Xeplion (Suspension) Instructions for Use

Marketing Authorization Holder

Johnson & Johnson, LLC (Russia)

Manufactured By

Janssen Pharmaceutica, NV (Belgium)

Or

Cilag, AG (Switzerland)

Contact Information

JANSSEN, a pharmaceutical division of Johnson & Johnson LLC

ATC Code

N05AX13 (Paliperidone)

Active Substance

Paliperidone (Rec.INN registered by WHO)

Dosage Forms

	Xeplion	Prolonged-release suspension for intramuscular administration 25 mg/0.25 ml: 1 syringe in a kit with injection needles (2 pcs.)
		Prolonged-release suspension for intramuscular administration 50 mg/0.5 ml: 1 syringe in a kit with injection needles (2 pcs.)
		Prolonged-release suspension for intramuscular administration 75 mg/0.75 ml: 1 syringe in a kit with injection needles (2 pcs.)
		Prolonged-release suspension for intramuscular administration 100 mg/1 ml: 1 syringe in a kit with injection needles (2 pcs.)
		Prolonged-release suspension for intramuscular administration 150 mg/1.5 ml: 1 syringe in a kit with injection needles (2 pcs.)

Dosage Form, Packaging, and Composition

Prolonged-release suspension for intramuscular administration white or almost white, free from foreign particles.

Excipients: polysorbate 20 – 12 mg, macrogol 4000 (polyethylene glycol 4000) – 30 mg, citric acid monohydrate – 5 mg, sodium hydrogen phosphate – 5 mg, sodium dihydrogen phosphate monohydrate – 2.5 mg, sodium hydroxide – 2.84 mg, water for injections – up to 1 ml.

0.25 ml – syringes made of cycloolefin copolymer with a bromobutyl tip and a bromobutyl plunger seal with FluroTec^® coating, equipped with a plunger stopper (1) in a kit with 2 needles for intramuscular injections (into the deltoid and gluteal muscles) – plastic trays, sealed with polyethylene film (1) – cardboard boxes.
0.5 ml – syringes made of cycloolefin copolymer with a bromobutyl tip and a bromobutyl plunger seal with FluroTec^® coating, equipped with a plunger stopper (1) in a kit with 2 needles for intramuscular injections (into the deltoid and gluteal muscles) – plastic trays, sealed with polyethylene film (1) – cardboard boxes.
0.75 ml – syringes made of cycloolefin copolymer with a bromobutyl tip and a bromobutyl plunger seal with FluroTec^® coating, equipped with a plunger stopper (1) in a kit with 2 needles for intramuscular injections (into the deltoid and gluteal muscles) – plastic trays, sealed with polyethylene film (1) – cardboard boxes.
1 ml – syringes made of cycloolefin copolymer with a bromobutyl tip and a bromobutyl plunger seal with FluroTec^® coating, equipped with a plunger stopper (1) in a kit with 2 needles for intramuscular injections (into the deltoid and gluteal muscles) – plastic trays, sealed with polyethylene film (1) – cardboard boxes.
1.5 ml – syringes made of cycloolefin copolymer with a bromobutyl tip and a bromobutyl plunger seal with FluroTec^® coating, equipped with a plunger stopper (1) in a kit with 2 needles for intramuscular injections (into the deltoid and gluteal muscles) – plastic trays, sealed with polyethylene film (1) – cardboard boxes.

Clinical-Pharmacological Group

Antipsychotic drug (neuroleptic)

Pharmacotherapeutic Group

Psycholeptics; antipsychotics; other antipsychotics

Pharmacological Action

Mechanism of action

Paliperidone palmitate is hydrolyzed to paliperidone. The latter is a centrally active antagonist primarily of serotonin 5-HT_2A receptors, as well as dopamine D₂ receptors, α₁– and α₂-adrenergic receptors, and histamine H₁ receptors. Paliperidone does not bind to muscarinic cholinergic receptors or β₁– and β₂-adrenergic receptors. The pharmacological activity of the (+) and (-) enantiomers of paliperidone is quantitatively and qualitatively similar.

The therapeutic efficacy of the drug in schizophrenia is presumed to be due to the combined blockade of D₂ and 5-HT_2A receptors.

Pharmacokinetics

Absorption and distribution

Due to its extremely low water solubility, paliperidone palmitate dissolves and is absorbed into the systemic circulation slowly after intramuscular administration. After a single intramuscular administration, the plasma concentration of paliperidone increases slowly, reaching a maximum after 13-14 days (median) following administration into the deltoid muscle and after 13-17 days following administration into the gluteal muscle. Drug release is detected 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 prolonged maintenance of therapeutic concentrations.

After a single administration of a 25-150 mg dose into the deltoid muscle, the maximum concentration (C_max) is on average 28% higher than after administration into the gluteal muscle. At the start of therapy, administration into the deltoid muscle helps achieve therapeutic concentrations of paliperidone more rapidly (150 mg on day 1 and 100 mg on day 8) than administration into the gluteal muscle. After multiple injections, the difference in exposure is less pronounced.

The mean ratio of C_max to steady-state concentration (C_ss) of paliperidone after administration of 4 injections of Xeplion at a dose of 100 mg into the gluteal muscle was 1.8, and after administration into the deltoid muscle it was 2.2. At paliperidone doses of 25-150 mg, the area under the concentration-time curve (AUC) of paliperidone changed proportionally with the dose, while C_max at doses above 50 mg increased less than proportionally with the dose.

The median half-life (T_1/2) of paliperidone after administration of Xeplion in doses of 25-150 mg ranged from 25 to 49 days.

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

In a population analysis, the apparent volume of distribution (V_d) of paliperidone was 391 L; Paliperidone is 74% bound to plasma proteins.

Metabolism and excretion

Within one week after a single oral dose of 1 mg of ¹⁴C-paliperidone with immediate release of the active ingredient, 59% of the administered dose is excreted unchanged in the urine; this indicates the absence of 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 metabolic pathways of the drug are known in vivo, but none accounts for the metabolism of more than 6.5% of the administered dose: dealkylation, hydroxylation, dehydrogenation, and benzisoxazole scission. Although in vitro studies suggest a role for the CYP2D6 and CYP3A4 isoenzymes in the metabolism of paliperidone, there is no evidence of a significant role for these isoenzymes in the metabolism of paliperidone in vivo. A population pharmacokinetic analysis did not reveal a noticeable difference in the clearance of paliperidone after oral administration between people with active and poor CYP2D6 metabolism. In vitro studies using human liver microsomes showed that Paliperidone does not significantly inhibit the metabolism of drugs by the CYP1A2, CYP2A6, CYP2D6, CYP2E1, CYP3A4, and CYP3A5 isoenzymes.

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

Overall, the plasma concentration of paliperidone during the loading phase after intramuscular administration of Xeplion was in the same range as after oral administration of prolonged-release paliperidone with active ingredient release in doses between 6 and 12 mg. The loading regimen used for paliperidone ensures maintenance of concentrations within this range even at the end of the interdose interval (day 8 and day 36). The interindividual variability in the pharmacokinetics of paliperidone after administration of Xeplion was less than that after oral administration of prolonged-release paliperidone. Due to the difference in the pattern of change in the median plasma concentration of paliperidone with the two drugs, caution should be exercised when directly comparing their pharmacokinetics.

Special patient categories

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

Renal impairment. For patients with mild renal impairment, the dose of paliperidone should be reduced; Xeplion is not recommended for use in patients with moderate or severe renal impairment. The distribution of paliperidone after a single oral dose of a 3 mg prolonged-release paliperidone tablet was studied in patients with varying degrees of renal impairment. As creatinine clearance (CrCl) decreased, the excretion of paliperidone decreased: in mild renal impairment (CrCl 50-80 ml/min) – by 32%, in moderate renal impairment (CrCl 30-50 ml/min) – by 64%, in severe renal impairment (CrCl 10-30 ml/min) – by 71%, resulting in an increase in AUC_0-∞ compared to healthy volunteers by 1.5, 2.6, and 4.8 times, respectively. Based on limited data on the use of Xeplion in patients with mild renal impairment and pharmacokinetic modeling results, the recommended loading dose of paliperidone for such patients is 75 mg on day 1 and day 8; thereafter, 50 mg is administered monthly (every 4 weeks).

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

Race. A population pharmacokinetic analysis of the results of the oral paliperidone study did not reveal a difference in the pharmacokinetics of paliperidone after administration among people of different races.

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

Effect of smoking on drug pharmacokinetics. According to in vitro studies using human liver microsomes, Paliperidone is not a substrate for CYP1A2, so smoking should not affect the pharmacokinetics of paliperidone. Consistent with these in vitro data, a population pharmacokinetic analysis did not reveal a difference in the pharmacokinetics of paliperidone between smokers and non-smokers.

Indications

• Treatment of schizophrenia in adult patients;
• Prevention of relapse of schizophrenia in adult patients;
• Therapy of schizoaffective disorders as monotherapy or as part of combination therapy with mood stabilizers and antidepressants in adult patients.

ICD codes

Dosage Regimen

In patients who have never taken oral Paliperidone or oral or parenteral risperidone, it is recommended to check tolerance to oral paliperidone or risperidone for 2-7 days before starting treatment with Xeplion.

When treatment with long-acting injectable drugs is necessary in patients with mild to moderate psychotic conditions who have previously shown a response to therapy with oral forms of paliperidone or risperidone, Xeplion may be used without prior stabilization with oral drugs of this group.

Schizophrenia

It is recommended to start treatment with Xeplion with a dose of 150 mg on day 1 and 100 mg after 1 week (both injections into the deltoid muscle). A maintenance dose of 75 mg once a month is recommended; effect may be observed with higher or lower doses, in the range of 25-150 mg depending on individual tolerance and/or efficacy. After the second initial dose, subsequent maintenance injections can be administered into the deltoid or gluteal muscle.

Schizoaffective disorder

It is recommended to start treatment with Xeplion with a dose of 150 mg on day 1 and 100 mg after 1 week (both injections into the deltoid muscle). A maintenance dose in the range of 25-150 mg is recommended depending on individual tolerance and/or efficacy. The use of a 25 mg dose in schizoaffective disorder has not been studied. After the 2nd initial dose, subsequent maintenance injections can be administered into the deltoid or gluteal muscle.

The maintenance dose can be adjusted monthly. The prolonged release of the active ingredient from paliperidone palmitate should be taken into account, as the full effect of a dose change may only become apparent after several months.

Missed dose

Avoiding missed doses. The second loading dose of paliperidone is recommended to be administered 1 week after the first dose. If this is not possible, it can be administered 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 given 7 days earlier or later.

If the second injection of Xeplion was not administered on time (1 week ± 4 days), resumption of treatment is recommended depending on the time that has passed since the first injection.

Missed second initial dose (less than 4 weeks). If less than 4 weeks have passed since the first injection, the patient should receive the second injection at a dose of 100 mg into the deltoid muscle as soon as possible. The third injection of Xeplion at a dose of 75 mg should be administered into the deltoid or gluteal muscle 5 weeks after the first injection (regardless of the time of the second injection). Thereafter, a monthly course of injections at a dose of 25 mg to 150 mg into the deltoid or gluteal muscle should be maintained, depending on individual tolerance and/or efficacy.

Missed second initial dose (4 to 7 weeks). If 4 to 7 weeks have passed since the first injection of Xeplion, treatment is resumed by administering two injections at a dose of 100 mg according to the following scheme: the first injection is given into the deltoid muscle as soon as possible; after 1 week, a second injection is given into the deltoid muscle, then the monthly course of injections into the deltoid or gluteal muscle is continued at a dose of 25 mg to 150 mg depending on individual tolerance and/or efficacy.

Missed second initial dose (more than 7 weeks). If more than 7 weeks have passed since the first injection of Xeplion, treatment is started in the same way as when initiating treatment with Xeplion.

Missed maintenance dose (1 month to 6 weeks). After starting treatment, it is recommended to administer Xeplion injections monthly. 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. Thereafter, administer the drug monthly.

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

For patients stabilized on a dose of 25 mg to 100 mg

1. Administer the drug injection into the deltoid muscle as soon as possible at the dose at which the patient was stabilized before the missed injection.
2. The next injection into the deltoid muscle (same dose) is given one week later on day 8.
3. Then resume the monthly course of injections into the deltoid or gluteal muscle at a dose of 25 mg to 150 mg depending on individual tolerance and/or efficacy.

For patients stabilized on a dose of 150 mg

1. Administer a dose of 100 mg into the deltoid muscle as soon as possible.
2. After 1 week, administer another 100 mg dose (day 8) into the deltoid muscle.
3. Then resume the monthly course of injections into the deltoid or gluteal muscle at a dose of 25 mg to 150 mg depending on individual tolerance and/or efficacy.

Missed maintenance dose (period >6 months). If more than 6 months have passed since the last injection of Xeplion, treatment is restarted as described above for treatment initiation.

Method of administration

Xeplion is for intramuscular administration only. The drug is injected slowly deep into the muscle. Injections should only be performed by a healthcare professional. The entire dose is administered at once; the dose must not be administered in multiple injections. The drug must not be administered into blood vessels or subcutaneously. Accidental entry into a blood vessel should be avoided. To do this, before starting the administration of the drug, the syringe plunger is pulled back to check if the needle has entered a large blood vessel. If blood enters the syringe, the needle and syringe should be removed from the patient’s muscle and disposed of.

The recommended needle size for administering Xeplion into the deltoid muscle is determined by the patient’s body weight. For patients with a body weight ≥90 kg, the long needle with a gray hub from the kit is recommended. For patients with a body weight <90 kg, the short needle with a blue hub from the kit is recommended. The drug should be administered alternately into the right and left deltoid muscles.

For administering Xeplion into the gluteal muscle, the long needle with a gray hub from the kit is recommended. Injections should be performed into the upper outer quadrant of the gluteal region. The drug should be administered alternately into the right and left gluteal muscles.

Since Paliperidone is the main active metabolite of risperidone, caution should be exercised when using Xeplion and risperidone or an oral form of paliperidone concomitantly for a prolonged period. Data on the safety of concomitant use of Xeplion and other antipsychotics are limited.

Patients with hepatic impairment

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

Patients with renal impairment

The use of Xeplion in patients with renal impairment has not been systematically studied. In patients with mild renal impairment (CrCl from ≥50 to <80 ml/min), it is recommended to initiate Xeplion with a dose of 100 mg on day 1 and 75 mg after 1 week (both injections into the deltoid muscle). Thereafter, a 50 mg injection is administered after 1 month into the deltoid or gluteal muscle, and the dose is then adjusted from 25 mg to 100 mg based on individual tolerance and/or efficacy.

Xeplion is not recommended for use in patients with moderate or severe renal impairment (CrCl <50 ml/min).

Elderly patients

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

Adolescents and children

The safety and efficacy of Xeplion in patients under 18 years of age have not been studied.

Other special patient categories

No dose adjustment of Xeplion is required based on patient sex, race, or smoking status.

Switching from other antipsychotics

Data on switching patients with schizophrenia or schizoaffective disorder from other antipsychotics to Xeplion or on its use concomitantly with other antipsychotics have not been systematically collected. For patients who have never taken oral Paliperidone or oral or injectable risperidone, tolerance should be tested with oral paliperidone or oral risperidone before initiating treatment with Xeplion. At the start of treatment with Xeplion, previously used oral antipsychotics can be gradually discontinued. Xeplion should be prescribed as described above. If a patient is receiving long-acting injectable antipsychotics, treatment with Xeplion is initiated with the maintenance dose at the time of the next scheduled injection. Treatment with Xeplion once a month should be continued. An initial dose in the first week of treatment is not required.

In patients who were stabilized on various doses of Risperdal Consta^®, prolonged-release suspension for intramuscular injection, steady-state concentrations of the active substance may reach similar values during maintenance therapy with Xeplion once a month according to the following scheme

Discontinuation of the previous antipsychotic should be carried out in accordance with the prescribing information. When discontinuing Xeplion, the prolonged release of the active component should be taken into account. As with other antipsychotics, the need for continued use of prophylactic agents for extrapyramidal disorders should be periodically assessed.

Instructions for use

The syringe is for single use only.

1. Shake the syringe vigorously for 10 seconds to obtain a homogeneous suspension.
2. Select the appropriate needle.

For administration into the deltoid muscle in patients with a body weight <90 kg, use the short needle (with a blue hub), and in patients with a body weight ≥90 kg, use the long needle (with a gray hub).

For administration into the gluteal muscle, use the long needle (with a gray hub).

1. Holding the syringe vertically, remove the rubber cap by gently rotating it clockwise.
2. Partially open the safe needle package, grasp the needle cap through the package, and attach the needle to the Luer cap of the syringe by gently rotating it clockwise.
3. Remove the needle cap by pulling it straight off along the needle. Do not rotate the cap, as this may loosen the needle connection to the syringe.
4. Point the syringe needle upwards and expel air from the syringe by pressing the plunger slightly.
5. Inject the entire contents of the syringe into the chosen muscle (deltoid or gluteal). Do not inject the drug into a blood vessel or subcutaneously.
6. After completing the injection, activate the needle protection using the thumb or index finger or by pressing the syringe against a hard surface. The needle protection should click into place. Dispose of the syringe with the needle as appropriate.

Adverse Reactions

The most frequent adverse reactions reported in clinical studies were insomnia, headache, anxiety, upper respiratory tract infections, injection site reactions, parkinsonism, weight gain, akathisia, agitation, sedation, somnolence, nausea, constipation, dizziness, musculoskeletal pain, tachycardia, tremor, abdominal pain, vomiting, diarrhea, fatigue, dystonia. Of these, sedation and somnolence were found to be dose-dependent.

Most adverse drug reactions (ADRs) were mild or moderate in severity.

Below are the adverse reactions observed in patients with schizophrenia. The frequency of adverse reactions was classified as follows: very common (≥10%), common (≥1% and <10%), uncommon (≥0.1% and <1%), rare (≥0.01% and <0.1%), and very rare (<0.01%).

Infections common – urinary tract infections, influenza, upper respiratory tract infections; uncommon – acarodermatitis, bronchitis, cellulitis, ear infections, eye infections, pneumonia, respiratory tract infections, sinusitis, subcutaneous abscess, tonsillitis, cystitis; rare – onychomycosis.

Immune system disorders : uncommon – hypersensitivity; rare – anaphylactic reactions.

Blood and lymphatic system disorders: uncommon – anemia, decreased hematocrit, increased eosinophil count, decreased white blood cell count; rare – thrombocytopenia, neutropenia, agranulocytosis.

Endocrine system disorders common – hyperprolactinemia; rare – inappropriate antidiuretic hormone secretion; frequency not known – glucose urine present.

Metabolism and nutrition disorders common – hyperglycemia, decreased weight, increased plasma triglycerides, increased weight; uncommon – hyperinsulinemia, anorexia, decreased appetite, increased appetite, diabetes mellitus, increased blood cholesterol; rare – polydipsia, hypoglycemia, water intoxication, diabetic ketoacidosis.

Psychiatric disorders very common – insomnia; common – anxiety, depression, agitation; uncommon – decreased libido, nervousness, nightmares, confusional state, sleep disorder, mania; rare – anorgasmia, emotional flattening.

Nervous system disorders very common – headache; common – sedation, dystonia, dyskinesia, tremor, akathisia, dizziness, extrapyramidal symptoms, somnolence, parkinsonism; uncommon – convulsions (including epileptic seizures), attention disturbance, postural dizziness, dysarthria, hypoesthesia, paresthesia, psychomotor hyperactivity, syncope, severe dyskinesia, dysgeusia; rare – neuroleptic malignant syndrome, cerebral ischemia, unresponsiveness to stimuli, loss of consciousness, decreased level of consciousness, diabetic coma, balance disorder, coordination abnormal, head titubation.

Eye disorders uncommon – dry eye, blurred vision, conjunctivitis; rare – glaucoma, photophobia, increased lacrimation, eye redness, nystagmus, rotary nystagmus.

Ear and labyrinth disorders: uncommon – vertigo, tinnitus, ear pain.

Cardiac disorders common – bradycardia, tachycardia, increased blood pressure; uncommon – decreased blood pressure, atrioventricular block, conduction disorder, electrocardiogram abnormalities, electrocardiogram QT prolonged, palpitations, postural orthostatic tachycardia syndrome, atrial fibrillation, orthostatic hypotension; rare – deep vein thrombosis, sinus arrhythmia, pulmonary embolism, ischemia, flushing.

Respiratory, thoracic and mediastinal disorders common – cough, nasal congestion; uncommon – dyspnea, epistaxis, oropharyngeal pain, wheezing, pulmonary congestion; rare – hyperventilation, aspiration pneumonia, respiratory tract congestion, dysphonia, sleep apnea syndrome.

Gastrointestinal disorders common – dyspepsia, upper abdominal pain, constipation, diarrhea, nausea, toothache, vomiting; uncommon – abdominal discomfort, dry mouth, flatulence, gastroenteritis; rare – pancreatitis, fecal incontinence, tongue edema, dysphagia, intestinal obstruction, fecaloma, cheilitis.

Hepatobiliary disorders common – increased hepatic transaminases; uncommon – increased gamma-glutamyltransferase, increased liver enzymes; rare – jaundice.

Musculoskeletal and connective tissue disorders : common – back pain, pain in extremity, musculoskeletal pain; uncommon – arthralgia, joint stiffness, muscle spasms, neck pain; rare – joint swelling, rhabdomyolysis, increased creatine phosphokinase, muscle weakness, posture abnormal.

Skin and subcutaneous tissue disorders common – skin rash; uncommon – acne, dry skin, eczema, erythema, urticaria, pruritus, alopecia; rare – angioedema, hyperkeratosis, skin discoloration, seborrheic dermatitis, dandruff, drug eruption.

Renal and urinary disorders uncommon – dysuria, pollakiuria, urinary incontinence; rare – urinary retention.

Reproductive system and breast disorders uncommon – delayed menstruation, menstrual disorder, amenorrhea, galactorrhea, gynecomastia, sexual dysfunction, ejaculation disorder, erectile dysfunction, vaginal discharge; rare – priapism, breast pain, breast discomfort, breast engorgement, breast enlargement, breast discharge.

Pregnancy, puerperium and perinatal conditions rare – neonatal withdrawal syndrome.

General disorders and administration site conditions common – pyrexia, asthenic disorders, asthenia, injection site reactions (pain, pruritus, induration); uncommon – chest pain, chest discomfort, face edema, gait disturbance, malaise, injection site induration, edema (including generalized edema, peripheral edema, pitting edema), fall; rare – chills, body temperature increased, body temperature decreased, thirst, withdrawal syndrome, injection site cyst, hypothermia, injection site abscess, injection site cellulitis, injection site hematoma.

Adverse reactions reported with risperidone use

Paliperidone is an active metabolite of risperidone; therefore, the adverse reaction profiles of risperidone and paliperidone are related. In addition to those listed above, the following adverse reactions have been observed with risperidone use, which may also occur with Xeplion

Nervous system disorders: cerebrovascular accident.

Eye disorders : intraoperative floppy iris syndrome.

Respiratory, thoracic and mediastinal disorders: rales.

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

Schizoaffective disorder

The safety profile of Xeplion in patients with schizoaffective disorder is similar to that in patients with schizophrenia.

Description of selected adverse reactions

Anaphylactic reactions

Rare cases of anaphylactic reactions upon administration of Xeplion have been recorded in the post-marketing period in patients who previously tolerated therapy with oral forms of risperidone or paliperidone well.

Injection site reactions

The most frequently reported injection site reaction was pain, which was mild or moderate in severity in most cases. According to assessment using a visual analog scale, the frequency and intensity of pain decreased over time in all phase II and III clinical studies. Injections into the deltoid muscle are perceived as slightly more painful compared to injections into the gluteal muscle. Other injection site reactions were mostly mild in severity and included induration (common), pruritus (uncommon), and nodules (rare).

Extrapyramidal symptoms (EPS)

EPS include the following terms: parkinsonism (includes hypersalivation, musculoskeletal stiffness, parkinsonism, drooling, cogwheel rigidity, bradykinesia, hypokinesia, mask-like facies, muscle tightness, akinesia, nuchal rigidity, muscle rigidity, parkinsonian gait, glabellar reflex abnormal, and parkinsonian rest tremor), akathisia (includes akathisia, restless legs syndrome, restlessness, and hyperkinesia), dyskinesia (includes dyskinesia, muscle twitching, choreoathetosis, athetosis, and myoclonus), dystonia (includes dystonia, hypertonia, torticollis, involuntary muscle contractions, muscle contracture, blepharospasm, oculogyration, tongue paralysis, facial spasm, laryngospasm, myotonia, opisthotonus, oropharyngeal spasm, pleurothotonus, tongue spasm, and trismus) and tremor. This list includes a broader range of symptoms that may not be of extrapyramidal origin.

Weight increased

In a 13-week clinical study using an initial dose of 150 mg, abnormal weight gain >7% was shown to be dose-dependent. Weight gain was reported with a frequency of 5% in the placebo group and with frequencies of 6%, 8%, and 13% with Xeplion doses of 25 mg, 100 mg, and 150 mg, respectively.

During the 33-week open-label period of switching to Xeplion or maintenance therapy with Xeplion in a long-term clinical study in patients with schizophrenia, 12% of patients treated with Xeplion met this criterion (weight increase of >7% from the double-blind phase to the endpoint).

Class-effects

With the use of antipsychotics, QT interval prolongation, ventricular arrhythmias (ventricular fibrillation, ventricular tachycardia), sudden unexplained death, cardiac arrest, and torsade de pointes may occur. Cases of venous thromboembolism, including pulmonary embolism and deep vein thrombosis, have been reported (with unknown frequency) with the use of antipsychotics.

Contraindications

• Hypersensitivity to paliperidone or any component of the drug;
• Since Paliperidone is an active metabolite of risperidone, Xeplion is contraindicated in patients with known hypersensitivity to risperidone.

With caution

Xeplion should be used with caution in the following cases (see more detailed information in the “Special warnings and precautions for use” section)

• In patients with cardiovascular diseases (e.g., heart failure, myocardial infarction or ischemia, cardiac conduction disorders), cerebrovascular disorders, or conditions predisposing to hypotension (e.g., dehydration, hypovolemia, use of antihypertensive drugs);
• In patients with a history of seizures or other conditions where the seizure threshold may be lowered;
• In patients who may be exposed to factors that increase body temperature, such as strenuous exercise, exposure to high ambient temperatures, exposure to drugs with anticholinergic activity, and dehydration;
• In patients with a history of arrhythmia or congenital long QT syndrome, or who are taking drugs that prolong the QT interval;
• When used in combination with other centrally acting drugs and alcohol. Paliperidone may antagonize the effect of levodopa and dopamine agonists;
• In patients with dementia, Parkinson’s disease, or dementia with Lewy bodies;
• In patients with possible prolactin-dependent tumors.
• In patients with hepatic or renal impairment.

Use in Pregnancy and Lactation

Pregnancy

The safety of intramuscular Xeplion or oral paliperidone during human pregnancy has not been established. A small increase in fetal mortality was observed in animals with high doses of oral paliperidone. Intramuscular Xeplion did not affect the course of pregnancy in rats, but high doses were toxic to pregnant females. Doses of oral paliperidone and intramuscular Xeplion, which produce exposures exceeding the maximum human therapeutic exposure by 20-22 times and 6 times, respectively, did not affect the offspring of laboratory animals.

Xeplion should be used during pregnancy only if the expected 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 antipsychotic drugs (including Paliperidone) in the third trimester of pregnancy, newborns are at risk of extrapyramidal disorders and/or withdrawal syndrome of varying severity. These symptoms may include agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder.

Breastfeeding

Studies of paliperidone in animals and risperidone in humans have found excretion of paliperidone in breast milk. Therefore, women receiving Xeplion should not breastfeed.

Use in Hepatic Impairment

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

The use of Xeplion in patients with severe hepatic impairment has not been studied.

Use in Renal Impairment

The use of Xeplion in patients with renal impairment has not been systematically studied. In patients with mild renal impairment (CrCl from ≥50 to <80 ml/min) it is recommended to initiate Xeplion with a dose of 100 mg on day 1 and 75 mg after 1 week (both injections into the deltoid muscle). Thereafter, 50 mg is administered monthly into the deltoid or gluteal muscle, and the dose is then adjusted from 25 mg to 100 mg based on individual tolerance and/or efficacy.

Xeplion is not recommended for use in patients with moderate or severe renal impairment (CrCl <50 mL/min).

Pediatric Use

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

Geriatric Use

Caution should be exercised when prescribing Xeplion to elderly patients with dementia.

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

Special Precautions

Use of Xeplion in acute psychomotor agitation or severe psychotic states

Xeplion is not recommended for use in acute psychomotor agitation or severe psychotic states where immediate symptom control is required.

QT interval

Caution should be exercised when using paliperidone in patients with known cardiovascular disease or a history of QT prolongation, and when co-administering with drugs that may cause QT prolongation.

Neuroleptic Malignant Syndrome

Neuroleptic Malignant Syndrome (NMS), characterized by hyperthermia, muscle rigidity, autonomic instability, altered consciousness, and elevated serum creatine phosphokinase, has been reported with antipsychotics, including paliperidone. Myoglobinuria (rhabdomyolysis) and acute renal failure may also occur. If symptoms suggestive of NMS appear, all antipsychotics, including Xeplion, should be discontinued.

Tardive Dyskinesia

The use of drugs with dopamine receptor antagonist properties is associated with the development of tardive dyskinesia, characterized by rhythmic, involuntary movements, primarily of the tongue and/or facial muscles. If symptoms of tardive dyskinesia appear, discontinuation of all antipsychotics, including Xeplion, should be considered.

Hypersensitivity reactions

Although the tolerability of oral forms of paliperidone or risperidone should be checked prior to initiating therapy with Xeplion, very rare cases of anaphylactic reactions have been reported during post-marketing use in patients who previously tolerated oral forms of paliperidone or risperidone.

In case of hypersensitivity reactions, Xeplion should be discontinued, necessary supportive clinical measures should be taken, and the patient should be monitored until symptoms resolve.

Hyperglycemia and diabetes mellitus

Hyperglycemia, diabetes mellitus, and exacerbation of pre-existing diabetes have been observed during treatment with Xeplion. Establishing a causal relationship between the use of atypical antipsychotics and glucose metabolism disturbances is complicated by the increased risk of diabetes in patients with schizophrenia and schizoaffective disorder and the prevalence of diabetes in the general population. Given these factors, the relationship between the use of atypical antipsychotics and the development of hyperglycemia-related adverse effects is not fully established. All patients should be clinically monitored for symptoms of hyperglycemia and diabetes mellitus (see section “Adverse Reactions”).

Weight gain

Significant weight gain has been observed during treatment with atypical antipsychotics. Patient weight should be monitored.

Hyperprolactinemia

Tissue culture studies indicate that human breast tumor growth may be prolactin-dependent. Although clinical and epidemiological studies have not yet demonstrated a direct association with antipsychotic use, caution should be exercised when using paliperidone in patients with possible prolactin-dependent tumors.

Orthostatic hypotension

Due to its alpha-adrenergic blocking activity, Paliperidone may cause orthostatic hypotension in some patients. Xeplion should be used with caution in patients with cardiovascular disease (e.g., heart failure, myocardial infarction or ischemia, conduction disturbances), cerebrovascular disease, or conditions predisposing to hypotension (e.g., dehydration, hypovolemia, use of antihypertensive drugs).

Seizures

As with other antipsychotics, 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. Dose adjustment is recommended in patients with mild renal impairment. Xeplion is not recommended for use in patients with moderate or severe renal impairment (CrCl <50 mL/min).

Hepatic impairment

The use of Xeplion in patients with severe hepatic impairment (Child-Pugh class C) has not been studied. Caution should be exercised when using paliperidone in such patients.

Elderly patients with dementia

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

The use of Xeplion in elderly patients with dementia has not been studied. Since Paliperidone is an active metabolite of risperidone, the experience with risperidone should be considered. Among elderly dementia patients 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 pathophysiological mechanisms explaining this observation have been established. Nevertheless, special caution should be exercised when prescribing the drug in such cases. No increased mortality was found in patients taking other diuretics concomitantly with risperidone. Regardless of treatment, dehydration is a common risk factor for mortality and should be carefully monitored in elderly patients with dementia.

Cerebrovascular events

According to placebo-controlled studies, the incidence of cerebrovascular events (transient ischemic attacks and stroke), including fatal events, was approximately 3 times higher in elderly patients with dementia treated with some atypical antipsychotics, including risperidone, aripiprazole, and olanzapine, compared with placebo. The mechanism of this phenomenon is unknown.

Leukopenia, neutropenia, agranulocytosis

Leukopenia, neutropenia, and agranulocytosis have been reported with antipsychotic agents, including with the use of Xeplion. Agranulocytosis has been reported very rarely during post-marketing surveillance. Patients with a history of clinically significant decrease in white blood cell count or drug-induced leukopenia/neutropenia are recommended to have a complete blood count during the first few months of therapy; discontinuation of Xeplion should be considered at the first clinically significant decrease in white blood cell count in the absence of other possible causes. Patients with clinically significant neutropenia should be monitored for fever or other symptoms of infection and treatment should be initiated immediately if such symptoms occur. Patients with severe neutropenia (absolute neutrophil count less than 1×10⁹/L) should discontinue Xeplion until the white blood cell count normalizes.

Venous thromboembolism

Cases of venous thromboembolism have been reported with antipsychotic drugs. Since patients taking antipsychotic drugs often have a risk of 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 Lewy bodies

The physician should weigh the risks and benefits of using antipsychotics, including Xeplion, in patients with Parkinson’s disease or Dementia with Lewy bodies, as both categories of patients may have an increased risk of Neuroleptic Malignant Syndrome (NMS) and increased sensitivity to antipsychotics. Manifestations of increased sensitivity may include confusion, obtundation, postural instability with frequent falls, and extrapyramidal symptoms.

Priapism

Drugs with alpha-adrenergic blocking properties have been reported to cause priapism. Priapism has been reported during post-marketing surveillance of paliperidone. The patient should seek medical attention if symptoms of priapism do not resolve within 3-4 hours.

Effect on body temperature regulation

Antipsychotics have been associated with impaired body temperature reduction. Caution is recommended when prescribing Xeplion to patients who may be exposed to conditions that increase body temperature, such as strenuous physical exertion, high ambient temperature, exposure to drugs with anticholinergic activity, and dehydration.

Antiemetic effect

Preclinical studies of paliperidone have revealed an antiemetic effect. The appearance of this effect in a patient may mask signs and symptoms of overdose of certain drugs or conditions such as intestinal obstruction, Reye’s syndrome, or brain tumor.

Administration

During intramuscular injection, caution should be exercised to avoid accidental intravascular injection.

Intraoperative Floppy Iris Syndrome (IFIS)

IFIS has been observed during cataract surgery in patients receiving therapy with drugs that are α₁-adrenergic antagonists, such as Xeplion.

IFIS increases the risk of eye-related complications during and after surgery. The operating surgeon should be informed in advance that the patient is or has been taking drugs with α₁-adrenergic antagonist activity. The potential benefit of discontinuing α₁-adrenergic antagonist therapy prior to surgery has not been established and should be weighed against the risks associated with discontinuing antipsychotic therapy.

Effect on ability to drive and operate machinery

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

Overdose

Since Xeplion is intended for administration by healthcare professionals, the likelihood of patient overdose is low.

Symptoms

In general, the expected signs and symptoms correspond to an exaggeration of the known pharmacological effects of paliperidone, i.e., drowsiness, sedation, tachycardia, hypotension, QT prolongation, extrapyramidal symptoms. Polymorphic ventricular tachycardia (torsades de pointes) and ventricular fibrillation have been reported with overdose of oral paliperidone. In cases of acute overdose, the possibility of the patient having taken multiple drugs should be considered.

Treatment

The prolonged release of the active substance and the long half-life of paliperidone should be considered when assessing the need for treatment and patient recovery. There is no specific antidote for paliperidone. General supportive measures should be implemented, ensuring and maintaining a patent airway, adequate ventilation, and oxygenation. Cardiovascular function should be monitored immediately, including continuous ECG monitoring to detect possible arrhythmias. In case of hypotension and circulatory collapse, appropriate measures should be taken, such as intravenous administration of fluids and/or sympathomimetics. Anticholinergic drugs should be used if severe extrapyramidal symptoms develop. The patient should be carefully monitored until recovery.

Drug Interactions

Like other antipsychotics, Paliperidone may prolong the QT interval, so it should be used with caution in combination with other drugs that prolong the QT interval, such as antiarrhythmic drugs (including quinidine, disopyramide, procainamide, amiodarone, sotalol), antihistamines, antipsychotics (chlorpromazine, thioridazine); antibiotics (including gatifloxacin, moxifloxacin), some antimalarial drugs (including mefloquine).

Since paliperidone palmitate is hydrolyzed to paliperidone, the results of oral paliperidone studies should be considered when assessing the potential for drug interactions.

Effect of Xeplion on other drugs

Paliperidone is not expected to exhibit clinically significant pharmacokinetic interactions with drugs metabolized by cytochrome P450 isoenzymes. In vitro studies using human liver microsomes showed that Paliperidone does not significantly inhibit the metabolism of substrates by CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and CYP3A5 isoenzymes. Therefore, Paliperidone is not expected to clinically significantly reduce the clearance of drugs metabolized by these isoenzymes. Paliperidone is also not expected to exhibit inducing properties on these isoenzymes, as in vitro studies showed that Paliperidone did not induce the activity of CYPA2, CYPC19, or CYP3A4 isoenzymes.

Paliperidone at 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 is unknown.

Given the effect of paliperidone on the CNS, Xeplion should be used with caution in combination with other centrally acting drugs and alcohol. Paliperidone may antagonize the effects of levodopa and dopamine agonists.

Due to the ability of Xeplion to cause orthostatic hypotension, an additive enhancement of this effect may be observed when Xeplion is used concomitantly with other drugs having this potential.

Paliperidone should be used with caution in combination with drugs that lower the seizure threshold, such as phenothiazines, butyrophenones, tricyclic derivatives, selective serotonin reuptake inhibitors, tramadol, mefloquine, etc.

Concomitant administration of oral paliperidone 12 mg once daily and divalproex sodium extended-release tablets (at a dose of 500-2000 mg once daily) did not affect the pharmacokinetics of valproate.

A pharmacokinetic interaction between Xeplion and lithium is unlikely.

Effect of other drugs on Xeplion

Paliperidone is not a substrate for CYP1A2, CYP2A6, CYP2C9, CYP2C19, or CYP3A5 isoenzymes. This suggests a low likelihood of interaction with inhibitors and inducers of these isoenzymes. Although in vitro studies suggest minimal involvement of CYP2D6 and CYP3A4 in the metabolism of paliperidone, there are currently no data indicating that these enzymes play a significant role in the metabolism of paliperidone in vitro or in vivo. In vitro data indicate that Paliperidone is a substrate of P-glycoprotein.

Paliperidone is metabolized to a limited extent by the CYP2D6 isoenzyme. In a drug interaction study of oral paliperidone with the potent CYP2D6 inhibitor paroxetine in healthy volunteers, no clinically significant change in the pharmacokinetics of paliperidone was found.

Concomitant administration of oral extended-release paliperidone (once daily) with carbamazepine (200 mg twice daily) resulted in an approximately 37% decrease in the mean C_max and AUC of paliperidone. This decrease is largely due to a 35% increase in the renal clearance of paliperidone, likely due to induction of renal P-glycoprotein by carbamazepine. The very small decrease in the amount of drug excreted unchanged in the urine suggests that carbamazepine has only a weak effect on the hepatic metabolism or bioavailability of paliperidone. When initiating carbamazepine, the dose of Xeplion should be re-evaluated and, if necessary, increased. Conversely, upon discontinuation of carbamazepine, the dose of Xeplion should be re-evaluated and, if necessary, decreased.

Paliperidone is a cation at physiological pH and is primarily excreted unchanged by the kidneys – half by filtration and half by active secretion. Concomitant use of trimethoprim, which inhibits the renal cationic active transport system, did not affect the pharmacokinetics of paliperidone.

Concomitant administration of oral extended-release paliperidone 12 mg once daily and divalproex sodium extended-release tablets (2 tablets of 500 mg once daily) resulted in a 50% increase in C_max and AUC of paliperidone, likely due to increased oral absorption of the drug. Since no significant effect on total clearance was observed, no clinically significant interaction is expected between divalproex sodium extended-release tablets and Xeplion. A dose reduction of Xeplion should be considered when co-administered with valproate based on clinical assessment of the patient. No interaction studies with Xeplion have been conducted.

A pharmacokinetic interaction between lithium and paliperidone is unlikely.

Concomitant use of Xeplion with risperidone or oral paliperidone

Since Paliperidone is an active metabolite of risperidone, caution should be exercised during long-term concomitant use of Xeplion and risperidone or oral paliperidone. Data on the safety of concomitant use of Xeplion and other antipsychotics are limited.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 30°C (86°F).

Shelf Life

The shelf life is 2 years. Do not use after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.