Trevikta - instructions for use, dose, side effects, contraindications

Active substancePaliperidonePaliperidone

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Trevikta

suspension w / m

Johnson & Johnson, LLC Russia

Dosage form: & nbspsuspension for intramuscular administration of prolonged action

Composition:

In 1 ml of the suspension contains:

Active substance:

200 mg of paliperidone (equivalent to 312 mg of paliperidone palmitate).

Excipients:

polysorbate 20-10 mg, macrogol 4000 (polyethylene glycol 4000) 75 mg, citric acid monohydrate 7.5 mg, sodium dihydrogen phosphate monohydrate 6.0 mg, sodium hydroxide 5.4 mg, water for injection up to 1 ml.

Description:White or almost white suspension, free from foreign inclusions.

Pharmacotherapeutic group:Antipsychotic agent (antipsychotic)

ATX: & nbsp

N.05.A.X Other antipsychotics

N.05.A.X.13 Paliperidone

Pharmacodynamics:

Mechanism of action

Paliperidone belongs to the class of benzisoxazole derivatives and is an atypical antipsychotic. Paliperidone palmitate hydrolyzes to paliperidone. The latter is a central antagonist of predominantly serotonin 5-HT_2A-receptors, as well as dopamine D₂receptors, adrenergic α1 and α2 receptors, and H 1-histamine receptors. Paliperidone does not bind to cholinergic m-receptors and to adrenergic β1 and β2 receptors. 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 a combined blockade D₂ and 5-HT_2Areceptors.

Pharmacokinetics:

Suction and distribution

Due to the extremely low solubility in water of paliperidone, palmitate is slowly dissolved after intramuscular injection, hydrolyzed to paliperidone and absorbed into the systemic bloodstream. The release of the substance begins already on the 1st day and lasts for 18 months. After a single intramuscular injection, the concentration of paliperidone in the blood plasma gradually increases, reaching a maximum after 30 - 33 days (median T_m_Oh) - After intramuscular injection of the drug TREVITA in doses of 175 - 525 mg in deltoid muscles, the value of C_m_Oh on average, 11-12% higher than the corresponding figure after injection in the gluteal muscles. The release characteristics of the active component and the dosage regimen of the TREVITA preparation ensure a sustained maintenance of the therapeutic concentration. Value AUC (area under the concentration-time curve) of paliperidone after administration of the TREVITA preparation is proportional to the dose in the range 175-525 mg, the dynamics of C_ma_xapproaches the proportionality of the dose. The average ratio of maximum and minimum values was 1.6 after the administration of TREVITA in the gluteus muscles and 1.7 after administration to the deltoid muscles. The apparent volume of distribution of paliperidone after the administration of TREVITA is 1960 liters. Paliperidone binds to blood plasma proteins by 74%.

After administration of the preparation (-) and (+) - enantiomers of paliperidone mutually turn into each other, reaching a ratio AUC (+) - and (-) - enantiomers of about 1.7 to 1.8.

Metabolism and excretion

For a week after a single oral intake 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 withdrawn; this indicates a lack of significant metabolism of the drug in the liver. Approximately 80 % introduced 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 a metabolism of more than 10% of the administered dose: dealkylation, hydroxylation, dehydrogenation and elimination of the benzisoxazole group.Although research in vitro allow to assume a certain role of isoenzymes CYP2D6 and CYP3A4 in the metabolism of paliperidone, data on the significant role of these isoenzymes in the metabolism of paliperidone in vivo no. Population pharmacokinetic analysis did not reveal a significant difference in clearance of paliperidone after oral administration of the drug by people with active and weak metabolism CYP2D6. Studies using human liver microsomes in vitro showed that paliperidone does not substantially inhibit the metabolism of drugs by isoenzymes CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4 and CYP3A5.

In studies in vitro paliperidone showed the properties of the P-glycoprotein substrate, and in high concentrations - the properties of a weak P-glycoprotein inhibitor. Relevant data in vivo No, the clinical significance of this information is unclear. According to the results of the population pharmacokinetic analysis, the median of the apparent half-life of paliperidone after administration of the drug TREVITA in doses of 175-525 mg was from 84 to 95 days in the case of injections into the deltoid muscles to 118-139 days in the case of injections into the gluteus muscles. The residual concentration of paliperidone in the blood 18 months after the last injection of TREVITA in a dose of 525 mg is 3 and 7% of the average equilibrium concentration in the case of injection into the deltoid and gluteus muscle respectively.

Comparison of TREVITA and other preparations of paliperidone

The frequency of administration of the drug TREVIKTA is 1 time in 3 months, in contrast to the drug KSEPLION (paliperidone palmitate in a drug form suspension for intramuscular administration of prolonged action, intended for administration monthly). With the administration of TREVITA in doses 3.5 times higher than the corresponding dose in the preparation KSEPLION, the drug TREVIKTA allowed to achieve systemic levels of paliperidone, similar to the similar values achieved with the monthly administration of appropriate doses of the drug KSEPLION. as well as by oral administration of appropriate doses of paliperidone in sustained-release tablets.

The variability of the pharmacokinetics of paliperidone between patients is similar to that of reception of paliperidone in the form of tablets with delayed release. Care should be taken at comparison of pharmacokinetic properties of different forms Paliperidone in connection with various pharmacokinetic profiles bythe last.

Special Categories patients

Elderly patients (65 years and older)

Age is not a factor requiring dose adjustment. However, such correction may be required because of an age-related decrease in creatinine clearance.

Impaired renal function

The drug TREVITA was not systematically studied in patients with impaired renal function. The distribution of paliperidone after a single oral intake of sustained-release tablets at a dose of 3 mg was studied in patients with different renal function. With the decrease in creatinine clearance (CC), the excretion of paliperidone was weakened: in the case of disturbance of the functions of the kidneys of mild severity (KC 50-80 ml / min) - by 32%, at an average severity (CK 30-50 ml / min) - 64% at a severe degree (CC 10-30 ml / min) - by 71%, resulting in AUC₀-∞ increased compared with healthy volunteers, respectively, at 1.5, 2.6 and 4.8 times. Based on a small amount of data on the use of the drug TREVIKTA in patients with impaired renal function of mild severity and from the results of pharmacokinetic modeling, patients with impaired renal function of mild severity should reduce both the initial and maintenance dose of the drug KSEPLION.Patients can be transferred to therapy with the drug TREVIKTA, increasing by 3.5 times the corresponding dose, intended for appointment to patients with impaired renal function of mild degree. Additional dose adjustment after starting therapy with the drug TREVITA is not required.

Impaired liver function

Paliperidone does not undergo significant metabolism in the liver. Although the use of the drug TREVIKTA in patients with impaired liver function has not been studied, dose adjustment is not required for violations of liver function of mild and moderate severity. In a study of the use of paliperidone orally in patients with impaired liver function of moderate severity (Child-Pugh class B), the concentration of free paliperidone in plasma was the same as in healthy volunteers. In patients with impaired liver function of a severe degree, the use of paliperidone has not been studied.

Race

Population pharmacokinetic analysis of the results of paliperidone for oral administration revealed no difference in the pharmacokinetics of paliperidone after taking the drug by people of different races.

Special Categories patients

Elderly patients (65 years and older)

Age is not a factor requiring dose adjustment. However, such correction may be required because of an age-related decrease in creatinine clearance.

Impaired renal function

Impaired liver function

Race

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 CYP1A2, so smoking should not affect the pharmacokinetics of paliperidone. According to the results of the population pharmacokinetic analysis based on the data of the study of the KSEPLION preparation, no differences were found between smokers and non-smokers, which corresponds to the experimental results mentioned above in vitro.

Body mass index

Correction of the dose, depending on the body mass index, is not required. In persons with excessive body weight, as well as in the presence of obesity, there was a decrease in C_m_Oh. The minimum residual concentrations under conditions of apparent equilibrium were similar in individuals with normal body weight, overweight and obese.

Indications:

Treatment of schizophrenia in adult patients who have previously received maintenance therapy with XEPLION for at least 4 months.

Contraindications:

Hypersensitivity to paliperidone or any component of the drug.

Because the paliperidone is an active metabolite of risperidone, the drug TREVITA is contraindicated in patients with known hypersensitivity to risperidone.

In patients treated with risperidone or paliperidone, the occurrence of hypersensitivity reactions has been reported. including anaphylactic reactions and angioedema.

Carefully:

Caution is advisable to use the drug TREVITA in the following cases (see more details under "Special instructions"):

- in patients with cardiovascular diseases (for example, heart failure, myocardial infarction or ischemia, cardiac conduction disorder), cerebral circulation disorders or conditions, predisposing to lower blood pressure (eg, dehydration, a decrease in the volume of circulating blood, the use of antihypertensive drugs);

- in patients who have a history of convulsions or other conditions in which the convulsive threshold may be reduced;

- in patients who may be exposed to effects that increase body temperature, for example, severe physical exertion, high ambient temperature, effects of drugs with m-cholinolytics activity, and also dehydration;

- in patients who have a history of arrhythmia or congenital lengthening of the interval Q-T, or taking drugs that extend the interval Q-T;

- when used in combination with other drugs acting on the central nervous system and alcohol. Paliperidone can weaken the effect of levodopa and dopamine agonists;

- in patients with dementia, patients with Parkinson's disease or dementia with Levy bodies;

- in patients with possible prolactin-dependent tumors;

- in patients with impaired liver or kidney function.

Pregnancy and lactation:

Pregnancy

The safety of the use of paliperidone palmitate intramuscularly or paliperidone orally during pregnancy in humans has not been established. Teratogenic effect was not observed in animal studies. When high doses of paliperidone were administered orally, there was a slight increase in fetal mortality in animals. The drug KSEPLION did not affect the course of pregnancy in rats, but high doses of it were toxic to pregnant females. Doses of paliperidone when ingested and the drug KSEPLION with intramuscular injection, which create concentrations exceeding the maximum therapeutic dose in humans, respectively, 20 - 22 times and 6 times, did not affect the offspring of laboratory animals.

If a woman took antipsychotic drugs (including paliperidone) in the third trimester of pregnancy, neonates have a risk of extrapyramidal disorders and / or withdrawal syndrome of varying severity. These symptoms may include agitation, hypertension, hypotension, tremor, drowsiness, respiratory disorders, and breast-feeding disorders. It is necessary to monitor the condition of newborns for extrapyramidal disorders and / or withdrawal and provide them with appropriate medical care. Some neonates have symptoms in for several days or hours without specific treatment, some may require long hospitalization. Because the paliperidone was detected in the blood plasma for 18 months from the moment of a single injection of the drug TREVITA, the duration of the drug should be taken into account, since newborns may be at risk of exposure to TREVITA taken before pregnancy or in the first or second trimester.

The drug TREVITA can be used during pregnancy only in the case,if the intended use for the mother exceeds the potential risk to the fetus. The effect of the drug TREVIKTA on labor and birth in humans is unknown.

It is necessary to inform pregnant women about potential risks to the fetus. The effect of TREVITA on the risk of developing serious birth defects and miscarriages is unknown.

Breast-feeding

In studies of the use of paliperidone in animals and risperidone in humans, paliperidone has been excreted in breast milk, therefore women receiving the drug TREVITA should not breast-feed their children. Because the paliperidone was found in the blood plasma for 18 months from the moment of a single injection of the drug TREVITA, it is necessary to take into account the duration of the drug, because infants may be at risk of exposure to the drug TREVITA, taken long before the initiation of breastfeeding.

Dosing and Administration:

Mode of application

The drug TREVITA must be administered 1 time in 3 months. See the illustrated application "Instructions for use and handling of the drug. "

Before administration, parenteral drugs should be inspected for foreign particles and discoloration. No more than 5 minutes before injection, the syringe should be shaken vigorously for at least 15 seconds to obtain a homogeneous suspension.

The drug is intended only for intramuscular injection. Not allowed subcutaneous or intravascular injection. Avoid accidental ingestion in a blood vessel. The drug should be administered by health professionals. Required Enter the drug for one injection, it is forbidden to divide the dose into several injections. The drug should be administered slowly, deep into the gluteus or deltoid muscle.

For the introduction of the drug TREVITA can only use the supplied thin-walled needles. Do not use needles from the KSEPLION package or other commercially available needles.

The recommended size of needles for the administration of TREVITA to the deltoid muscle is determined by the patient's body weight. Patients weighing ≥ 90 kg are recommended to use needles 25 mm long. In patients weighing ≥ 90 kg, it is recommended to use 51 mm long needles. The drug should be injected into the center of the deltoid muscle. It is necessary to alternate injections between two deltoid muscles.

For the administration of the drug TREVIKTA in the gluteus muscle is recommendedUse needles 51 mm long, regardless of body weight. The drug is injected into the outer upper quadrant of the gluteus muscle. It is necessary to alternate injections between two gluteal muscles.

Because the paliperidone is an active metabolite of risperidone, caution should be exercised while using the drug TREVITA and risperidone or the oral form of paliperidone for a long period of time. Data on the safety of simultaneous use of the drug TREVIKTA and other antipsychotics are limited.

Introduction of an incomplete dose

In order to avoid the introduction of incomplete dose TREVIKTA drug necessary to shake vigorously syringe with medication for at least 15 seconds is not more than 5 minutes before the administration to obtain a homogeneous suspension (see. The section "Instructions for use and the treatment of drug" ). However, in case of incomplete dose administration, it is forbidden to administer the drug remaining in the syringe, it is also forbidden to administer another dose. It is necessary to carefully monitor the patient and provide proper therapy until the next scheduled injection of TREVITA in 3 months.

Dosage

TREVIKTA drug can only be used after applying KSEPLION medication for at least 4 months. To correctly determine the maintenance dose prior to application of the drug should enter TREVIKTA 2 past monthly injections of the same dose.

Application TREVIKTA drug should be started on the day corresponding to the next scheduled drug injection KSEPLION using TREVIKTA dose formulation, calculated based on the previous dose KSEPLION formulation according to Table 1. The drug may be administered TREVIKTA 7 days earlier or later date of the next scheduled KSEPLION injection preparation.

Table 1. Scheme of transfer from the drug XEPLION to the drug TREVIKTA (recalculation using the coefficient of 3.5)

The dose of the last injection of the drug KSEPLION	Initial dose of TREVITA
50 mg	175 mg
75 mg	263 mg
100 mg	350 mg
150 mg	525 mg
Translation from the drug KSEPLION in a dose of 25 mg has not been studied

After the initial injection, the drug TREVIKTA should be administered every 3 months. If necessary, the allowed speed correction doses every 3 months in the range from 175 to 525 mg based on individual tolerance and / or efficacy.Due to the duration of action of the drug TREVIKTA, the patient's response to dose adjustment may appear only after a few months (see section "Pharmacokinetic properties").

Dose skip

Do not skip the dose. In exceptional cases, the supporting injection can be done 2 weeks earlier or later than the day of the next scheduled injection.

Dose skipping (3.5-4 months)

If more than 3.5 months have elapsed from the date of the previous injection (up to 4 months), the patient should be administered the next injection at the same dose as soon as possible. In the future, the frequency of injections should be observed once every 3 months.

Dose skip (4-9 months)

If more than 4 months (up to 9 months) have passed since the day of the previous injection, do not enter the next dose of TREVITA. Renewal of therapy should be carried out according to the scheme given in table 2.

Table 2. Scheme of the resumption of therapy with TREVITA, if after the previous injection 4-9 months have passed

The dose of the last injection of the drug TREVIKTA	Enter the drug KSEPLION, 2 doses with an interval of 1 week (in the deltoid muscle)		Enter the drug TREVIKTA (in the deltoid^a or gluteus muscle)
	Day 1	Day 8	1 month after Day 8
175 mg	50 mg	50 mg	175 mg
263 mg	75 mg	75 mg	263 mg
350 mg	100 mg	100 mg	350 mg
525 mg	100 mg	100 mg	525 mg
^a See "Instructions for use and handling of the drug" for selecting a needle for injection into the deltoid muscle, depending on body weight.

Dose skipping (more than 9 months)

If more than 9 months have elapsed since the last injection of TREVITA, start treatment with XEPLION in accordance with the instructions for use of this drug. Transfer to the drug TREVITA can be performed only after using the drug XEPLION for at least 4 months.

Special patient groups

Children (up to 18 years)

The safety and efficacy of TREVITA in patients younger than 18 years of age has not been studied. The use of TREVITA is not recommended v patients younger than 18 years due to the potentially longer duration of side effects compared to drugs with shorter period of action. In clinical studies of paliperidone for oral administration there was no increase in the incidence of dystonia, hyperkinesia, tremor and Parkinsonism in adolescents compared with adults patients.

Elderly patients (65 years and older)

Clinical studies did not include enough patients aged 65 years and over to determine whether their response to therapy differs from younger patients. The experience of clinical use has not revealed differences in the response between elderly and younger patients.

Paliperidone is largely excreted by the kidneys, clearance of paliperidone is lower in patients with impaired function kidney. For elderly patients with normal renal function, the same dose of TREVITA is recommended as for younger patients with normal renal function. In elderly patients, kidney function may be reduced, and these recommendations are subject to the following recommendations for patients with impaired renal function.

Patients with impaired renal function

The use of the drug TREVIKTA in patients with impaired renal function has not been systematically studied. In patients with impaired renal function of mild degree (creatinine clearance from 50 to 80 ml / min) dose correction is performed at the stage of initiation of therapy with XEPLION; additional correction of the dose of TREVITA is not required.Transfer to therapy with the drug TREVITA using a dose 3.5 times higher than the dose of the previously used drug KSEPLION, is performed in accordance with the description above. The maximum recommended dose of TREVITA in patients with impaired renal function of mild degree is 350 mg.

It is not recommended to use the drug TREVIKTA in patients with impaired renal function of medium or severe degree (creatinine clearance <50 ml / min).

Impaired liver function

The use of TREVITA in patients with impaired liver function has not been studied. Based on the results of the study of paliperidone for oral administration, for patients with impaired liver function of mild or moderate degree, dose adjustment is not required. The use of paliperidone in patients with impaired hepatic function was not studied.

Other special categories of patients

Correction dose of the drug TREVITA depending on sex, patient race and smoking is not required.

Transition from other antipsychotics

TREVIKTA drug can only be used after applying KSEPLION medication for at least 4 months.In the case of withdrawal of the drug TREVITA, it is necessary to take into account the duration of release of the active component. As in the case of other neuroleptics, the need to continue the use of prophylaxis for the development of extrapyramidal disorders should be periodically evaluated.

Transition from the drug TREVIKTA to the drug KSEPLION

For the transition from the drug TREVIKTA to the drug XEPLION this drug should be administered on the day corresponding to the administration of the next dose of the drug TREVIKTA, while it is necessary to use a 3.5 times smaller dose in accordance with Table 3. Further, the XESPLION drug should be continued on a monthly basis.

Table 3 Scheme of translation from the drug TREVIKTA to the preparation XEPLION

(recalculation using a coefficient of 3.5)

The dose of the last injection of the drug TREVIKTA	Dose of the drug XEPLION
175 mg	50 mg
263 mg	75 mg
350 mg	100 mg
525 mg	150 mg
Initiation of therapy as described in the instructions for use of the drug KSEPLION is not required.

Transition from the drug TREVIKTA to paliperidone in tablets of prolonged action for oral administration

For the transition from the drug TREVIKTA to tablets paliperidoneprolonged action, the daily intake of these tablets should begin 3 months after the last injection of the TREVITA preparation, the transition is carried out over the next several months according to the description in Table 4. Table 4 contains the dose conversion regimes that allow similar concentrations of paliperidone in plasma to be obtained upon admission tablets of paliperidone prolonged action once a day in patients with a previously achieved stable condition at various doses of the drug TREVITA.

Table 4 Doses of TREVITA and regimens for the administration of paliperidone in prolonged-release tablets, which are necessary to provide similar concentrations of paliperidone in plasma

	Weeks since the last injection of the drug TREVIKTA
	3 months - 18 weeks	18-24 weeks	more than 24 weeks
The dose of the last injection of the drug TREVIKTA	The daily dose of paliperidone in the form of long-acting tablets
175 mg	3 mg	3 mg	3 mg
263 mg	3 mg	3 mg	6 mg
350 mg	3 mg	6 mg	9 mg
525 mg	6 mg	9 mg	12 mg
You should individually choose a dose of paliperidone in prolonged-release tablets, taking into account the reason for the transfer from the drug TREVITA, the response to paliperidone therapy in the past, the severity of psychotic symptoms and / or tolerability.

Side effects:

This section provides information on unwanted reactions. Undesirable reactions are undesirable phenomena that, on the basis of a comprehensive assessment of available information, are judiciously associated with the use of paliperidone palmitate. In some cases it is impossible to establish reliably the relationship with paliperidone palmitate. In addition, because clinical trials are conducted under different conditions, the incidence of adverse reactions recorded in clinical studies can not be compared with the frequency in clinical trials of other drugs, and they may not reflect the frequency of the corresponding phenomena in actual clinical practice.

Clinical Trials Data

The information described in this section includes information from three clinical studies.

One study is a long-term randomized study of the prevention of relapse with the participation of 506 patients with schizophrenia who received an open-label therapy with XEPLION: 379 of them subsequently received one injection of TREVITA. In the double blind placebo-controlled phase of 160 patients were randomized to the group receiving at least one injection of TREVITA. 145 patients in group placebo. Average duration of application of the drug in the double-blind phase was equal to 150 (standard deviation of 79) days in the placebo group and 175 (standard deviation of 90) days in the TREVITA group.

In the second long-term, double-blind, active control study, no less efficacy involving 1,429 patients with acute disease, patients were randomized to the group that continued to receive the drug XEEPLION, and to the group transferred to the drug TREVITA, for 48 weeks. The average duration of application of the drug in the phase of double-blind therapy was 295 (standard deviation of 88) days in the group of the drug TREVIKTA and 287 (standard deviation of 96) days in the group of the drug KSEPLION.

In addition, a Phase 1 study was conducted in which 308 patients with schizophrenia or schizoaffective disorder received a single injection of TREVITA in combination with other oral antipsychotics.

Most adverse reactions were mild or moderate.

The undesirable reactions observed in the long-term study of the prevention of relapse are presented in Table 5. The most frequent adverse reactions noted in this study were reactions at the site of administration, weight gain, headache, upper respiratory tract infections, akathisia and parkinsonism. 5.1 % of patients interrupted the therapy in the open phase because of side effects. In the double The blind phase due to adverse events was interrupted by therapy 1 patient who received a placebo: none of the patients receiving the drug TREVIKTA, not interrupted therapy. The safety profile of the drug TREVIKTA was similar to that of the drug KSEPLION.

Table 5, Undesirable reactions identified with the use of TREVITA in a long-term study of the prevention of relapse in patients with schizophrenia

System-Organ Class	Open period KSEPLION^a (N = 506) n (%)^from	Double blind period
	Open period KSEPLION^a (N = 506) n (%)^from	Placebo (N = 145) n (%)^from	ТЕРВ�?КТА (N = 160) n (%)^from
Infections and invasions
Upper respiratory tract infection^b	26 (5,1)	6(4,1)	16(10,0)
Urinary tract infection	2 (0,4)	2(1,4)	5(3,1)
Disorders from the metabolism and nutrition
Hyperglycaemia	0	7 (4,8)	3(1,9)
Hyperinsulinemia	0	1 (0,7)	1 (0,6)
Weight gain^b	52(10,3)	5 (3,4)	14(8,8)
Mental disorders
Anxiety	44 (8,7)	16(11,0)	13(8,1)
Disturbances from the nervous system
Akathisia^b	23 (4,5)	3(2,1)	8 (5,0)
Dyskinesia	1 (0,2)	2(1,4)	1 (0,6)
Dystonia^b	6(1,2)	0	1 (0,6)
Headache	33 (6,5)	6(4,1)	14(8,8)
Parkinsonism^b	23 (4,5)	0	7 (4,4)
Drowsiness^b	20 (4,0)	0	1 (0,6)
Disorders from the cardiovascular system
Tachycardia^b	8(1,6)	1 (0,7)	1 (0,6)
Orthostatic hypotension	2 (0,4)	0	0
Disorders from the gastrointestinal tract
Nausea	11 (2,2)	0	2(1,3)
Vomiting	9(1,8)	0	0
Violations of the reproductive system and mammary glands
Amenorrhea	6(1,2)	0	1 (0,6)
Galactorrhea	4 (0,8)	0	0
General disorders and reactions at the site of administration
Reaction at the site of administration^b	62(12,3)	0	5 (3,1)

^aIn the open phase, patients received several doses of the XEplion preparation followed by a single administration of the TREVITA preparation before randomization into the placebo or TREVITA group receiving groups in the subsequent double blind phase.

^b Term "tachycardia" includes tachycardia, sinus tachycardia.

Term "reactions at the injection site" includes reactions at the site of administration, erythema at the injection site, extravasation at the injection site, compaction at the site of administration, inflammation in the place of administration, volume formation at the site of injection, a nodule at the site of injection, pain in the place of injection, swelling at the injection site.

Term "weight gain" includes an increase in body weight, an increase in the circumference of the waist.

Term "upper respiratory tract infection" includes infection of the upper respiratory tract, nasopharyngitis, pharyngitis, rhinitis.

Term "drowsiness" includes drowsiness, sedation.

Term "akathisia" includes akathisia, anxiety.

Term "parkinsonism" includes parkinsonism, rigidity as a cogwheel, drooling, extrapyramidal disorders, hypokinesia, rigidity of muscles, muscle tension, musculoskeletal stiffness, hypersecretion of saliva.

Term "dystonia" includes dystonia, blepharospasm.

^fromThe frequency is based on the number of patients with at least one undesirable phenomenon, not the number of events.

Data from other clinical trials

Paliperidone palmitate hydrolyzes to paliperidone. Paliperidone is an active metabolite of risperidone, thus the profiles of undesirable reactions of risperidone and paliperidone (including both oral and injectable dosage forms) are interrelated. This subsection includes additional adverse reactions that have been reported in clinical studies of paliperidone and / or risperidone.

Below are the undesirable reactions identified in the clinical trials of TREVITA, not included in Table 5.

Infections and invasions

Akarodermatit, bronchitis, inflammation of the subcutaneous fat, cystitis, ear infection, eye infection, influenza, onychomycosis, pneumonia, respiratory tract infection, sinusitis, subcutaneous abscess, tonsillitis.

Violations of the blood and lymphatic system

Anemia, neutropenia. decrease in the number of white blood cells.

Immune system disorders

Hypersensitivity.

Disorders from the endocrine system

The presence of glucose in the urine, hyperprolactinemia.

Disorders from the metabolism and nutrition

Increasing the concentration of cholesterol in blood, increase in the concentration of triglycerides in the blood, reduced appetite, increased appetite, polydipsia, weight loss^a.

Mental disorders

Excitation^a, anorgasmia, emotional flatness, depression^a, insomnia^a, decreased libido, nervousness, nightmares, sleep disturbances.

Disturbances from the nervous system

Cerebral ischemia, attention disorders, dizziness, postural dizziness, dysarthria, hypoesthesia, paresthesia,psychomotor hyperactivity, fainting, tardive dyskinesia, tremor^a.

Disturbances on the part of the organ of sight

Conjunctivitis, dry eyes, glaucoma, increased lacrimation, blurred vision.

Violations from the organ of hearing and labyrinth

Pain in the ear, ringing in the ears, vertigo.

Disorders from the cardiovascular system

Atrioventricular block, bradycardia, conduction disturbance, ECG deviation, lengthening of the interval QT on an electrocardiogram, palpitation, postural orthostatic tachycardia syndrome, hypertension^a, hypotension.

Disturbances from the respiratory system, thorax and mediastinum

Cough, shortness of breath, nosebleed, nasal congestion, pain in the oropharynx, stagnant

phenomena in the airways.

Disorders from the gastrointestinal tract

Discomfort in the abdomen, abdominal pain, cheilitis, constipation^a, diarrhea^a, dry mouth, indigestion, dysphagia, flatulence, gastroenteritis, toothache^a.

Disturbances from the liver and bile ducts

Increased activity of γ-glutamyltransferase, increased activity of liver enzymes, increased activity of transaminases.

Disturbances from the skin and subcutaneous tissue

Acne, drug rash, dry skin, eczema, erythema, pruritus, rash, urticaria.

Disorders from the musculoskeletal system and connective tissue

Arthralgia, back pain^a, increased activity of creatine phosphokinase of blood, joint stiffness, joint swelling, muscle spasms, muscle weakness, musculoskeletal pain^a, pain in the neck.

Disorders from the kidneys and urinary tract

Dysuria, pollakiuria, urinary incontinence.

Violations of the reproductive system and mammary glands

Discomfort in the area of mammary glands, breast enlargement, pain in the mammary glands, violation of ejaculation, erectile dysfunction, gynecomastia, menstrual irregularity^b, sexual dysfunction.

General disorders and conditions from the area of drug administration

Asthenia, fever, chest discomfort, chest pain, chills, withdrawal syndrome, face swelling, fatigue^a, gait disturbance, malaise, swelling^b, fever.

Injury, poisoning and complications of procedures

A fall.

^a It was reported in ≥ 2% of patients who received the drugs TREVITA or XEPLION.

^b The term "edema" includes generalized edema, peripheral edema, edema with fossa formation upon pressing. The term "disorders of the menstrual cycle" includes irregular menstruation, oligomenorrhoea.

The following are other undesirable reactions observed in clinical studies of paliperidone (the drug KSEPLION and paliperidone for oral administration) and risperidone, and not observed in clinical studies of the drug TREVITA.

Violations of the blood and lymphatic system

Increase in the number of eosinophils.

Immune system disorders

Anaphylactic reactions.

Disorders from the metabolism and nutrition

Anorexia.

Disturbances from the nervous system

Impaired balance, convulsions^a, impaired coordination, decreased level of consciousness, diabetic coma, trembling of the head, loss of consciousness, malignant neuroleptic syndrome, lack of response to stimuli, bradykinesia, stroke,

hypertension, lethargy, oromandibular dystonia, parkinsonian gait. transient impairment of cerebral circulation.

Disturbances on the part of the organ of sight

Violation of eyeball movements, circular eyeball movements, eye hyperemia, photophobia, oculogic crisis.

Disorders from the cardiovascular system

Blockade of the bundle of Guiss, sinus arrhythmia, hot flashes, ischemia.

Disturbances from the respiratory system, thorax and mediastinum

Dysphonia, hyperventilation, aspiration pneumonia, congestion in the lungs, wet wheezing, wheezing.

Disorders from the gastrointestinal tract

Incontinence of stool, fecaloma, intestinal obstruction, swelling of the tongue, pain in the upper abdomen, obstruction of the small intestine.

Disturbances from the skin and subcutaneous tissue

Dandruff, hyperkeratosis, seborrheic dermatitis, skin discoloration, general itching, papular rash.

Disorders from the musculoskeletal system and connective tissue Violation of the posture, rhabdomyolysis. pain in the muscles, pain in the limbs, muscle cramps, rigidity of the occipital muscles, torticollis, trismus.

Violations of the reproductive system and mammary glands

Breaking of mammary glands, discharge from the vagina, discharge from the mammary glands, delay in menstruation, irregular menstruation, painful sensitivity of the mammary glands, retrograde ejaculation.

General disorders and conditions from the area of drug administration

Decrease in body temperature, compaction, thirst, peripheral edema.

^a The term "convulsions" includes convulsive seizures of the type grand mal.

Phenomena of special interest for this class of drugs

Extrapyramidal symptoms (EPS).

The results of a double-blind, placebo-controlled phase of a long-term study on the prevention of recurrence suggest that an increase in the incidence of extrapyramidal symptoms associated with extrapyramidal symptoms was observed in the TREVITA group compared with the placebo group (13 patients [8.1%] and 5 patients [3.4 %], respectively).

To assess the EPC used a number of methods: (1) the Simpson-Angus scale (SAS) for the evaluation of parkinsonism, (2) the Barnes akathisia scoring scale (BAS), (3) scale of assessment of abnormal (pathological) involuntary movements (AIMS), which assesses dyskinesia, (4) the use of anticholinergic drugs for EPS therapy, (5) frequency of spontaneous reports of EPS. The evaluation of extrapyramidal symptoms included a summary analysis of the following symptom groups: dyskinesia, dystonia, hyperkinesia, parkinsonism and tremor.

Estimating the incidence of extrapyramidal symptoms using assessment scales and for the use of anticholinergic drugs
	Percentage of patients
	Open phase	Double blind phase
	Paliperidone palmitate^a N = 506 %	Placebo N = 145 %	ТЕРВ�?КТА N = 160 %
Parkinsonism^b	6	3	6
Akathisia^at	3	1	4
Dyskinesia^g	1	3	3
The use of anticholinergic drugs^d	11	9	11
^a Openly faz patients received several doses of the drug KSEPLION followed by a single administration of the drug TREVITA. ^bThe proportion of patients with a SAS score of> 0.3 at all times. ^atThe proportion of patients with a scale score BAS ≥ 2 at all times. ^g The proportion of patients with a scale score AIMS ≥ 3 on any of the first 7 points or ≥ 2 on the 2nd or more of first 7 items throughout the time. ^dProportion of patients who received anticholinergic drugs for EPS

Undesirable reactions associated with EPS
	Percentage of patients
	Open phase	Double blind phase
	Paliperidone palmitate^a N = 506 %	Placebo N = 145 %	ТЕРВ�?КТА N = 160 %
The total proportion of patients who experienced adverse reactions associated with EPS	10	3	8
Parkinsonism	4	0	4
Hyperkinesia	5	2	5
Tremor	2	0	1
Dyskinesia	<1	1	1
Dystonia	1	0	1
^a Openly phase, patients received multiple drug vines KSEPLION followed TREVIKTA single administration of the drug. The parkinsonism group includes parkinsonism, type rigidity cogwheel, drooling, extrapyramidal disorders, hypokinesia, muscle rigidity, muscle tension, musculoskeletal stiffness. The hyperkinesia group includes akathisia, restlessness. The dystonia group includes dystonia, blepharospasm, muscle spasms.

After injection of the drug TREWIKTA in the openase in 12 patients (3.2%), extrapyramidal symptoms were observed, which appeared for the first time or in a more severe degree, the phenomenon of the group hyperkinesia (1,6%) and Parkinsonism (1.3%) were most often noted. One patient interrupted therapy in open sourceaza because of the restless state.

Estimate of the time before the onset of EPS during the double-blind phase showed no clustering of these phenomena can be expected that such a grouping to be associated with peak plasma concentrations of paliperidone in the placebo group.

Dystonia. Symptoms of dystonia, prolonged abnormal contraction of muscle groups, can occur in susceptible patients during the first few days of treatment. Symptoms of dystonia include spasm of the neck muscles, sometimes progressing to a tightness in the throat, difficulty swallowing, difficulty breathing, bulging tongue. These symptoms can arise at use of low doses, nevertheless they occur more often and in a more severe application of higher doses of antipsychotics of the 1st generation. A higher risk of acute dystonia is observed in men and younger patients.

Pain and reaction at the injection site. Redness and swelling are marked with no more than 2 % patients in both groups in during the double blind phase of the long-term studies on the prevention of recurrences and were classified as mild events (on a 4-point scale, where 0 = absence.1 = mild, 2 = medium, 3 = severe). In none of the groups during the double-blind Phase there were no seals at the site of administration, none of the patients interrupted the therapy in connection with the administration of the drug TREVITA.

Assessment of pain at the site of administration by patients was similar in the placebo and TREVICA groups during the double blind phase.

Assessment of pain at the site of administration by patients in the Phase I clinical trial with the introduction of a single dose of XEPLION allowed studying change pain at the injection site over time. The residual pain was exacerbated after 1 or 6 hours after administration, after which it decreased within 3 days. Injections into the deltoid muscle were more painful compared to injections in the gluteal muscle, although all pain ratings were below 10 points on a 100-point scale.

Weight gain. In a double-blind, placebo-controlled phase of a long-term relapse prevention study, a pathological increase in body weight> 7% of the baseline assessment of the double-blind phase until its end was reported in 15 patients (10%) in the TREVITA group and 1 patient (1%) in the placebo group . On the contrary, a pathological decrease in body weight> 7% of the baseline assessment of the double-blind phase before its end was reported in 2 patients (1%) in the TREVITA group and 12 patients (8%) in the placebo group. The mean change in body weight from baseline assessment of the double-blind phase to its end was + 0.94 kg and -1.28 kg for TREVITA and placebo, respectively.

Laboratory indicators: serum prolactin. During a double-blind, placebo-controlled phase of a long-term relapse prevention study; an increase in the concentration of prolactin relative to the reference values (> 13.13 ng / ml in men and> 26.72 ng / ml in women) was more frequent in men and women who took the drug TREVIKTA, compared with the placebo group (9% vs. 3% and 5% vs. 3%, respectively). In the TREVITA group, the mean change from baseline assessment of the double-blind phase to its end was + 2.90 ng / mL for men (vs. 10.26 ng / mL in the placebo group) and +7.48 ng / mg for women (vs. - 32.93 ng / ml in the placebo group). Amenorrhea was observed in one woman (2.4%) in the TREVITA group, while there were no adverse events potentially associated with prolactin concentration in the placebo group. Among the men of both groups, there were no side effects potentially associated with the concentration of prolactin.

Post-registration data

In addition to the adverse reactions reported during the clinical trials and listed above, the following adverse reactions were observed during the post-marketing application of paliperidone and / or risperidone.

The frequency of undesired reactions was classified as follows: Often (≥ 10 %), often (≥ 1% and <10%), infrequently (≥ 0.1% and <1%), rarely (≥ 0.01% and <0.1%) and very rarely (< 0.01%, including isolated cases).

Table 6 shows the undesirable reactions observed during post-registration observation of the use of paliperidone and / or risperidone.

These frequencies are determined on the basis of the frequency of spontaneous reports on the use of paliperidone and on the basis of clinical studies using injectable dosage forms of paliperidone.

Table 6. Undesirable reactions observed during post-registration

monitoring the use of paliperidone and / or risperidone.

System-Organ Class	frequency of spontaneous messages	frequency in clinical trials
Violations of the blood and lymphatic system
agranulocytosis	rarely	unknown
thrombocytopenia	rarely	infrequently
Disorders from the endocrine system
inadequate secretion of antidiuretic hormone	unknown	rarely
Disorders from the metabolism and nutrition
diabetes	highly rarely	infrequently^a
diabetic ketoacidosis	highly rarely	rarely
hypoglycemia	highly rarely	rarely
water intoxication	unknown	unknown
Mental disorders
mania	rarely	rarely
Disturbances from the nervous system
dysgeusia	rarely	infrequently
Disturbances on the part of the organ of sight
intraoperative syndrome of sagging iris	unknown	unknown
Disorders from the cardiovascular system
atrial fibrillation	highly rarely	rarely
venous thrombosis	highly rarely	rarely
pulmonary embolism	highly rarely	unknown
Disturbances from the respiratory system, thorax and mediastinum
sleep apnea syndrome	rarely	rarely
Disorders from the gastrointestinal tract
pancreatitis	rarely	rarely
intestinal obstruction	rarely	unknown
Disturbances from the liver and bile ducts
jaundice	unknown	unknown
Disturbances from the skin and subcutaneous tissue
angioedema	rarely	unknown
alopecia	highly rarely	infrequently
Disorders from the kidneys and urinary tract
retention of urine	highly rarely	rarely
Pregnancy, childbirth and perinatal conditions
withdrawal syndrome in newborns	rarely	unknown
Violations of the reproductive system and mammary glands
priapism	rarely	unknown
General disorders and reactions at the site of administration
hypothermia	rarely	rarely
abscess at insertion site	rarely	rarely
inflammation of the subcutaneous fat cellulose at the site of administration	rarely	rarely
hematoma at the site of administration	rarely	rarely
cyst at the site of administration	unknown	rarely
necrosis at the site of administration	unknown	unknown
ulcer at the site of administration	unknown	unknown

^a In placebo-controlled clinical trials of the drug KSEPLION diabetes was observed with a frequency of 0.32% in the group of patients receiving the drug, compared with a frequency of 0.39% in the placebo group. In a double-blind, placebo-controlled phase of a long-term study on the prevention of relapses with TREVITA, diabetes was observed at a rate of 0.6% in the group of patients receiving the drug, compared with 0% in the placebo group. The total incidence of diabetes in all patients, calculated from the results of all clinical studies, was 0.63%.

In addition to the above, during the post-marketing application of paliperidone and / or risperidone, thrombotic thrombocytopenic purpura was noted.

In very rare cases, in the course of post-marketing use in patients,previously received oral preparations of risperidone or paliperidone, there were cases of anaphylactic reactions after the administration of the drug XEPLION.

Overdose:

Since the drug TREVIKTA is intended for administration by medical personnel, the likelihood of its overdose by patients is small.

Symptoms

A limited number of cases of paliperidone overdose are known. Among the few cases recorded during pre-registration studies of paliperidone for oral administration, the maximum reception on the basis of the assessments was 405 mg. The observed signs and symptoms included extrapyramidal symptoms and unsteadiness of gait. Other expected signs and symptoms correspond to an increase in the known pharmacological action of paliperidone, i. E. drowsiness, retardation, tachycardia, lowering blood pressure, lengthening the QT interval. In case of an overdose of oral paliperidone, polyformal ventricular tachycardia of the "pirouette" type and ventricular fibrillation were noted. In the case of acute overdose, consideration should be given to the possibility of obtaining several drugs by patients.

Treatment

When assessing the need for treatment and rehabilitation patients should take into account the long-term release of the active substance and a long half-life of paliperidone. There is no specific antidote for paliperidone. General support measures should be implemented, the airway patency should be ensured and maintained, sufficient ventilation of the lungs and oxygen saturation of the blood. Immediately begin monitoring the function of the cardiovascular system, including continuous monitoring of the ECG, to identify possible arrhythmia. In the event of a reduction in blood pressure and circulatory collapse, appropriate measures should be taken, for example, intravenous administration of solutions and / or sympathomimetics. When developing severe extrapyramidal symptoms, anticholinergic drugs are used. Careful monitoring of the condition the patient before its restoration.

Interaction:

Like other antipsychotics, paliperidone can increase the interval Q-T, therefore it is necessary to combine with caution the drug TREVIKTA with other drugs that increase the interval Q-T, such as antiarrhythmic drugs (incl. quinidine, disopyramide, procainamide, amiodarone. sotalol), antihistamines, antipsychotic drugs (chlorpromazine, thioridazine); antibiotics (incl. gatifloxacin, moxifloxacin), some medicines against malaria (incl. mefloquine).

Since paliperidone palmitate is hydrolyzed to paliperidone, the results of studies of paliperidone for oral administration should be taken into account when evaluating the possibility of drug interaction.

The ability of the drug TREVIKTA to influence other drugs

It is not expected that paliperidone will exhibit clinically significant pharmacokinetic interaction with drugs metabolized by cytochrome P450 isoenzymes. Research in vitro using microsomes human liver showed that paliperidone essentially does not weaken the metabolism of substances with isoenzymes of cytochrome P450, 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. It is also not expected that paliperidone will exhibit the properties of the isoenzyme inductor.

Paliperidone in high concentrations is a weak inhibitor of P-glycoprotein. However, data in vivo in this respect, no, and the clinical significance of this phenomenon is unknown.

Given the action of paliperidone on the central nervous system, caution should be taken with the preparation of TREVITA in combination with other central drugs and alcohol. Paliperidone can weaken the effect of levodopa and dopamine receptor agonists. At simultaneous application it is necessary to supervise a status of the patient.

Because of the ability of the drug TREVIKTA to cause orthostatic hypotension, there can be an additive increase in this effect when the drug is used in conjunction with other drugs that have this ability. Patients prone to hypotension should be treated observation of orthostatic physiological parameters.

It should be carefully combined paliperidone with drugs that reduce the convulsive threshold, such as phenothiazines, butyrophenones, tricyclic derivatives, selective serotonin reuptake inhibitors, tramadol, mefloquine etc.

Simultaneous administration of oral paliperidone at a dosage of 12 mg once a day and sodium divalproex tablets of prolonged action (at a dose of 500-2000 mg once a day) does not affect the pharmacokinetics of valproate. With the simultaneous use of paliperidone and valproate, dose adjustment of paliperidone and valproate is not required. The pharmacokinetic interaction between the drug TREVIKTA and lithium is unlikely.

The ability of other drugs to influence the preparation of TREVITA

Clinically important interactions between paliperidone and drugs metabolized by isoenzymes of the cytochrome P450 system. not expected. Paliperidone is not a substrate of isoenzymes CYP1A2, CYP2A6, CYP2C9, CYP2C19 and CYP3A5. This suggests a weak probability of interaction with the inhibitors and inducers of these isoenzymes. Although research in vitro show the possibility of a minimum participation of isoenzymes CYP2D6 and CYP3A4 in the metabolism of paliperidone, there is currently no evidence that these enzymes can play a significant role in the metabolism of paliperidone in vivo. Research in vitro evidence that paliperidone is a substrate of P-glycoprotein.

Paliperidone is metabolized to a limited extent by isoenzyme CYP2D6. In a study of the interaction of paliperidone for oral administration with an active inhibitor CYP2D6 paroxetine in healthy volunteers there was no clinically significant change in the pharmacokinetics of paliperidone.

Simultaneous use of paliperidone and strong isoenzyme inducers CYP3A4 and P-glycoprotein may cause to a decrease in the concentration of paliperidone in plasma. If possible, simultaneous use of paliperidone and strong inducers should be avoided isoenzyme CYP3A4 and P-glycoprotein. If the use of strong inductors it is necessary to consider the possibility of transferring the patient to sustained release paliperidone tablets. Receiving paliperidone with a sustained release of the active ingredient (1 time per day) orally simultaneously with carbamazepine (200 mg twice daily) resulted in a decrease in the mean C_m_Oh and AUC paliperidone by about 37%. This decrease is largely due to an increase in renal clearance of paliperidone by 35%, probably due to the activation of renal P-glycoprotein carbamazepine.A very small decrease in the amount of the drug, excreted through the kidneys in an unchanged form, suggests that carbamazepine only slightly affects the metabolism in the liver or the bioavailability of paliperidone. When the carbamazepine is administered, the dose of TREVITA should be reviewed and, if necessary, increased. Conversely, with the withdrawal of carbamazepine, the dose of TREVITA should be reviewed and, if necessary, reduced. It should take into account the duration of the drug TREVITA.

Paliperidone at a physiological pH is a cation, and is mostly excreted unchanged by the kidneys - half by filtration, and half by active secretion. The simultaneous use of trimethoprim, which inhibits the active cation transport system in the kidneys, did not affect the pharmacokinetics of paliperidone. With the simultaneous administration of oral paliperidone prolonged action in a dose of 12 mg 1 time per day and tablets of prolonged action of sodium divalproex (2 tablets 500 mg once a day) there was an increase in C_m_Oh and AUC paliperidone by about 50%, probably as a result of an increase in oral absorption of the drug.Since there was no significant effect on overall clearance, no clinically significant interaction between sodium divalproex, sustained-release tablets, and TREVITA is expected. Studies of this interaction with the drug TREVITA have not been conducted. The pharmacokinetic interaction of lithium and paliperidone is unlikely.

The use of the drug TREVITA together with risperidone or with the oral form of paliperidone

Special instructions:

Increased mortality among elderly patients with psychosis in the background of dementia

The drug TREVITA has not been studied in elderly patients with dementia.

Older patients with psychosis on the background of dementia, taking antipsychotics, have an increased risk of death. Cross-sectional analysis of the results of studies showed an increased mortality of elderly patients with dementia,who received atypical antipsychotics, including risperidone, aripiprazole, olanzapine and quetiapine, compared with placebo. Among patients who received risperidone and placebo, mortality was 4% and 3.1%, respectively %. An analysis of 17 placebo-controlled clinical trials revealed an increased risk of death in patients taking atypical antipsychotics 1.6-1.7 times compared with patients taking placebo. During a typical 10-week controlled study, patients who received the drug and placebo had mortality rates of 4.5% and 2.6%. Despite the fact that the causes of death were varied, most of them had cardiovascular (eg, heart failure, sudden death) or infectious (eg pneumonia) nature. Observational studies suggest that typical neuroleptics, like atypical antipsychotics, can increase mortality. It is unclear how much higher mortality in observational studies is due to the use of antipsychotics, and not to other characteristics of patients. The drug TREVITA is not indicated for the treatment of psychosis against the background of dementia.

Disorders of cerebral circulation, including stroke, in elderly patients with psychosis on the background of dementia

In placebo-controlled studies, an increased incidence of cerebral circulation (transient and stroke), including fatal, was found in elderly patients with dementia who received some atypical antipsychotics, including risperidone, aripiprazole and olanzapine, compared with placebo. Studies of oral paliperidone, drugs KSEPLION and TREVITA in elderly patients with dementia were not performed, these drugs are not indicated for the treatment of psychosis against the background of dementia.

Malignant neuroleptic syndrome

With the use of neuroleptics, including paliperidone, the development of a potentially lethal symptom complex, sometimes called malignant neuroleptic syndrome (CNS), and characterized by hyperthermia, muscle rigidity, instability in the autonomic nervous system (irregular heartbeat or blood pressure, tachycardia, diaphoresis, cardiac arrhythmia) is recorded. a violation of consciousness.In addition, there may be an increase in serum creatinophosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. Diagnosis of patients with this syndrome is difficult. When diagnosing, it is important to identify cases in which clinical manifestations include serious medical conditions (eg, pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal symptoms. Other important assumptions in differential diagnosis are central anticholinergic toxicity, body overheating, drug fever, and primary pathology of the central nervous system.

In case of ZNS development it is necessary: (1) immediately cancel neuroleptics and other drugs not essential for concomitant therapy; (2) to conduct intensive symptomatic treatment and medical supervision of the patient; (3) to treat concomitant medical conditions with specific treatment. A single opinion about the specific pharmacological treatment of simple cases of CNS is absent.

If, after recovery from the ZNS, the patient needs to take an antipsychotic, careful monitoring of the resumption of therapy should be monitored, since repeated cases of CNS are reported.

Interval QT

Paliperidone causes a slight increase in the corrected interval QT (QTc). It should avoid the simultaneous use of paliperidone and drugs that can lead to lengthening of the interval QTc, such as antiarrhythmic drugs of class 1A (quinidine, procainamide) or class III (amiodarone, sotalol), antipsychotics (chlorpromazine, thioridazine), antibiotics (gatifloxacin, moxifloxacin), etc. Caution should be exercised when using TREVITA in patients with a history of cardiac arrhythmias or with congenital lengthening of the interval QT.

Some conditions, in particular bradycardia, hypokalemia, hypomagnesemia, simultaneous use of other drugs that can lead to lengthening of the interval QTc, as well as congenital lengthening of the interval QT may increase the risk of polymorphic ventricular tachycardia such as "pirouette" and / or sudden death with simultaneous use with drugs that may lead to lengthening of the interval QTc.

Effect of paliperidone on the interval QT evaluated in a double blind, actively controlled (moxifloxacin, a single dose of 400 mg), a multicenter study of the use of oral paliperidone in adult patients, in 4 efficacy trials and in one study of the use of the XEPLION drug for maintenance therapy.

In the first study (n = 141) with the use of 8 mg of immediate-release paliperidone (n = 50) there was an increase QTcLD (interval QT, Corrected according to the heart rate using a population-specific linear method) at 12.3 msec on day 8 after 1.5 hours after the dose taken. The mean steady-state peak plasma concentration after administration of 8 mg of immediate-release oral paliperidone (C_m_Oh = 113 ng / ml) was approximately 2 times higher than the plasma concentration after administration of the TREVITA preparation at a maximum dose of 525 mg injected into the deltoid muscle (median C_m_Oh = 56 ng / ml), In the same study, when 4 mg of immediate-release sustained release paliperidone was administered C_max was 35 ng / ml, while there was an increase QTcLD at 6.8 msec on day 2 after 1.5 hours after the dose.

In 4 studies of the effectiveness of the drug KSEPLION none of the patients observed a change QTcLD more than 60 msec, none of the patients QTcLD did not exceed 500 msec at any time. In a study of maintenance therapy, none of the patients experienced a change QTcLD more than 60 msec, in 1 patient QTcLD was 507 msec (corrected interval QT, calculated according to the Basetta formula (QTcB), was 483 msec); In the same patient, the heart rate was 45 beats per minute.

In a long-term study of the use of the drug TREVIKTA for maintenance therapy of schizophrenia in 1 patient (<1%), the increase QTcLD more than 60 msec in the open phase, none of the patients observed a change QTcLD more than 60 ms after application of the drug TREVIKTA in the double blind phase, none of the patients QTcLD did not exceed 480 msec at any time.

Late 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.

The syndrome of potentially irreversible, involuntary, dyskinetic movements can develop with the use of antipsychotics. Despite the fact that the prevalence of the syndrome is higher in elderly patients, especially older women, it is impossible to predict which patients will develop the syndrome. It is not known whether antipsychotics differ in their ability to cause tardive dyskinesia.

Although the risk of developing tardive dyskinesia and the likelihood that it will become irreversible increases with the duration of treatment and the total dose of antipsychotics administered, the syndrome can develop after a relatively short period of treatment with low doses, although such incidents are infrequent.

The therapy of tardive dyskinesia is unknown, but with the cancellation of antipsychotics, the syndrome may partially or completely cease. The use of an antipsychotic alone can suppress (or partially suppress) the signs and symptoms of late dyskinesia syndrome and thus mask the aforementioned processes. The effect of suppression of symptoms on the long-term course of the syndrome is unknown.

You should prescribe the drug TREVITA in such a way as to minimize the likelihood of the emergence of tardive dyskinesia.Long-term therapy with antipsychotics should be delayed in patients with other chronic diseases responding to taking antipsychotics. In patients requiring long-term treatment, minimal doses should be used with minimal duration of therapy, providing a satisfactory clinical response. Periodic evaluation of the need for continuation of therapy should be made.

When symptoms of tardive dyskinesia should be considered, the possibility of reversing all antipsychotics, including the drug TREVITA, should be considered. It should take into account the duration of the drug TREVITA. Some patients may require treatment with TREVITA, despite the onset of the syndrome.

Metabolic disorders

Hyperglycemia and diabetes mellitus

In the treatment with antipsychotics, hyperglycemia and diabetes mellitus were observed, in some cases leading to ketoacidosis, hyperosmolar coma, or death. Most of these cases were observed in post-registration and epidemiological studies. The cases of hyperglycemia and diabetes were also registered with the use of the drug TREVIKTA.Establishing the relationship between the use of atypical antipsychotics and impaired glucose metabolism is complicated by an increased risk of developing diabetes in patients with schizophrenia and the prevalence of diabetes mellitus in the general population. Given these factors, the relationship between the use of atypical antipsychotics and the development of side effects associated with hyperglycemia has not been fully established. However, the results of epidemiological studies suggest an increased risk of adverse reactions associated with hyperglycemia in patients receiving atypical antipsychotics.

Patients diagnosed with diabetes mellitus who start using atypical antipsychotics should be checked regularly for impaired glucose control. In patients with risk factors for diabetes mellitus (obesity, family history of diabetes) who start using atypical antipsychotics, at the beginning of treatment and periodically during treatment, the fasting blood glucose test should be performed. In all patients, it is necessary to conduct clinical monitoring for the presence of symptoms of hyperglycemia and diabetes mellitus, such as polydipsia, polyuria, polyphagia, weakness.In patients who have symptoms of hyperglycemia during atypical antipsychotics, a fasting blood glucose test should be performed. In some cases, hyperglycemia was resolved with the abolition of atypical antipsychotics, but some patients required continuation of antidiabetic therapy despite the withdrawal of the antipsychotic.

Below are the data obtained during a long-term clinical trial of the use of the drug TREVIKTA for maintenance therapy of schizophrenia.

	The open phase (relative to the initial level in the open phase)	The double-blind phase (relative to the original level in the double-blind phase)
	Paliperidone	Placebo	ТЕРВ�?КТА
	palmitate^a
Mean change from baseline (mg / dl)
	n = 397	n = 120	n = 138
Concentration of glucose in serum	1,2	-1,6	-1,2

change from the original level)

Share of patients with changes n = 397 n = 128 n = 148

Concentration of glucose in serum 2,3 % 2,3 % 4,1%

(norm - less than 100 mg / dl, increased (9/397) (3/128) (6/148)

level - more than 126 mg / dl)

^a During the open phase, patients received several doses of the drug KSEPLION, and then one dose of the drug TREVIKTA

Dyslipidaemia

In patients receiving treatment with atypical antipsychotics, undesirable lipid changes were observed.

Below are the data obtained during a long-term clinical trial of the use of the drug TREVIKTA for maintenance therapy of schizophrenia.

	Open phase	Double blind phase
	(relative to the original	(relative to the baseline level
	level in the open phase)	in a double blind phase)
	Paliperidone	Placebo	ТЕРВ�?КТА
	palmitate^a
Mean change from baseline (mg / dl)
Cholesterol	n = 400	n = 120	n = 138
change from baseline	0,5	-0,4	0,9
LDL	n = 396	n = 119	n = 138
change from baseline	1,1	-0,4	1,1
HDL	n = 397	n = 119	n = 138
change from baseline	-0,2	-0,5	-1,3
Triglycerides	n = 400	n = 120	n = 138
change from baseline	0,1	-0,2	5,1
Share of patients with changes
Concentration of cholesterol	2,0%	3,9%	1,4%
(norm - less than 200 mg / dl, increased	(8/400)	(5/128)	(2/148)
level - more than 240 mg / dl)
Concentration of LDL	0,3%	0,8%	0%
(norm - less than 100 mg / dl, increased	(1/396)	(1/127)	(6/148)
level - more than 160 mg / dl)
Concentration of HDL	8,6%	9,4%	13,5%
(norm or rate - not less than 40 mg / dl, lowered	(34/397)	(12/127)	(20/148)
level - less than 40 mg / dl)
Triglycerides	4,5%	1,6%	8,1%
(norm or rate - less than 150 mg / dl, raised or increased	(18/400)	(2/128)	(12/148)
level - more than 200 mg / dL)

During the open phase, patients received several doses of the drug KSEPLION, and then one dose of the drug TREVIKTA

Weight gain

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

Below are the data obtained during a long-term clinical trial of the use of the drug TREVIKTA for maintenance therapy of schizophrenia, the average changes in body weight and the proportion of patients who have an increase in body weight of more than 7%.

	The open phase (relative to the initial level in the open phase)	The double-blind phase (relative to the original level in the double-blind phase)
	Paliperidone palmitate^a	Placebo	Paliperidone palmitate^a
	n = 466	n = 142	n = 157
Change in body weight (kg) relative to baseline	1,42	-1,28	0,94
The proportion of patients who had an increase in body weight relative to the baseline was more than 7%	15,2 %	0,7 %	9,6 %
^a During the open phase, patients received several doses of the drug KSEPLION, and then one dose of the drug TREVIKTA

Orthostatic hypotension and fainting

Having alpha-adrenoblocker activity, paliperidone in some patients may cause orthostatic hypotension and fainting. In a long-term clinical study of maintenance therapy, syncope was observed in <1% (1/506)who received treatment with XEPLION during the open phase; During the double-blind phase, no cases of syncope were observed in any of the groups. In a long-term clinical study of maintenance therapy, orthostatic hypotension was noted in <1% (1/506) of patients treated with KSEPLION and <1% (1/379) patients after a single dose of TREVITA was administered during the open phase; During the double-blind phase, no cases of arterial hypotension were observed in any of the groups.

Caution should be exercised in patients with cardiovascular diseases (eg, heart failure, myocardial infarction or ischemia in the anamnesis, impaired cardiac conduction), impaired cerebral circulation or conditions predisposing to lowering blood pressure (eg, dehydration, decreased circulating blood volume, use of antihypertensive drugs). Patients prone to hypotension should be monitored for orthostatic physiological indicators.

Leukopenia, neutropenia, agranulocytosis

In clinical trials and during post-registration use, cases of leukopenia and neutropenia were observed with the use of antipsychotics, including with the use of the drug TREVIKTA. Agranulocytosis was also noted.

Possible risk factors for the development of leukopenia / neutropenia include a baseline low white blood cell count / absolute neutrophil count and leukopenia / neutropenia caused by medication, in anamnesis. Such patients are recommended to conduct a full blood test frequently during the first months of therapy; discontinuation of treatment with TREVITA 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 observed for fever or symptom onset and should begin treatment immediately if symptoms occur. Patients with severe neutropenia (absolute number of neutrophils less than 1 x 10⁹ / l) should stop using the drug TREVIKTA until the number of white blood cells is not normalized.

It should take into account the duration of the drug TREVITA.

Hyperprolactinemia

Paliperidone, like other drugs that are antagonists of dopamine D₂ receptors, leads to an increase in the concentration of prolactin, which persists with prolonged use of the drug. An increase in the concentration of prolactin with paliperidone is close to that of risperidone, with a higher concentration of prolactin compared with other antipsychotics.

Regardless of the etiology, hyperprolactinaemia can help suppress the hypothalamic gonadotropin-releasing hormone, which leads to a decrease in the secretion of the pituitary gonadotropin. This, in turn, can reduce reproductive function due to violation of gonadal steroidogenesis in women and men. In patients taking drugs that increase the concentration of prolactin, there were galactorrhea, amenorrhea, gynecomastia and impotence.

Prolonged hyperprolactinaemia with simultaneous hypogonadism can lead to a decrease in bone density in women and men.

Studies of tissue cultures indicate that in about a third of cases, breast cancer in humans is prolactin-dependent in vitro, which is an important factor in the appointment of drugs that increase the concentration of prolactin, patients with previously detected breast cancer. In studies of the carcinogenicity of risperidone in mice and rats, there was an increase in the incidence of neoplasia of the pituitary gland, breast and pancreatic islet cells (mammary adenocarcinoma, pituitary adenoma and pancreatic adenoma). So far, in clinical and epidemiological studies, a direct link between oncogenesis and the use of antipsychotics has not been demonstrated, however, the available data are not sufficient to conclude that such a link exists or is not present. Caution should be exercised when using paliperidone in patients with possible prolactin-dependent tumors.

In a long-term study of the use of TREVITA for maintenance therapy, an increase in prolactin concentration above the range of reference values (> 13.13 ng / ml in men and> 26.72 ng / ml in women) relative to baseline in the open phase was noted with a higher frequency in men and women,who took the drug TREVIKTA in comparison with the placebo group (46 % against 25% and 32% against 15%, respectively). Amenorrhea was observed in one woman (2.4%) in the TREVITA group, while there were no adverse events potentially associated with prolactin concentration in the placebo group. Among the men of both groups, there were no side effects potentially associated with the concentration of prolactin.

Prior to the double-blind phase (during the 29-week open phase of a long-term study of maintenance therapy), the mean prolactin concentration was 17.1 ng / mL in men (N = 368) and 51.6 ng / ml in women (N = 122). Twelve weeks after a single injection of TREVITA at the end of the open phase, the mean concentration of prolactin was 25.8 ng / ml in men (N = 322) and 70.6 ng / ml in women (N = 107). During the open phase, 27% of women and 42% of men had an increase in prolactin concentration above the range of reference values relative to the baseline level; the incidence of prolactin-dependent adverse reactions was higher in women than in men (7.9% and 3.7%, respectively). The most frequent (> 3%) potentially prolactin-dependent adverse reactions in women were amenorrhea (4.7%) and galactorrhea (3.1%).In men, in the open phase, there were no potentially prolactin-dependent adverse reactions with a frequency greater than 3%.

Convulsions

In a long-term clinical study of maintenance therapy, there were no reports of convulsions or convulsions. In a baseline clinical study of the XEEPLON preparation and in a double-blind, placebo-controlled clinical trial, convulsions were observed in patients with schizophrenia in <1% of patients (1/1293) who received therapy with KSEPLION, and <1% of patients (1/510), who received placebo, had convulsive seizures of the type grand mal.

Like other antipsychotics, the drug TREVITA should be used with caution in patients who have a history of seizures or other conditions in which the convulsive threshold may be reduced. Conditions in which the convulsive threshold may be reduced may be more common in patients 65 years of age or older.

Dysphagia

With the use of antipsychotics, esophageal dyskinesia and aspiration were associated. Patients at risk of aspiration pneumonia should be cautioned to use the drug TREVIKTA and other antipsychotic drugs.

Priapism

There are data on the ability of drugs that have the properties of alpha-adrenoblockers to cause priapism. In clinical trials of the drug TREVIKTA, cases of priapism were not registered, nevertheless priapism was registered as part of the post-registration control of the oral paliperidone application. Priapism of severe degree may require surgical intervention.

Influence on body temperature regulation

With the use of neuroleptics attributed to the deterioration of the body's ability to lower body temperature. It is advisable to use caution when prescribing TREVITA to patients who may be exposed to the effects of increasing body temperature, for example, extreme physical exertion, high ambient temperature, effects of drugs with m-cholinolytics activity, and also dehydration.

Hypersensitivity reactions

It is reported that very rare cases of the occurrence of anaphylactic reactions during post-registration use of the drug KSEPLION in patients who have previously tolerated oral forms of paliperidone or risperidone.

In case of hypersensitivity reactions, it is necessary to stop using TREVITA, take the necessary supporting clinical measures and monitor the patient's condition until the symptoms disappear.

Venous thromboembolism

When using antipsychotic drugs, cases of venous thromboembolism were noted. Since patients taking antipsychotics often have a risk of developing venous thromboembolism, all possible risk factors should be identified before and during treatment with TREVITA, and precautionary measures should be taken.

Parkinson's disease and dementia with Levi bodies

The physician should compare the risk and benefit of using antipsychotics, including the TREVITA preparation, in patients with Parkinson's disease or Lewy body dementia, since both these categories of patients may have a higher risk of developing neuroleptic malignant syndrome (CNS) and a risk of hypersensitivity to neuroleptics. Manifestations of hypersensitivity can include confusion, dulling of pain sensitivity, unstable posture with frequent falls,as well as extrapyramidal symptoms.

Antiemetic action

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 drugs or, for example, conditions such as bowel obstruction, Reye's syndrome or a brain tumor.

Introduction

When intramuscular introduction, care should be taken to avoid accidental ingestion of the drug into the blood vessel.

Intraoperative syndrome of sagging iris (ISDR)

ISDR was observed during an operative intervention for the presence of cataracts in patients receiving antagonist therapy α1-adrenoceptors, such as the drug TREVIKTA.

ISDR increases the risk of complications associated with the organ of vision, during and after an operation. The physician conducting such an operation should be informed in advance that the patient has taken or is currently taking drugs with antagonist activity a₁- adrenergic receptors. Potential benefit of discontinuing therapy with antagonists a₁- adrenergic receptors before surgical intervention is not established, and should be evaluated taking into account the risks associated with the abolition of antipsychotic drugs.

Renal insufficiency

The concentration of paliperidone in plasma is increased in patients with impaired renal function. Correction of dose is recommended in patients with impaired renal function of mild degree. It is not recommended to use the drug TREVIKTA in patients with impaired renal function of medium or severe degree (creatinine clearance <50 ml / min)

Liver failure

The use of TREVITA in patients with severe hepatic dysfunction (class C on the Child-Pugh scale) has not been studied. Care should be taken when using paliperidone in these patients.

Effect on the ability to drive transp. cf. and fur:

With the use of the drug TREVITA, drowsiness, sedation and dizziness were noted. ТЕРВ�?КТА can violate the performance of actions that require concentration of attention and speed of psychomotor reactions, and can also affect vision. Therefore, patients should be advised not to drive vehicles and moving mechanisms until their individual sensitivity is established.

Form release / dosage:

Suspension for intramuscular administration of prolonged action, 200 mg / ml.

Packaging:

0.875, 1.315, 1.75, 2.625 ml of preparation (corresponding to 175 mg, 263 mg, 350 mg, 525 mg of paliperidone) in a syringe from a cyclolefin copolymer equipped with a piston backstop. The kit includes 2 needles for intramuscular injection (in the deltoid and gluteus muscle). The pre-filled syringe with the preparation and 2 needles in a plastic pallet covered with polyethylene film are placed together with the instruction for use in a cardboard pack.

Storage conditions:

Store at a temperature not exceeding 30 ° C.

Keep out of the reach of children.

Shelf life:

2 years. Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-003861

Date of registration:27.09.2016

Expiration Date:27.09.2021

The owner of the registration certificate:Johnson & Johnson, LLC Johnson & Johnson, LLC Russia

Manufacturer: & nbsp

JANSSEN PHARMACEUTICA, N.V. Belgium