Description
Pharmacological action
Paliperidone belongs to the class of benzisoxazole derivatives and is an atypical antipsychotic. Paliperidone palmitate is hydrolyzed to paliperidone. The latter is a central antagonist of predominantly 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 the (+) and (-) enantiomers of paliperidone is quantitatively and qualitatively the same.
assumed that the therapeutic effectiveness of the drug in schizophrenia is due to the combined blockade of D2 and 5-HT2A receptors.
Pharmacokinetics
Absorption and distribution of
Due to the extremely low solubility of paliperidone in water, palmitate after intramuscular administration slowly dissolves, hydrolyzes to paliperidone and is absorbed into the systemic circulation. 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 Tmax). After intramuscular injection of Trevikta in doses of 175-525 mg into the deltoid muscles, the Cmax value is on average 11-12% higher than the corresponding indicator after injection into the gluteal muscles. The release characteristics of the active component and the dosage regimen of the Trevikta preparation ensure long-term maintenance of the therapeutic concentration. The value of AUC (the area under the concentration-time curve) of paliperidone after administration of the Trevikta preparation is proportional to the dose in the range of 175-525 mg, the Cmax dynamics approaches the dose proportionality. The average ratio of maximum and minimum values ​​was 1.6 after administration of the drug Trevikta in the gluteal muscles and 1.7 after administration in the deltoid muscles. The apparent volume of distribution of paliperidone after administration of the drug Trevikta is 1960 liters. Paliperidone binds to plasma proteins by 74%.
After administration of the drug (-) and (+) – the enantiomers of paliperidone mutually transform into each other, reaching the ratio of AUC (+) – and (-) – enantiomers of about 1.7 – 1.8.
Metabolism and excretion of
A week after a single oral administration of 1 mg of 14C-paliperidone with immediate release of the active component in the urine, 59% of the administered dose is excreted unchanged, which indicates the absence of a significant metabolism of the drug in the liver. About 80% of the administered radioactivity was found in urine and 11% in feces. There are 4 known ways of metabolism of the drug in vivo, but none of them determines the metabolism of more than 10% of the administered dose: dealkylation, hydroxylation, dehydrogenation and cleavage of the benzisoxazole group. Although in vitro studies suggest a certain role for the isoenzymes of CYP2D6 and CYP3A4 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 did not reveal a noticeable difference in paliperidone clearance after oral administration of the drug by people with active and weak CYP2D6 metabolism. In vitro studies using human liver microsomes have shown that paliperidone does not significantly inhibit drug metabolism by the isoenzymes CYP1A2, CYP2A6, CYP2C8 / 9/10, CYP2D6, CYP2E1, CYP3A4 and CYP3A5.
In in vitro studies, paliperidone showed the properties of a P-glycoprotein substrate, and in high concentrations, the properties of a weak P-glycoprotein inhibitor. There is no relevant data in vivo, the clinical significance of this information is unclear. According to a population pharmacokinetic analysis, the median of the apparent half-life of paliperidone after administration of Trevikta at doses of 175-525 mg ranged from 84-95 days in the case of injections into the deltoid muscles to 118-139 days in the case of injections into the gluteal muscles. The residual concentration of paliperidone in the blood 18 months after the last injection of Trevikta at 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 the drug Trevikta and other drugs paliperidone
The frequency of administration of the drug Trevikta is 1 time in 3 months, unlike the drug Xeplion (paliperidone palmitate in the dosage form suspension for intramuscular administration of prolonged action, intended for administration monthly). With the introduction of Trevikta in doses of 3. 5 times higher than the corresponding dose in Xeplion, Trevikta allowed achieving systemic paliperidone levels similar to those achieved with the monthly administration of the corresponding doses of Xeplion, as well as by oral administration of the corresponding doses of paliperidone in sustained release tablets.
The pharmacokinetic variability of paliperidone between patients is similar to that of paliperidone in the form of sustained release tablets. Caution should be exercised when comparing the pharmacokinetic properties of different forms of paliperidone in connection with the various pharmacokinetic profiles of the latter.
Special patient categories
Elderly patients (65 years of age and older)
Age is not a factor requiring dose adjustment. However, such a correction may be required due to an age-related decrease in creatinine clearance.
Impaired renal function
Trevikta has not been systematically studied in patients with impaired renal function. The distribution of paliperidone after a single oral administration of 3 mg sustained-release tablets was studied in patients with various indicators of renal function. With a decrease in creatinine clearance (CC), paliperidone excretion was weakened: with impaired renal function of mild severity (CC 50-80 ml / min) – by 32%, with moderate severity (CC 30-50 ml / min) – 64%, in severe cases (CC 10-30 ml / min) – by 71%, as a result of which AUC0- increased in comparison with healthy volunteers by 1.5, 2.6 and 4.8 times, respectively. Based on a small amount of data on the use of Trevikta in patients with mild renal impairment and the results of pharmacokinetic modeling, in patients with mild renal impairment, both the initial and maintenance doses of Xeplion should be reduced. Patients can be transferred to Trevikta therapy, increasing the corresponding doses by 3.5 times, intended for administration to patients with mild renal impairment. Additional dose adjustment after initiation of Trevikta therapy is not required.
Impaired liver function
Paliperidone is not significantly metabolized in the liver. Although the use of Trevikta in patients with impaired liver function has not been studied, dose adjustment is not required for impaired liver function of mild to moderate severity. In a study of oral administration of paliperidone in patients with impaired liver function of moderate severity (Child-Pugh class B), 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.
Race
A population-based pharmacokinetic analysis of paliperidone oral test results did not reveal differences in paliperidone pharmacokinetics after administration of the drug by people of different races.
Sex
No clinically significant differences in the pharmacokinetics of paliperidone in men and women were found.
Effect of smoking on the pharmacokinetics of
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 the results of a population pharmacokinetic analysis based on data from studies of the drug Xeplion, no differences were found between smokers and non-smokers, which corresponds to the above-mentioned results of in vitro experiments.
Body mass index
Dose adjustment based on body mass index is not required. In individuals with excess body weight, as well as in the presence of obesity, a decrease in C max. Minimum residual concentrations under conditions of an apparent equilibrium state 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
because paliperidone is an active metabolite of risperidone, Trevikta is contraindicated in patients with known hypersensitivity to patients including anaphylactic reactions and angioedema.
With caution
Caution is advised to use Trevikta in the following cases:
in patients with cardiovascular diseases (e.g. heart failure, myocardial infarction or myocardial ischemia, impaired cardiac conduction), cerebrovascular accidents, or conditions predisposing to lower blood pressure (e.g. dehydration, decreased circulating blood volume, use of antihypertensive drugs)
in patients with a history of seizures or other conditions in which the seizure threshold of
may decrease in patients who may be exposed , The body temperature rises, such as strong physical load, a high temperature environment, the effects of drugs with activity of m-anticholinergics and
dehydration in patients with a history of congenital arrhythmia or lengthening the interval QT, or taking drugs, prolonging the QT
interval when used in combination with other central nervous system drugs and alcohol. Paliperidone may attenuate the effect of levodopa and dopamine
agonists in patients with dementia, patients with Parkinson’s disease or dementia with Levi
bodies in patients with possible prolactin-dependent
tumors in patients with impaired liver or kidney function.
Composition of
In 1 ml of suspension contains:
Active ingredient:
200 mg paliperidone (equivalent to 312 mg 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.
Dosing and Administration
Trevikta should be administered once every 3 months.
Parenteral drugs should be examined for foreign particles and discoloration before administration. Not more than 5 minutes before the injection, the syringe must be shaken vigorously for at least 15 seconds to obtain a homogeneous suspension.
The drug is intended for intramuscular administration only. Subcutaneous or intravascular administration is not allowed. Avoid accidental entry into a blood vessel. The drug should be administered by medical professionals. It is necessary to administer the drug in 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.
Only thin-walled needles included in the kit can be used to administer Trevikta. Do not use needles from the packaging of the drug Xeplion or other commercially available needles.
Recommended needle size for introducing Trevikta into the deltoid muscle is determined by the patient’s body weight. In patients weighing less than 90 kg, it is recommended to use needles 25 mm long. In patients weighing 90 kg, it is recommended to use needles 51 mm long. The drug should be injected into the center of the deltoid muscle. It is necessary to alternate injections between two deltoid muscles.
To inject Trevikta into the gluteus, it is recommended to use needles 51 mm long regardless of body weight. The drug is injected into the outer upper quadrant of the gluteal muscle. It is necessary to alternate injections between the two gluteal muscles.
Since paliperidone is an active metabolite of risperidone, caution should be exercised while using Trevikta and risperidone or the oral form of paliperidone for a long period of time. Safety data for the simultaneous use of Trevikta and other antipsychotics is limited.
Introduction of a partial dose of
In order to avoid the introduction of a partial dose of Trevikta, it is necessary to vigorously shake the syringe with the drug for at least 15 seconds no more than 5 minutes before administration to obtain a homogeneous suspension. However, in case of incomplete administration of the dose, it is forbidden to administer the drug remaining in the syringe, and it is also forbidden to administer another dose. It is necessary to carefully monitor the patient and ensure proper therapy until the next Trevikta injection, scheduled after 3 months.
Dosage
The drug Trevikta can be used only after using the drug Xeplion for at least 4 months. For the correct determination of the maintenance dose, before starting the use of Trevikta, it is recommended to administer the last 2 monthly injections in the same dosage.
The use of Trevikta should be started on the day corresponding to the next planned injection of Xeplion, using a dose of Trevikta calculated based on the previous dose of Xeplion.
After the initial injection, Trevikta should be administered every 3 months. If necessary, a stepwise dose adjustment is allowed every 3 months in the range from 175 to 525 mg based on individual tolerance and / or effectiveness of the drug. Due to the duration of the Trevikta preparation, the patient’s response to dose adjustment can occur only after a few months (see Pharmacokinetics section).
Skip dose
Skip dose. In exceptional cases, a maintenance injection may be given 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 (up to 4 months) have elapsed since the day of the previous injection, the patient should administer the next injection as soon as possible in the same dose. In the future, the frequency of injections should be observed once every 3 months.
Skip dose (4–9 months)
If more than 4 months (up to 9 months) have passed since the day of the previous injection, do not administer the next dose of Trevikta.
Dose skipping (more than 9 months)
If more than 9 months have passed since the last injection of Trevikta, you should start treatment with Xeplion in accordance with the instructions for use of this drug. Transfer to the drug Trevikta can be carried out only after the use of the drug Xeplion for at least 4 months.
Special patient groups
Children (under 18 years of age)
The safety and effectiveness of Trevikta in patients younger than 18 years of age have not been studied. The use of the drug TREVICT is not recommended in patients younger than 18 years of age due to the potentially longer duration of side effects compared with drugs with a 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 adult patients.
Elderly patients (65 years of age and older)
Insufficient patients aged 65 years and older were included in clinical trials to determine whether their response to therapy is different from younger patients. Existing clinical experience has not revealed differences in response between elderly and younger patients.
Paliperidone is significantly excreted by the kidneys, paliperidone clearance is reduced in patients with impaired renal function. For elderly patients with normal renal function, the same dose of Trevikta is recommended as for younger patients with normal renal function. In elderly patients, renal function may be impaired, and the following recommendations for patients with impaired renal function apply to such patients.
Patients with impaired renal function
The use of Trevikta in patients with impaired renal function has not been systematically studied. In patients with mild renal impairment (CC from 50 to 80 ml / min), dose adjustment is performed at the stage of initiation of therapy with Xeplion drug, an additional dose adjustment of Trevikta is not required. Transfer to therapy with Trevikta using a dose of 3. 5 times the dose of the previously used drug Xeplion, is made in accordance with the description above. The maximum recommended dose of Trevikta in patients with mild renal impairment is 350 mg.
Trevikta is not recommended for use in patients with moderate or severe renal impairment (CC <50 ml / min). Impaired liver function The use of Trevikta 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, mild or moderate dose adjustment is not required. The use of paliperidone in patients with severely impaired hepatic function has not been studied. Other special patient categories Trevikta dose adjustment based on gender, patient race and smoking are not required. Switching from other antipsychotic drugs Trevikta can only be used after using Xeplion for at least 4 months. In case of discontinuation of the drug Trevikta, it is necessary to take into account the duration of the release of the active component. As in the case of other antipsychotics, it is necessary to periodically assess the need to continue using means of preventing the development of extrapyramidal disorders. Switching from Trevikta to Xeplion To switch from Trevikta to Xeplion, this drug should be administered on the day corresponding to the next dose of Trevikta, and a 3.5 times lower dose should be used. Instructions for use and handling Enter once every 3 months. Shake the syringe vigorously for at least 15 seconds before injection. Intramuscular administration only. No other routes of administration are allowed. It is necessary to administer the drug in one injection, it is forbidden to divide the dose into several injections. The drug should be administered by medical professionals. The drug Trevikta is intended only for intramuscular administration. The drug should be injected slowly into the deeper layers of the muscle, taking precautions in order to avoid getting the drug into the blood vessel. Drug Interactions Like other antipsychotics, paliperidone can increase the QT interval, so you should be careful to combine Trevikta with other drugs that increase the QT interval, such as antiarrhythmic drugs (including quinidine, disopyramide, procinide , sotalol), antihistamines, antipsychotic drugs (chlorpromazine, thioridazine) antibiotics (including gatifloxacin, moxifloxacin), some drugs with anti-malaria drugs (including mefloquine). Since paliperidone palmitate is hydrolyzed to paliperidone, the results of paliperidone oral studies should be considered when assessing the possibility of drug interactions. The ability of the drug to influence other drugs Paliperidone is not expected to exhibit a clinically significant pharmacokinetic interaction with drugs metabolized by cytochrome P450 isoenzymes. In vitro studies using human liver microsomes have shown that paliperidone does not significantly impair the metabolism of substances by cytochrome P450 isoenzymes, including 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, then, when evaluating the possibility of drug interaction, the results of paliperidone studies for oral administration should be taken into account. The ability of the drug to influence other drugs Paliperidone is not expected to exhibit a clinically significant pharmacokinetic interaction with drugs metabolized by cytochrome P450 isoenzymes. In vitro studies using human liver microsomes have shown that paliperidone does not significantly impair the metabolism of substances by cytochrome P450 isoenzymes, including 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, then, when evaluating the possibility of drug interaction, the results of paliperidone studies for oral administration should be taken into account. The ability of the drug to influence other drugs Paliperidone is not expected to exhibit a clinically significant pharmacokinetic interaction with drugs metabolized by cytochrome P450 isoenzymes. In vitro studies using human liver microsomes have shown that paliperidone does not significantly impair the metabolism of substances by cytochrome P450 isoenzymes, including 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, that paliperidone will exhibit a clinically significant pharmacokinetic interaction with drugs metabolized by cytochrome P450 isoenzymes. In vitro studies using human liver microsomes have shown that paliperidone does not significantly impair the metabolism of substances by cytochrome P450 isoenzymes, including 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, that paliperidone will exhibit a clinically significant pharmacokinetic interaction with drugs metabolized by cytochrome P450 isoenzymes. In vitro studies using human liver microsomes have shown that paliperidone does not significantly impair the metabolism of substances by cytochrome P450 isoenzymes, including 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 an isoenzyme inducer. Paliperidone in high concentrations is a weak inhibitor of P-glycoprotein. However, there are no in vivo data in this regard, and the clinical significance of this phenomenon is unknown. Given the effects of paliperidone on the central nervous system, Trevikta should be used with caution in combination with other centrally acting drugs and alcohol. Paliperidone may attenuate the effect of levodopa and dopamine receptor agonists. With simultaneous use, the condition of the patient should be monitored. Due to the ability of the drug Treict to cause orthostatic hypotension, an additive amplification of this effect may be observed when using the drug in conjunction with other drugs with this ability. In patients prone to hypotension, orthostatic physiological parameters should be monitored. Caution is advised to combine paliperidone with drugs that lower the seizure threshold, such as phenothiazines, butyrophenones, tricyclic derivatives, selective serotonin reuptake inhibitors, tramadol, mefloquine, etc. Concomitant use of oral dose of 1 mg of paliperid and sodium tablets of divalproex 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. Pharmacokinetic interaction between Trevikta and lithium is unlikely. The ability of other drugs to affect the drug Trevikta Clinically important interactions between paliperidone and drugs metabolized by isoenzymes of the cytochrome P450 system are not expected. Paliperidone is not a substrate of the isoenzymes CYP1A2, CYP2A6, CYP2C9, CYP2C19 and CYP3A5. This suggests a low probability of interaction with inhibitors and inducers of these isoenzymes. Although in vitro studies show the possibility of minimal participation of CYP2D6 and CYP3A4 isoenzymes in paliperidone metabolism, there is currently no evidence that these enzymes can play a significant role in paliperidone metabolism in vivo. In vitro studies indicate that paliperidone is a substrate of P-glycoprotein. Paliperidone is metabolized to a limited extent by the CYP2D6 isoenzyme. In a study of the interaction of paliperidone for oral administration with an active CYP2D6 inhibitor paroxetine in healthy volunteers, no clinically significant change in the pharmacokinetics of paliperidone was found. The simultaneous use of paliperidone and potent inducers of the isoenzyme CYP3A4 and P-glycoprotein can lead to a decrease in plasma concentrations of paliperidone. If possible, the simultaneous use of paliperidone and strong inducers of the isoenzyme CYP3A4 and P-glycoprotein should be avoided. If strong inducers are necessary, consideration should be given to transferring the patient to sustained release paliperidone tablets. The administration of paliperidone with prolonged release of the active component (1 time per day) orally simultaneously with carbamazepine (200 mg 2 times per day) led to a decrease in the average C max and AUC of 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 by carbamazepine. A very small decrease in the amount of the drug excreted through the kidneys unchanged suggests that carbamazepine only slightly affects the metabolism in the liver or the bioavailability of paliperidone. At the beginning of the use of carbamazepine, the dose of Trevikta should be reviewed and, if necessary, increased. On the contrary, with the abolition of carbamazepine, the dose of Trevikta should be reviewed and, if necessary, reduced. The duration of action of the drug Trevikta should be taken into account. Paliperidone is a cation at physiological pH, and is mainly 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 a prolonged-acting oral paliperidone at a dose of 12 mg once a day and sodium divalproex sustained-release tablets (2 tablets of 500 mg once a day), an increase of Cmax and AUC of paliperidone by about 50% was observed, probably as a result of increased absorption the drug when taken orally. Since there was no significant effect on overall clearance, no clinically significant interaction is expected between divalproex sodium, sustained release tablets, and Trevikta. Studies of this interaction with Trevikta have not been conducted. Use of Trevikta in combination with risperidone or with the oral form of paliperidone Since paliperidone is an active metabolite of risperidone, caution should be exercised while using Trevikta and risperidone or the oral form of paliperidone for a long time. Safety data for the simultaneous use of Trevikta and other antipsychotics is limited The pharmacokinetic interaction of lithium and paliperidone is unlikely. Overdose Since the drug Trekvita is intended for administration by health workers, then the probability 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 intake was estimated to be 405 mg. Observed signs and symptoms included extrapyramidal symptoms and gait instability. Other expected signs and symptoms correspond to an increase in the known pharmacological action of paliperidone, i.e. drowsiness, lethargy, tachycardia, lowering blood pressure, lengthening the QT interval. With an overdose of oral paliperidone, polyformal ventricular tachycardia such as pirouette and ventricular fibrillation were noted. In case of acute overdose, the possibility of patients receiving several drugs should be considered. treatment. When assessing the need for treatment and recovery of patients, the prolonged release of the active substance and the long half-life of paliperidone should be considered. There is no specific antidote for paliperidone. General supportive measures should be taken to ensure and maintain airway, adequate ventilation and oxygen saturation of the blood. Immediately begin monitoring the function of the cardiovascular system, including continuous monitoring of the ECG, to identify possible arrhythmias. In the event of a decrease in blood pressure and circulatory collapse, appropriate measures should be taken, for example, intravenous administration of solutions and / or sympathomimetics. With the development of severe extrapyramidal symptoms, anticholinergics are used. The patient should be carefully monitored until recovery. active substance Paliperidone Terms of delivery from pharmacies Prescription dosage form suspension for injection