Xeplion suspension of prolonged action 100mg/ml syringe, 1pc

Composition

Auxiliary substances:

polysorbate 20-12 mg,

macrogol 4000 (polyethylene glycol 4000) – 30 mg,

citric acid monohydrate-5 mg,

sodium hydrophosphate-5 mg,

sodium dihydrogen phosphate monohydrate-2.5 mg,

sodium hydroxide-2.84 mg,

water for injection-up to 1 ml

Pharmacological action

An antipsychotic drug (neuroleptic). Paliperidone palmitate is hydrolyzed to paliperidone. The latter is a centrally active antagonist of mainly serotonin 5-HT2A_receptors, as well_{as dopamine D2}receptors, adrenergic ?₁-and ?₂-receptors and H1-histamine receptors. Paliperidone does not bind to cholinergic m-receptors and to adrenergic ones ?₁-and ?₂-receptors. The pharmacological activity of the ( + ) and ( – ) enantiomers of paliperidone is quantitatively and qualitatively the same.

It is assumed that the therapeutic efficacy of the drug in schizophrenia is due to the combined blockade_{of D2} and 5-HT2A_receptors.

Pharmacokinetics

Absorption and distribution Due to the exceptionally low water solubility of paliperidone, palmitate slowly dissolves after intramuscular use 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 in 13-14 days (median) after use to the deltoid muscle and 13-17 days after use to the gluteal muscle. The release of the substance is detected as early as day 1 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 the therapeutic concentration.

After a single dose of 25-150 mg administered to the deltoid muscle, the maximum concentration (cmax) is on average 28% higher than after use to the gluteal muscle. At the beginning of therapy, use of the drug to the deltoid muscle helps to reach the therapeutic concentration of paliperidone faster (150 mg on day 1 and 100 mg on day 8) than use to the gluteal muscle. After multiple injections, the time difference is less obvious.

The average ratio of the maximum and the equilibrium concentrations of paliperidone after use of 4 injections of the drug Xalion at a dose of 100 mg in the gluteus muscle was equal to 1.8, and after injection in the deltoid muscle and 2.2. At doses of paliperidone 25-150 mg, the area under the curve “concentration-time” (AUC) of paliperidone was changed in proportion to dose, and_max at doses of 50 mg increased less than proportionally to the dose.

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

After use 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 of paliperidone was 391 liters; paliperidone binds to plasma proteins by 74%.

Metabolism and excretion A 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 that there is 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. There are 4 known ways of drug metabolism in vivo, but none of them causes the metabolism of more than 6.5% of the administered dose: dealkylation, hydroxylation, dehydrogenation, cleavage of the benzisoxazole group.

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

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

In general, the concentration of paliperidone in blood plasma during the exercise period after intramuscular use of Xeplion was in the same range as after taking paliperidone prolonged-acting 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 inter-dose interval (day 8 and day 36). Individual differences in the pharmacokinetics of paliperidone after use of Xeplion in different patients were less than after oral use of prolonged-acting paliperidone. Due to the difference in the nature of changes in the median concentration of paliperidone in blood plasma with the use of two drugs, caution should be exercised when comparing their pharmacokinetics directly.

Special categories of patients with impaired liver function. 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 for such hepatic impairment. In a study using paliperidone orally in patients with moderate hepatic impairment (Child-Pugh class B), the concentration of free paliperidone in blood plasma was the same as in healthy volunteers. Paliperidone has not been studied in patients with severe hepatic impairment.

Impaired renal function. 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 after a single oral use of a 3 mg long-acting paliperidone tablet in patients with varying degrees of renal dysfunction was studied. With a decrease in creatinine clearance (creatinine clearance), paliperidone excretion decreased: in mild renal impairment (creatinine clearance 50-80 ml/min) – by 32%, in moderate renal impairment (creatinine clearance 30-50 ml/min) – by 64%, in severe renal impairment (creatinine clearance 10-30 ml / min)-by 71%, resulting in AUC0 -? it increased in comparison with 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 from the results of pharmacokinetic modeling, the recommended loading dose of paliperidone for such patients is 75 mg on the 1st and 8th days; after that,50 mg is administered monthly (every 4 weeks).

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

Race. Population pharmacokinetic analysis of the results of the oral paliperidone study did not reveal differences in the pharmacokinetics of paliperidone after taking the drug in people of different races.

Gender. There were no clinically significant differences in the pharmacokinetics of paliperidone in men and women.

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

Indications

• treatment of schizophrenia;
• prevention of relapses of schizophrenia.

Use during pregnancy and lactation

The safety of using Xeplion IV or paliperidone orally during pregnancy in humans has not been established. When paliperidone was administered orally in high doses, there was a slight increase in fetal mortality in animals. Xeplion, when administered intravenously, did not affect the course of pregnancy in rats, but high doses of it were toxic to pregnant females. Oral doses of paliperidone and intravenous use of Xeplion, which create concentrations that exceed the maximum therapeutic doses in humans by 20-22 times and 6 times, respectively, did not affect the offspring of laboratory animals.

Xeplion can only be used during pregnancy if the intended benefit to the mother exceeds the potential risk to the fetus. The effect of Xeplion on contractions and labor in humans is unknown.

If a woman has taken antipsychotic medications (including paliperidone) in the third trimester of pregnancy, there is a risk of extrapyramidal disorders and/or withdrawal symptoms of varying severity in newborns. These symptoms may include restlessness, hypertension, hypotension, tremor, drowsiness, respiratory problems, and feeding disorders.

Studies on the use of paliperidone in animals and risperidone in humans have found that paliperidone is excreted in breast milk.Therefore, breast-feeding should be discontinued during treatment with Xeplion.

Use in children

The safety and efficacy 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 the active metabolite of risperidone).

With caution

Xeplion has alpha-adrenoblocking activity and may cause orthostatic hypotension in some patients, so caution should be exercised when used in patients with cardiovascular diseases (for example, heart failure, myocardial infarction or ischemia, cardiac conduction disorders), cerebrovascular disorders or conditions predisposing to a decrease in blood pressure (for example, dehydration, BCC reduction, 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 cause a decrease in the seizure threshold.

The use of neuroleptics is associated with a deterioration in the body’s ability to reduce body temperature, so caution is needed when using the drug in patients who may be exposed to effects that increase body temperature, for example, heavy physical exertion, high ambient temperature, exposure to drugs with m-cholinolytic activity, as well as dehydration.

As with other antipsychotics, caution should be exercised when prescribing Xeplion to patients with a history of arrhythmia or congenital QT prolongation, or who are taking medications 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 weaken the effects 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 common (≥10%), common (≥1% and < 10%), infrequent (≥0.1% and

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

Immune system disorders: infrequently-hypersensitivity.

From the hematopoietic system: infrequently-neutropenia, a decrease in the number of white blood cells; rarely-thrombocytopenia; very rarely-agranulocytosis.

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

From the side of metabolism: often-weight gain; infrequently – 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 disorders, mania.

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

From the side of the visual organ: infrequently-dry eyes, increased lacrimation, ocular hyperemia, involuntary movement of the eyeball, blurred visual perception.

From the side of the organ of hearing and balance: infrequently-vertigo, ear pain.

From the cardiovascular system: often-increased blood pressure; infrequently-AV block, bradycardia, conduction disorders, ECG disorders, increased QT interval on the ECG, palpitation, 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, dyspnoea, nosebleeds, nasal congestion, pain in the pharyngopharyngeal region, airway congestion, wheezing, lung congestion; very rarely-sleep apnea syndrome.

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

From the musculoskeletal system: often-pain in the extremities, musculoskeletal pain; infrequently-arthralgia, back pain, joint stiffness, joint swelling, muscle spasms, neck pain.

Skin disorders: infrequently-acne, dry skin, eczema, erythema, hyperkeratosis, pruritus, rash, 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.

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

From the laboratory parameters: infrequently-increased GGT activity, increased liver enzyme activity, 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, compaction at the injection site); infrequently-chest discomfort, chills, facial edema, gait disorders, compaction at the injection site, edema (including generalized edema, peripheral edema, mild edema), thirst, elevated 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 can increase the Q-T interval, so it should be combined with caution with other drugs that increase the Q-T interval (antiarrhythmic drugs, including quinidine, procainamide, amiodarone, sotalol; antipsychotic drugs (chlorpromazine, thioridazine); antibiotics, including gatifloxacin, moxifloxacin. Since Paliperidone palmitate is hydrolyzed to paliperidone, the results of oral paliperidone studies should be taken into account when evaluating the possibility of drug interaction.

Ability of Xeplion to influence other drugs

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

Given the 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 weaken the effects of levodopa and dopamine receptor agonists. Due to the ability of Xeplion to cause orthostatic hypotension, an additive increase in this effect may occur when Xeplion is used together with other drugs that have this ability.

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 probability of interaction with inhibitors and inducers of these isoenzymes.Although in vitro studies show the possibility of minimal involvement of CYP2D6 and CYP3A4 in paliperidone metabolism, there is currently no evidence that these enzymes can play a significant role in paliperidone metabolism in vitro or in vivo. In vitro studies indicate that paliperidone is a P-glycoprotein substrate.

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

Taking paliperidone with a long-term release of the active component (1 time per day) orally simultaneously with carbamazepine (200 mg 2 times a day) resulted in a decrease in the average_cmax and AUC of paliperidone by approximately 37%. This decrease is largely due to a 35% increase in renal clearance of paliperidone, probably due to activation of renal P-glycoprotein by carbamazepine. A very small decrease in the amount of the drug excreted unchanged through the kidneys suggests that carbamazepine only weakly affects the liver-mediated metabolism or bioavailability of paliperidone. When starting the use of carbamazepine, the dose of Xeplion should be reviewed and, if necessary, increased. Conversely, when carbamazepine is discontinued, the dose of Xeplion should be reviewed and, if necessary, reduced. Paliperidone at physiological pH is a cation and is mainly 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 Xeplion in combination with risperidone

The use of Xeplion in combination with risperidone has not been studied. Since paliperidone is an active metabolite of risperidone, the concomitant use of Xeplion and risperidone should take into account an increase in the concentration of paliperidone in blood plasma.

How to take, course of use and dosage

In patients who have never taken paliperidone orally or risperidone orally or parenterally, it is recommended to check the tolerability of paliperidone or risperidone orally for 2-7 days before starting treatment with Xeplion.

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). In the future, a dose of 75 mg 1 time/month is recommended. The dose can be increased or decreased in the range of 25-150 mg depending on individual tolerability and / or efficacy. After the second dose, subsequent injections can be given to the deltoid or gluteal muscle.

The maintenance dose can be adjusted monthly. This should take into account the long-term release of the active component from paliperidone palmitate, since the effect of changing the dose may not fully manifest itself until several months later.

Skipping a dose

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

If the second injection of Xeplion was not made on time (1 week±2 days), it is recommended to resume treatment depending on the time that has passed since the first injection.

Skipping the second initial dose (less than 4 weeks). If less than 4 weeks have passed since the first injection, the patient should receive a second 100 mg injection into the deltoid muscle as soon as possible. The third 75 mg dose of Taxeplion should be given to the deltoid or gluteal muscle 5 weeks after the first injection (without taking into account the time of the second injection). In the future, follow a monthly course of injections at a dose of 25 mg to 150 mg in the deltoid or gluteal muscle, depending on individual tolerance and/or effectiveness.

Skipping the second initial dose (4 to 7 weeks). If 4 to 7 weeks have passed since the first injection of Xeplion, treatment is resumed with 2 injections at a dose of 100 mg according to the following scheme: the 1st injection into the deltoid muscle is made as soon as possible; after 1 week, a second injection is made into the deltoid muscle, then continue the monthly course of injections into the deltoid or gluteal muscle at a dose of 25 mg to 150 mg, depending on individual tolerability and/or effectiveness.

Skipping the second initial dose (more than 7 weeks). If more than 7 weeks have passed since the first injection of Xeplion, treatment is initiated in the same way as in the case of initiation of treatment with Xeplion.

Skipping the maintenance dose (1 month to 6 weeks). After starting treatment, it is recommended to inject Xeplion monthly. If less than 6 weeks have passed since the last injection, then the next dose should be administered as soon as possible, equal to the previous one. After that, enter the drug monthly.

Skipping the 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 whose condition is stable by the use of the drug in a dose of 25 mg to 100 mg:

1) an injection of the drug into the deltoid muscle as soon as possible to the dose of which was to stabilize the patient’s condition to pass injection;

2) make the following injection in the deltoid muscle (the same dose) doing in a week on the 8th day;

3) resume next monthly injections in the deltoid or gluteal muscle at a dose of 25 mg to 150 mg based on individual tolerability and/or efficacy.

For patients whose condition is stable by the use of the drug in a dose of 150 mg:

1) as soon as possible, injecting a dose of 100 mg in the deltoid muscle;

2) after 1 week, injected another dose of 100 mg (8-day) in the deltoid muscle;

3) resume next monthly injections in the deltoid or gluteal muscle at a dose of 25 mg to 150 mg based on individual tolerability and/or efficacy.

Skipping the maintenance dose (duration > 6 months). If more than 6 months have passed since the last injection of Xeplion, then treatment is started again, as described above to start treatment.

Translation from other antipsychotics

Data on the transfer of patients with schizophrenia from other neuroleptics to Xeplion or on its use simultaneously with other neuroleptics are not systematized. For patients who have never received oral paliperidone or oral or injectable risperidone, tolerability with oral paliperidone or oral risperidone should be investigated before starting treatment with Xeplion. At the beginning of treatment with Xeplion, previously used intravenous antipsychotics can be canceled. Patients receiving long-acting injectable antipsychotics should start treatment with Xeplion immediately with a maintenance dose at the time of the next scheduled injection. You should continue treatment with Xeplion 1 time a month. The initial dose in the first week of treatment is not required.

In patients whose condition was stabilized by various doses of Rispolept Consta®, a suspension for intravenous use of prolonged action, C_ss of the Active ingredient can reach similar values during maintenance therapy with Xeplion 1 time/month according to the following scheme:

Discontinuation of the previous antipsychotic should be carried out in accordance with the instructions for medical use. Long-term release of the active ingredient should be considered when discontinuing Xeplion. As with other antipsychotics, the need for continued use of extrapyramidal disorder prevention agents should be periodically evaluated.

Concomitant use of paliperidone palmitate and paliperidone orally or risperidone orally or parenterally has not been studied. Since paliperidone is the main active metabolite of risperidone, the possibility of an additive effect of paliperidone should be considered when using these drugs simultaneously with Xeplion.

Use in special patient groups

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

The use of Xeplion in patients with impaired renal function has not been systematically studied. In patients with mild renal impairment (creatinine clearance ≥ 50 to After that, after 1 month,50 mg is administered monthly to the deltoid or gluteal muscle, and then the dose is changed from 25 mg to 100 mg, depending on individual tolerability and/or effectiveness.Xeplion is not recommended for use in patients with moderate or severe renal impairment (CC).

For elderly patients with normal renal function, the same dose of Xeplion is recommended as for younger patients with normal renal function. In elderly patients, renal function may be reduced, and these patients are subject to the above recommendations for patients with impaired renal function.

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

No dose adjustment of Xeplion is required depending on the gender, race of patients and smoking.

Rules for the use of the drug

Xeplion is intended for intravenous use only. The drug is slowly injected deep into the muscle. Injections should only be performed by a healthcare professional. The entire dose is administered at one time; do not administer the dose in multiple injections. Do not inject the drug into blood vessels or subcutaneously. Avoid accidental contact with a blood vessel. To do this, before starting the drug use, the plunger of the syringe is pulled back to check for needle penetration into a large blood vessel. If blood enters the syringe, remove the needle and syringe from the muscle and dispose of them.

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

To inject Xeplion into the gluteal muscle, a long needle with a gray body from the kit is recommended. Injections should be made in the upper outer quadrant of the buttock. You should alternately inject the drug into the right and left gluteal muscles.

Introduction of the drug

The syringe is intended only for a single injection.

1. Shake the syringe vigorously for 10 seconds to obtain a homogeneous suspension.

2. Select the appropriate needle.

For insertion into the deltoid muscle, a short needle (with a blue body) is used for patients with a body weight of > 90 kg, and a long needle (with a gray body) is used for patients with a body weight of > 90 kg.

For insertion into the gluteal muscle, use a long needle (with a gray body).

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

4. Open the safety needle package halfway, take the needle cap through the package, and insert the syringe into the Luer needle cap by gently rotating it clockwise.

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

6. Point the syringe with the needle up and squeeze the air out of the syringe by pressing lightly on the plunger.

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

8. After the injection is completed, bring the needle guard to the working position with your thumb or index finger or by pressing the syringe against a hard surface. The needle guard should snap into place. The syringe and needle should be destroyed in accordance with the requirements.

Overdose

Since Xeplion is intended to be administered by health workers, the probability of its overdose by patients is low.

Symptoms: In general, the expected signs and symptoms correspond to an increase in the known pharmacological action of paliperidone, i. e. drowsiness, lethargy, tachycardia, decreased blood pressure, prolongation of the QT interval, extrapyramidal symptoms. In the case of acute overdose, the possibility of patients receiving multiple medications should be considered.

Polyforme ventricular tachycardia of the “pirouette” type and ventricular fibrillation were observed with an overdose of oral palineridone. In the case of acute overdose, the possibility of patients receiving multiple medications should be considered.

Treatment: Long-term release of the Active ingredient and high T 1/2 of paliperidone should be considered when assessing the need for treatment and recovery of patients. There is no specific antidote for paliperidone. General supportive measures should be implemented, airway patency, adequate ventilation, and oxygen saturation should be ensured and maintained.

Cardiovascular function monitoring should be initiated immediately, including continuous ECG monitoring to detect possible arrhythmias. If blood pressure decreases and vascular collapse occurs, appropriate measures should be taken, for example, intravenous use of solutions and/or sympathomimetics. With the development of severe extrapyramidal symptoms, anticholinergic drugs are used. The patient’s condition should be carefully monitored before recovery.

Special instructions

of the NMS

When using neuroleptics, including paliperidone, the development of NMS was recorded, which is characterized by hyperthermia, muscle rigidity, instability of the autonomic nervous system, impaired consciousness and an increase in the concentration of CPK in serum. In addition, myoglobinuria (rhabdomyolysis) and acute renal failure may occur. All antipsychotics, including Xeplion, should be discontinued if symptoms suggest NMS.

Tardive dyskinesia

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

Hyperglycemia and diabetes mellitus

Hyperglycemia, diabetes mellitus, and exacerbation of pre – existing diabetes mellitus were observed during treatment with Xeplion. Identification of the relationship between the use of atypical antipsychotic drugs and glucose metabolism disorders is complicated by an increased risk of diabetes in patients with schizophrenia and the prevalence of diabetes 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

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

Elderly patients with dementia

A cross-sectional analysis of the study results showed increased mortality in elderly patients with dementia treated with atypical antipsychotics, including risperidone, aripiprazole, olanzapine and quetiapine, compared with placebo. Among patients treated with risperidone and placebo, the mortality rate was 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, experience with risperidone should be considered. For elderly patients with dementia taking risperidone, increased mortality was observed in patients taking furosemide and risperidone compared to the 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 elderly patients with dementia.

Disorders of cerebral circulation

Placebo-controlled studies have found an increased incidence of cerebral circulatory disorders (transient and stroke), including fatal ones, in elderly patients with dementia treated with certain atypical antipsychotics, including risperidone, aripiprazole and olanzapine, compared with placebo.

Leukopenia, neutropepia, agranulocytosis

Leukopenia, neutropenia, and agranulocytosis have been reported with antipsychotic medications, including Xeplion. Agranulocytosis was observed very rarely during post-marketing observations. Patients with a clinically significant decrease in the number of white blood cells in the anamnesis or drug-dependent leukopenia/neutropenia are recommended to perform a complete blood test during the first months of therapy, discontinuation of treatment with Xeplion should be considered at the first clinically significant decrease in the number of white blood cells in the absence of other possible causes. Patients with clinically significant neutropenia should be monitored for fever or symptoms of infection, and treatment should be initiated immediately. Patients with severe neutropenia (absolute neutrophil count less than 1 × 109/l) should stop using Xeplion until the white blood cell count returns to normal.

Venous thromboembolism

Cases of venous thromboembolism have been reported with the use of antipsychotic drugs. Since patients taking antipsychotic medications 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 should compare the risks and benefits of using antipsychotics, including Xeplion, in patients with Parkinson’s disease or dementia with Lewy bodies, as these categories of patients may have an increased risk of developing NMS and the risk of hypersensitivity to antipsychotics.Hypersensitivity symptoms may include confusion, blunted pain sensitivity, unstable posture with frequent falls, and extrapyramidal symptoms.

Priapism

There is evidence of the ability of drugs with the properties of alpha-blockers to cause priapism. Priapism was registered as part of the post-marketing monitoring of paliperidone use.

Antiemetic effect

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

Introduction

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

Influence on the ability to drive motor vehicles and manage mechanisms

Xeplion may interfere with the performance of activities that require concentration and speed of psychomotor reactions, and may affect vision. Therefore, patients should be advised not to drive vehicles or moving mechanisms until their individual sensitivity is established.

Form of production

Suspension for intramuscular use of prolonged action

Storage conditions

At a temperature not exceeding 30 °C

Shelf life

2 years

Active ingredient

Paliperidone

Conditions of release from pharmacies

By prescription

Dosage form

solution for injection