Xeplion, 150 mg/1.5 ml 1.5 ml

An antipsychotic drug (neuroleptic). Paliperidone palmitate is hydrolyzed to paliperidone. The latter is a centrally acting active antagonist of predominantly serotonin 5-HT_2A receptors, but also of dopamine D₂ receptors, adrenergic ?₁– and ?₂-receptors and H1-histamine receptors. Paliperidone does not bind to cholinergic m-receptors and to adrenergic ?₁– and ?₂– receptors. The pharmacological activity of the (+) and (-) enantiomers of paliperidone is quantitatively and qualitatively the same.

Therapeutic efficacy of the drug in schizophrenia is thought to be due to the combined blockade of D₂ and 5-HT_2A -receptors.

Pharmacokinetics

Absorption and distribution

Because of paliperidone palmitate’s extremely low water solubility, it dissolves slowly after intramuscular administration and is absorbed into the systemic bloodstream. After a single intramuscular injection the plasma concentration of paliperidone increases slowly, reaching a maximum after 13-14 days (median) after injection in the deltoid muscle and 13-17 days after injection in the gluteal muscle. Release is detectable as early as day 1 and persists for at least 126 days. The release characteristics of the active ingredient and the dosing regimen of Xeplion provide long-term maintenance of the therapeutic concentration.

After a single dose of 25 – 150 mg in the deltoid muscle, the maximum concentration (C_max) is on average 28% greater than after injection in the gluteal muscle. At the beginning of therapy, administration to the deltoid muscle helps to reach the therapeutic concentration of paliperidone more quickly (150 mg on day 1 and 100 mg on day 8) than administration to the gluteal muscle. After multiple injections, the difference in effect is less obvious.

The mean ratio of maximum to equilibrium paliperidone concentrations after 4 injections of Xeplion at a dose of 100 mg in the gluteal muscle was 1.8 and after injection in the deltoid muscle was 2.2. At doses of 25-150 mg, the area under the concentration-time curve (AUC) of paliperidone varied in proportion to the dose, and the C_max at doses greater than 50 mg increased less than in proportion to the dose.

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

The (-)-enantiomer of paliperidone partially converts to the (+)-enantiomer after administration, and the AUC of the (+)- and (-)-enantiomers is approximately 1.6-1.8.

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

Metabolism and excretion
One week after a single oral dose of 1 mg of ¹⁴C-paliperidone with immediate release of the active component, 59% of the administered dose is excreted unchanged in the urine; this indicates no significant metabolism of the drug in the liver. Approximately 80% of the administered radioactivity was detected in the urine and 11% in the feces. Four pathways are known for in vivo metabolism of the drug, but none of them caused metabolism of more than 6.5% of the administered dose: dealkylation, hydroxylation, dehydrogenation, and detachment of the benzisoxazole group.

While in vitro studies suggest a role for the CYP2D6 and CYP3A4 isoenzymes in paliperidone metabolism, there is no data on a significant role of these isoenzymes in paliperidone metabolism in vivo. Population pharmacokinetic analysis showed no appreciable difference in paliperidone clearance after oral administration in subjects with active and weak CYP2D6 metabolism. Studies using human liver microsomes in vitro showed that paliperidone does not significantly inhibit drug metabolism by CYP1A2, CYP2A6, CYP2D6, CYP2E1, CYP3A4 and CYP3A5 isoenzymes.

In in vitro studies, paliperidone showed properties of a P-glycoprotein substrate and in high concentrations showed properties of a weak P-glycoprotein inhibitor. Corresponding in vivo data are not available, and the clinical relevance of this information is unclear.

In general, plasma concentrations of paliperidone during loading after intramuscular administration of Xeplion lay in the same range as after oral prolonged-acting paliperidone administration with release of the active ingredient at doses between 6 and 12 mg. The paliperidone loading regimen used ensured that concentrations were maintained in this range even at the end of the interdose interval (day 8 and day 36). Individual differences in paliperidone pharmacokinetics after administration of Xeplion were smaller in different patients than after oral prolonged-acting paliperidone administration. Because of the different nature of the change in median plasma concentrations of paliperidone with the two drugs, caution should be exercised when directly comparing their pharmacokinetics.

Particular categories of patients

Hepatic impairment.

Paliperidone is not significantly metabolized in the liver. Although the use of Xeplion in patients with mild to moderate hepatic impairment has not been studied, no dose adjustment is required in such hepatic impairment. In the study of oral paliperidone administration in patients with moderate hepatic impairment (class B according to Child-Pugh) the plasma concentration of free paliperidone was the same as in healthy volunteers. The use of paliperidone has not been studied in patients with severe hepatic dysfunction.

Kidney dysfunction.

For patients with mild renal dysfunction, the dose of paliperidone should be reduced; Xeplion is not recommended for use in patients with moderate to severe renal dysfunction. The distribution of paliperidone after a single oral intake of paliperidone sustained release tablet 3 mg by patients with different degrees of renal impairment has been studied. With decreasing creatinine clearance (CC) excretion of paliperidone was decreasing: in mild renal dysfunction (CC 50-80 ml/min) – by 32%, in moderate renal dysfunction (CC 30-50 ml/min) – by 64%, in severe renal dysfunction (CC 10-30 ml/min) – by 71%, which resulted in AUC0 increase versus healthy volunteers by 1.5, 2.6 and 4.8 times respectively. Based on the few data on the use of Xeplion in patients with mild renal dysfunction and the results of pharmacokinetic modeling, the recommended loading dose of paliperidone for these patients is 75 mg on day 1 and 8; 50 mg is administered monthly (every 4 weeks) thereafter.

Elderly patients.
Age alone is not a factor requiring dose adjustment. However, this adjustment may be necessary because of the age-related decrease in CK.

Race.
A population-based pharmacokinetic analysis of the results of an oral study of paliperidone showed no differences in the pharmacokinetics of paliperidone after administration of the drug in people of different races.

Pol.
No clinically significant differences in the pharmacokinetics of paliperidone were found in men and women.

The effect of smoking on the pharmacokinetics of the drug.
According to in vitro studies using human liver microsomes, paliperidone is not a CYP1A2 substrate, so smoking should not affect the pharmacokinetics of paliperidone. Consistent with these in vitro data, population pharmacokinetic analysis showed no difference in the pharmacokinetics of paliperidone in smokers and nonsmokers.

Indications

Active ingredient

Composition

Associates:

Polysorbate 20 – 12 mg,

Macrogol 4000 (polyethylene glycol 4000) – 30 mg,

citric acid monohydrate – 5 mg,

sodium hydrophosphate – 5 mg,

sodium dihydrophosphate monohydrate – 2.5 mg,

sodium hydroxide – 2.84 mg,

d/i water – up to 1 ml.

How to take, the dosage

In patients who have never taken oral paliperidone or risperidone or parenterally, it is recommended that oral paliperidone or risperidone tolerance be tested for 2-7 days before starting Xeplion treatment.

It is recommended that treatment with Xeplion be started with a dose of 150 mg on day 1 and 100 mg after 1 week (both injections into the deltoid muscle). Thereafter, a dose of 75 mg once/month is recommended. The dose may be increased or decreased between 25 and 150 mg, depending on individual tolerance and/or efficacy. After the second dose, subsequent injections can be given in the deltoid or gluteal muscle.

The maintenance dose can be adjusted monthly. The prolonged release of the active ingredient from paliperidone palmitate should be considered, as it may take several months for the full effect of the dose adjustment to become apparent.

Dose skipping

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

If the second Xeplion injection is not given on time (1 week±2 days), resumption of treatment is recommended based on the time since the first injection.

Missing the second initial dose (less than 4 weeks). If less than 4 weeks have elapsed since the first injection, the patient should receive a second injection of 100 mg in the deltoid muscle as soon as possible. A third injection of Xeplion at a dose of 75 mg should be given in the deltoid or gluteal muscle 5 weeks after the first injection (not including the time of the second injection). Thereafter, follow a monthly course of injections at a dose of 25 mg to 150 mg into the deltoid or gluteal muscle, depending on individual tolerance and/or effectiveness.

Missing the second initial dose (period of 4 to 7 weeks). If 4 to 7 weeks have elapsed since the first Xeplion injection, treatment is resumed with 2 injections at a dose of 100 mg according to the following schedule: The 1st injection in the deltoid muscle is given as soon as possible; a second injection in the deltoid muscle is given 1 week later, then the monthly course of injections in the deltoid or gluteal muscle is continued at a dose of 25 mg to 150 mg, depending on individual tolerance and/or effectiveness.

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

Missing a maintenance dose (1 month to 6 weeks). After treatment initiation, monthly Xeplion injections are recommended. If less than 6 weeks have elapsed since the last injection, another dose equal to the previous dose should be administered as soon as possible. Thereafter, the drug should be administered monthly.

Missing a maintenance dose (period of > 6 weeks to 6 months). If more than 6 weeks have passed since the last Xeplion injection, the following is recommended.

For patients whose condition is stabilized by use of the drug at 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 was stabilized before missing the injection;

2) inject the next injection into the deltoid muscle (same dose) one week later on day 8;

3) then resume the monthly course of injections in the deltoid or gluteal muscle at a dose of 25 mg to 150 mg, depending on individual tolerance and/or effectiveness.

For patients whose condition is stabilized by using the drug at a dose of 150 mg:

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

2) after 1 week, administer another 100 mg dose (day 8) to the deltoid muscle;

3) then resume a monthly course of injections in the deltoid or gluteal muscle at a dose of 25 mg to 150 mg, depending on individual tolerance and/or effectiveness.

Missing a maintenance dose (period > 6 months). If more than 6 months have elapsed since the last Xeplion injection, treatment should be restarted as described above to initiate treatment.

Transferring from other neuroleptics

The data on transferring schizophrenic patients from other neuroleptics to Xeplion or its use concomitantly with other neuroleptics are not systematic. For patients who have never received oral paliperidone or oral or injectable risperidone, tolerability with oral paliperidone or oral risperidone should be investigated before starting treatment with Xeplion. Previously used oral neuroleptics may be discontinued at the start of Xeplion treatment. Patients receiving injectable prolonged-acting neuroleptics will start Xeplion immediately with a maintenance dose at the time of the next scheduled injection. Xeplion should be continued once a month. The initial dose in the first week of treatment is not required.

In patients whose condition has been stabilized by different doses of Rispolettes Consta®, sustained release I/M suspension, the Css active ingredient may reach similar values during maintenance therapy with Xeplion once/month according to the following schedule:

Cancellation of the previous antipsychotic should be done according to the instructions for medical use. When cancelling Xeplion, the prolonged release of the active ingredient should be considered. As with other neuroleptics, the need for continued use of agents to prevent the development of extrapyramidal disorders should be evaluated periodically.

The concomitant 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 considered when using these drugs concomitantly with Xeplion.

The use in special groups of patients

The use of Xeplion has not been studied in patients with impaired liver function. Based on the results of the oral paliperidone study, no dose adjustment is required for patients with mild to moderate hepatic impairment. The use of Xeplion in patients with severe hepatic impairment has not been studied.

The use of Xeplion in patients with impaired renal function has not been systematically studied. In patients with mild renal dysfunction (CKR ≥ 50 to 80 ml/min) it is recommended to start Xeplion administration with the dose 100 mg on the 1st day and 75 mg after 1 week (both injections into deltoid muscle). After that, after 1 month, inject 50 mg monthly in the deltoid or gluteal muscle, and then change the dose from 25 mg to 100 mg depending on individual tolerance and/or efficacy. Xeplion is not recommended for use in patients with moderate or severe renal dysfunction (CK < 50 ml/min).

In elderly patients with normal renal function, the same dose of Xeplion as in younger patients with normal renal function is recommended. In elderly patients, renal function may be impaired, and the above recommendations for patients with impaired renal function apply to such patients.

The safety and effectiveness of Xeplion in children and adolescents younger than 18 years has not been studied.

There is no need to adjust the dose of Xeplion depending on the gender, race of patients and smoking.

The rules of administration of the drug

Xeplion is only for administration in m/v. The drug is slowly injected deep into the muscle. The injection should only be given by a healthcare professional. The entire dose must be given at once; no multiple injections may be given. The drug should not be injected into vessels or subcutaneously. Accidental contact with a blood vessel must be avoided. To do this, the syringe plunger is pulled back before starting the injection to check if the needle enters a large blood vessel. If this results in blood entering the syringe, the needle and syringe should be removed from the muscle and disposed of.

The recommended needle size for guiding Xeplion into the deltoid muscle is determined by the patient’s body weight. For patients with a body weight ≥90 kg, a long needle with a gray body from the kit is recommended. For patients with body weight

Injection of Xeplion into the gluteal muscle is recommended with the long needle with the gray body of the kit. Injections should be made in the upper outer quadrant of the buttock. The drug should be injected alternately into the right and left gluteal muscles.

Injection

The syringe is only for single injections.

Shake the syringe vigorously for 10 seconds to create a homogenous suspension.

2. select the appropriate needle.

The short needle (blue needle) is used to inject into the deltoid muscle in patients with a body weight and the long needle (gray needle) is used in patients with a body weight of > 90 kg.

The long needle (gray body) is used to inject into the gluteal muscle.

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

4. Half-open the safety needle package, take the needle cap through the package, and insert the syringe into the luer needle cap by gently rotating it clockwise.

5. remove the needle cap from the needle by pulling it along the needle. Do not rotate the cap, because this may loosen the connection between the needle and the syringe.

6: Point the syringe up with the needle up and squeeze the air out of the syringe by pushing the plunger down slightly.

7…inject the entire contents of the syringe into the selected muscle (deltoid or gluteal). Do not inject into a blood vessel or pelvic muscle.

8. After completing the injection, bring the needle shield into the working position with your thumb or index finger or by pressing the syringe against a hard surface. The needle shield should click into place. The syringe with the needle should be disposed of as required.

Interaction

Paliperidone may prolong the Q-T interval, therefore it should be carefully combined with other drugs that prolong the Q-T interval (antiarrhythmic medicines, including quinidine, procainamide, amiodarone, sotalol; antipsychotic drugs (chlorpromazine, thioridazine); antibiotics, including gatifloxacin and moxifloxacin).
Since Paliperidone palmitate is hydrolyzed to paliperidone, the results of studies of paliperidone for oral administration should be considered when assessing the possibility of drug interaction.

The ability of Xeplion to affect other drugs

Paliperidone is not expected to exhibit clinically significant pharmacokinetic interactions with drugs metabolized by cytochrome P450 isoenzymes. Studies using human liver microsomes in vitro have shown that paliperidone does not significantly impair the metabolism of substances by CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4 and CYP3A5 isoenzymes. Therefore, paliperidone is not expected to clinically significantly decrease the clearance of drugs metabolized by these isoenzymes. Also, paliperidone is not expected to exhibit isoenzyme inducer properties, as paliperidone did not induce the activity of CYPA2, CYPC19 or CYP3A4 isoenzymes in in vitro studies. Paliperidone in high concentrations is a weak inhibitor of P-glycoprotein. However, there are no in vivo data in this regard, and the clinical significance of this phenomenon is unknown.

Given the effects of paliperidone on the CNS, caution should be exercised when using Xeplion in combination with other centrally acting drugs and alcohol. Paliperidone may weaken the effects of levodopa and dopamine receptor agonists. Due to the ability of Xeplion to induce orthostatic hypotension, an additive enhancement of this effect may be observed when Xeplion is used together with other drugs with this ability.

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

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

Administration of paliperidone with a long-release active ingredient (once daily) orally concomitantly with carbamazepine (200 mg 2 times daily) resulted in a decrease in the mean Cmax and AUC of paliperidone by approximately 37%. This decrease was largely due to a 35% increase in renal clearance of paliperidone, probably due to renal P-glycoprotein activation by carbamazepine. The very small decrease in the amount of drug excreted unchanged through the kidneys suggests that carbamazepine has only a weak effect on the hepatic metabolism mediated or bioavailability of paliperidone. When starting carbamazepine, the dose of Xeplion should be reconsidered and, if necessary, increased.

On the contrary, when carbamazepine is withdrawn, the dose of Xeplion should be reconsidered and, if necessary, reduced. Paliperidone at physiological pH is cationic and is mostly excreted unchanged through the kidneys – half by filtration and half by active secretion. Concomitant use of trimethoprim, which inhibits the system of active renal cation transport, had no effect on the pharmacokinetics of paliperidone.

The use of Xeplion together with risperidone

The use of Xeplion together with risperidone has not been studied. As paliperidone is an active metabolite of risperidone, it is necessary to take into account increase of plasma concentration of paliperidone when concomitant use of Xeplion and risperidone.

Special Instructions

MNS

When using neuroleptics, including paliperidone, the development of MNS has been reported, which is characterized by hyperthermia, muscle rigidity, autonomic nervous system instability, impaired consciousness and elevated serum CPK concentrations. In addition, myoglobinuria (rhabdomyolysis) and acute renal failure may be observed. If symptoms suggestive of MNS occur, all neuroleptics, including Xeplion, should be discontinued.

Late dyskinesia

The use of drugs that have the properties of dopamine receptor antagonists is accompanied by the development of late dyskinesia, characterized by rhythmic, involuntary movements, primarily of the tongue and/or facial muscles. Withdrawal of all neuroleptics, including Xeplion, should be considered if symptoms of tardive dyskinesia occur.

Hyperglycemia and diabetes mellitus

Hyperglycemia, diabetes mellitus and worsening of existing diabetes mellitus have been observed during treatment with Xeplion. Finding a relationship between the use of atypical antipsychotic drugs and impaired glucose metabolism is complicated by the increased risk of diabetes mellitus in patients with schizophrenia and the prevalence of diabetes mellitus in the general population. Given these factors, the relationship between the use of atypical antipsychotic drugs and the development of adverse events associated with hyperglycemia has not been fully established. All patients should be clinically monitored for symptoms of hyperglycemia and diabetes mellitus.

Body weight gain

A significant increase in body weight has been observed during treatment with atypical antipsychotics. Patients’ body weight should be monitored.

Elderly patients with dementia

A cross-sectional analysis of study results showed increased mortality in elderly patients with dementia receiving atypical neuroleptics, including risperidone, aripiprazole, olanzapine and quetiapine, compared with placebo. Among patients receiving risperidone and placebo, the mortality rates were 4% and 3.1%, respectively.

The use of Xeplion in elderly patients with dementia has not been studied. Since paliperidone is the active metabolite of risperidone, experience with risperidone should be considered. For elderly patients with dementia taking risperidone, increased mortality was observed in patients taking furosemide and risperidone compared to the group taking risperidone alone and the group taking furosemide alone. No pathophysiologic mechanisms have been identified to explain this observation. Nevertheless, special caution should be exercised when prescribing the drug in such cases. No increase in mortality has been found in patients taking other diuretics concomitantly with risperidone. Regardless of treatment, dehydration is a common risk factor for mortality and should be closely monitored in elderly patients with dementia.

Cerebral circulation disorders

In placebo-controlled studies, an increased incidence of cerebral circulation disorders (transient and stroke) has been found, including death.

In older patients with dementia who received some atypical neuroleptics, including risperidone, aripiprazole and olanzapine, compared to placebo use, an increased incidence of cerebral circulation disorders (transient stroke, including fatal stroke) was found.

Leukopenia, neutropenia, agranulocytosis

Leukopenia, neutropenia and agranulocytosis have been reported with antipsychotic agents, including Xeplion. Agranulocytosis was very rare during the post-marketing observations. For patients with a history of clinically significant decrease in white blood cell counts or drug-dependent leukopenia/neutropenia, a complete blood count during the first months of therapy is recommended; discontinuation of Xeplion should be considered at the first clinically significant decrease in white blood cell counts in the absence of other possible causes. Patients with clinically significant neutropenia should be monitored for fever or symptoms of infection, for which treatment should be started immediately. Patients with severe neutropenia (absolute neutrophil count less than 1×109/L) should discontinue Xeplion until the leukocyte count normalizes.

Venous thromboembolism

Cases of venous thromboembolism have been reported with antipsychotic drugs. Because patients taking antipsychotics are often at risk for venous thromboembolism, all possible risk factors should be identified before and during treatment with Xeplion and preventive measures should be taken.

Parkinson’s disease and dementia with corpuscles

The physician should compare the risks and benefits of neuroleptics, including Xeplion, in patients with Parkinson’s disease or dementia with Lewy bodies, as these categories of patients may be at increased risk for MNS and risk of hypersensitivity to neuroleptics. Manifestations of hypersensitivity may include confusion, blunting of pain sensitivity, unsteady posture with frequent falls, and extrapyramidal symptoms.

P priapism

There is evidence of the ability of drugs with alpha-adrenoblocker properties to cause priapism. Priapism has been reported in the post-marketing monitoring of paliperidone use.

Antipyretic effects

In preclinical studies of paliperidone an anti-emetic effect was found. The appearance of this effect in a patient may mask the signs and symptoms of overdose of certain medications or conditions such as intestinal obstruction, Reye’s syndrome or a brain tumor.

Injection

When administered by injection, caution should be taken to avoid accidental ingestion of the drug into a blood vessel.

Impact on driving and operating machinery

Xeplion may impair performance of activities requiring concentration and rapid psychomotor reactions and may affect vision. Therefore, patients should be advised not to drive vehicles and moving machinery until their individual sensitivity has been established.

Contraindications

With caution

Xeplion has alpha-adrenoblocking activity and may cause orthostatic hypotension in some patients, so caution is necessary when used in patients with cardiovascular disease (e.g., heart failure, myocardial infarction or ischemia, cardiac conduction disorders), cerebrovascular disorders or conditions that predispose to lower BP (e.g., dehydration, decreased RBC, use of hypotensive drugs).

As with other neuroleptics, Xeplion should be used with caution in patients with a history of seizures or other conditions that may lower the seizure threshold.

The use of neuroleptics has been associated with a decrease in the ability of the body to lower body temperature, so caution is necessary when using the drug in patients who may be exposed to conditions that increase body temperature, such as heavy exercise, high ambient temperatures, exposure to drugs with m-cholinolytic activity, and dehydration.

As with other neuroleptics, caution is necessary when prescribing Xeplion for patients with a history of arrhythmias or congenital prolongation of the QT interval or who are taking medications that prolong the QT interval.

In view of the effect of paliperidone on the CNS, caution should be exercised when Xeplion is used in combination with other CNS-acting drugs and alcohol.

Paliperidone may weaken the effects of levodopa and dopamine agonists.

Caution should be exercised when prescribing Xeplion in elderly patients with dementia, patients with Parkinson’s disease or dementia with Lewy bodies.

Side effects

Most adverse reactions were mild to moderate in severity.

Frequency determination of adverse reactions: very common (≥10%), common (≥1% and < 10%), infrequent (≥0.1% and

Infections: frequent – upper respiratory tract infections; infrequent – acarodermatitis, bronchitis, inflammation of subcutaneous fatty tissue, ear infections, eye infections, flu, onychomycosis, pneumonia, respiratory tract infections, sinusitis, subcutaneous abscess, tonsillitis, urinary tract infections.

Immune system disorders: infrequent hypersensitivity.

Hematopoietic system: infrequent neutropenia, decreased number of leukocytes; rarely – thrombocytopenia; very rarely – agranulocytosis.

Endocrine system: rarely – inadequate secretion of ADH.

Metabolism disorders: frequent – weight gain; infrequent – anorexia, hyperglycemia, decreased appetite, increased appetite, decreased body weight, polydipsia, diabetes mellitus; rare – hypoglycemia; very rare – diabetic ketoacidosis, water intoxication.

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

Nervous system disorders: very common – headache; common – akathisia, dizziness, extrapyramidal symptoms, somnolence, parkinsonism (including akinesia, bradykinesia, cogwheel-like rigidity, salivation, extrapyramidal symptoms, deviation of glabral reflex, muscle rigidity, stiffness in muscles, musculoskeletal immobility); Infrequent – coordination disorders, cerebrovascular disorders, seizures (including epileptic seizures).In rare – coordination disorders, cerebrovascular disorders, seizures (including epileptic seizures), distraction, postural dizziness, dysarthria, dyskinesia (incl.Athetosis, chorea, movement disorders, muscle contractions, clonic spasms), dystonia (incl. Blepharospasm, neck spasm, emprostotonus, facial spasm, hypertonia, laryngospasm, involuntary muscle contractions, myotonia, eyeball movements, opisthotonus, oropharyngeal spasm, pleurotonus, sardonic smile, tetany, tongue paralysis, tongue spasm, torticollis, convulsive clenching of the jaw), hypoesthesia, paresthesia, psychomotor hyperactivity, syncope, severe dyskinesia, tremor.

An organ of vision: infrequent – dry eyes, increased lacrimation, ocular hyperemia, involuntary movement of the eyeball, blurred vision.

Hearing and balance: infrequent – vertigo, ear pain.

Cardiovascular system disorders: frequent – increased BP; infrequent – AV-blockade, bradycardia, conduction disturbances, abnormalities on ECG, QT interval increase on ECG, palpitations, postural orthostatic tachycardia syndrome, sinus arrhythmia, tachycardia, atrial fibrillation, orthostatic hypotension; rare – deep vein thrombosis; very rare – pulmonary embolism.

Respiratory system disorders: infrequent – cough, dyspnea, nasal bleeding, nasal congestion, pain in the pharyngeal area, stuffy airways, wheezing, stuffy lungs; very rare – sleep apnea syndrome.

The digestive system: frequently – upper abdominal pain, constipation, diarrhea, dry mouth, nausea, toothache, vomiting, abdominal discomfort; rarely – dyspepsia, dysphagia, fecal incontinence, flatulence, gastroenteritis, tongue swelling, dysgeusia; rarely – pancreatitis; very rarely – jaundice.

Muscular system: often – pain in the extremities, musculoskeletal pain; infrequent – arthralgia, back pain, joint stiffness, joint swelling, muscle cramps, neck pain.

Skin disorders: infrequent – acne, dry skin, eczema, erythema, hyperkeratosis, itching, sores, alopecia.

Allergic reactions: infrequent – urticaria; rarely – angioedema.

The urinary system: infrequent dysuria, semilakiuria, urinary incontinence; rarely – urinary retention.

Reproductive system disorders: infrequent – amenorrhea, galactorrhea, gynecomastia, sexual dysfunction, ejaculation disorders, erectile dysfunction, vaginal discharge; very rare – priapism.

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

Laboratory findings: infrequent – increased GGT activity, increased liver enzyme activity, increased transaminase activity, increased blood cholesterol concentration, increased blood TG concentration, hyperglycemia.

Others: often – asthenic disorders, weakness, local reactions (pain, itching, thickening at the injection site); infrequently – discomfort in the chest, chills, facial edema, gait disturbance, thickening at the injection site, edema (including generalized edema, peripheral edema, mild edema), thirst, fever; rarely – hypothermia, abscess at the injection site, inflammation of subcutaneous tissue at the injection site, hematoma at the injection site; very rare – cyst at the injection site, necrosis at the injection site, ulceration at the injection site.

Overdose

Because Xeplion is intended to be administered by healthcare professionals, the likelihood of patient overdose is small.

Symptoms: In general, the expected signs and symptoms are consistent with an increase in the known pharmacological effects of paliperidone, i.e., drowsiness, lethargy, tachycardia, decreased BP, prolonged QT interval, extrapyramidal symptoms. In case of acute overdose, the possibility of patients receiving more than one drug should be considered.

Polyform ventricular tachycardia of the “pirouette” type and ventricular fibrillation have been reported in overdose of oral palineridone. In the case of acute overdose, the possibility of patients receiving more than one drug should be considered.

Treatment: The long release of the active ingredient and the long T1/2 paliperidone should be considered when assessing the treatment and recovery needs of patients. There is no specific antidote for paliperidone. General supportive measures should be implemented, ensuring and maintaining airway patency, adequate ventilation of the lungs and oxygen saturation of the blood. Cardiovascular function control should be started immediately, including continuous ECG monitoring to detect possible arrhythmias. In case of decreased BP and vascular collapse, appropriate measures should be taken, such as intravenous administration of solutions and/or sympathomimetics. If severe extrapyramidal symptoms develop, anticholinergic drugs should be used. The patient’s condition should be carefully monitored until recovery.

Pregnancy use

The safety of Xeplion v/m or paliperidone oral administration during pregnancy in humans has not been established. A slight increase in fetal mortality in animals was observed when paliperidone was administered orally in high doses. Xeplion when administered v/m had no effect on the course of pregnancy in rats, but high doses were toxic to pregnant females. Doses of paliperidone when administered orally and Xeplion when administered i/m, which produce concentrations 20-22 times and 6 times the maximum therapeutic doses in humans, respectively, had no effect on the offspring of laboratory animals.

Xeplion may be used in pregnancy only if the anticipated benefit to the mother outweighs the potential risk to the fetus. The effect of Xeplion on labor and delivery in humans is unknown.

If a woman has taken antipsychotics (including paliperidone) in the third trimester of pregnancy, there is a risk of extrapyramidal disorders and/or withdrawal syndrome of varying severity in the newborn. These symptoms may include agitation, hypertension, hypotension, tremor, somnolence, respiratory disturbances, and feeding disorders.

In studies of paliperidone in animals and risperidone in humans, paliperidone has been found to be excreted with breast milk. Therefore, breastfeeding should be stopped when treating with Xeplion.

Perhaps in children

The safety and effectiveness of Xeplion in children and adolescents under 18 years of age has not been studied.