Paliperidone is a centrally acting dopamine D2 receptor antagonist that also exhibits high serotonin 5-HT2 receptor antagonism. In addition, it is an antagonist of α1- and α2-adrenergic receptors and H1- histamine receptors. does not have affinity for cholinergic, muscarinic, and β1- and β2-adrenergic receptors. The pharmacological activity of the (+) and (−) enantiomers of paliperidone is the same in qualitative and quantitative terms.

Antipsychotic effect caused by blockade of D2-dopaminergic receptors of the mesolimbic and mesocortical systems. Balanced central antagonism to serotonin and dopamine helps reduce extrapyramidal side effects and expanding the therapeutic impact of the drug to cover negative and productive symptoms of schizophrenia.

After oral administration, it is absorbed into gastrointestinal tract up to 28%. After intramuscular injection Due to low solubility in water, it is slowly absorbed into systemic blood flow. The maximum concentration in blood plasma is achieved 13-14 days after intramuscular injection and 24 hours later - after oral administration. Plasma protein binding is 74%.

Metabolism in the liver.

The half-life is 23 hours. Elimination by the kidneys (80%) and feces (20%), unchanged - about 56%.

It is used to treat schizophrenia and to prevent relapses of schizophrenia.

Individual intolerance.

Use with caution in the following diseases: ischemic heart disease, post-infarction conditions, myocardial conduction disorders, arterial hypotension, epilepsy, diabetes mellitus, obesity. Dose adjustment required when physical activity related to increased sweating(dehydration).

Inside in the morning 3-12 mg/day.

Intramuscularly(in the deltoid muscle): 150 mg on the first day and 100 mg after 1 week, then 75 mg monthly in the deltoid or gluteal muscle.

Higher daily dose: 12 mg orally and 150 mg for intramuscular administration.

Higher single dose: 12 mg orally and 150 mg for intramuscular administration.

General reactions: flu-like intoxication syndrome, a feeling of heaviness in the head, dizziness, bloating, heat stroke.

Central and peripheral nervous system : insomnia at night and drowsiness during the day, tremors, dizziness, suicidal tendencies, nervousness, changes in libido (increase or decrease), "syndrome restless legs", slowing down of mental activity. Rarely - delirium, intrusive thoughts, depression of consciousness.

Circulatory system: orthostatic hypotension, arrhythmia, vasovagal syndrome, thrombophlebitis.

Respiratory system: shortness of breath, pneumonia, hiccups.

Digestive system: nausea, dyspepsia, vomiting, caries, swelling of the tongue, stool incontinence.

Sense organs: pain and tinnitus, dry eye syndrome, loss or distortion of taste, photophobia.

Musculoskeletal system: myalgia, convulsive syndrome, myasthenia gravis.

Dermatological reactions: urticaria, dry skin, hyperhidrosis, alopecia, seborrhea.

Urinary system: urinary incontinence, cystitis, painful erection.

Allergic reactions.

Symptoms: orthostatic collapse, asthenia, tachycardia, extrapyramidal disorders.

Treatment: symptomatic.

Potentiates the effect of α1-blockers, increasing the risk of orthostatic hypotension.

When treated with the drug, alcohol intake increases the depression of the central nervous system.

When interacting with anticholinergic drugs, the risk of developing hyperthermia increases.

The risk of toxic effects increases when used simultaneously with intraconazole, ketonazole, fluoxetine, and paroxetine.

CYP3A4 inducers () reduce the effectiveness of treatment with paliperidone, which requires dosage to be doubled.

When treating with paliperidone, it is necessary to monitor blood glucose levels, check the condition of the fundus and tendon reflexes.

Persons taking the drug on an outpatient basis are prohibited from driving a car or working in production with moving machinery.

Active substance: Paliperidone - 3 mg.

Excipients: Macrogol 200K - 81.43 mg, macrogol 7000K - 73.70 mg, sodium chloride - 30 mg, povidone (K29-32) - 10 mg, hyethylose - 10.45 mg, stearic acid- 0.75 mg, butylated hydroxytoluene - 0.11 mg, iron oxide red - 1.0 mg, iron oxide yellow - 0.03 mg, macrogol 3350 - 1.0 mg, cellulose acetate (398-10) - 44.55 mg, white dye (hypromellose, titanium dioxide, lactose monohydrate, triacetin) - 33 mg, carnauba wax - 0.03 mg.

Active substance: Paliperidone - 6 mg.

Excipients: Macrogol 200K - 78.45 mg, macrogol 7000K - 73.70 mg, sodium chloride - 30 mg, povidone (K29-32) - 10 mg, hyethylose - 10.45 mg, stearic acid - 0.75 mg, butylated hydroxytoluene - 0.11 mg, iron oxide red - 1.01 mg, macrogol 3350 - 1.00 mg, cellulose acetate (398-10) - 44.55 mg, beige dye (hypromellose, titanium dioxide, polyethylene glycol 400, iron oxide yellow, iron oxide red) - 18 mg, carnauba wax - 0.03 mg.

Active substance: Paliperidone - 9 mg.

Excipients: Macrogol 200K - 75.45 mg, macrogol 7000K - 73.70 mg, sodium chloride - 30 mg, povidone (K29-32) - 10 mg, hyethylose - 10.45 mg, stearic acid - 0.75 mg, butylated hydroxytoluene - 0.11 mg, iron oxide black - 0.01 mg, iron oxide red - 1.00 mg, macrogol 3350 - 1.00 mg, cellulose acetate (398-10) - 44.55 mg, pink dye (hypromellose , titanium dioxide, polyethylene glycol 400, red iron oxide) - 15 mg, carnauba wax - 0.03 mg.

Active substance: Paliperidone - 12 mg.

Excipients: Macrogol 200K - 72.43 mg, macrogol 7000K - 73.70 mg, sodium chloride - 30 mg, povidone (K29-32) - 10 mg, hyethylose - 10.45 mg, stearic acid - 0.75 mg, butylated hydroxytoluene - 0.11 mg, iron oxide red - 1.00 mg, iron oxide yellow - 0.03 mg, macrogol 3350 - 1.00 mg, cellulose acetate (398-10) - 44.55 mg, dark yellow dye (hypromellose, titanium dioxide, polyethylene glycol 400, iron oxide yellow) - 12 mg, carnauba wax - 0.03 mg. The inscription on tablets of all dosages is made with water-soluble black ink (ink composition: hypromellose, black iron oxide, purified water, isopropanol, propylene glycol).

Description.

White, light orange (a slight brownish tint is allowed), pink (a grayish tint is allowed) or dark yellow (a grayish tint is allowed) (according to the dosage - 3, 6, 9 or 12 mg) capsule-shaped tablets. The tablets are labeled “PAL 3”, “PAL 6”, “PAL 9” or “PAL 12” (corresponding to the dosage - 3, 6, 9 or 12 mg).

Outlets may or may not be visible by visual inspection.

Pharmacodynamics.

Mechanism of action.

Paliperidone is a centrally acting dopamine D2 receptor antagonist that also exhibits high serotonin 5-HT2 receptor antagonism. In addition, paliperidone is an antagonist of alpha1 and alpha2 adrenergic receptors and histamine H1 receptors. Paliperidone does not have affinity for cholinergic, muscarinic, or beta1- and beta2-adrenergic receptors. The pharmacological activity of the (+) and (-) enantiomers of paliperidone is the same in qualitative and quantitative terms.

The antipsychotic effect is due to the blockade of D2-dopaminergic receptors of the mesolimbic and mesocortical systems. Causes less suppression of motor activity and induces catalepsy to a lesser extent than classical antipsychotics (neuroleptics).

Balanced central antagonism of serotonin and dopamine may reduce the tendency to extrapyramidal side effects and expand therapeutic effect drug covering negative and productive symptoms.

Paliperidone affects sleep structure: it reduces latent period before falling asleep, reduces the number of awakenings after falling asleep, increases the total duration of sleep, increases sleep time and increases the sleep quality index. It has an antiemetic effect and may cause an increase in the concentration of prolactin in the blood plasma.

Pharmacokinetics.

Unless otherwise stated, pharmacokinetic data presented in this section based on data obtained for adult patients. The pharmacokinetic characteristics of paliperidone after oral administration are proportional dose taken in the recommended therapeutic range (3-12 mg once daily).

Absorption.

After taking one dose of the drug, the concentration of paliperidone in plasma steadily increased, and the maximum concentration (Cmax) was reached after 24 hours. In most patients, equilibrium concentrations of paliperidone were achieved after 4-5 days of dosing the drug once a day. Paliperidone is an active metabolite of risperidone. Release Features active substance from Invega® provided less variation in maximum and minimum concentrations of paliperidone than those observed with conventional dosage forms(concentration fluctuation index 38% compared to 125% for conventional dosage forms).

After administration of paliperidone tablets, the (+) and (-) enantiomers are converted to each other, and the area under the concentration-time curve (AUC) AUC (+)/AUC (-) ratio at steady state is approximately 1.6. The absolute bioavailability of paliperidone after oral administration is 28% (23%-33%, 90% confidence interval).

After a single dose of 15 mg of paliperidone extended-release tablet with a high-fat, high-calorie meal, Cmax and AUC increased by an average of 42 and 46%, respectively, relative to the same values ​​when taking the tablet on an empty stomach. In another study, following a single dose of 12 mg paliperidone extended-release tablet with a high-fat, high-calorie meal, Cmax and AUC increased by an average of 60% and 54%, respectively, relative to those when the tablet was administered on an empty stomach. Therefore, the presence or absence of food in the stomach while taking paliperidone may alter the plasma concentration of paliperidone.

Distribution.

Paliperidone is rapidly distributed into tissues and body fluids. Apparent volume of distribution - 487 l. The degree of binding to plasma proteins is 74%. Paliperidone binds predominantly to alpha1-acid glycoprotein and albumin.

Biotransformation and elimination.

1 week after taking one standard tablet containing 1 mg of paliperidone, 59% of the dose was excreted unchanged in the urine; this indicates that paliperidone is not extensively metabolized in the liver. About 80% of the drug was found in urine and approximately 11% in feces. There are four known pathways for paliperidone metabolism in vivo, none of which account for more than 6.5% of the dose: dealkylation, hydroxylation, dehydrogenation and benzisoxazole degradation. In vitro studies have shown that cytochrome P450 isoenzymes CYP2D6 and CYP3A4 may play a role in the metabolism of paliperidone, but evidence that they play a significant role in the metabolism of paliperidone in vivo has not been obtained. Although the activity of CYP2D6 isoenzyme varies significantly in the general population, population pharmacokinetic studies have not revealed significant differences in the apparent clearance of paliperidone in patients with extensive metabolism of CYP2D6 isoenzyme substrates and in patients with poor metabolism of CYP2D6 isoenzyme substrates. In vitro studies using microsomal preparations of heterologous systems have shown that the isoenzymes CYP1A2, CYP2A6, CYP2C9, CYP2C19 and CYP3A5 are not involved in the metabolism of paliperidone.

The terminal half-life of paliperidone is approximately 23 hours. In vitro studies have shown that paliperidone is a substrate of P-glycoprotein and high concentrations weakly inhibits it. No in vivo data available, clinical significance unknown.

Special groups.

Paliperidone is not extensively metabolized in the liver. In patients with mild to moderate hepatic impairment, there is no need to reduce the dose of paliperidone. A study involving patients with moderate impairment liver function tests (Child-Pugh class B) showed that in these patients the plasma concentrations of unbound paliperidone were similar to those in healthy people. The use of Invega® in patients with severe liver dysfunction has not been studied.

The dose of paliperidone should be reduced in patients with moderate to severe severe violation kidney function. The excretion of paliperidone was studied in patients with to varying degrees renal dysfunction. It was found that the elimination of paliperidone decreased as creatinine clearance decreased. The overall clearance of paliperidone was reduced by 32% in patients with mild impairments renal function (creatinine clearance from 50 to<80 мл/мин), на 64% у пациентов с умеренными нарушениями функции почек (клиренс креатинина от 30 до <50 мл/мин) и на 71% у пациентов с тяжелыми нарушениями функции почек (клиренс креатинина от 10 до <30 мл/мин). Средний конечный период полувыведения палиперидона составил 24, 40 и 51 ч у пациентов с легкими, умеренными и тяжелыми нарушениями функции почек соответственно; у людей с нормальной функцией почек (клиренс креатинина ≥80 мл/мин) этот показатель составлял 23 ч.

Teenagers.

Systemic exposure to paliperidone in adolescents was comparable to that in adults. Plasma concentrations of paliperidone in overweight adolescents<51 кг на 23% выше, чем у подростков с массой тела ≥51 кг, что не клинически значимо. Возраст не влияет на концентрацию палиперидона в плазме.

Elderly patients.

It is not recommended to change the dose of paliperidone depending on the patient's age. The results of a pharmacokinetic study in elderly patients aged 65 years and older showed that the apparent clearance of paliperidone at steady state after taking Invega in this group was 20% lower than in adult patients aged 18-45 years. However, after adjusting for an age-related decrease in creatinine clearance, a population analysis did not reveal the effect of the age of patients with schizophrenia on the pharmacokinetics of paliperidone.

Race.

No dose adjustments are required for patients of different races. Population pharmacokinetic analysis showed no racial differences in the pharmacokinetics of paliperidone when using Invega®. No differences in pharmacokinetics were found in studies in Japanese and Caucasians.

Floor.

Recommended doses of paliperidone are the same for men and women. The apparent clearance of paliperidone after taking the drug in women is approximately 19% lower than in men. This difference is primarily due to differences in lean body mass and creatinine clearance between men and women, as population-based studies, after adjusting for lean body mass and creatinine clearance, did not show clinically significant differences in the pharmacokinetics of paliperidone in men and women taking the drug .

Smoking.

It is not recommended to change the dose of paliperidone in smokers. In vitro studies using human liver enzymes have shown that paliperidone is not a substrate of the CYP1A2 isoenzyme and therefore smoking should not affect the pharmacokinetics of paliperidone. Consistent with the results of in vitro studies, population studies did not reveal differences in the pharmacokinetics of paliperidone between smokers and non-smokers.

Schizophrenia, including in the acute phase in adult patients. Prevention of exacerbations of schizophrenia in adults.

Treatment of schizophrenia in adolescents aged 12 to 17 years.

Treatment of schizoaffective disorders: as monotherapy or as part of combination therapy with antidepressants and/or mood stabilizers in adult patients.

The drug is intended for oral administration. The tablets should be swallowed whole with liquid and should not be chewed, divided or crushed.

Schizophrenia.

Adults (over 18 years old).

The recommended dose in adults is 6 mg once a day, in the morning, regardless of meals. A gradual increase in the initial dose is not required. In some patients, lower or higher doses within the recommended range of 3-12 mg once daily produce a therapeutic effect. There is a general tendency to enhance the effect when using large doses of the drug. If an increase in dose is necessary, it is recommended to increase the dose by 3 mg per day at intervals of more than 5 days.

Teenagers (12-17 years old).

The recommended dose in adolescents is 3 mg once daily, in the morning, regardless of meals. A gradual increase in the initial dose is not required. In some patients, higher doses within the recommended range of 6-12 mg once daily produce a therapeutic effect. Dose increases are possible only after clinical reassessment, with the dose increasing by 3 mg per day at intervals of more than 5 days.

Schizoaffective disorders.

Adults (over 18 years old).

The recommended dose in adults is 6 mg once daily, in the morning. A gradual increase in the initial dose is not required. In some patients, lower or higher doses within the recommended range of 6-12 mg once daily produce therapeutic benefits. Increasing the dose, if necessary, should be carried out only after assessing the clinical condition of the patient. If an increase in dose is necessary, it is recommended to increase the dose by 3 mg per day at intervals of more than 4 days. Maintenance therapy has not been studied in patients with schizoaffective disorders.

Patients with impaired liver function.

In patients with mild or moderate liver dysfunction, no dose reduction is required. The use of Invega® in patients with severe liver dysfunction has not been studied.

Patients with impaired renal function.

For patients with mild renal impairment (creatinine clearance ≥ 50, but<80 мл/мин) рекомендуемая начальная доза составляет 3 мг один раз в сутки. Эта доза может быть увеличена до 6 мг один раз в сутки после оценки состояния пациента и с учетом переносимости препарата. Для пациентов с умеренным или тяжелым нарушением функции почек (клиренс креатинина ≥10, но <50 мл/мин) рекомендуемая доза препарата составляет 3 мг один раз в сутки. Применение препарата Инвега® у пациентов с клиренсом креатинина <10 мл/мин не изучалось, в связи с чем, не рекомендуется назначать препарат этим пациентам.

Elderly patients.

For elderly patients with normal renal function (creatinine clearance ≥80 ml/min), the same doses of the drug are recommended as for adult patients with normal renal function. However, in elderly patients, renal function may be reduced, in which case the dose of the drug should be adjusted according to the renal function of the individual patient (see section "Patients with impaired renal function"). Caution should be exercised when using the drug in elderly patients with dementia due to the increased risk of stroke. The effectiveness and safety of Invega® in patients over 65 years of age with schizoaffective disorders has not been studied.

Children and teenagers.

The effectiveness and safety of Invega® for the treatment of schizophrenia in children under 12 years of age has not been studied. The effectiveness and safety of the drug Invega® for the treatment of schizoaffective disorders in patients under 18 years of age has not been studied.

Special groups of patients.

Transfer of patients to treatment with other antipsychotic drugs Currently, there are no systematically collected data on the transfer of patients from treatment with paliperidone to treatment with other antipsychotic drugs. The pharmacodynamics and pharmacokinetics of different antipsychotic drugs are not the same, and therefore physicians should carefully monitor the condition of patients when transferring them from one antipsychotic drug to another.

Neuroleptic malignant syndrome.

Antipsychotics, including paliperidone, are known to cause neuroleptic malignant syndrome (NMS), which is characterized by hyperthermia, muscle rigidity, instability of the autonomic nervous system, depression of consciousness, and increased serum concentrations of creatine phosphokinase. Patients with NMS may also experience myoglobinuria (rhabdomyolysis) and. If a patient experiences objective or subjective symptoms of NMS, all antipsychotic medications, including paliperidone, should be immediately discontinued.

Tardive dyskinesia.

Drugs with dopamine receptor antagonist properties can cause tardive dyskinesia, which is characterized by rhythmic involuntary movements, mainly of the tongue and/or facial muscles. If a patient experiences objective or subjective symptoms indicating tardive dyskinesia, the advisability of discontinuing all antipsychotic drugs, including paliperidone, should be considered.

Prolongation of the QT interval.

As with other antipsychotics, caution should be exercised when prescribing Invega® to patients with a history of cardiac arrhythmias, congenital prolongation of the QT interval, and concomitant use with drugs that prolong the QT interval.

Hyperglycemia and.

Diabetes mellitus and exacerbation of existing diabetes mellitus were observed during treatment with Invega®. Establishing a relationship between the use of atypical antipsychotic drugs and disorders of glucose metabolism is complicated by the increased risk of developing diabetes mellitus in patients with schizophrenia and the prevalence of diabetes mellitus in the general population. Given these factors, the relationship between the use of atypical antipsychotic drugs and the development of side effects associated with hyperglycemia is not fully established. In patients diagnosed with diabetes mellitus, glucose levels should be regularly monitored. Patients with risk factors for diabetes mellitus (eg, family history of diabetes) should have their fasting blood glucose levels monitored at the start of treatment and periodically during treatment. All patients should be clinically monitored for symptoms of hyperglycemia and diabetes mellitus. Patients who develop symptoms of hyperglycemia while being treated with atypical antipsychotics should have their blood glucose levels monitored. In some cases, symptoms of hyperglycemia have resolved with discontinuation of atypical antipsychotic medications, but some patients require antidiabetic treatment despite discontinuation of the suspected drug.

Increase in body weight.

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

Hyperprolactinemia.

Like other D2 dopamine receptor antagonists, paliperidone increases prolactin levels and this increase persists throughout drug administration. The effect of paliperidone is comparable to that of risperidone, the drug with the greatest effect on prolactin levels among other antipsychotic drugs. , regardless of etiology, can suppress the expression of GnRH (gonadotropin-releasing hormone) of the hypothalamus, which leads to a decrease in the secretion of gonadotropins by the pituitary gland. This, in turn, can suppress reproductive function, reducing sexual steroidogenesis in women and men. Impotence has also been reported in patients taking drugs that increase prolactin levels. Long-term hyperprolactinemia associated with hypogonadism can lead to decreased bone density in women and men.

In vitro tissue culture studies have shown that approximately one third of human cases are prolactin dependent. This should be taken into account when prescribing drugs that increase prolactin levels to patients with previously diagnosed breast cancer. Clinical and epidemiological studies conducted to date have shown no association between use of atypical antipsychotic drugs and tumor formation in humans. However, the available data are too limited to draw definitive conclusions.

Orthostatic hypotension.

Paliperidone has alpha-blocking activity and may therefore cause orthostatic hypotension in some patients. Paliperidone should be used with caution in patients with cardiovascular disease (eg, myocardial infarction or ischemia, cardiac conduction disorders), cerebrovascular disease, and contributing conditions (eg, dehydration, hypovolemia, and therapy with antihypertensive drugs).

Regulation of body temperature.

Antipsychotic drugs are associated with such undesirable effects as disruption of the body's ability to regulate temperature. Caution should be exercised when prescribing paliperidone to patients with conditions that may contribute to an increase in core body temperature, such as intense exercise, dehydration, exposure to high external temperatures, or concomitant use of drugs with anticholinergic activity.

Antiemetic effect.

Preclinical studies have demonstrated the antiemetic effect of paliperidone. This effect, when observed in humans, may mask the objective and subjective symptoms of overdose of some drugs, as well as diseases such as intestinal obstruction, Reye's syndrome, and brain tumors.

Priapism.

Drugs with alpha-adrenergic blocking effects can cause. Priapism has been reported in post-marketing studies of paliperidone.

Suicidal attempts.

The possibility of suicide attempts is characteristic of, therefore, treatment of patients at high risk should be carried out under close supervision. In these cases, Invega® should be prescribed in a minimum number of tablets to reduce the risk of overdose.

Leukopenia, agranulocytosis.

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

Intraoperative floppy iris syndrome (ISID).

ISDR was observed during surgery due to the presence of α1-adrenergic receptor antagonists in patients receiving therapy with drugs of the α1-adrenergic receptor antagonist group. ISDR increases the risk of complications associated with the organ of vision during and after surgery. The doctor performing such an operation should be informed in advance that the patient has taken or is currently taking drugs that have α1-adrenergic receptor antagonist activity. The potential benefit of discontinuing α1-adrenergic antagonist therapy before surgery has not been established and should be weighed against the risks associated with discontinuing antipsychotic therapy.

Pregnancy and child care.

The patient must notify his or her physician of pregnancy or planning to become pregnant during treatment with Invega®. Caution should be exercised when prescribing Invega® to nursing mothers. (see section “Use during pregnancy and lactation”).

Drinking alcohol.

Patients should avoid drinking alcohol during treatment with Invega®.

Conditions leading to a decrease in the presence of the drug in the gastrointestinal tract.

Conditions that reduce the presence of the drug in the gastrointestinal tract, for example, diseases associated with chronic diarrhea, may cause a decrease in the absorption of paliperidone.

Invega® tablets are manufactured using osmotic release technology, in which osmotic pressure releases paliperidone at a controlled rate. The system, which looks like a capsule-shaped tablet, consists of an osmotically active three-layer core surrounded by an intermediate shell and a semi-permeable membrane. The three-layer core consists of two medicinal layers containing the drug substance and excipients, as well as an ejector layer containing osmotically active components. On the dome side of the drug layers there are two outlet holes made using a laser. In the gastrointestinal tract, the colored shell quickly dissolves, and water begins to flow into the tablet through a semi-permeable control membrane. The membrane controls the level of water intake, and this, in turn, controls the level of drug release.

The hydrophilic polymers in the tablet core absorb water and swell into a gel containing paliperidone, which is then expelled through holes in the dome. The insoluble components of the tablet are excreted from the body in the stool. Patients should not worry if they notice something that looks like a pill in their stool. Effects on driving and operating machinery Paliperidone may interfere with activities requiring rapid mental response and may also have visual effects, so patients should refrain from driving and operating machinery until their individual sensitivity to paliperidone has been established.

The following are undesirable effects observed in patients. The frequency of adverse effects was classified as follows: very common (≥10%), common (≥1% and< 10 %), нечастые (≥0,1 % и <1 %), редкие (≥0,01 % и <0,1 %) и очень редкие (<0,01 %).

Infections: frequent -, nasopharyngitis; uncommon - urinary tract infections, acarodermatitis, inflammation of subcutaneous fat, ear infections, respiratory tract infections.

Immune system disorders:

Uncommon: anaphylactic reaction, hypersensitivity.

Disorders of the hematopoietic and lymphatic system:

Uncommon - decreased hematocrit, neutropenia, decreased white blood cell count;

Very rare - diabetic.

Mental disorders:

Frequent - insomnia (including initial and moderate insomnia), mania;

Infrequent - “nightmare” dreams.

Nervous system disorders:

Very frequent - ;

With unknown frequency: floppy iris syndrome (intraoperative).

Hearing and labyrinthine disorders:

Uncommon: ear pain, vertigo, ringing in the ears.

Cardiovascular system disorders:

Uncommon - palpitations, atrioventricular block, conduction disturbances, ECG changes, increased QT interval, ischemia, flushing, increased blood pressure, decreased blood pressure;

Rare - atrial fibrillation;

Very rare - pulmonary artery.

Gastrointestinal disorders:

Disorders of the liver and biliary tract:

Very rare - jaundice.

Respiratory system disorders:

Uncommon - pain in the pharyngo-larynx area, nasal congestion, hyperventilation, wheezing;

Rare - sleep apnea syndrome.

Musculoskeletal and connective tissue disorders:

Renal and urinary tract disorders:

Infrequent - urinary retention;

Disorders of the genital organs and breast:

Uncommon - decreased libido, anorgasmia, nipple discharge, erectile dysfunction, gynecomastia, menstrual cycle changes, breast discomfort, sexual dysfunction, vaginal discharge, ejaculation disorders, breast engorgement;

Very rare - priapism.

Effect on the course of pregnancy, postpartum and perinatal conditions:

Very rare - withdrawal syndrome in newborns.

Others: frequent - weight gain;

Uncommon - weight loss, facial swelling, gait disturbance (including generalized edema, peripheral edema, mild edema), increased body temperature, fever, thirst, chest discomfort;

Very rare - hypothermia.

Laboratory tests:

Uncommon - increased gamma-glutamyltransferase activity, increased liver enzyme activity, increased transaminase activity, increased blood cholesterol concentration, increased blood triglyceride concentration.

Table 1. Adverse effects reported in ≥2% of adult patients with schizophrenia receiving Invega® in clinical trials.

Organ System/Side Effects

From the nervous system:

Headache: 11% (3 mg once daily); 12% (6 mg once a day); 14% (9 mg once a day); 14% (12 mg once daily); 12% (placebo);

Dizziness: 6% (3 mg once daily); 5% (6 mg 1 time per day); 4% (9 mg once a day); 5% (12 mg 1 time per day); 4% (placebo);

Extrapyramidal disorders: 5% (3 mg once daily); 2% (6 mg once a day); 7% (9 mg 1 time per day); 7% (12 mg once a day); 2% (placebo);

Drowsiness: 5% (3 mg once daily); 3% (6 mg 1 time per day); 7% (9 mg 1 time per day); 5% (12 mg 1 time per day); 3% (placebo);

Akathisia: 4% (3 mg once daily); 3% (6 mg 1 time per day); 8% (9 mg once a day); 10% (12 mg once a day); 4% (placebo);

Tremor: 3% (3 mg once daily); 3% (6 mg 1 time per day); 4% (9 mg once a day); 3% (12 mg 1 time per day); 3% (placebo);

Hypertension: 2% (3 mg once daily); 1% (6 mg 1 time per day); 4% (9 mg once a day); 3% (12 mg 1 time per day); 1% (placebo);

Dystonia: 1% (3 mg once daily); 1% (6 mg 1 time per day); 4% (9 mg 1 time per day); 4% (12 mg 1 time per day); 1% (placebo);

Sedation: 1% (3 mg 1 time per day); 5% (6 mg 1 time per day); 3% (9 mg 1 time per day); 6% (12 mg once a day); 4% (placebo);

Parkinsonism: 0% (3 mg once daily);<1 % (6 мг 1 раз в день); 2 % (9 мг 1 раз в день); 1 % (12 мг 1 раз в день); 0 % (плацебо).

From the organs of vision:

Oculogyric crises: 0% (3 mg once daily); 0% (6 mg 1 time per day); 2% (9 mg 1 time per day); 0% (12 mg once daily); 0% (placebo).

From the cardiovascular system:

Other recorded cases.

Extrapyramidal symptom.

In the clinical studies conducted, there was no difference between placebo, 3 mg dosage and 6 mg dosage. Dose-dependent extrapyramidal symptoms were recorded when taking high doses of Invega® (9 mg and 12 mg). In clinical studies of schizoaffective disorders, cases of extrapyramidal syndrome were detected at higher doses of Invega® than with placebo in all patient groups, without a clear relationship with dosage. Extrapyramidal disorders included a pooled analysis and the following symptoms: dyskinesia, dystonia, hyperkinesia, parkinsonism, and tremor.

Increase in body weight.

In clinical studies in patients with schizophrenia, the proportion of cases of weight gain of more than 7% of constant body weight was compared. Approximately the same ratio was found with Invega® 3 mg and 6 mg compared with placebo, and a higher likelihood of weight gain was found with Invega® 9 mg and 12 mg compared with placebo. In clinical studies in patients with schizoaffective disorders, a higher percentage of patients taking Invega ® (5%) experienced an increase in body weight of more than 7% compared to patients taking placebo (1%). In this study, 27 patients were divided into 2 groups; weight gain of more than 7% when taking low doses of Invega® (3 mg and 6 mg) was 3% for patients taking high doses of Invega® (9 mg and 12 mg) - 7%, and 1% in the group where patients took placebo.

Laboratory indicators.

In clinical studies in patients with schizophrenia, an increase in serum prolactin concentrations was noted when taking Invega® in 67% of patients. Adverse reactions that may suggest an increase in prolactin levels (eg, amenorrhea, galactorrhea, gynecomastia) were reported in more than 2% of cases. The maximum increase in serum prolactin concentrations was observed on the 15th day of treatment, and remained above normal levels until the end of treatment.

Class effects.

When taking antipsychotic drugs, the following side effects may occur: increased QT interval, ventricular arrhythmia (atrial fibrillation, ventricular tachycardia), unexpected and unexplained death, and torsade de pointes. Cases of venous thromboembolism, including embolism, have been identified while taking antipsychotic drugs. lungs and deep vein cases.

Caution should be exercised when prescribing Invega® with drugs that prolong the QT interval.

Effect of paliperidone on other drugs.

Paliperidone is not likely to be involved in clinically significant pharmacokinetic interactions with drugs that are metabolized by cytochrome P450 isoenzymes. In vitro studies using human liver microsomes have shown that paliperidone does not significantly inhibit the bioconversion of drugs that are metabolized by cytochrome P450 isoenzymes, including CYP1A4, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4 and CYP3A5. Based on this, there is no reason to assume that paliperidone will inhibit to a clinically significant extent the clearance of drugs that are metabolized by these enzymes. In in vitro studies, paliperidone did not induce the activity of CYP1A2, CYP2C19 or CYP3A4.

At high concentrations, paliperidone is a weak inhibitor of P-glycoprotein. No in vivo data available, clinical significance unknown.

Given the fact that paliperidone acts primarily on the central nervous system, it should be used with caution in combination with other centrally acting drugs and alcohol. Paliperidone may counteract the effects of levodopa and other dopamine agonists. Due to the ability of paliperidone to cause orthostatic hypotension, additive effects may occur when the drug is used concomitantly with other drugs that cause orthostatic hypotension.

A pharmacokinetic interaction between paliperidone and lithium is unlikely. The simultaneous administration of Invega® at a dosage of 12 mg 1 time per day and extended-release divalproex sodium tablets (at a dosage of 500-2000 mg 1 time per day) does not affect the pharmacokinetics of valproate. In clinical studies in patients taking a constant dose of valproate, the concentration of valproate in the blood plasma did not differ from that of patients taking Invega® together with valproate at a dosage of 3-15 mg.

The ability of other drugs to affect paliperidone. Paliperidone is not a substrate of the isoenzymes CYP1A2, CYP2A6, CYP2C9, CYP2C19 and CYP3A5. This indicates a low probability of its interaction with inhibitors or inducers of these enzymes. In vitro studies have revealed minimal involvement of the CYP2D6 and CYP3A4 isoenzymes in the metabolism of paliperidone, however, there is no evidence that these isoenzymes play a significant role in the metabolism of paliperidone in vitro or in vivo. In vitro studies have shown that paliperidone is a substrate of P-glycoprotein.

Paliperidone is metabolized to a limited extent by the CYP2D6 isoenzyme (see section “Pharmacokinetics”). In a study in adult volunteers, the interaction of paliperidone with paroxetine, a potential inhibitor of the CYP2D6 isoenzyme, did not observe a clinically significant change in the pharmacokinetics of paliperidone.

Coadministration of paliperidone with carbamazepine 200 mg twice daily caused a decrease in paliperidone Cmax and AUC by approximately 37%. This decrease is caused by an increase in paliperidone clearance by 35% as a result of carbamazepine induction of renal P-glycoprotein. The small decrease in the amount of drug excreted unchanged suggests that carbamazepine has little effect on CYP metabolism or the bioavailability of paliperidone when coadministered. When prescribing carbamazepine, the dose of paliperidone should be re-evaluated and increased if necessary. Conversely, when carbamazepine is discontinued, the dose of paliperidone should be re-evaluated and reduced if necessary.

Paliperidone, which is a cation at physiological pH values, is excreted predominantly unchanged by the kidneys; Moreover, about half of the excretion is due to filtration and about half is due to active secretion. The use of paliperidone concomitantly with trimethoprim, which is known to inhibit the active renal transport of cationic drugs, did not affect the pharmacokinetics of paliperidone.

With the simultaneous administration of Invega® at a dosage of 12 mg 1 time per day and extended-release divalproex sodium tablets (2 tablets of 500 mg 1 time per day), an increase in Cmax and AUC of paliperidone by 50% was observed. Consideration should be given to reducing the dose of Invega® when co-administered with valproate based on the clinical assessment of the patient.

The concomitant use of paliperidone and risperidone has not been the subject of scientific research. Paliperidone is an active metabolite of risperidone and therefore increased paliperidone blood levels may occur when paliperidone and risperidone are used concomitantly.

Contraindicated in patients with hypersensitivity to paliperidone, risperidone, as well as to any auxiliary ingredient of the drug.

With caution.

History of seizures and diseases that lower the seizure threshold As with other antipsychotics, paliperidone should be used with caution in patients with a history of seizures or other diseases that lower the seizure threshold.

Dysphagia and narrowing of the lumen of the gastrointestinal tract (possibility of obstruction). Invega® tablets do not deform and hardly change their shape in the gastrointestinal tract, and therefore they should not be prescribed to patients with severe narrowing of the lumen of the gastrointestinal tract (pathological or iatrogenic), as well as to patients who suffer from dysphagia or who have difficulty swallowing tablets . There are rare reports of symptoms of gastrointestinal obstruction associated with the ingestion of non-deformable controlled release dosage forms. Paliperidone also belongs to such dosage forms, and therefore it can only be prescribed to those patients who can swallow tablets whole.

Elderly patients with dementia. The efficacy and safety of paliperidone have not been evaluated in elderly patients with dementia. A meta-analysis of 17 placebo-controlled studies found that older patients with dementia treated with atypical antipsychotics such as risperidone, aripiprazole, olanzapine, and quetiapine had a higher mortality rate compared with patients treated with placebo. Placebo-controlled studies in elderly patients with dementia have demonstrated an increased incidence of cerebrovascular adverse events (stroke and transient ischemic attack), including deaths, in patients receiving certain atypical antipsychotic drugs, including risperidone, aripiprazole, and olanzapine. compared to patients who received placebo.

Parkinson's disease and Lewy bodies. Clinicians should carefully weigh the risks and potential benefits when prescribing antipsychotic drugs, including paliperidone, to patients with Parkinson's disease or dementia with Lewy bodies, as these patients may be at increased risk of developing neuroleptic malignant syndrome or have increased sensitivity to antipsychotic drugs. Manifestations of this increased sensitivity include, in addition to extrapyramidal symptoms, confusion, dullness of reactions, and postural hypotension with frequent falls.

In general, objective and subjective symptoms of paliperidone overdose are increased pharmacologic effects of this drug, i.e., drowsiness and sedation, tachycardia and hypotension, QT prolongation, and extrapyramidal symptoms. Bidirectional tachycardia has been observed with overdose of oral paliperidone. In case of acute overdose, it is necessary to consider the possibility of toxic effects of several drugs. When assessing the therapeutic needs of the patient and the effectiveness of overdose relief, it must be remembered that Invega® is a drug with a prolonged release of the active substance. There is no specific antidote for paliperidone. Generally accepted supportive measures should be implemented. A good airway, as well as adequate oxygenation and ventilation, should be established and maintained. It is necessary to immediately organize monitoring of cardiovascular activity (ECG monitoring to identify possible arrhythmias). Arterial hypotension and collapsed states are treated with intravenous administration of plasma-substituting solutions and/or sympathomimetic agents. In certain situations, it is indicated (after intubation, if the patient is unconscious), the administration of activated charcoal and laxatives. If severe extrapyramidal symptoms occur, m-anticholinergic blockers must be administered. Monitoring the patient's condition and monitoring basic physiological functions must be continued until the effects of the overdose are completely eliminated.

Invega is a drug with antipsychotic action used in the treatment of schizophrenia and schizoaffective disorders.

Release form and composition

Dosage form – long-acting, film-coated tablets: capsule-shaped, the outlet holes may be invisible or visible upon visual inspection, the inscription is made with water-soluble black ink; dosage 3 mg – white, with the inscription “PAL 3”; dosage 6 mg – light orange (a slight brownish tint is acceptable), with the inscription “PAL 6”; dosage 9 mg – pink (a grayish tint is acceptable), with the inscription “PAL 9”; dosage 12 mg – dark yellow (a grayish tint is acceptable), with the inscription “PAL 12” (30 pieces in a polyethylene bottle, 1 bottle in a cardboard pack; 7 tablets in a blister, 4 or 8 blisters in a cardboard pack and instructions for application of Invega).

Composition of 1 tablet:

• active substance: paliperidone – 3, 6, 9 or 12 mg;
• auxiliary components: macrogol 200K, macrogol 7000K, sodium chloride, povidone (K29-32), hyethylose, stearic acid, butylated hydroxytoluene, macrogol 3350, cellulose acetate (398-10), red iron oxide, carnauba wax; for tablets of 3 and 12 mg – yellow iron oxide; for 9 mg tablets – black iron oxide;
• ink: propylene glycol, hypromellose, isopropanol, black iron oxide, purified water;
• dye: dosage 3 mg – white (titanium dioxide, hypromellose, lactose monohydrate, triacetin); dosage 6 mg – beige (titanium dioxide, hypromellose, polyethylene glycol 400, iron oxide yellow and red); dosage 9 mg – pink (titanium dioxide, hypromellose, polyethylene glycol 400, red iron oxide); dosage 12 mg – dark yellow (titanium dioxide, hypromellose, polyethylene glycol 400, iron oxide yellow).

Pharmacological properties

Pharmacodynamics

Paliperidone, the active substance of Invega, is a centrally acting antagonist of dopamine D 2 receptors. It has high antagonism towards serotonin 5-HT 2A receptors. It also exhibits antagonism to α 1 - and α 2 -adrenergic receptors and H 1 -histamine receptors. The substance does not have affinity for muscarinic, cholinergic, β 1 - and β 2 -adrenergic receptors. The pharmacological activity of the (+) and (−) enantiomers of paliperidone is the same in quantitative and qualitative terms.

The antipsychotic effect of paliperidone is due to the blockade of D 2 -dopaminergic receptors of the mesocortical and mesolimbic systems. In comparison with classical antipsychotics (neuroleptics), it leads to less suppression of motor activity and induces catalepsy to a lesser extent.

Balanced central antagonism to dopamine and serotonin can reduce the tendency to develop extrapyramidal side effects and expand the therapeutic effect of Invega to cover productive and negative signs of schizophrenia.

Paliperidone affects sleep structure, reducing the number of awakenings after falling asleep and the latency period before falling asleep; increasing the total duration, time and sleep quality index.

May lead to an increase in plasma concentrations of prolactin. Has an antiemetic effect.

Pharmacokinetics

Pharmacokinetic data presented below are based on results from studies in adult patients (unless otherwise stated).

The pharmacokinetic characteristics of the substance after oral administration are dose-dependent in the recommended therapeutic range (once a day, 3–12 mg).

The plasma concentration of paliperidone after taking one dose increases steadily, C max (maximum concentration) is reached within 24 hours. Steady-state concentrations of paliperidone are achieved in most cases within 4–5 days.

Paliperidone is an active metabolite of risperidone. The peculiarities of the release of the active substance from Invega provide smaller fluctuations in the maximum and minimum concentrations of the substance than those observed when using conventional dosage forms (concentration fluctuation index - 38%, for conventional dosage forms - 125%).

After oral administration of paliperidone, mutual conversion of the (+) and (−) enantiomers occurs, the AUC (+)/AUC (–) ratio (area under the concentration-time curve) at steady state is about 1.6. Absolute bioavailability – 28% (ranges from 23 to 33% with a confidence interval of 90%).

After a single dose of 15 mg of paliperidone simultaneously with a high-calorie fatty meal, Cmax and AUC values ​​increased relative to fasting by 42 and 46%, respectively. Another study found an increase of 60% and 54% (with 12 mg paliperidone). Thus, it has been established that the presence/absence of food in the stomach affects the plasma concentration of the substance.

Paliperidone is distributed quickly into body fluids and tissues. The apparent volume of distribution is 487 l. The substance binds to plasma proteins at a level of 74%. Binding occurs predominantly with albumin and α 1 -acid glycoprotein.

7 days after taking 1 mg of paliperidone, 59% of the dose of unchanged substance was excreted in the urine, indicating the absence of intensive metabolism of paliperidone in the liver. Approximately 80% of the drug is found in urine, and about 11% in feces.

Metabolism can occur in four ways - dealkylation, hydroxylation, dehydrogenation and cleavage of benzisoxazole. None of them cover more than 6.5% of the dose. Cytochrome P450 isoenzymes CYP2D6 and CYP3A4 play some role in the metabolism of paliperidone, but reliable evidence of their significant participation has not been obtained. The isoenzymes CYP2C9, CYP2A6, CYP1A2, CYP3A5 and CYP2C19 are not involved in the metabolism of paliperidone.

The final T1/2 (half-life) of paliperidone is ~ 23 hours.

Paliperidone is a P-glycoprotein substrate and, when used in high concentrations, weakly inhibits it. The clinical significance of this has not been established.

The use of Invega in severe liver dysfunction has not been studied.

It has been established that the elimination of the substance decreases as CC (creatinine clearance) decreases. Decrease in the total clearance of paliperidone and the value of the average final T1/2 depending on CC:

• 50–80 ml/min (mild renal impairment): 32%; 24 hours;
• 30–50 ml/min (moderate renal impairment): 64%; 40 hours;
• 10–30 ml/min (severe renal impairment): 71%; 51 hours

In patients with moderate/severe renal impairment, the dose of paliperidone should be reduced.

Indications for use

• schizophrenia in adults, including in the acute phase: treatment;
• schizophrenia in adults: prevention of exacerbations;
• schizophrenia in adolescents 12–17 years old: treatment;
• schizoaffective disorders in adults: treatment as monotherapy or in combination with mood stabilizers and/or antidepressants.

Contraindications

Absolute:

• lactation period;
• age up to 12 (for the treatment of schizophrenia) or 18 years (for the treatment of schizoaffective disorders);
• individual intolerance to the components of the drug, as well as risperidone.

Relative (Invega tablets are used under medical supervision):

• diseases that lower the threshold of convulsive readiness, aggravated history of convulsive conditions;
• narrowing of the lumen of the gastrointestinal tract, dysphagia (associated with the possibility of obstruction);
• dementia with Lewy bodies, Parkinson's disease (associated with the risk of developing neuroleptic malignant syndrome or hypersensitivity to neuroleptics);
• old age (during the treatment of dementia);
• pregnancy.

Invega, instructions for use: method and dosage

Invega is taken orally, swallowed whole and washed down with liquid. The tablets must not be crushed or chewed.

The drug should be taken in the morning, regardless of meals. There is no need to gradually increase the dose.

For adults, Invega is prescribed 6 mg once a day.

Some patients may require dose adjustment:

• schizophrenia: recommended range is 3–12 mg per day; when using large doses of Invega, there is a general tendency to increase the effect; increasing the dose, if necessary, is carried out in increments of 3 mg at intervals of more than 5 days;
• Schizoaffective Disorders: Recommended Range: 6–12 mg per day; the dose is increased only after assessing the patient’s clinical condition in increments of 3 mg at intervals of more than 4 days; maintenance therapy has not been studied.

For adolescents 12–17 years old, Invega is prescribed 3 mg once a day. If necessary, the dose is adjusted in the range of 6–12 mg; the dose should be increased in increments of 3 mg at intervals of more than 5 days.

The use of Invega in severe hepatic impairment has not been studied.

Features of therapy in patients with impaired renal function depending on CC:

• 50–80 ml/min: initial daily dose – 3 mg; after assessing the patient’s condition and tolerability of the drug, the dose can be increased by 2 times;
• 10–50 ml/min: daily dose – 3 mg;
• more than 10 ml/min: the use of the drug is not recommended, since the safety profile has not been studied.

The dose of Invega for elderly patients is selected according to renal function. Due to the increased risk of stroke, caution is required when prescribing the drug to elderly patients with dementia. The safety profile in patients over 65 years of age with schizoaffective disorders has not been studied.

When transferring to Invega from other antipsychotic drugs, the doctor must carefully assess the patient's condition.

Side effects

Possible adverse reactions [> 10% – very common; (>1% and< 10%) – часто; (>0.1% and< 1%) – нечасто; (>0.01% and< 0,1%) – редко; < 0,01% – крайне редко]:

• nervous system: very often – headache; often – drooling, parkinsonism, akathisia, dysarthria, dystonia, increased muscle tone, sedation, drowsiness, tremor; infrequently - disturbance of attention, hypoesthesia, loss of consciousness, hypokinesia, psychomotor hyperactivity, paresthesia, opisthotonus, tardive dyskinesia, dyskinesia, fainting, convulsions, cerebrovascular disorders, postural dizziness;
• hematopoietic/lymphatic system: uncommon – anemia, decreased hematocrit and leukocyte count, neutropenia; rarely - thrombocytopenia; extremely rarely - agranulocytosis;
• immune system: uncommon – hypersensitivity, anaphylactic reaction;
• endocrine system: uncommon – hyperprolactinemia; extremely rarely - inadequate secretion of antidiuretic hormone;
• metabolism and nutrition: uncommon – anorexia, hyperglycemia, increased creatine phosphokinase activity; rarely – hypoglycemia, diabetes mellitus, water intoxication; extremely rarely - diabetic ketoacidosis;
• digestive system: often – dyspepsia, nausea, constipation, diarrhea, discomfort in the upper abdomen, increased appetite; uncommon – fecal incontinence, small intestinal obstruction, gastroenteritis, decreased appetite, lip inflammation, dysphagia, flatulence, swelling of the tongue, toothache, dysgeusia; extremely rarely - intestinal obstruction, pancreatitis;
• respiratory system: infrequently - wheezing, hyperventilation, nasal congestion, pain in the pharyngolaryngeal area, shortness of breath, cough; rarely - sleep apnea syndrome;
• cardiovascular system: uncommon - increased QT interval, conduction disturbances, palpitations, bradycardia, atrioventricular block, changes in the electrocardiogram (ECG), ischemia, decreased/increased blood pressure, flushing; rarely - atrial fibrillation; extremely rarely - pulmonary embolism, deep vein thrombosis;
• infections: often – nasopharyngitis, upper respiratory tract infections; uncommon – cystitis, tonsillitis, urinary tract and respiratory tract infections, bronchitis, acarodermatitis, inflammation of subcutaneous fat, ear infections, sinusitis, influenza, pneumonia, onychomycosis;
• psyche: often – insomnia (including initial and moderate insomnia), mania; uncommon – sleep disturbances, nightmares, depression;
• sense organs: uncommon – vertigo, ear pain, ringing in the ears, dry eyes, conjunctivitis, photophobia, lacrimation; with an unknown frequency - ISDR (intraoperative floppy iris syndrome);
• liver and biliary tract: extremely rarely - jaundice;
• skin and subcutaneous tissues: uncommon - seborrheic dermatitis, skin discoloration, acne, rash, itching, dry skin, erythema, eczema; rarely - alopecia, Quincke's edema;
• musculoskeletal system: often – musculoskeletal pain, myalgia; uncommon – joint stiffness, muscle spasms/weakness, neck and back pain, arthralgia, joint swelling;
• genitals and mammary gland: uncommon - erectile/sexual dysfunction, anorgasmia, decreased libido, nipple discharge, gynecomastia, breast discomfort, menstrual cycle changes, vaginal discharge, breast engorgement, ejaculation disorders; extremely rarely - priapism;
• kidneys and urinary tract: uncommon – urinary incontinence, dysuria, urinary retention, pollakiuria;
• laboratory data: infrequently - increased activity of gamma-glutamyltransferase, liver enzymes, transaminases, increased concentrations of triglycerides and cholesterol in the blood;
• others: often – weight gain; uncommon – weight loss, facial swelling, chills, gait disturbance, edema (including peripheral and generalized edema, mild edema), chest discomfort, increased body temperature, thirst, fever; extremely rarely - withdrawal syndrome in newborns, hypothermia.

It has been established that paliperidone can cause NMS (neuroleptic malignant syndrome). It is characterized by the following symptoms: increased activity of creatine phosphokinase, rhabdomyolysis, myoglobinuria, muscle rigidity, hyperthermia, instability of the autonomic nervous system, depression of consciousness, acute renal failure.

Dose-related side effects reported in clinical trials in ≥ 2% of adult patients with schizophrenia:

• nervous system: headache, dizziness;
• cardiovascular system: first degree atrioventricular block, sinus arrhythmia/tachycardia, tachycardia, bundle branch block, orthostatic hypotension;
• digestive system: pain in the upper abdomen, dry mouth, vomiting, hypersalivation;
• organ of vision: oculogyric crises;
• extrapyramidal disorders: sedation, drowsiness, akathisia, tremor, dystonia, hypertension, parkinsonism;
• general disorders: fatigue, asthenia.

Dose-related side effects reported in clinical studies in ≥ 2% of adolescents 12 to 17 years of age with schizophrenia:

• respiratory system: nosebleeds;
• cardiovascular system: tachycardia;
• digestive system: hypersalivation, dry mouth, vomiting, swelling of the tongue;
• nervous system: dizziness, akathisia;
• organ of vision: blurred visual perception;
• genitals and mammary gland: amenorrhea, swelling of the mammary glands, galactorrhea;
• infections: nasopharyngitis;
• psyche: anxiety;
• laboratory data: weight gain;
• extrapyramidal disorders: tongue paralysis, headache, drowsiness, lethargy;
• general disorders: asthenia, fatigue.

Paliperidone is an active metabolite of risperidone, but the pharmacokinetic characteristics and release profile of Invega differ significantly from immediate-release oral forms of risperidone. The development of side effects, which are reported with the use of risperidone, may also be observed with the use of paliperidone.

Elderly patients with dementia have an increased risk of stroke (the safety profile for this group of patients has not been studied).

Dose-dependent extrapyramidal symptoms have been documented in clinical studies of high-dose therapy (9 and 12 mg).

Cases of extrapyramidal syndrome in clinical studies of schizoaffective disorders were detected at higher doses of Invega than with placebo in all patients, without a clear relationship with the dose received. Extrapyramidal disorders included dyskinesia, dystonia, hyperkinesia, tremor, and parkinsonism.

The greatest likelihood of weight gain in the treatment of schizophrenia and schizoaffective disorders is observed when using Invega in doses of 9 and 12 mg.

The maximum increase in serum prolactin concentrations was observed on the fifteenth day of drug use; until the end of treatment they exceeded the normal level.

The following disorders may occur while taking Invega: ventricular tachycardia of the torsade de pointes type, cardiac arrest, increased QT interval, ventricular arrhythmia (ventricular tachycardia, atrial fibrillation), unexplained and unexpected death. There is also information about cases of venous thromboembolism, including episodes of deep vein thrombosis and pulmonary embolism.

Overdose

Main symptoms: enhanced pharmacological effects of paliperidone, including drowsiness, sedation, tachycardia, arterial hypotension, extrapyramidal disorders, prolongation of the QT interval. It is also possible to develop bidirectional tachycardia and ventricular fibrillation.

In case of acute overdose of paliperidone, the possibility of toxic effects of several drugs must be taken into account.

When assessing the therapeutic need and effectiveness of overdose reversal, the extended release of paliperidone should be kept in mind.

Therapy: General supportive measures including establishing and maintaining a good airway, as well as adequate ventilation and oxygenation. Monitoring of cardiovascular activity should be immediately organized (to identify possible arrhythmias - ECG monitoring). Collaptoid states and arterial hypotension are relieved by intravenous administration of sympathomimetic agents and/or plasma-substituting solutions. Some patients are prescribed gastric lavage (including after intubation, if the patient is unconscious), administration of laxatives and activated charcoal. For severe extrapyramidal symptoms, m-anticholinergic drugs are indicated. Monitoring the patient's condition and monitoring the main physiological functions should be carried out until the consequences of the overdose are completely eliminated.

A specific antidote for paliperidone is unknown.

Special instructions

During the period of use of Invega, like other antipsychotic drugs, the development of NMS is possible. It is characterized by an increase in serum concentrations of creatine phosphokinase, depression of consciousness, muscle rigidity, hyperthermia, and instability of the function of the autonomic nervous system. Disorders such as acute renal failure and rhabdomyolysis may also occur. In cases where the patient has objective or subjective symptoms of NMS, Invega is canceled.

Therapy can cause tardive dyskinesia, which is characterized by rhythmic involuntary movements mainly of the facial muscles and/or tongue. If there are objective/subjective suspicions of the development of this disorder, it is necessary to evaluate the advisability of further use of Invega.

When prescribing Invega to patients with a history of cardiac arrhythmias, congenital prolongation of the QT interval, as well as when combined with drugs that prolong the QT interval, caution is required.

During the therapy period, cases of hyperglycemia, diabetes mellitus and exacerbation of existing diabetes mellitus were observed. It is difficult to reliably establish a connection between Invega and these disorders. If a patient has a confirmed diagnosis of diabetes mellitus, regular monitoring of glucose levels is indicated. If there are risk factors (including obesity, family history of diabetes mellitus), patients should undergo fasting blood glucose monitoring at the beginning of therapy and periodically during it. All patients are indicated for clinical monitoring for symptoms of diabetes mellitus and hyperglycemia. Sometimes signs of hyperglycemia after stopping Invega went away on their own, but some patients require antidiabetic therapy even if they stop taking paliperidone.

All patients need weight control, since a significant increase in body weight is observed during the period of use of Invega.

Invega, along with other D2-dopamine receptor antagonists, increases prolactin levels. This increase persists throughout the entire period of therapy. The effect of paliperidone can be compared with that of risperidone, a drug that, among other antipsychotics, has the greatest effect on prolactin levels.

Regardless of the etiology, hyperprolactinemia can suppress the expression of GnRH (gonadotropin-releasing hormone) in the hypothalamus, which causes a decrease in the secretion of gonadotropins by the pituitary gland and, as a consequence, suppression of reproductive function and weakening of sexual steroidogenesis in men and women. During therapy, the development of galactorrhea, amenorrhea, gynecomastia and impotence is possible. Long-term hyperprolactinemia associated with hypogonadism in men and women can cause decreased bone density.

According to studies, approximately 1/3 of breast cancer cases are prolactin-dependent. This should be taken into account when prescribing Invega to patients who have previously been diagnosed with breast cancer. Epidemiological and clinical studies do not prove the connection between the use of atypical antipsychotics and the formation of tumors. However, it is believed that the available information is too limited to draw definitive conclusions.

Paliperidone has α-blocking activity, so Invega may cause orthostatic hypotension in some patients. Therefore, therapy should be carried out with caution in patients with cardiovascular diseases (for example, with heart failure, myocardial infarction or ischemia, cardiac muscle conduction disorders), cerebrovascular diseases, as well as in the presence of conditions that contribute to arterial hypotension (for example, with dehydration, hypovolemia and therapy with antihypertensive drugs).

It is believed that antipsychotics are characterized by such undesirable effects as impaired ability to regulate temperature. When prescribing Invega to patients with conditions that can lead to an increase in core body temperature (during intense physical activity, dehydration, exposure to high external temperatures, or when used in combination with drugs with anticholinergic activity), caution must be exercised.

The antiemetic effect of paliperidone, identified in preclinical studies, may mask objective/subjective signs of overdose of certain drugs, as well as diseases, such as brain tumors, intestinal obstruction and Reye's syndrome.

There is information about the development of priapism during the use of drugs with α-adrenergic blocking effects. Priapism has also been reported during post-marketing studies of paliperidone.

Mental illnesses are characterized by the possibility of suicide attempts; therefore, when using Invega, the condition of high-risk patients should be monitored. In order to reduce the risk of overdose, the drug is prescribed to such patients in a minimal dose.

During the use of Invega, cases of leukopenia, neutropenia and agranulocytosis were observed. During post-marketing surveillance, agranulocytosis has been observed in very rare cases. If there is a history of a clinically significant decrease in the number of leukocytes or drug-dependent leukopenia/neutropenia, a complete blood count is recommended during the first months of therapy. At the first clinically significant decrease in the number of leukocytes, if all possible causes are excluded, the possibility of discontinuing Invega should be considered.

Patients with clinically significant neutropenia should be monitored for fever or symptoms of infection. If such symptoms occur, treatment should be started immediately. In cases of severe neutropenia (in patients with an absolute neutrophil count less than 1×10 9 /l), Invega is discontinued until the leukocyte count normalizes.

There is information about the development of venous thromboembolism. Since patients taking Invega often have a high risk of venous thromboembolism, before and during therapy it is necessary to identify all possible risk factors and take preventive measures.

ISDR may occur during cataract surgery in patients taking α1-adrenergic receptor antagonist drugs. Because of ISDR, the likelihood of vision-related complications increases both during and after surgery. The doctor performing such an operation should be warned in advance that the patient has taken/is taking Invega. The potential benefit of discontinuing the drug before surgery has not been established; the physician must evaluate it taking into account the risks associated with such withdrawal.

If you are pregnant or planning to become pregnant while using Invegi, you must notify your doctor.

It is recommended to abstain from drinking alcohol during therapy.

Conditions/diseases in which conditions are created to reduce the presence of the drug in the gastrointestinal tract, in particular those associated with chronic diarrhea, may lead to a decrease in the absorption of paliperidone.

In the production of Invega tablets, technologies for osmotic release of the active component are used, while the release of paliperidone at a controlled rate provides osmotic pressure. The system, which looks like a capsule-shaped tablet, consists of a three-layer osmotically active core. It is surrounded by an intermediate shell and a semi-permeable membrane. Composition of the tablet core: two medicinal layers that contain the drug substance and auxiliary components + an ejector layer with osmotically active substances.

On the side of the medicinal layers on the dome there are two outlets, which are made using a laser. The colored shell quickly dissolves in the gastrointestinal tract, and water gradually enters the tablet through a semi-permeable control membrane. The level of water intake is controlled by the membrane, which in turn controls the release of paliperidone.

Hydrophilic polymers contained in the tablet core swell by absorbing water and turn into a paliperidone-containing gel, which is then expelled through holes in the dome. Insoluble substances are excreted from the body in feces. If you find something that looks like a pill in your stool, you should not worry.

Impact on the ability to drive vehicles and complex mechanisms

Until the individual sensitivity of the action of Invega is established, patients are advised to refrain from driving.

Use during pregnancy and lactation

During pregnancy, Invega can be used only in cases where the expected benefit is higher than the possible harm.

There is no data confirming the safety of paliperidone for women during pregnancy and fetal development. The effect of Invega on labor is unknown.

When taking paliperidone in the third trimester of pregnancy, newborns are likely to develop withdrawal syndrome and/or extrapyramidal disorders of varying severity. Main symptoms: feeding disorders, hypertension, agitation, hypotension, tremor, drowsiness, respiratory disorders. Thus, the condition of newborns should be monitored. If it is necessary to interrupt treatment during pregnancy, the dose is reduced gradually.

During lactation, therapy is contraindicated since paliperidone passes into breast milk in clinically significant doses.

Use in childhood

Age restrictions in pediatrics when using Invega tablets:

• schizophrenia: up to 12 years;
• schizoaffective disorders: up to 18 years.

For impaired renal function

For moderate/severe renal impairment (in patients with CC< 50 мл/мин) Инвега назначается в сниженной дозе (3 мг в день).

For liver dysfunction

Patients with functional liver disorders do not require dose reduction.

Use in old age

The dose of Invega in elderly patients is selected according to renal function.

Caution is required when prescribing the drug to elderly patients with dementia.

Drug interactions

• drugs that prolong the QT interval: the combination requires caution;
• centrally acting drugs, alcohol: the combination requires caution, since paliperidone primarily affects the central nervous system;
• levodopa and other dopamine agonists: paliperidone helps neutralize their effects;
• drugs that cause orthostatic hypotension: an additive effect is possible;
• carbamazepine: Cmax and AUC of paliperidone decreases, which may require dose adjustment of Invega;
• extended-release divalproex sodium: Cmax and AUC of paliperidone increases, which may require dose adjustment;
• Risperidone: Blood levels of paliperidone may increase.

Analogs

Analogues of Invega are Trevicta, Xeplion, Torendo, Rispolept, Rileptid, Risset, etc.

Terms and conditions of storage

Store at 15–30 °C. Keep away from children.

Shelf life – 2 years.