Xeplion®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KSEPLION® (XEPLION®)

Composition:

Active substance: paliperidone palmitate;

1 ml of suspension contains paliperidone palmitate equivalent to 100 mg of paliperidone;

Excipients: polysorbate 20; polyethylene glycol 4000; citric acid monohydrate; disodium hydrogen phosphate anhydrous; sodium dihydrogen phosphate monohydrate; sodium hydroxide; water for injections.

Pharmaceutical form. Prolonged-release injectable suspension.

Main physicochemical characteristics: white or almost white suspension, free from foreign particles.

Pharmacotherapeutic group. Antipsychotics. ATC code: N05A X13.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of Action.

Paliperidone is a selective monoaminergic blocking agent whose pharmacological properties differ from those of traditional neuroleptics. Paliperidone binds strongly to serotonin 5-HT2 and dopamine D2 receptors. Paliperidone also blocks alpha-1 adrenergic receptors and, to a lesser extent, alpha-2 adrenergic and histamine H1 receptors. The pharmacological activity of the (+)- and (-)-enantiomers of paliperidone is quantitatively and qualitatively equivalent.

Paliperidone does not bind to cholinergic receptors. Although paliperidone is a potent D2 antagonist that attenuates the positive symptoms of schizophrenia, it causes less catalepsy and impairs motor function to a lesser extent than traditional neuroleptics. Predominant central antagonism of serotonin may reduce the tendency of paliperidone to cause extrapyramidal symptoms.

Pharmacokinetics.

Absorption and Distribution.

Paliperidone palmitate is an inactive ester of paliperidone and palmitic acid. Due to its low water solubility, paliperidone palmitate dissolves slowly after intramuscular injection, then undergoes hydrolysis to paliperidone and is absorbed into systemic circulation. After a single intramuscular injection, plasma concentration of paliperidone (Tmax) increases slowly, reaching a peak at 13 days. Release of the drug is detectable as early as day 1 and persists for at least 4 months.

After a single dose of 25–150 mg administered into the deltoid muscle, Cmax is on average 28% higher than after administration into the gluteal muscle. Two initial injections into the deltoid muscle (150 mg on day 1 and 100 mg on day 8) help achieve therapeutic drug concentrations rapidly. The release characteristics of the active component and the dosing regimen of paliperidone palmitate ensure prolonged maintenance of therapeutic concentrations. At paliperidone palmitate doses of 25–150 mg, total systemic exposure to paliperidone increased proportionally with dose, while Cmax at doses above 50 mg increased less than proportionally to dose. The mean ratio of maximum to steady-state concentration of paliperidone after administration of 100 mg paliperidone palmitate into the gluteal muscle was 1.8, and after administration into the deltoid muscle was 2.2. The median elimination half-life of paliperidone after administration of paliperidone palmitate at doses of 25–150 mg ranged from 25 to 49 days.

The absolute bioavailability of XEPLION® is 100%.

After administration of paliperidone palmitate, its (-)-enantiomer is partially converted to the (+)-enantiomer, and the ratio of AUC (+)- to (-)-enantiomers is approximately 1.6–1.8.

Racemic paliperidone is 74% bound to plasma proteins.

Metabolism and Elimination.

Within one week after a single oral dose of 1 mg of 14C-labeled paliperidone with immediate release of the active component, 59% of the administered dose was excreted unchanged in urine, indicating minimal hepatic metabolism of the drug. Approximately 80% of the administered radioactivity was recovered in urine and 11% in feces. Four metabolic pathways of the drug in vivo are known, but none accounts for more than 6.5% of the administered dose: dealkylation, hydroxylation, dehydrogenation, and cleavage of the benzisoxazole group. Although in vitro studies suggest a potential role of CYP2D6 and CYP3A4 in paliperidone metabolism, there is no evidence of a significant role of these isoenzymes in paliperidone metabolism in vivo. Population pharmacokinetic analysis did not reveal any notable difference in paliperidone clearance after oral administration between patients who are extensive and poor metabolizers of CYP2D6 substrates. In vitro studies using human liver microsomes showed that paliperidone does not significantly inhibit the metabolism of drugs by cytochrome P450 isoenzymes CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and CYP3A5.

In vitro studies demonstrated that paliperidone exhibits properties of a P-glycoprotein substrate and, at high concentrations, weak inhibitory properties toward P-glycoprotein. There are no corresponding in vivo data, and the clinical significance of these findings is unknown.

Long-acting paliperidone palmitate injections compared to oral extended-release paliperidone.

XEPLION® is designed to provide sustained release of paliperidone over one month, whereas oral extended-release paliperidone tablets must be taken daily. The initiation regimen for XEPLION® (150 mg/100 mg into the deltoid muscle on day 1/day 8) is necessary to rapidly achieve steady-state concentrations of paliperidone at the beginning of treatment without the need for oral formulations.

Overall, plasma concentrations of paliperidone during the XEPLION® loading phase were within the same range as those achieved with oral extended-release paliperidone at doses of 6–12 mg. The XEPLION® loading regimen ensures maintenance of concentrations within this range even at the end of the dosing interval (days 8 and 36). Due to differences in the profile of median plasma paliperidone concentration changes between the two formulations, caution should be exercised when directly comparing their pharmacokinetics.

Special Patient Populations.

Hepatic Impairment.

Paliperidone undergoes minimal hepatic metabolism. Although the use of XEPLION® in patients with hepatic impairment has not been studied, dose adjustment is not required in patients with mild or moderate hepatic impairment. In a study of oral paliperidone in patients with moderate hepatic impairment (Child-Pugh class B), free paliperidone plasma concentrations were similar to those in healthy volunteers. The use of paliperidone in patients with severe hepatic impairment has not been studied.

Renal Impairment.

The pharmacokinetics of paliperidone were studied after a single 3 mg dose of oral extended-release paliperidone in patients with varying degrees of renal impairment. As creatinine clearance decreased, paliperidone elimination was reduced. Total paliperidone clearance decreased on average by 32% in mild renal impairment (ClCr 50–80 mL/min), by 64% in moderate impairment (ClCr 30–50 mL/min), and by 71% in severe impairment (ClCr 10–30 mL/min), resulting in mean systemic exposure (AUCinf) increases of 1.5-, 2.6-, and 4.8-fold, respectively, compared to healthy volunteers. Given the limited number of patients with mild renal impairment and pharmacokinetic modeling, dose reduction is recommended in these patients (see section "Dosage and Administration").

Elderly Patients.

Population pharmacokinetic analysis did not demonstrate dependence of pharmacokinetic parameters on age.

Body Mass Index / Body Weight.

Pharmacokinetic studies of paliperidone palmitate demonstrated slightly lower (10–20%) plasma concentrations of paliperidone in patients with overweight or obesity compared to patients with normal body weight (see section "Dosage and Administration").

Race.

Population pharmacokinetic analysis of studies of oral paliperidone after XEPLION® administration did not demonstrate dependence of pharmacokinetic parameters on race.

Gender.

No clinically significant differences between women and men were observed.

Smoking Habit.

Based on in vitro data using human liver enzymes, paliperidone is not a substrate of CYP1A2; therefore, smoking is not expected to affect paliperidone pharmacokinetics. The effect of smoking on paliperidone pharmacokinetics with XEPLION® administration has not been studied. Population pharmacokinetic analysis based on data from oral paliperidone demonstrated slightly lower concentrations in patients who smoke. This difference is not clinically significant.

Clinical characteristics.

Indications.

Maintenance therapy of symptoms of schizophrenia in adults whose condition has been stabilized with paliperidone or risperidone.

In individual cases, for adult patients with schizophrenia who have previously been effectively treated with paliperidone or risperidone, Xeplion® may be used without prior stabilization with oral formulations of these agents, provided that the patient's psychotic symptoms are mild to moderate in severity and treatment with long-acting injectable formulations is indicated.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients of the medicinal product, or to risperidone.

Interaction with other medicinal products and other forms of interaction.

Concomitant administration of paliperidone palmitate with drugs that prolong the QT interval, such as Class IA antiarrhythmics (e.g., quinidine, disopyramide) and Class III antiarrhythmics (e.g., amiodarone, sotalol), certain antihistamines, antipsychotics, and antimalarials (e.g., mefloquine), is recommended with caution. This list is informative and may not be complete.

Ability of Xeplion® to affect other medicinal products.

Clinically significant pharmacokinetic interactions between paliperidone and drugs metabolized by cytochrome P450 isoenzymes are not expected.

Due to the primary effect of paliperidone on the CNS (see section "Adverse reactions"), Xeplion® should be used with caution in combination with other substances affecting the CNS, such as anxiolytics, most neuroleptics, hypnotics, opioids, or alcohol.

Paliperidone may reduce the effect of levodopa and other dopamine agonists. If such a combination is necessary, particularly in the terminal stage of Parkinson's disease, the lowest effective dose of the drug should be prescribed.

Since paliperidone palmitate may cause orthostatic hypotension (see section "Special precautions"), additive enhancement of this effect may occur when paliperidone palmitate is used concomitantly with other drugs having the same effect, such as other antipsychotics or tricyclic antidepressants.

Xeplion® should be used with caution in combination with drugs that lower the seizure threshold (e.g., phenothiazines or butyrophenones, tricyclic antidepressants, serotonin reuptake inhibitors, tramadol, mefloquine, etc.).

Co-administration of oral prolonged-release paliperidone (12 mg once daily) and sodium valproate (500–2000 mg once daily) does not affect the pharmacokinetics of sodium valproate.

There are no clinical data on the interaction between Xeplion® and lithium preparations; however, a pharmacokinetic interaction is not expected.

Ability of other medicinal products to affect Xeplion®.

In vitro studies indicate minimal involvement of CYP2D6 and CYP3A4 in the metabolism of paliperidone. Currently, there are no data suggesting that these enzymes play a significant role in its metabolism. Concomitant administration of oral paliperidone with paroxetine, a potent CYP2D6 inhibitor, had no clinically significant effect on the pharmacokinetics of paliperidone.

Concomitant administration of oral prolonged-release paliperidone (once daily) and carbamazepine (200 mg twice daily) resulted in a reduction of the mean Cmax and AUC of paliperidone by approximately 37%. This reduction is largely due to a 35% increase in renal clearance of paliperidone, likely due to carbamazepine-induced activation of renal P-glycoprotein. The very slight decrease in the amount of unchanged drug excreted renally suggests that carbamazepine has only a weak effect via CYP on the metabolism or bioavailability of paliperidone. At the initiation of carbamazepine therapy, the dose of paliperidone palmitate should be reviewed and increased if necessary. Conversely, upon discontinuation of carbamazepine, the dose of paliperidone palmitate should be reviewed and reduced if necessary.

Concomitant administration of oral prolonged-release paliperidone (12 mg tablets) with prolonged-release sodium valproate (two 500 mg tablets once daily) resulted in an increase in Cmax and AUC of paliperidone by approximately 50%, likely due to increased oral absorption. Since paliperidone does not affect systemic clearance, a clinically significant interaction between prolonged-release sodium valproate and Xeplion® for intramuscular injection is not expected. This type of interaction has not been studied for Xeplion®.

Concomitant use of Xeplion® with risperidone or oral paliperidone.

Since paliperidone is the principal active metabolite of risperidone, caution should be exercised when administering risperidone or oral paliperidone concomitantly with Xeplion® over a prolonged period. Safety data on concomitant use of Xeplion® with other antipsychotics are limited.

Concomitant use of Xeplion® with psychostimulants.

Concomitant use of psychostimulants (e.g., methylphenidate) with paliperidone may lead to the emergence of extrapyramidal symptoms when either or both agents are changed during treatment (see section "Special precautions").

Special precautions for use.

Use in patients in the acute phase or with severe mental condition.

Xeplion® should not be administered to unstable patients in the acute phase or with severe mental condition when rapid symptom control is required.

QT interval.

As with other antipsychotics, caution should be exercised when administering paliperidone palmitate to patients with cardiovascular disorders or a family history of QT interval prolongation, as well as when used concomitantly with other medicinal products that may prolong the QT interval.

Malignant neuroleptic syndrome.

Cases of malignant neuroleptic syndrome (MNS), characterized by hyperthermia, muscular rigidity, autonomic instability, altered consciousness, and elevated serum creatine phosphokinase levels, have been reported with paliperidone use. Additionally, myoglobinuria (rhabdomyolysis) and acute renal failure may occur. If symptoms suggestive of MNS develop, paliperidone should be discontinued.

Tardive dyskinesia / extrapyramidal symptoms.

Treatment with dopamine receptor antagonists may lead to tardive dyskinesia, characterized by rhythmic involuntary movements, primarily of the tongue and/or facial muscles. If symptoms of tardive dyskinesia occur, discontinuation of all antipsychotics, including paliperidone palmitate, should be considered.

Patients receiving both psychostimulants (e.g., methylphenidate) and paliperidone concurrently should be cautious, as there is a risk of developing extrapyramidal symptoms when adjusting the dose of either medicinal product. Gradual withdrawal of psychostimulants is recommended (see section "Interaction with other medicinal products and other forms of interaction").

Leukopenia, neutropenia, and agranulocytosis.

Cases of leukopenia, neutropenia, and agranulocytosis have been reported during treatment with Xeplion®. Agranulocytosis has been reported very rarely (<1/10,000 patients) in the post-marketing period. Patients with a history of clinically significant leukocyte reduction or drug-induced leukopenia/neutropenia should be monitored during the first few months of treatment. If clinical signs of significant leukopenia occur, treatment with Xeplion® should be interrupted in the absence of other causative factors. Patients with clinically significant neutropenia should be carefully examined for signs of fever or other symptoms of infection, and appropriate measures should be taken promptly if such symptoms occur. Patients with severe neutropenia (absolute neutrophil count <1×10⁹/L) should discontinue treatment with Xeplion® until adequate leukocyte counts are restored.

Hypersensitivity reactions.

Rare cases of anaphylactic reactions have been reported during the post-marketing period in patients who previously tolerated oral risperidone or oral paliperidone well (see sections "Contraindications" and "Side effects").

If hypersensitivity reactions occur, treatment with Xeplion® should be discontinued, and appropriate clinically indicated supportive measures and patient monitoring should be provided until symptoms resolve (see sections "Contraindications" and "Side effects").

Hyperglycemia and diabetes mellitus.

Cases of hyperglycemia, onset of diabetes, and worsening of pre-existing diabetes, including diabetic coma and ketoacidosis, have been reported during paliperidone treatment. Appropriate monitoring according to recommendations for antipsychotic medicinal products is recommended. Patients receiving Xeplion® should be monitored for symptoms of hyperglycemia (such as polydipsia, polyuria, polyphagia, and weakness), and glucose levels should be closely monitored in patients with pre-existing diabetes.

Weight gain.

Significant weight gain has been reported with the use of Xeplion®. Body weight should be monitored regularly.

Use in patients with prolactin-dependent tumors.

Tissue culture studies suggest that pathological growth of breast tissue cells may be stimulated by prolactin. Although clinical and epidemiological studies have not clearly demonstrated a link with antipsychotic use, this class of drugs should be used cautiously in patients with a history of such conditions. Paliperidone should be used with caution in patients with tumors that may be prolactin-dependent.

Orthostatic hypotension.

Due to its alpha-blocking activity, paliperidone may cause orthostatic hypotension in some patients. According to pooled data from three 6-week placebo-controlled fixed-dose studies of oral paliperidone extended-release tablets (3 mg, 6 mg, 9 mg, and 12 mg), orthostatic hypotension was reported in 2.5% of patients in the paliperidone group compared to 0.8% in the placebo group. Xeplion® should be used with caution in patients with cardiovascular disorders (such as heart failure, myocardial infarction or ischemia, conduction abnormalities), cerebrovascular disorders, or conditions leading to hypotension (such as dehydration, reduced blood volume).

Seizures.

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.

Renal impairment.

Plasma concentrations of paliperidone are increased in patients with renal impairment; therefore, dosage should be individually adjusted in patients with mild renal impairment. Xeplion® is not recommended in patients with moderate to severe renal impairment (creatinine clearance <50 mL/min) (see sections "Dosage and administration" and "Pharmacological properties").

Hepatic impairment.

There are no data on the use of paliperidone in patients with severe hepatic impairment (Child-Pugh class C). Paliperidone should be used with caution in such patients.

Elderly patients with dementia.

The use of paliperidone palmitate in elderly patients with dementia has not been studied. Xeplion® should be used with caution in these patients due to the risk of stroke. Since paliperidone is the active metabolite of risperidone, experience with risperidone use should be considered, as outlined below.

Overall mortality.

A meta-analysis of 17 controlled clinical studies involving elderly patients with dementia treated with other atypical antipsychotics, including risperidone, aripiprazole, olanzapine, and quetiapine, showed an increased mortality rate compared to patients receiving placebo. Among patients receiving risperidone and placebo, mortality rates were 4% and 3.1%, respectively.

Cerebrovascular reactions.

During placebo-controlled, randomized clinical trials of certain atypical antipsychotics, including risperidone, aripiprazole, and olanzapine, in elderly patients with dementia, a threefold increased risk of cerebrovascular adverse reactions was observed. The mechanism of this increased risk is unknown.

Parkinson’s disease and dementia with Lewy bodies.

Physicians should consider the risk-benefit ratio when using antipsychotics, including paliperidone palmitate, in patients with Parkinson’s disease or dementia with Lewy bodies, as both patient groups may have an increased risk of developing malignant neuroleptic syndrome (MNS) and heightened sensitivity to antipsychotics. Manifestations of heightened sensitivity may include confusion, reduced pain sensitivity, gait instability with frequent falls, and extrapyramidal symptoms.

Priapism.

Antipsychotic agents (including risperidone) with alpha-adrenergic blocking properties have been reported to cause priapism. Cases of priapism have been reported during the post-marketing period with oral paliperidone, which is the active metabolite of risperidone. Patients should be advised to seek medical attention if priapism persists for more than 4 hours.

Body temperature regulation.

Neuroleptics have been associated with impaired ability of the body to reduce core body temperature. Caution is advised when administering paliperidone palmitate to patients who may be exposed to factors that increase body temperature, such as strenuous physical activity, high ambient temperature, anticholinergic agents, or dehydration.

Venous thromboembolism.

Cases of venous thromboembolism have been reported with the use of antipsychotic agents. Since patients receiving antipsychotics often have risk factors for venous thromboembolism, this should be considered before and during treatment with paliperidone palmitate, and appropriate preventive measures should be taken.

Anti-emetic effect.

Preclinical studies with paliperidone have demonstrated anti-emetic effects. This effect in humans may mask symptoms of overdose of certain drugs or conditions such as intestinal obstruction, Reye’s syndrome, or brain tumors.

Administration.

Care should be taken during administration of Xeplion® to avoid accidental intravascular injection.

Intraoperative floppy iris syndrome (IFIS).

Cases of intraoperative floppy iris syndrome have been observed during cataract surgery in patients taking medicinal products with alpha-1 adrenergic blocking activity, such as Xeplion® (see section "Side effects").

IFIS may increase the risk of ocular complications during and after surgery. Physicians should be informed about the use of alpha-1 adrenergic blockers prior to surgery. The potential benefits of discontinuing the drug before surgery are not established; therefore, the risks of interrupting antipsychotic therapy should be carefully weighed.

Use during pregnancy or breastfeeding.

Pregnancy.

There are insufficient data on the use of paliperidone during pregnancy. Teratogenic effects were not observed in animal studies with intramuscular paliperidone palmitate or oral paliperidone; however, other forms of reproductive toxicity were observed. Newborns whose mothers used antipsychotics, including paliperidone, during the third trimester of pregnancy may develop adverse reactions such as extrapyramidal symptoms and withdrawal symptoms of varying severity and duration. Excitability, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorders have been reported. Therefore, newborns should be closely monitored. Xeplion® should be administered to pregnant women only if clearly needed, after careful consideration of benefit versus risk.

Breastfeeding.

Paliperidone passes into breast milk in amounts sufficient to affect the newborn if the mother is on therapeutic doses. Xeplion® should not be used during breastfeeding.

Fertility.

No relevant effects were observed in preclinical studies.

Ability to drive and operate machinery.

Paliperidone may have a slight or moderate influence on the ability to drive and operate machinery due to possible nervous system and visual side effects such as sedation, somnolence, loss of consciousness, and blurred vision (see section "Side effects"). Patients should therefore be advised to avoid driving or operating moving machinery until individual sensitivity to Xeplion® is established.

Method of Administration and Dosage

The recommended initial dose of Xeplion® is 150 mg on day 1 of treatment and 100 mg one week later (day 8 of treatment). To achieve a rapid attainment of therapeutic concentration, both injections should be administered into the deltoid muscle (see section "Pharmacokinetics*"). The third dose should be administered one month after the second initial dose. The recommended monthly maintenance dose is 75 mg; depending on individual tolerability and/or efficacy, the dose may be increased or decreased within the range of 25–150 mg. Patients with overweight or obesity may require dose escalation. After the second initial dose, subsequent maintenance injections may be administered into either the deltoid or gluteal muscle.

The maintenance dose may be adjusted monthly. However, due to the prolonged release of the active substance, the full effect of a dosage adjustment may not be evident until several months later.

Switching from oral prolonged-release paliperidone or risperidone to Xeplion®.

Treatment with Xeplion® should be initiated as described above. During ongoing monthly maintenance treatment with Xeplion®, patients previously stabilized on various doses of prolonged-release paliperidone tablets may achieve comparable steady-state concentrations of paliperidone. The recommended maintenance doses of Xeplion® required to achieve comparable steady-state concentrations are shown in Table 1.

Table 1

Doses of prolonged-release paliperidone tablets and corresponding Xeplion® doses to achieve comparable steady-state concentrations during maintenance treatment

Oral paliperidone or risperidone may be discontinued at the time of initiation of treatment with XEPLION®. In some patients, gradual discontinuation of oral paliperidone or risperidone may be appropriate. In some patients switching from higher oral paliperidone doses (e.g., 9–12 mg daily) to XEPLION® gluteal injections, lower plasma concentrations of paliperidone may be observed for up to 6 months after the switch. Therefore, deltoid injections should be considered during the first 6 months of treatment.

Switching from long-acting risperidone to XEPLION®.

For patients previously receiving long-acting risperidone injections, therapy with XEPLION® should be initiated according to the next scheduled injection date. Thereafter, XEPLION® should be administered once monthly. The initial one-week regimen (days 1–8), as described above, is not required. Patients previously stabilized on various doses of long-acting risperidone may achieve comparable efficacy during maintenance treatment with monthly XEPLION® injections when dosed according to the regimen shown in Table 2.

Table 2

Doses of long-acting risperidone injections and corresponding maintenance doses of XEPLION® required to achieve comparable efficacy in terms of paliperidone exposure during maintenance treatment

Discontinuation of antipsychotic treatment should be carried out according to the instructions for medical use of these medicinal products. When discontinuing therapy with XEPLION^®, the prolonged release period of the active substance should be taken into account. The need for continued use of agents for prevention of extrapyramidal symptoms should also be periodically evaluated.

Missed dose

Recommendations to avoid missed doses

The second initial dose of XEPLION^® is recommended to be administered one week after the first dose. To avoid missed doses, the second dose may be administered up to four days before or after the scheduled day (day 8). The third and subsequent injections following the initial treatment regimen should be administered monthly. To avoid missing a scheduled monthly dose, the injection may be given up to seven days earlier or later than the scheduled administration date.

If the time for administration of the second dose (day 8 ± 4 days) is missed, the recommended approach depends on the duration elapsed since the first injection.

Missed second initial dose (< 4 weeks from the first injection)

If less than 4 weeks have passed since the first injection, the second injection of 100 mg should be administered as soon as possible into the deltoid muscle. The third dose of XEPLION^® 75 mg should be administered 5 weeks after the first injection into the deltoid or gluteal muscle (regardless of the date of the second injection). Thereafter, XEPLION^® should be administered once monthly into the deltoid or gluteal muscle at a dose of 25–150 mg depending on individual tolerability and/or efficacy.

Missed second dose (4–7 weeks from the first injection)

If 4 to 7 weeks have passed since the first injection, the following steps should be followed:

1. Administer an injection of 100 mg into the deltoid muscle as soon as possible.
2. Administer the next injection of 100 mg into the deltoid muscle one week later.
3. Thereafter, monthly administration of 25–150 mg is recommended depending on individual tolerability and/or efficacy.

Missed second dose (> 7 weeks from the first injection)

If more than 7 weeks have passed since the first dose, treatment should be restarted from the beginning.

Missed monthly maintenance dose (1 month to 6 weeks)

After initiation of XEPLION^® therapy, maintenance doses are recommended to be administered monthly. If 1 month to 6 weeks have passed since the last maintenance dose, the next maintenance dose should be administered as soon as possible. Thereafter, regular monthly administration of the prescribed dose of XEPLION^® should be resumed.

Missed monthly maintenance dose (6 weeks to 6 months)

If more than 6 weeks have passed since the last XEPLION^® injection, treatment should be resumed as follows:

Patients previously receiving a maintenance dose of 25–100 mg

1. Administer the same dose as previously into the deltoid muscle as soon as possible.
2. Administer the next injection at the same dose into the deltoid muscle one week later (day 8).
3. Resume monthly administration into the deltoid or gluteal muscle at a dose of 25–150 mg depending on individual tolerability and/or efficacy.

Patients previously receiving a maintenance dose of 150 mg

1. Administer a dose of 100 mg into the deltoid muscle as soon as possible.
2. Administer the next injection at the same dose into the deltoid muscle one week later (day 8).
3. Resume monthly administration into the deltoid or gluteal muscle at a dose of 25–150 mg depending on individual tolerability and/or efficacy.

Missed monthly maintenance dose (> 6 months)

If more than 6 months have passed since the last dose, treatment should be restarted from the beginning.

Special patient populations

Elderly patients

The efficacy and safety of XEPLION^® in patients over 65 years of age have not been established.

In general, for elderly patients with normal renal function, the standard dosing regimen of paliperidone palmitate is recommended. However, renal function may be reduced in elderly patients; therefore, dose adjustment considerations for patients with renal impairment should be taken into account (dosing recommendations for patients with renal impairment are provided below).

Patients with renal impairment

The use of XEPLION^® in patients with renal impairment has not been systematically studied. For patients with mild renal impairment (creatinine clearance ≥ 50 to < 80 mL/min), treatment with paliperidone palmitate should be initiated with a dose of 100 mg on day 1 and 75 mg on day 8 (both injections administered into the deltoid muscle). The recommended monthly maintenance dose is 50 mg into the deltoid or gluteal muscle, although the dose may be increased or decreased within the range of 25–100 mg depending on individual tolerability and/or efficacy.

XEPLION^® is not recommended for patients with moderate or severe renal impairment (creatinine clearance < 50 mL/min) (see section "Special precautions for use").

Patients with hepatic impairment

Based on data from studies of oral paliperidone in patients with mild to moderate hepatic impairment, no dose adjustment is required. The use of paliperidone in patients with severe hepatic impairment has not been studied; therefore, XEPLION^® should be used with caution in such patients (see section "Pharmacokinetics").

Method of administration

XEPLION^® is intended for intramuscular use only. XEPLION^® must not be administered by any other route. The drug should be administered slowly and deeply into the deltoid or gluteal muscle. Injections must be performed exclusively by a healthcare professional. The entire contents of one syringe should be administered at once; the dose must not be divided into multiple injections.

To achieve therapeutic concentration rapidly, the injections on day 1 and day 8 of treatment should be administered into the deltoid muscle (see section "Pharmacokinetics"). Subsequent monthly maintenance doses may be administered into either the deltoid or gluteal muscle. Consider alternating injection sites (deltoid and gluteal muscles) if pain at the injection site occurs (see section "Adverse reactions"). Alternating left and right sides for administration should also be considered.

Administration of injections into the deltoid muscle

The needle size recommended for administration of XEPLION^® into the deltoid muscle is determined by the patient's body weight. For patients with body weight ≥ 90 kg, the long needle from the kit is recommended. For patients with body weight < 90 kg, the short needle from the kit is recommended. Alternating between left and right deltoid muscles should be considered.

Administration of injections into the gluteal muscle

For administration of XEPLION^® into the gluteal muscle, the long needle from the kit is recommended. Injections should be administered into the upper outer quadrant of the buttock. Alternating between right and left gluteal muscles should be considered.

Instructions for use (information intended exclusively for healthcare professionals)

The suspension is intended for single use only. Prior to administration, inspect for the presence of foreign particulate matter. Do not use if visible particles are present.

1. Shake the syringe vigorously for 10 seconds to ensure the contents form a uniform suspension.

2. Select the appropriate needle.

The initial dose of XEPLION^® (150 mg) is administered by intramuscular injection into the deltoid muscle on day 1 of treatment. The second initial dose of XEPLION^® (100 mg) is also administered into the deltoid muscle one week later (day 8 of treatment). For administration into the deltoid muscle, use the short needle (blue hub) for patients with body weight < 90 kg and the long needle (gray hub) for patients with body weight ≥ 90 kg.

For patients previously receiving long-acting risperidone injections, the first injection of XEPLION^® (dose range 25–150 mg) may be administered into either the deltoid or gluteal muscle on the day of the next scheduled injection.

Monthly maintenance doses should be administered into the deltoid or gluteal muscle. For administration into the gluteal muscle, the long needle (gray hub) should be used.

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

4. Partially open the safety needle packaging, grasp the needle cap through the packaging, and attach the syringe to the luer-lock needle cap by gently twisting clockwise.

5. Remove the needle cap by pulling it straight off along the needle. Do not twist the cap, as this may loosen the connection between the needle and syringe.

6. Point the syringe with needle upward and expel air from the syringe by gently depressing the plunger.

7. Inject the entire contents of the syringe into the selected muscle (deltoid or gluteal).

Subcutaneous or intravascular injection must be avoided.

8. After completing the injection, activate the needle safety mechanism using the thumb (Fig. 8a), index finger (Fig. 8b), or a hard surface (Fig. 8c). The safety mechanism is activated if a click is heard. Dispose of the syringe with needle appropriately.

8a

8b

8c

Children

The safety and efficacy of XEPLION^® in children have not been established. No data are available.

Overdose

Symptoms

In general, symptoms of overdose with XEPLION^® correspond to an intensification of the known pharmacological effects of paliperidone, such as somnolence and sedation, tachycardia, hypotension, QT interval prolongation, and extrapyramidal symptoms. Ventricular tachycardia of the torsades de pointes type and ventricular fibrillation have been observed in cases of overdose with oral formulations of paliperidone. In cases of acute overdose, the possibility of concomitant use of multiple drugs should be considered.

Treatment

When treating overdose, the prolonged release and long elimination half-life of paliperidone should be taken into account. There is no specific antidote for paliperidone. Management of paliperidone overdose includes symptomatic treatment and monitoring of the patient's clinical status.

General supportive measures should be implemented, ensuring and maintaining airway patency, adequate ventilation, and oxygenation.

Cardiovascular function should be monitored immediately, including continuous ECG monitoring, to detect possible arrhythmias. In cases of hypotension and circulatory collapse, appropriate measures such as intravenous fluid administration and/or sympathomimetics should be initiated. Anticholinergic agents should be used in the event of severe extrapyramidal symptoms. The patient's condition should be closely monitored until full recovery.

Adverse reactions.

Safety profile.

The most common adverse reactions observed during clinical trials were insomnia, headache, anxiety, upper respiratory tract infections, injection site reactions, parkinsonism, weight gain, akathisia, agitation, sedation/somnolarity, nausea, constipation, dizziness, musculoskeletal pain, tachycardia, tremor, abdominal pain, vomiting, diarrhea, weakness, and dystonia. Among these, akathisia and sedation/somnolence were identified as dose-dependent adverse reactions.

Adverse reactions observed with paliperidone use are listed in Table 3 by system organ class and frequency of occurrence in clinical studies of paliperidone palmitate. Within each frequency subgroup, adverse reactions are listed in order of decreasing severity. Frequency is defined as very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1,000, < 1/100), rare (≥ 1/10,000, < 1/1,000), very rare (< 1/10,000), and not known (cannot be estimated from available data).

Table 3

a The frequency of adverse reactions is defined as "unknown" because they were not observed during clinical trials of paliperidone palmitate. Such adverse reactions have been reported in spontaneous reports during the post-marketing period, and their frequency cannot be determined, or these adverse reactions were observed during clinical trials of risperidone (any dosage form) or oral paliperidone.

b See subsection "Hyperprolactinaemia" below.

c See subsection "Extrapyramidal symptoms" below.

d During placebo-controlled studies, diabetes mellitus was reported in 0.32% of patients in the Xeplion® group compared to 0.39% of patients in the placebo group. The overall frequency in all clinical studies of paliperidone palmitate was 0.65%.

e Insomnia includes disorders of sleep onset and intrasomnic sleep disorders. Seizures include grand mal epileptic seizure. Edema includes generalized edema, peripheral edema, and localized edema. Menstrual disorders include irregular menstruation, amenorrhea, and oligomenorrhea.

Adverse reactions observed with risperidone use

Paliperidone is the active metabolite of risperidone; therefore, the adverse reaction profiles of these substances are comparable (including oral and parenteral dosage forms).

Description of selected adverse reactions

Anaphylactic reactions.

Rare cases of anaphylactic reactions after Xeplion® injections have been reported during the post-marketing period in patients whose condition had previously been stabilized with oral risperidone or oral paliperidone (see section "Special precautions").

Injection site reactions.

Pain was the most commonly reported adverse reaction associated with administration of the medicinal product. Most of these reactions were of mild to moderate severity. Throughout all Phase II and III studies, assessment of injection site pain using a visual analogue scale demonstrated a trend toward decreasing frequency and intensity of pain over time. Injections into the deltoid muscle were perceived as more painful than those into the gluteal muscle. Other injection site reactions were mostly of mild severity and included induration (common), pruritus (uncommon), and nodule formation (rare).

Extrapyramidal symptoms.

Extrapyramidal symptoms include: parkinsonism (including hypersalivation, musculoskeletal rigidity, parkinsonism, sialorrhea, cogwheel rigidity, bradykinesia, hypokinesia, mask-like facies, muscle tension, akinesia, rigidity of neck muscles, parkinsonian gait, disturbances of glabellar reflex, and parkinsonian resting tremor), akathisia (including akathisia, restlessness, hyperkinesia, and restless legs syndrome), dyskinesia (including dyskinesia, muscle twitching, choreoathetosis, athetosis, and myoclonus), dystonia (including dystonia, hypertonia, torticollis, involuntary muscle contractions, muscle contractures, blepharospasm, involuntary eye movements, tongue paralysis, facial muscle tics, laryngospasm, myotonia, opisthotonus, oropharyngeal spasm, pleurotonus, tongue spasm, and trismus), and tremor. It should be noted that a broader list of symptoms is included, which may not necessarily have an extrapyramidal origin.

Weight gain.

In the 13-week study using an initial dose of 150 mg, weight gain ≥ 7% in patients was dose-dependent and occurred with a frequency of 5% in the placebo group compared to 6%, 8%, and 13% in the Xeplion® 25 mg, 100 mg, and 150 mg groups, respectively.

During the 33-week open-label transitional/maintenance period of the long-term relapse prevention study, 12% of patients receiving Xeplion® met this criterion (weight gain ≥ 7% from double-blind baseline to endpoint); mean weight gain (standard deviation) from open-label baseline was +0.7 (4.79) kg.

Hyperprolactinaemia.

During clinical studies, an increase in serum prolactin levels was observed in patients of both sexes receiving Xeplion®. Adverse reactions possibly related to elevated prolactin levels (e.g., amenorrhea, galactorrhea, menstrual disorders, gynecomastia) were reported in less than 1% of patients overall.

Adverse reactions typical of this class of medicinal products.

QT interval prolongation, ventricular arrhythmias (ventricular fibrillation, ventricular tachycardia), sudden unexplained death, cardiac arrest, and atrial flutter/fibrillation may occur with the use of antipsychotic agents. Cases of venous thromboembolism, including pulmonary embolism and deep vein thrombosis, have been reported during the use of antipsychotic medicinal products (frequency unknown).

Shelf life.

2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 30 °C. Keep out of the reach of children.

Incompatibilities.

Xeplion® must not be mixed with other medicinal products.

Packaging.

0.5 ml, 0.75 ml, 1.0 ml, or 1.5 ml in a pre-filled syringe; 1 syringe and 2 needles for intramuscular injection in a cardboard box.

Prescription status.

Prescription only.

Manufacturers.

Responsible for batch release:

Janssen Pharmaceutica NV
Cilag AG

Manufacturers' locations and addresses of places of business.

Turnhoutseweg 30, Beerse, 2340, Belgium
Hochstrasse 201, 8200 Schaffhausen, Switzerland