Xeplion, 150 mg/1.5 ml 1.5 ml

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

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

Pharmacokinetics

Absorption and distribution

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

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

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

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

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

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

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

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

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

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

Particular categories of patients

Hepatic impairment.

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

Kidney dysfunction.

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

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

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

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

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

Indications

treatment of schizophrenia;
prevention of relapse of schizophrenia.

Pharmacological effect

Antipsychotic drug (neuroleptic). Paliperidone palmitate is hydrolyzed to paliperidone. The latter is a centrally acting active antagonist of predominantly serotonin 5-HT2A receptors, as well as dopamine D2 receptors, adrenergic β1 and β2 receptors and H1 histamine receptors. Paliperidone does not bind to cholinergic m receptors or adrenergic α1 and β2 receptors. The pharmacological activity of the (+) and (-) enantiomers of paliperidone is quantitatively and qualitatively the same.

It is assumed that the therapeutic effectiveness of the drug in schizophrenia is due to the combined blockade of D2 and 5-HT2A receptors.

Pharmacokinetics

Suction and distribution

Due to the exceptionally low water solubility of paliperidone, palmitate dissolves slowly after intramuscular administration and is absorbed into the systemic circulation. After a single intramuscular injection, the concentration of paliperidone in the blood plasma slowly increases, reaching a maximum 13-14 days (median) after injection into the deltoid muscle and 13-17 days after injection into the gluteal muscle. The release of the substance is detected already on the 1st day and persists for at least 126 days. The release characteristics of the active component and the dosage regimen of Xeplion ensure long-term maintenance of therapeutic concentrations.

After a single dose of 25 – 150 mg into the deltoid muscle, the maximum concentration (Cmax) is on average 28% higher than after injection into the gluteal muscle. At the beginning of therapy, administration of the drug into the deltoid muscle helps to achieve therapeutic concentrations of paliperidone faster (150 mg on day 1 and 100 mg on day 8) than administration into the gluteal muscle. After multiple injections, the difference in effect is less obvious.

The average ratio of the maximum and equilibrium concentrations of paliperidone after administration of 4 injections of the drug Xeplion at a dose of 100 mg into the gluteal muscle was 1.8, and after injection into the deltoid muscle – 2.2. At paliperidone doses of 25-150 mg, the area under the concentration-time curve (AUC) of paliperidone varied dose proportionally, and Cmax at doses greater than 50 mg increased less than dose proportionally.

The median half-life 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-based analysis, the apparent volume of distribution of paliperidone was 391 L; paliperidone binds to plasma proteins by 74%.

Metabolism and excretion
Within a week after a single oral dose of 1 mg of 14C-paliperidone with immediate release of the active component in the urine, 59% of the administered dose is excreted unchanged; this indicates that there is no significant metabolism of the drug in the liver. Approximately 80% of the administered radioactivity was detected in urine and 11% in feces. There are 4 known pathways of drug metabolism in vivo, but none of them determines the metabolism of more than 6.5% of the administered dose: dealkylation, hydroxylation, dehydrogenation, elimination of the benzisoxazole group.

Although in vitro studies suggest a role for CYP2D6 and CYP3A4 in the metabolism of paliperidone, there is no evidence of a significant role for these isoenzymes in the metabolism of paliperidone in vivo. Population pharmacokinetic analysis did not reveal a significant difference in the clearance of paliperidone after oral administration of the drug in subjects with strong and poor metabolizers of CYP2D6. In vitro studies using human liver microsomes have shown that paliperidone does not significantly inhibit drug metabolism by CYP1A2, CYP2A6, CYP2D6, CYP2E1, CYP3A4 and CYP3A5.

In in vitro studies, paliperidone was a P-gp substrate and, at high concentrations, a weak P-gp inhibitor. There are no corresponding in vivo data, and the clinical significance of these data is unclear.

In general, the concentration of paliperidone in the blood plasma during the exercise period after intramuscular administration of the drug Xeplion was in the same range as after taking prolonged-release paliperidone orally with the release of the active component in doses between 6 and 12 mg. The paliperidone loading scheme used ensures that the concentration is maintained in this range even at the end of the interdose interval (8th and 36th day). Individual differences in the pharmacokinetics of paliperidone after administration of Xeplion in different patients were less than after oral administration of extended-release paliperidone. Due to the different patterns of change in median plasma concentrations of paliperidone between the two drugs, caution should be exercised when directly comparing their pharmacokinetics.

Special categories of patients

Liver dysfunction.

Paliperidone does not undergo significant metabolism 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 for such 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 has not been studied in patients with severe hepatic impairment.

Renal dysfunction.

For patients with mild renal impairment, the dose of paliperidone should be reduced; Xeplion is not recommended for use in patients with moderate to severe renal impairment. The distribution of paliperidone was studied after a single oral dose of paliperidone extended-release 3 mg tablet in patients with varying degrees of renal impairment. With a decrease in creatinine clearance (CC), the excretion of paliperidone was weakened: in cases of mild renal dysfunction (CR 50-80 ml/min) – by 32%, in moderate severity (CR 30-50 ml/min) – by 64%, in severe cases (CR 10-30 ml/min) – by 71%, as a result of which AUC0 increased compared to healthy volunteers by 1.5, 2.6 and 4.8 times, respectively. Based on the small amount of data on the use of Xeplion in patients with mild renal impairment and on the results of pharmacokinetic modeling, the recommended loading dose of paliperidone for such patients is 75 mg on days 1 and 8; after this, 50 mg is administered monthly (every 4 weeks).

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

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

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

The effect of smoking on the pharmacokinetics of the drug.
Based on in vitro studies using human liver microsomes, paliperidone is not a CYP1A2 substrate and smoking should not affect the pharmacokinetics of paliperidone. Consistent with these in vitro data, population pharmacokinetic analysis did not reveal differences in the pharmacokinetics of paliperidone between smokers and non-smokers.

Special instructions

ZNS

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

Tardive dyskinesia

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

Hyperglycemia and diabetes mellitus

Hyperglycemia, diabetes mellitus, and exacerbation of existing diabetes mellitus were observed during treatment with Xeplion. Identifying the relationship between the use of atypical antipsychotic drugs and impaired glucose metabolism is complicated by the increased risk of developing diabetes mellitus in patients with schizophrenia and the prevalence of diabetes mellitus in the general population. Given these factors, the relationship between the use of atypical antipsychotic drugs and the development of side effects associated with hyperglycemia is not fully established. All patients should be clinically monitored for symptoms of hyperglycemia and diabetes mellitus.

Weight gain

Significant weight gain was observed during treatment with atypical antipsychotics. It is necessary to monitor patients’ body weight.

Elderly patients with dementia

A cross-sectional analysis of study results showed an increased mortality in elderly patients with dementia receiving atypical antipsychotics, incl. risperidone, aripiprazole, olanzapine and quetiapine, compared with placebo. Among patients receiving risperidone and placebo, mortality was 4% and 3.1%, respectively.

The use of Xeplion in elderly patients with dementia has not been studied. Because paliperidone is an active metabolite of risperidone, experience with risperidone should be considered. For elderly patients with dementia taking risperidone, increased mortality was observed in patients taking furosemide and risperidone compared with the risperidone-only group and the furosemide-only group. No pathophysiological mechanisms have been established to explain this observation. However, special care should be taken when prescribing the drug in such cases. There was no increase in mortality 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 older patients with dementia.

Cerebrovascular disorders

Placebo-controlled studies found an increased incidence of cerebrovascular accidents (transient and stroke), incl. with a fatal outcome in elderly patients with dementia who received some atypical antipsychotics, incl. risperidone, aripiprazole and olanzapine compared with placebo.

Leukopenia, neutropepia, agranulocytosis

Leukopenia, neutropenia and agranulocytosis were observed with the use of antipsychotics, incl. when using the drug Xeplion. Agranulocytosis has been observed very rarely during post-marketing surveillance. In patients with a history of a clinically significant decrease in white blood cell count or drug-related leukopenia/neutropenia, a full blood count is recommended during the first months of therapy, and discontinuation of Xeplion treatment should be considered at the first clinically significant decrease in the white blood cell count in the absence of other possible causes. Patients with clinically significant neutropenia are advised to be monitored for fever or symptoms of infection, for which treatment should be initiated immediately. Patients with severe neutropenia (absolute neutrophil count less than 1 x 109/L) should stop using Xeplion until the white blood cell count normalizes.

Venous thromboembolism

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

Parkinson’s disease and dementia with corpuscles

The physician must weigh the risks and benefits of using antipsychotics, including Xeplion, in patients with Parkinson’s disease or dementia with Lewy bodies, because These categories of patients may have an increased risk of developing NMS and the risk of increased sensitivity to antipsychotics. Manifestations of hypersensitivity may include confusion, dullness of pain sensitivity, postural instability with frequent falls, and extrapyramidal symptoms.

Priapism

There is evidence of the ability of drugs with alpha-blocker properties to cause priapism. Priapism has been reported during post-marketing surveillance of paliperidone.

Antiemetic effect

Paliperidone has been shown to have antiemetic effects in preclinical studies. The appearance of this effect in a patient may mask signs and symptoms of overdose of some drugs or, for example, conditions such as intestinal obstruction, Reye’s syndrome, or a brain tumor.

Introduction

When administered intramuscularly, care should be taken to avoid accidental entry of the drug into a blood vessel.

Impact on the ability to drive vehicles and operate machinery

Xeplion may interfere with activities requiring concentration and psychomotor speed, and may affect vision. Therefore, patients should be advised not to drive vehicles or moving machinery until their individual sensitivity has been established.

Active ingredient

Paliperidone

Composition

1 ml
paliperidone palmitate
156 mg,
which corresponds to the content of paliperidone
100 mg

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 d/i – up to 1 ml.

Pregnancy

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

Xeplion can 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 took antipsychotic drugs (including paliperidone) in the third trimester of pregnancy, the newborns are at risk of extrapyramidal disorders and/or withdrawal syndrome of varying severity. These symptoms may include agitation, hypertension, hypotonia, tremor, somnolence, respiratory distress, and feeding problems.

In studies of paliperidone in animals and risperidone in humans, paliperidone was found to be excreted in breast milk. Therefore, during treatment with Xeplion, breastfeeding should be stopped.

Use in children

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

Contraindications

hypersensitivity to the components of the drug;
hypersensitivity to risperidone (since paliperidone is an active metabolite of risperidone).

With caution

Xeplion has alpha-adrenergic blocking activity and may cause orthostatic hypotension in some patients, so caution is required when used in patients with cardiovascular diseases (for example, heart failure, myocardial infarction or ischemia, cardiac conduction disorders), cerebrovascular accidents, or conditions predisposing to a decrease in blood pressure (for example, dehydration, decreased blood volume, use of antihypertensive drugs).

Like other antipsychotics, Xeplion should be used with caution in patients with a history of seizures or other conditions that may reduce the seizure threshold.

The use of antipsychotics is associated with a deterioration in the body’s ability to reduce body temperature, so caution is required when using the drug in patients who may be exposed to influences that increase body temperature, for example, intense physical activity, high ambient temperatures, exposure to drugs with m-anticholinergic activity, and dehydration.

As with the use of other antipsychotics, caution is required when prescribing Xeplion to patients with a history of arrhythmia or congenital prolongation of the QT interval, or taking drugs that prolong the QT interval.

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

Paliperidone may reduce the effect of levodopa and dopamine agonists.

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

Side Effects

Most adverse reactions were mild or moderate in severity.

Determination of the frequency of adverse reactions: very often (≥10%), often (≥1% and <10%), infrequently (≥0.1% and

Infections: often – upper respiratory tract infections; uncommon – acarodermatitis, bronchitis, inflammation of subcutaneous fat, ear infections, eye infections, influenza, onychomycosis, pneumonia, respiratory tract infections, sinusitis, subcutaneous abscess, tonsillitis, urinary tract infections.

From the immune system: rarely – hypersensitivity.

From the hematopoietic system: infrequently – neutropenia, decrease in the number of leukocytes; rarely – thrombocytopenia; very rarely – agranulocytosis.

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

Metabolism: often – weight gain; uncommon – anorexia, hyperglycemia, decreased appetite, increased appetite, weight loss, polydipsia, diabetes mellitus; rarely – hypoglycemia; very rarely – diabetic ketoacidosis, water intoxication.

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

From the nervous system: very often – headache; often – akathisia, dizziness, extrapyramidal symptoms, drowsiness, parkinsonism (including akinesia, bradykinesia, cogwheel rigidity, drooling, extrapyramidal symptoms, deviation of the globeral reflex, muscle rigidity, muscle stiffness, musculoskeletal immobility); uncommon – impaired coordination, cerebrovascular disorders, convulsions (including epileptic convulsions), distraction, postural dizziness, dysarthria, dyskinesia (including athetosis, chorea, movement disorders, muscle contractions, clonic convulsions), dystonia (including blepharospasm, neck spasm, emprostotonus, facial spasm, hypertension, laryngospasm, involuntary muscle contractions, myotonia, eye movements, opisthotonus, oropharyngeal spasm, pleurototonus, sardonic smile, tetany, tongue paralysis, tongue spasm, torticollis, convulsive clenching of the jaw), hypoesthesia, paresthesia, psychomotor hyperactivity, syncope, severe dyskinesia, tremor

On the part of the organ of vision: infrequently – dry eyes, increased lacrimation, ocular hyperemia, involuntary movement of the eyeball, blurred visual perception.

On the part of the organ of hearing and balance: infrequently – vertigo, ear pain.

From the cardiovascular system: often – increased blood pressure; uncommon – AV block, bradycardia, conduction disturbances, ECG abnormalities, increased QT interval on ECG, palpitations, postural orthostatic tachycardia syndrome, sinus arrhythmia, tachycardia, atrial fibrillation, orthostatic hypotension; rarely – deep vein thrombosis; very rarely – pulmonary embolism.

From the respiratory system: infrequently – cough, dyspnea, nosebleeds, nasal congestion, pain in the pharyngo-laryngeal region, respiratory tract congestion, wheezing, pulmonary congestion; very rarely – sleep apnea syndrome.

From the digestive system: often – pain in the upper abdomen, constipation, diarrhea, dry oral mucosa, nausea, toothache, vomiting, discomfort in the abdominal area; infrequently – dyspepsia, dysphagia, fecal incontinence, flatulence, gastroenteritis, swelling of the tongue, dysgeusia; rarely – pancreatitis; very rarely – jaundice.

From the musculoskeletal system: often – pain in the limbs, musculoskeletal pain; uncommon – arthralgia, back pain, joint stiffness, joint swelling, muscle spasms, neck pain.

On the skin side: uncommon – acne, dry skin, eczema, erythema, hyperkeratosis, itching, suppuration, alopecia.

Allergic reactions: infrequently – urticaria; rarely – angioedema.

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

From the reproductive system: infrequently – amenorrhea, galactorrhea, gynecomastia, sexual dysfunction, ejaculation disorders, erectile dysfunction, vaginal discharge; very rarely – priapism.

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

From laboratory parameters: infrequently – increased GGT activity, increased activity of liver enzymes, increased transaminase activity, increased cholesterol concentration in the blood, increased TG concentration in the blood, hyperglycemia.

Other: often – asthenic disorders, weakness, local reactions (pain, itching, hardness at the injection site); uncommon – discomfort in the chest, chills, facial swelling, gait disturbance, hardening at the injection site, swelling (including generalized edema, peripheral edema, mild edema), thirst, increased body temperature; rarely – hypothermia, abscess at the injection site, inflammation of the subcutaneous tissue at the injection site, hematoma at the injection site; very rare cyst at the injection site, necrosis at the injection site, ulcer at the injection site.

Interaction

Paliperidone may increase the QT interval, so it should be combined with caution with other drugs that increase the QT interval (antiarrhythmic drugs, including quinidine, procainamide, amiodarone, sotalol; antipsychotic drugs (chlorpromazine, thioridazine); antibiotics, including gatifloxacin, moxifloxacin.
Because Paliperidone palmitate is hydrolyzed to paliperidone, the results of studies with oral paliperidone should be taken into account when assessing the possibility of drug interactions.

The ability of the drug Xeplion to affect 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 have shown that paliperidone does not significantly reduce the metabolism of substances by isoenzymes CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4 and CYP3A5. Therefore, paliperidone is not expected to clinically significantly reduce the clearance of drugs metabolized by these isoenzymes. It is also not expected that paliperidone will exhibit the properties of an isoenzyme inducer, because in in vitro studies, paliperidone did not induce the activity of CYPA2, CYPC19 or CYP3A4 isoenzymes. Paliperidone in high concentrations is a weak inhibitor of P-glycoprotein. However, there are no in vivo data in this regard, and the clinical significance of this phenomenon is unknown.

Given the effect of paliperidone on the central nervous system, Xeplion should be used with caution in combination with other centrally acting drugs and alcohol. Paliperidone may reduce the effect of levodopa and dopamine receptor agonists. Due to the ability of Xeplion to cause orthostatic hypotension, an additive increase in this effect may be observed when Xeplion is used in combination with other drugs that have this ability.

The ability of other drugs to affect Xeplion

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

Paliperidone is metabolized to a limited extent by the CYP2D6 isoenzyme. An interaction study of oral paliperidone with the active CYP2D6 inhibitor paroxetine in healthy volunteers did not detect a clinically significant change in the pharmacokinetics of paliperidone.

Taking extended-release paliperidone (once daily) orally concomitantly with carbamazepine (200 mg twice daily) resulted in a decrease in mean paliperidone Cmax and AUC by approximately 37%. This reduction is largely due to a 35% increase in renal clearance of paliperidone, likely due to activation of renal P-glycoprotein by carbamazepine. The very small decrease in the amount of drug excreted unchanged through the kidneys suggests that carbamazepine has only a minor effect on hepatic metabolism or bioavailability of paliperidone. When starting to use carbamazepine, the dose of Xeplion should be reviewed and, if necessary, increased.

On the contrary, when carbamazepine is discontinued, the dose of Xeplion should be reconsidered and, if necessary, reduced. Paliperidone is a cation at physiological pH and is primarily excreted unchanged through the kidneys—half by filtration and half by active secretion. Concomitant use of trimethoprim, which inhibits the active cation transport system in the kidneys, did not affect the pharmacokinetics of paliperidone.

Use of the drug Xeplion together with risperidone

The use of Xeplion in combination with risperidone has not been studied. Since paliperidone is an active metabolite of risperidone, an increase in the concentration of paliperidone in the blood plasma should be taken into account when using the drug Xeplion and risperidone simultaneously.

Overdose

Since Xeplion is intended for administration by health care workers, the likelihood of an overdose by patients is low.

Symptoms: In general, the expected signs and symptoms are consistent with an enhancement of the known pharmacological action of paliperidone, i.e. drowsiness, lethargy, tachycardia, decreased blood pressure, prolongation of the QT interval, extrapyramidal symptoms. In cases of acute overdose, the possibility of patients receiving multiple drugs should be considered.

Torsade de pointes and ventricular fibrillation have been reported with overdose of oral palineridone. In cases of acute overdose, the possibility of patients receiving multiple drugs should be considered.

Treatment: when assessing the need for treatment and recovery of patients, the prolonged release of the active substance and the large T1/2 of paliperidone should be taken into account. There is no specific antidote for paliperidone. General supportive measures should be implemented to ensure and maintain a patent airway, adequate ventilation of the lungs and oxygen saturation of the blood. Monitoring of cardiovascular function should be started immediately, including continuous ECG monitoring to detect possible arrhythmias. In the event of a decrease in blood pressure and vascular collapse, appropriate measures should be taken, for example, intravenous administration of solutions and/or sympathomimetics. If severe extrapyramidal symptoms develop, anticholinergic drugs are used. The patient’s condition should be carefully monitored until recovery.

Storage conditions

At a temperature not exceeding 30 °C

Shelf life

2 years

Manufacturer

Janssen Pharmaceuticals N.V., Belgium