Expiration date: 01/2026
Dosage formSuspension for intramuscular introduction of the prolonged action
50 mg / 0.5 ml, 75 mg / 0.75 ml, 100 mg/ 1 ml, 150 mg/1.5 ml
Composition
1 ml suspension contains
active substance-palmitate paliperidone 156.0 mg (equivalent to paliperidone 100.0 mg),
excipients: Polysorbate 20, macrogol 4000 (polyethylene glycol 4000), citric acid monohydrate, sodium hydrophosphate anhydrous, sodium dihydrophosphate monohydrate, sodium hydroxide, water for injection.
Description
White or almost white suspension, free from foreign inclusions
Pharmacotherapeutic group
Psychotropic drug. Neuroleptics (Antipsychotics). Neuroleptics are different. Paliperidone.
ATC code N05AX13
Pharmacokinetics
Due to the extremely low solubility in water paliperidone palmitate after intramuscular administration slowly dissolves and is absorbed into the systemic circulation. After a single intramuscular administration, the concentration of paliperidone in the blood plasma slowly increases, reaching a maximum in 13-14 days (median) after administration to the deltoid muscle and 13-17 days after administration to the gluteal muscle. The release of the substance is detected as early as the 1st day and persists for at least 4 months. The characteristics of the release of the active component and the dosage scheme of the drug Xeplion provide long-term maintenance of therapeutic concentration. After a single dose of 25-150 mg in the deltoid muscle maximum concentration (Cmax) on average 28% more than after administration to the gluteal muscle. At the beginning of therapy, the introduction of the drug into the deltoid muscle helps to quickly reach the therapeutic concentration of paliperidone (150 mg on the 1st day and 100 mg on the 8th day) than the introduction into the gluteal muscle. After multiple injections, the difference in exposure is less obvious. The average ratio of the maximum and equilibrium concentrations of paliperidone after the introduction of 4 injections of the drug Xeplion at a dose of 100 mg in the gluteal muscle was 1.8, and after administration to the deltoid muscle – 2.2. At doses of paliperidone 25-150 mg area under the curve "concentration-time" (AUC) paliperidone changed proportionally dose and Cmax at doses of more than 50 mg increased to a lesser extent than proportional to the dose.
The median half-life of paliperidone after administration of Xeplion in doses of 25-150 mg ranged from 25-49 days.
After administration of the drug (-)-the enantiomer of paliperidone is partially converted to (+)-enantiomer, and the ratio of AUC (+)- and (-)-enantiomers is approximately 1.6-1.8.
In population analysis, the apparent volume of distribution of paliperidone is 391 l equal to; paliperidone is associated with blood plasma proteins by 74%.
For a week after a single oral administration of 1 mg of the drug 14C-paliperidone with immediate release of the active component with urine in unchanged form, 59% of the administered dose is excreted; this indicates the absence of 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 ways of metabolism of the drug in vivo, but none of them causes the metabolism of more than 6.5% of the administered dose: desalkylation, hydroxylation, dehydrogenation, cleavage of the benzizoxazole group. Although in vitro studies suggest a role of CYP2D6 and CYP3A4 isoenzymes in the metabolism of paliperidone, there is no evidence of a significant role of these isoenzymes in the metabolism of paliperidone in vivo. Population pharmacokinetic analysis revealed no noticeable difference in paliperidone clearance after oral administration of the drug by people with active and weak metabolism of CYP2D6. Studies using human liver microsomes in vitro have shown that paliperidone does not significantly inhibit the metabolism of drugs isoenzymes CYP1A2, CYP2A6, CYP2D6, CYP2E1, CYP3A4 and CYP3A5.
In studies in vitro paliperidone showed the properties of the substrate P-glycoprotein, and in high concentrations-the properties of a weak inhibitor of P-glycoprotein. There are no relevant data in vivo, and the clinical significance of this information is unclear.
In General, the concentration of paliperidone in blood plasma during the period of loading after intramuscular administration of the drug Xeplion was in the same range as after administration of paliperidone of prolonged action orally with the release of the active component in doses between 6 and 12 mg.The used scheme of paliperidone loading ensures the maintenance of concentration in this range even at the end of the interval between doses (8th and 36th day). Individual differences in the pharmacokinetics of paliperidone after administration of the drug Xeplion in different patients were less than after oral administration of paliperidone prolonged action. Due to the difference in the nature of changes in the median concentration of paliperidone in plasma when using two drugs, caution should be exercised when comparing their pharmacokinetics.
Special patient groups
Impaired liver function. Paliperidone is not subjected to significant metabolism in the liver. Although the use of the drug Xeplion in patients with impaired liver function of mild or moderate severity has not been studied, with such violations of liver function dose adjustment is not required. In the study, the use of paliperidone orally in patients with impaired liver function of moderate severity (class B according to child-Pugh), the concentration of free paliperidone in blood plasma was the same as in healthy volunteers. In patients with severe hepatic impairment, the use of paliperidone has not been studied.
Impaired renal function. For patients with impaired renal function of mild severity paliperidone dose should be reduced; Xeplion is not recommended in patients with impaired renal function of moderate severity and severe. It was studied the distribution of paliperidone after a single oral tablet of paliperidone prolonged action 3 mg patients with varying degrees of renal dysfunction. With a decrease in creatinine clearance (CC) excretion of paliperidone was weakened: in violation of renal functions of mild severity (CC 50-80 ml/min) - 32%, with an average severity (CC 30-50 ml/min) – 64%, with a severe degree (CC 10-30 ml/min) – 71%, resulting in AUC0? increased compared with healthy volunteers, respectively 1.5, 2.6 and 4.8 times. Based on a small amount of data on the use of the drug Xeplion in patients with impaired renal function of mild severity and from the results of pharmacokinetic modeling, the recommended load dose of paliperidone for such patients is 100 mg on the 1st day and 75 mg after 1 week; after that, monthly (every 4 weeks) is administered at 50 mg; the dose can be increased or decreased in the range of 25-100 mg depending on individual tolerability and/or effectiveness.
Elderly patient. Age itself is not a factor that requires dose adjustment. However, correction may be required due to age-related reduction of creatinine clearance.
Race. Population pharmacokinetic analysis of the results of the study of paliperidone for oral administration revealed no differences in the pharmacokinetics of paliperidone after administration of the drug by people of different races.
Floor. Clinically significant differences in the pharmacokinetics of paliperidone in men and women were not found.
The effect of Smoking on the pharmacokinetics of the drug. According to studies using human liver microsomes in vitro, paliperidone is not a substrate of CYP1A2, so Smoking should not affect the pharmacokinetics of paliperidone. According to these data in vitro, the population pharmacokinetic analysis revealed no differences in the pharmacokinetics of paliperidone in smokers and non-smokers.
Pharmacodynamics
Paliperidone palmitate is hydrolyzed to paliperidone. The latter is a Central active antagonist 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 adrenergic ?1 - and ?2 - receptors.
The pharmacological activity of ( + ) 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.
Indications for use
- supportive care for schizophrenia in adult patients stabilized with paliperidone or risperidone.
Dosage and administration
IT IS IMPOSSIBLE TO INJECT THE DRUG INTO THE BLOOD VESSELS OR SUBCUTANEOUSLY!
It is recommended to start treatment with Xeplion with a dose of 150 mg on the 1st day and 100 mg after 1 week (day 8), in order to quickly achieve therapeutic concentrations, both injections are carried out in the deltoid muscle (see section "Pharmacokinetics"). The third dose is administered one month after the second initiating dose. The recommended monthly maintenance dose is 75 mg; the dose may be increased or decreased in the range of 25-150 mg depending on individual tolerability and/or efficacy. For patients who are obese or overweight may require doses in the upper range (see "Pharmacokinetics"). After the second initiating dose, subsequent monthly maintenance doses can be administered to either 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 of paliperidone palmitate, since the effect of dose changes can be fully manifested only after a few months.
Translation from oral paliperidone or oral risperidone
Oral paliperidone or oral risperidone may be discontinued at the time of initiation of treatment with Xeplion. Some patients it is advisable to carry out a gradual withdrawal of the drug. Start treatment with Xeplion should be in accordance with the described at the beginning of this section.
Translated with injectable risperidone prolonged action
When transferring patients with prolonged-acting injection risperidone, treatment with Xeplion begins at the time of the next scheduled injection. Then treatment with Xeplion should be carried out at intervals of one month. There is no need to carry out, described at the beginning of this section, one-week initiation of dosing regimen intramuscular injections (1st and 8th day, respectively), Patients, previously stabilized at different doses of injection risperidona prolonged action, can achieve such equilibrium concentrations of paliperidone with monthly maintenance of the drug Xeplion in accordance with the following scheme:
Doses of injection risperidone of prolonged action and the corresponding doses of the drug Xeplion, necessary to achieve such equilibrium concentrations of paliperidone
| Last dose | Initial dose |
| Rispolept® Consta® | Xeplion |
| 25 mg every 2 weeks | 50 mg 1 time per month |
| 37.5 mg every 2 weeks | 75 mg 1 time per month |
| 50 mg every 2 weeks | 100 mg 1 time per month |
Dose pass
Avoiding missing doses
The second initiating dose of the drug Xeplion is recommended to be administered 1 week after the first dose. To avoid missing the dose, the second dose can be administered to the patient 4 days earlier or later than the 8th day of injection (one-week period). Similarly, the third and subsequent injections after the initiating regime are recommended to be administered monthly. To avoid missing a dose, the injection can be done 7 days earlier or later.
If the second injection of the drug Xeplion was not made on time (8th day ± 4 days), the recommended resumption of treatment depends on the time passed from the date of the first injection.
Skip the second initiating dose (less than 4 weeks from the first injection)
If less than 4 weeks have passed since the first injection, the patient should inject a second injection at a dose of 100 mg into the deltoid muscle as soon as possible. The third injection of the drug Xeplion at a dose of 75 mg should be done in the deltoid or gluteal muscle 5 weeks after the first injection (not taking into account the time of the second injection). In the future, a monthly cycle of injections in the dose range from 25 mg to 150 mg in the deltoid or gluteal muscle should be observed, depending on individual tolerability and/or effectiveness.
Skip the second initiating dose (4 to 7 weeks from the date of the first injection).
If from the date of the first injection of the drug Xeplion passed from 4 to 7 weeks of treatment is resumed by the introduction of two injections at a dosage of 100 mg according to the following scheme: the first injection into the deltoid muscle is made as soon as possible; after 1 week, a second injection into the deltoid muscle is made, then continue the monthly course of injections into the deltoid or gluteal muscle in the dose range from 25 mg to 150 mg depending on individual tolerability and/or effectiveness.
Skip the second initiating dose (more than 7 weeks from the date of the first injection).
If more than 7 weeks have passed since the first injection of the drug Xeplion, the treatment begins in the same way as in the case of initiation of treatment with the drug Xeplion.
Skip monthly maintenance dose (from 1 month to 6 weeks).
After starting treatment, it is recommended to carry out injections of the drug Xeplion monthly. If less than 6 weeks have passed since the last injection, then another dose equal to the previous one should be administered as soon as possible, followed by the introduction of the drug at an interval of 1 month.
Skip maintenance dose (>6 weeks to 6 months)
If more than 6 weeks have passed since the last injection of the drug Xeplion, the following is recommended:
For stabilized dose patients in the range of 25 mg to 100 mg:
- make an injection of the drug into the deltoid muscle as soon as possible in the dose at which the stabilization of the patient's condition before skipping the injection;
- the next injection into another deltoid muscle (the same dose) is done after 1 week (on the 8th day);
- then resume the monthly course of injections into the deltoid or gluteal muscle in the dose range from 25 mg to 150 mg, depending on individual tolerability and/or effectiveness.
For patients stabilized by a dose of 150 mg:
- as soon as possible, enter a dose of 100 mg into the deltoid muscle;
- after 1 week administered one dose of 100 mg (8 day) in the other deltoid muscle;
- then resume the monthly course of injections into the deltoid or gluteal muscle in the dose range from 25 mg to 150 mg, depending on individual tolerability and/or effectiveness.
Pass a maintenance dose (duration >6 months)
If more than 6 months have passed since the last injection of the drug Xeplion, the treatment is started anew, as described above to initiate treatment.
Special patient groups
Patients with impaired liver function
Based on the experience of oral paliperidone, for patients with impaired liver function of mild or moderate severity dose adjustment is not required. Since the use of paliperidone has not been studied in patients with severe liver dysfunction, caution should be exercised when using the drug Xeplion in such patients.
Patients with impaired renal function
The use of Xeplion in patients with impaired renal function has not been systematically studied (see section "Pharmacokinetics"). In patients with impaired renal function of mild severity (creatinine clearance from ?50 to <80 ml / min), it is recommended to start using the drug with a dose of Xeplion 100 mg on the 1st day and 75 mg after 1 week (both injections into the deltoid muscle). After that, 50 mg is administered monthly to the deltoid or gluteal muscle; the dose may be increased or decreased in the range of 25-100 mg depending on individual tolerability and/or effectiveness.
Xeplion is not recommended in patients with moderate to severe renal impairment (creatinine clearance <50 ml/min) (see "Special instructions").
Elderly patient
Efficacy and safety of the drug in elderly patients >65 years have not been established.
In General, for elderly patients with normal renal function, the same dose of Xeplion is recommended as for younger patients with normal renal function. However, since not ruled out the possibility of the loss of kidney function in elderly patients, you may need to adjust dose in such patients apply the above recommendations for patients with impaired renal function.
Adolescents and children
The safety and efficacy of Xeplion has not been studied in patients under 18 years of age. No data available.
Method of application
Xeplion is intended for intramuscular administration only. The drug is injected slowly into the deeper layers of the muscles. Injections should only be performed by a medical professional. The entire dose is administered at once; it is impossible to administer the dose over several injections. Avoid accidental entry into the blood vessel.
Initiating doses on day 1 and day 8 should be administered to the deltoid muscle to rapidly achieve therapeutic concentrations (see section "Pharmacodynamics"). After the introduction of the second initiating dose, monthly maintenance doses can be administered either in the deltoid, or in the gluteal muscle. The transition from injections into the gluteal muscle to injections into the deltoid muscle (and Vice versa) should be considered in the case of pain at the injection site and in the case of poor patient tolerance of discomfort at the injection site. (see Side effects.) Also, it is recommended to alternate injections between the left and right sides.
Introduction to the deltoid muscle
The recommended needle size for administering initiating and maintaining doses of Xeplion to the deltoid muscle is determined by the patient's body weight. For patients weighing ?90 kg, a long needle with a gray body from the set (38.1 mm x 0.72 mm) is recommended. For patients weighing <90 kg, a short needle with a blue body from the kit (25.4 mm x 0.64 mm) is recommended. It should be alternately administered to the right and left deltoid muscle.
Introduction to gluteus Medius
A long needle with a gray body from the set (38.1 mm x 0.72 mm) is recommended for administration of xeplion maintenance doses into the gluteal muscle. Injections should be carried out in the upper outer quadrant of the buttock. It should be alternately administered to the right and left gluteal muscle.
