydipsia, hypoglycemia, water intoxication, diabetic ketoacidosis.

Psychiatric disorders:

Often - Insomnia;

often - anxiety, depression, excitation;

infrequently - decreased libido, nervousness, nightmares, confusion, sleep, mania;

rarely anorgasmia, emotional flatness.

Violations from the nervous systems:

Often - headache;

often - sedation, dystonia, dyskinesia, tremor, akathisia, dizziness, extrapyramidal symptoms, drowsiness, parkinsonism;

infrequently - seizures (including epileptic seizures), absent-mindedness, postural dizziness, dysarthria, gipoesteziya, paresteziya, psychomotor hyperactivity, syncope, severe dyskinesia, dysgeusia;

rarely - malignant antipsychotic syndrome, cerebral ischemia, the lack of response to stimuli, loss of consciousness, decreased level of consciousness, diabetic coma, disorders of balance, poor coordination, shaking his head.

Ophthalmic disorders:

infrequent - dry eyes, blurred vision, conjunctivitis;

rarely - glaucoma, photophobia, increased lacrimation, ocular hyperemia, involuntary movement of the eyeball, rotatory nystagmus.

Disturbances from the organ of hearing and balance:

infrequently - vertigo, noise in the ears, pain in the ear.

Disorders from the cardiovascular system:

often bradycardia, tachycardia, increased blood pressure;

infrequently - blood pressure, atrioventricular block, conduction disorders, electrocardiogram, increased QT interval in the electrocardiogram, palpitations, postural orthostatic tachycardia syndrome, atrial fibrillation, orthostatic hypotension;

rarely - deep vein thrombosis, sinus arrhythmia, pulmonary embolism, ischemia, hot flashes.

Disturbances from the respiratory system:

often - cough, nasal congestion;

infrequently - dyspnoea, nasal bleeding, pain in the pharyngeal-guttural area, wheezing breathing, obstruction of the lungs;

rarely - hyperventilation, aspiration pneumonia, obstruction of the respiratory tract, dysphonia, sleep apnea syndrome.

Gastrointestinal disorders:

often - dyspepsia, pain in the upper parts of the abdomen, constipation, diarrhea, nausea, tooth pain, vomiting;

infrequently - discomfort in the abdomen, dryness of the mucosa oral cavity, flatulence, gastroenteritis;

rarely - pancreatitis, fecal incontinence, edema of the tongue, dysphagia, intestinal obstruction, fecal stones, cheilitis.

Infringements from hepatobiliary system:

often - increased activity of hepatic granaminases;

infrequently - an increase in the activity of gamma-glutamyltransferase, an increase in the activity of enzymes liver;

rarely - jaundice.

Disturbances from the bone-muscular system and connective fabrics:

often - pain in the back, pain in the limbs, musculoskeletal pain;

infrequently - arthralgia, stiffness joints, muscle spasms, pain in the neck;

rarely - Swelling of the joints, rhabdomyolysis, increased activity of creatine phosphokinase, muscle weakness, abnormal position.

Skin disorders:

often - skin rash;

infrequently - Acne, dry skin, eczema, erythema, urticaria, pruritus, alopecia;

rarely - angioedema, hyperkeratosis, skin discoloration, seborrheic dermatitis, dandruff, drug rash.

Infringements from urinary system:

infrequently - dysuria, pollakiuria, urinary incontinence;

rarely - urinary retention.

Infringements from reproductive system and dairy glands:

infrequently - delay in menstruation, disorders of menstruation, amenorrhea, galactorrhea, gynecomastia, sexual dysfunction, ejaculation disorders, erectile dysfunction, vaginal discharge;

rarely - priapism, pain in the mammary glands, discomfort in the mammary glands, engorgement of the mammary glands, enlargement of mammary glands, discharge from the mammary glands.

Influence on the course of pregnancy, postpartum and perinatal condition:

rarely - withdrawal syndrome in newborns.

Other:

often - fever, asthenic disorders, weakness, local reactions (pain, itching, seals in place injections);

infrequently - chest pain, discomfort in chest area, facial edema, gait disturbance, malaise, compaction at the injection site, edema (including generalized edema, peripheral edema, mild edema), falling;

rarely - chills, fever, decrease body temperature, thirst, withdrawal syndrome, cyst at the injection site, hypothermia, abscess at the injection site, inflammation of the subcutaneous tissue at the injection site, hematoma at the site of injection.

Undesirable reactions registered with the use of risperidone

Paliperidone is an active metabolite of risperidone, therefore the profiles of adverse reactions of risperidone and paliperidone are interrelated. In addition to the above, when using risperidone, the following collateral reaction, which can arise and whenapplication of the drug Xseplion:

Violations from the nervous system: cerebral infarction blood circulation.

Ophthalmic violations: intraoperative syndrome of sagging iris.

Disturbances from the respiratory system, chest and mediastinal organs: wheezing.

General disorders and disorders at the site of administration (observed with the use of the risperidone injection form): necrosis at the site of injection, ulcer at the injection site.

Description of individual adverse reactions

Anaphylactic reactions

Rare cases of anaphylactic reactions with the introduction of the drug Xseplion were recorded in the postmarketing period in patients previously well

who tolerated oral risperidone or paliperidone.

Reactions at the site of administration

The most commonly reported reaction at the site of administration was pain, which in most cases was of mild or moderate severity. According to the assessment using the visual analogue scale, the frequency and intensity of pain decreased over time in all clinical studies of phases II and III. Injections into the deltoid muscle are perceived as slightly more painful compared to injections in the gluteus muscle. Other reactions at the site of administration were mostly of mild severity and included densification (often), itching (infrequently), and nodules (rarely).

Extrapyramidal symptoms (EC)

ES include the following terms: parkinsonism (includes hypersalivation, musculoskeletal stiffness, parkinsonism, drooling, rigidity as a "cogwheel", bradykinesia, hypokinesia, musco-like face, muscle tension, akinesia, stiff neck, muscle stiffness, parkinsonic gait, violation of the glabellar reflex and Parkinsonian resting tremor), akathisia (includes akathisia, excited state, hyperkinesia and restless legs syndrome), dyskinesia (includes dyskinesia, twitching muscle, choreoathetosis, athetosis and myoclonia), dystonia (includes dystonia, hypertension, torticollis, involuntary muscle contraction, myogea contracture, blepharospasm, eyeball movement, couple ich language, a spasm of the face, laryngospasm, myotonia, opisthotonos, oropharyngeal spasm, plevrototonus, tongue spasm, and convulsive clenching of the jaw) and tremor. This list includes a wider range of symptoms that may not extrapyramidal origin.

Weight loss

In a 13-week clinical trial using an initial dose of 150 mg, it was shown that an abnormal increase in body weight > 7% is dose-dependent. The increase in body weight was noted with a frequency of 5% in the placebo group and at a frequency of 6%, 8% and 13% with Xeplion applied at a dose of 25 mg, 100 mg and 150 mg, respectively.

During the 33-week open period of transition to Xeplion therapy or Xerplion maintenance therapy of a long-term clinical trial, 12% of patients treated with Xeplion met this criterion (weight gain for > 7% of the double blind phase to the end point).

Class Effects

When using antipsychotics, lengthening of the interval QT, occurrence of ventricular arrhythmias (ventricular fibrillation, ventricular tachycardia), sudden unexplained death, cardiac arrest and tachycardia such as pirouette. When using antipsychotics, cases of development (with unknown frequency) of venous thromboembolism, including cases of pulmonary embolism and deep vein thrombosis, are reported.

Overdose:

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

Symptoms

In general, the expected signs and symptoms correspond enhance the known pharmacological action of paliperidone, i.e. drowsiness, retardation, tachycardia, lowering blood pressure, lengthening the interval Q-T, 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 a long half-life of paliperidone. There is no specific antidote for paliperidone. General supportive measures should be implemented, and it should be ensured that airways are passable, that the lungs are well ventilated and oxygen is saturated with blood. Immediately begin monitoring the function of the cardiovascular system, including continuous monitoring of the ECG to detect possible arrhythmia. In the event 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.

Interaction:Like other antipsychotics, paliperidone can increase the interval Q-T, therefore it should be combined with caution with other drugs that increase the interval Q-T, such as antiarrhythmic drugs (incl. quinidine, disopyramide, procainamide, amiodarone, sotalol), antihistamines, antipsychotic drugs (chloromaromazine, thioridazine); antibiotics (including gatifloxation, moxifloxacin), some medicines against malaria (incl. mefloquine).

Since paliperidone palmitate hydrolyzes to paliperidone, evaluation of capabilities medicinal interactions the results of studies of paliperidone for oral administration should be taken into account.

The ability of the drug Xeplion to influence other drugs

It is not expected that paliperidone will show clinically significant

pharmacokinetic interaction with drugs,metabolized isoenzymes of the cytochrome P450 system. Studies using human liver microsomes in vitro showed 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 the inductor of isoenzymes, t. in in vitro studies paliperidone It did not induce the activity of isoenzymes CYPA2, CYPC19 or CYP3A4.

Paliperidone in high concentrations is a weak inhibitor of P-glycoprotein. However, data in vivo in this respect, no, and the clinical significance of this phenomenon is unknown.

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

Because of the ability of the drug Xseplion to cause orthostatic hypotension can be observed additive enhancement of this effect when using Xseplion together with other drugs with this ability.It should be carefully combined paliperidone with drugs that reduce the convulsive threshold, such as phenothiazines, butyrophenones, tricyclic derivatives, selective serotonin reuptake inhibitors, tramadol, mefloquine etc.)

Simultaneous reception 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.

Ability of other drugs to influence Xeplion

Paliperidone is not a substrate isozymes CYP1A2, CYP2A6, CYP2C9, CYP2C19 and CYP3A5. This suggests a weak probability of interaction with the inhibitors and inducers of these isoenzymes. Although research in vitro show the possibility of minimal participation 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. Research in vitro evidence that paliperidone is a substrate of P-glycoprotein. Paliperidone to a limited extent is metabolized by isoenzyme CYP2D6. AT research interaction between paliperidone for oral administration with an active inhibitor CYP2D6 paroxetine in healthy volunteers there was no clinically significant change in the pharmacokinetics of paliperidone.

Reception of paliperidone with long-term liberation active component (once a day) orally simultaneously with carbamazepine (200 mg twice daily) resulted in a decrease in the mean C_mOh and AUC 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. A very small decrease in the amount of the drug, excreted through the kidneys in an unchanged form, suggests that carbamazepine only slightly affects the metabolism in the liver or the bioavailability of paliperidone. When you start using carbamazepine, the dose of Xseplion should be reviewed and, if necessary, increased. Conversely, with the withdrawal of carbamazepine, the dose of Xseplion should be reviewed and, if necessary, reduced. Paliperidone at physiological pH 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 once a day and tablets of prolonged action of sodium divalproex (2 tablets 500 mg once a day) there was an increase in Cmah and AUC paliperidone by 50%, probably as a result of increased absorption of the drug in oral administration. Since there was no significant effect on overall clearance, no clinically significant interaction between sodium divalproex, long-lasting pills, and drug Xseplion. Should consider reducing dose Xreplion with simultaneous appointment with valproate on the basis of clinical evaluation of the patient.

Investigations of interaction with Xreplion was not carried out.

Pharmacokinetic interaction lithium and paliperidone is unlikely.

Application of the drug Xeplion together with risperidone or with the oral form of paliperidone

Because the paliperidone is an active metabolite of risperidone, Care should be taken when simultaneous application for a long period of time the drug Xseplion and risperidone or oral form paliperidone. Data on safety of simultaneous application of the drug Xseplion and other antipsychotics are limited.

Special instructions:Interval QT

Caution should be exercised when using paliperidone in patients with known cardiovascular disease or with lengthening of the interval QT in the anamnesis, and also at joint application of medical products which can lead to lengthening of an interval QT.

Malignant neuroleptic syndrome

With the use of neuroleptics, including paliperidone, the development of malignant neuroleptic syndrome (CNS) characterized by hyperthermia, muscle stiffness, instability of the autonomic nervous system, impaired consciousness and increased serum creatinophosphinase concentration. In addition, myoglobinuria (rhabdomyolysis) and acute renal failure may be observed. When there are symptoms suggesting the NSA, all neuroleptics, including Xseplion, cancel.

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 sugar diabetes in the general population. Given these factors, the relationship between application atypical antipsychotic drugs and the development of side effects associated with hyperglycemia, is not fully established. In all patients, it is necessary to conduct clinical monitoring for the presence of symptoms of hyperglycemia and diabetes mellitus (see section "Side effect").

Weight gain

When treating atypical antipsychotics was observed a significant increase in body weight. It is necessary to monitor the body weight of patients.

Hyperprolactinemia

Studies of tissue cultures indicate that the growth of a breast tumor in a person can be stimulated by prolactin.

Despite the fact that until now in clinical and epidemiological studies not was demonstrated a direct relationship with the use of antipsychotics, caution should be exercised when using paliperidone in patients with possible prolactin-dependent tumors.

Orthostatic hypotension

Having alpha-adrenoblocker activity, paliperidone in some patients may cause an orthostatic hypotens. Xenplion should be used with caution in patients with cardiovascular diseases (eg, heart failure, myocardial infarction or ischemia, cardiac conduction abnormality), disorders of cerebral circulation or conditions predisposing to lower blood pressure (for example, dehydration, a decrease in the volume of circulating blood, the use of antihypertensive drugs).

Convulsions

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

Renal insufficiency

The concentration of paliperidone in plasma is increased in patients with impaired renal function. Correction of dose is recommended in patients with impaired renal function of mild degree. Xeplion is not recommended for patients with impaired renal function of moderate or severe degree (creatinine clearance <50 ml / min).

Liver failure

The use of Xseplion in patients with severe hepatic dysfunction (class C on the Child-Pugh scale) has not been studied. Care should be taken when using paliperidone in these 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, including risperidone, aripiprazole, olanzapine and quetiapine, compared with placebo. Among patients who received risperidone and placebo, the death rate was 4% and 3.1%, respectively.The use of Xseplion in elderly patients with dementia has not been studied. Because the paliperidone is an active metabolite of risperidopa, then experience with risperidone should be considered. For elderly patients with dementia, taking risperidone, there was an increased mortality in patients taking furosemide and risperidone, in comparison with the group that received only risperidone, and the group that accepted only furosemide. 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 research detected increased frequency of disorders of the brain blood circulation (transient and stroke), including fatal cases, in elderly patients with dementia,who received some atypical antipsychotics, including risperidone, aripiprazole and olanzapine, compared with placebo.

Leukopenia, neutropenia, agranulocytosis

Leukopenia, neutropenia and Agranulocytosis was noted with the use of antipsychotic drugs, including with the use of the drug Xseplion. 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 are recommended to perform 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 number neutrophils less than 1 x 10%) should stop using Xseplion until the number of white blood cells is normalized.

Venous thromboembolism

When using antipsychotic drugs, cases of venous thromboembolism were noted. Because patients taking antipsychotic medications often have the risk of venous thromboembolism, all possible risk factors should be identified before and during treatment with Kseplion, and preventive measures must be taken.

Parkinson's disease and dementia with Levi bodies

The physician must weigh the risks and benefits of the use of antipsychotic drugs, including Kseplion in patients with Parkinson's disease or dementia with Lewy bodies, as both of these categories of patients may be at increased risk of neuroleptic malignant syndrome (NMS) and the risk of increased sensitivity to antipsychotics. 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 alpha-adrenoblockers to cause priapism. Priapism is registered in the post-marketing control of paliperidone.

Influence does not regulate body temperature

With the use of neuroleptics attributed to the deterioration of the body's ability to lower body temperature. Recommended manifest caution in prescribing the drug Xeplion to patients who may be exposed to exposures that increase body temperature, for example, strong physical exertion, high ambient temperature, effects of drugs with m-cholinolytics activity, and also dehydration.

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

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

Intraoperative syndrome of sagging iris (ISDR)

ISDR was observed during an operative intervention for the presence of cataracts in patients receiving therapy with antagonists of a1-adrenergic receptors, such as Xseplion.

ISDR increases the risk of complications associated with the organ of vision, during and after an operation. The physician conducting such an operation should be informed in advance that the patient has taken or is currently taking drugs that have antagonist activity a1adrenoreceptors. The potential benefit of the abolition of A1-adrenergic antagonist therapy before surgery is not established, and should be evaluated taking into account the risks associated with the abolition of antipsychotic medications.

Effect on the ability to drive transp. cf. and fur:

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.

Form release / dosage:

Suspension for intramuscular administration of prolonged action, 25 mg / 0.25 ml, 50 mg / 0.50 ml, 75 mg / 0.75 ml, 100 mg / 1 ml, 150 mg / 1.5 ml.

Packaging:

For 0.25, 0.50, 0.75, 1.00, 1.50 ml of the preparation in a syringe from the cyclolefin copolymer.The kit includes 2 needles for intramuscular injection (in the deltoid and gluteus muscle). The pre-filled syringe with the preparation and 2 needles in a plastic pallet covered with polyethylene film are placed together with the instruction for use in a cardboard pack.

Instructions for use

The syringe is intended for single administration only.

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

2. Select the appropriate needle.

For the introduction into the DELTOVID muscle, patients with a body weight <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).

For introduction into the Yagodic muscle, use a long needle (with a gray body).

3. While 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 Luhr needle cap by gently rotating clockwise.

5. Remove the cap from the needle by pulling it along the needle. Do not rotate the cap, as this may loosen the needle connection with the syringe.

6. Point the syringe with the needle upward and squeeze the air out of the syringe, lightly 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 subcutaneously.

8. After completion of the injection, protect the needle with the thumb or index finger, or by pressing the syringe against the hard surface Needle protection must lock with a click. Dispose of the syringe with the needle as it should be.

Storage conditions:

At a temperature of no higher than 30 ° C. Keep out of the reach of children.

Shelf life:

2 years. Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LSR-009014/10

Date of registration:31.08.2010

The owner of the registration certificate:Johnson & Johnson, LLC Johnson & Johnson, LLC Russia

Manufacturer: & nbsp

JANSSEN PHARMACEUTICA, N.V. Belgium

Information update date: & nbsp10.10.2015

Illustrated instructions

Instructions

Xseplion (Xeplion)