Invega^® (Tablets) Instructions for Use

Marketing Authorization Holder

Johnson & Johnson, LLC (Russia)

Manufactured By

Janssen-Cilag Manufacturing, LLC (Puerto Rico)

Quality Control Release

JANSSEN-CILAG S.p.A. (Italy)

Contact Information

JANSSEN, a pharmaceutical division of Johnson & Johnson LLC

ATC Code

N05AX13 (Paliperidone)

Active Substance

Paliperidone (Rec.INN WHO registered)

Dosage Forms

	Invega®	Extended-release film-coated tablets, 3 mg: 28, 30, or 56 pcs.
		Extended-release film-coated tablets, 6 mg: 28, 30, or 56 pcs.
		Extended-release film-coated tablets, 9 mg: 28, 30, or 56 pcs.

Dosage Form, Packaging, and Composition

Extended-release film-coated tablets white, capsule-shaped, imprinted with “PAL 3”; release orifices may be visible or not visible upon visual inspection.

Excipients: macrogol 200K – 81.43 mg, macrogol 7000K – 73.7 mg, sodium chloride – 30 mg, povidone (K29-32) – 10 mg, hydroxyethyl cellulose – 10.45 mg, stearic acid – 0.75 mg, butylated hydroxytoluene – 0.11 mg, iron oxide red – 1 mg, iron oxide yellow – 0.03 mg, macrogol 3350 – 1 mg, cellulose acetate (398-10) – 44.55 mg, white dye (hypromellose, titanium dioxide, lactose monohydrate, triacetin) – 33 mg, carnauba wax – 0.03 mg.

7 pcs. – blisters (4) – cardboard packs.
7 pcs. – blisters (8) – cardboard packs.
30 pcs. – polyethylene bottles (1) – cardboard packs.

Extended-release film-coated tablets light orange in color (a slight brownish tint is allowed), capsule-shaped, imprinted with “PAL 6”; release orifices may be visible or not visible upon visual inspection.

Excipients: macrogol 200K – 78.45 mg, macrogol 7000K – 73.7 mg, sodium chloride – 30 mg, povidone (K29-32) – 10 mg, hydroxyethyl cellulose – 10.45 mg, stearic acid – 0.75 mg, butylated hydroxytoluene – 0.11 mg, iron oxide red – 1.01 mg, macrogol 3350 – 1 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.

7 pcs. – blisters (4) – cardboard packs.
7 pcs. – blisters (8) – cardboard packs.
30 pcs. – polyethylene bottles (1) – cardboard packs.

Extended-release film-coated tablets pink in color (a grayish tint is allowed), capsule-shaped, imprinted with “PAL 9”; release orifices may be visible or not visible upon visual inspection.

Excipients: macrogol 200K – 75.45 mg, macrogol 7000K – 73.7 mg, sodium chloride – 30 mg, povidone (K29-32) – 10 mg, hydroxyethyl cellulose – 10.45 mg, stearic acid – 0.75 mg, butylated hydroxytoluene – 0.11 mg, iron oxide black – 0.01 mg, iron oxide red – 1 mg, macrogol 3350 – 1 mg, cellulose acetate (398-10) – 44.55 mg, pink dye (hypromellose, titanium dioxide, polyethylene glycol 400, iron oxide red) – 15 mg, carnauba wax – 0.03 mg.

7 pcs. – blisters (4) – cardboard packs.
7 pcs. – blisters (8) – cardboard packs.
30 pcs. – polyethylene bottles (1) – cardboard packs.

Extended-release film-coated tablets dark yellow in color (a grayish tint is allowed), capsule-shaped, imprinted with “PAL 12”; release orifices may be visible or not visible upon visual inspection.

Excipients: macrogol 200K – 72.43 mg, macrogol 7000K – 73.7 mg, sodium chloride – 30 mg, povidone (K29-32) – 10 mg, hydroxyethyl cellulose – 10.45 mg, stearic acid – 0.75 mg, butylated hydroxytoluene – 0.11 mg, iron oxide red – 1 mg, iron oxide yellow – 0.03 mg, macrogol 3350 – 1 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.

7 pcs. – blisters (4) – cardboard packs.
7 pcs. – blisters (8) – cardboard packs.
30 pcs. – polyethylene bottles (1) – cardboard packs.

The inscription on tablets of all dosages is made with water-soluble black ink (hypromellose, iron oxide black, purified water, isopropanol, propylene glycol).

Clinical-Pharmacological Group

Antipsychotic drug (neuroleptic)

Pharmacotherapeutic Group

Antipsychotic (neuroleptic) agent

Pharmacological Action

Mechanism of action

Paliperidone is a centrally acting dopamine D₂ receptor antagonist, which also has high antagonistic activity against serotonin 5-HT_2A receptors. In addition, Paliperidone is an antagonist of alpha₁– and alpha₂-adrenergic receptors and H₁-histamine receptors. Paliperidone has no affinity for cholinergic, muscarinic, or beta₁– and beta₂-adrenergic receptors. The pharmacological activity of the (+) and (-) enantiomers of paliperidone is qualitatively and quantitatively similar.

Antipsychotic effect is due to the blockade of D₂ dopaminergic receptors in the mesolimbic and mesocortical systems. It causes less suppression of motor activity and induces catalepsy to a lesser extent than classical antipsychotics (neuroleptics).

Balanced central antagonism to serotonin and dopamine may reduce the propensity for extrapyramidal side effects and extend the therapeutic effect of the drug to cover both negative and positive symptoms of schizophrenia.

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

Pharmacokinetics

Unless otherwise stated, the pharmacokinetic data presented in this section are based on results from studies in adult patients.

The pharmacokinetic characteristics of paliperidone after oral administration are proportional to the dose taken within the recommended therapeutic range (3-12 mg once daily).

Absorption

After a single dose of the drug, the plasma concentration of paliperidone increased steadily, and the maximum concentration (C_max) was reached after 24 hours. In most patients, steady-state concentrations of paliperidone were achieved after 4-5 days of once-daily dosing.

Paliperidone is an active metabolite of risperidone. The release characteristics of the active substance from Invega^® provided smaller fluctuations in peak and trough concentrations of paliperidone than those observed with conventional dosage forms (fluctuation index 38% compared to 125% for conventional dosage forms).

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

After a single dose of 15 mg paliperidone as an extended-release tablet with a high-fat, high-calorie meal, C_max and AUC increased on average by 42% and 46%, respectively, compared to taking the tablet on an empty stomach. In another study, after a single dose of 12 mg paliperidone as an extended-release tablet with a high-fat, high-calorie meal, C_max and AUC increased on average by 60% and 54%, respectively, compared to taking the tablet on an empty stomach. Thus, the presence or absence of food in the stomach when taking paliperidone may alter the plasma concentration of paliperidone.

Distribution

Paliperidone is rapidly distributed into body tissues and fluids. The apparent volume of distribution is 487 L. The degree of plasma protein binding is 74%. Paliperidone binds primarily to alpha₁-acid glycoprotein and albumin.

Biotransformation and elimination

One week after taking a single standard tablet containing 1 mg paliperidone, 59% of the dose was excreted unchanged in the urine; this indicates that Paliperidone does not undergo extensive hepatic metabolism. Approximately 80% of the drug was found in urine and about 11% in feces.

Four pathways of paliperidone metabolism in vivo are known, none of which accounts for more than 6.5% of the dose: dealkylation, hydroxylation, dehydrogenation, and benzisoxazole cleavage. 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 CYP2D6 isoenzyme activity varies significantly in the general population, population pharmacokinetic studies have found no significant differences in the apparent clearance of paliperidone between patients who are extensive metabolizers of CYP2D6 isoenzyme substrates and those who are poor metabolizers of CYP2D6 isoenzyme substrates. In vitro studies using microsomal preparations of heterologous systems have shown that CYP1A2, CYP2A6, CYP2C9, CYP2C19, and CYP3A5 isoenzymes are not involved in the metabolism of paliperidone.

The terminal half-life of paliperidone is about 23 hours.

In vitro studies have shown that Paliperidone is a substrate of P-glycoprotein and weakly inhibits it at high concentrations. In vivo data are lacking, clinical significance is unknown.

Special Populations

Patients with hepatic impairment

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

Patients with renal impairment

The dose of paliperidone should be reduced in patients with moderate and severe renal impairment. The excretion of paliperidone was studied in patients with varying degrees of renal impairment. It was found that the elimination of paliperidone decreased with decreasing creatinine clearance (CrCl). Total clearance of paliperidone was reduced by 32% in patients with mild renal impairment (CrCl from 50 to <80 ml/min), by 64% in patients with moderate renal impairment (CrCl from 30 to <50 ml/min), and by 71% in patients with severe renal impairment (CrCl from 10 to <30 ml/min). The mean terminal half-life of paliperidone was 24, 40, and 51 hours in patients with mild, moderate, and severe renal impairment, respectively; in people with normal renal function (CrCl ≥80 ml/min) this figure was 23 hours.

Adolescents

The systemic exposure to paliperidone in adolescents was comparable to that in adults. The plasma concentration of paliperidone in adolescents with body weight <51 kg is 23% higher than in adolescents with body weight ≥51 kg, which is not clinically significant. Age does not affect the plasma concentration of paliperidone.

Elderly patients

It is not recommended to adjust the dose of paliperidone based on the patient’s age. The results of a pharmacokinetic study involving elderly patients aged 65 years and older showed that the apparent steady-state clearance of paliperidone after taking Invega^® in this group was 20% lower than in adult patients aged 18-45 years. However, after adjusting for age-related decline in creatinine clearance, population analysis revealed no effect of age in 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.

Gender

The 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 mainly due to differences in lean body mass and creatinine clearance between men and women, since population studies, after adjusting for lean body mass and creatinine clearance, found no clinically significant differences in the pharmacokinetics of paliperidone between men and women taking the drug.

Smoking

It is not recommended to adjust the doses of paliperidone in smokers. In vitro studies using human liver enzymes have shown that Paliperidone is not a substrate for the CYP1A2 isoenzyme, and therefore smoking should not affect the pharmacokinetics of paliperidone. Consistent with in vitro findings, population studies have found no differences in the pharmacokinetics of paliperidone between smokers and non-smokers.

Indications

• Schizophrenia, including the acute phase in adults;
• Prevention of exacerbations of schizophrenia in adults;
• Treatment of schizophrenia in adolescents aged 12 to 17 years;
• Therapy of schizoaffective disorders: as monotherapy or as part of combination therapy with antidepressants and/or mood stabilizers in adults.

ICD codes

Dosage Regimen

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

Schizophrenia

Adults (over 18 years)

The recommended dose in adults is 6 mg once daily in the morning, regardless of meals. Gradual increase of the initial dose is not required. In some patients, therapeutic effect is achieved with lower or higher doses within the recommended range of 3-12 mg once daily. There is a general trend towards increased effect with higher doses of the drug. If a dose increase is necessary, it is recommended to increase the dose by 3 mg per day at intervals of more than 5 days.

Adolescents (12-17 years)

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

Schizoaffective disorders

Adults (over 18 years)

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

Patients with hepatic impairment

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

Patients with renal impairment

For patients with mild renal impairment (creatinine clearance (CrCl) ≥ 50 but <80 ml/min) the recommended initial dose is 3 mg once daily. This dose may be increased to 6 mg once daily after assessing the patient's condition and taking into account drug tolerance. For patients with moderate or severe renal impairment (CrCl≥10 but <50 ml/min) the recommended dose of the drug is 3 mg once daily. The use of Invega^® in patients with CrCl<10 ml/min has not been studied, therefore the use of the drug in these patients is not recommended.

Elderly patients

For elderly patients with normal renal function (CrCl ≥80 ml/min) the same doses of the drug are recommended as for adult patients with normal renal function. However, renal function may be impaired in elderly patients, and in this case the drug dose should be selected according to the renal function of the particular patient. Caution should be exercised when using the drug in elderly patients with dementia due to an increased risk of stroke.

The efficacy and safety of Invega^® in patients over 65 years of age with schizoaffective disorders has not been studied.

Children and adolescents

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

Special patient groups

It is not recommended to adjust the dose of paliperidone based on gender, age, or whether the patient smokes.

Switching patients to treatment with other antipsychotic drugs

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

Adverse Reactions

The adverse effects observed in patients are listed below. The frequency of adverse effects was classified as follows: very common (≥10%), common (≥1% and <10%), uncommon (≥0.1% and <1%), rare (≥0.01% and <0.1%), and very rare (<0.01%).

Infections common – upper respiratory tract infections, nasopharyngitis; uncommon – urinary tract infections, acarodermatitis, bronchitis, inflammation of subcutaneous adipose tissue, cystitis, ear infections, influenza, onychomycosis, pneumonia, respiratory tract infections, sinusitis, tonsillitis.

Immune system disorders : uncommon – anaphylactic reaction, hypersensitivity.

Blood and lymphatic system disorders : uncommon – anemia, decreased hematocrit, neutropenia, decreased white blood cell count; rare – thrombocytopenia; very rare – agranulocytosis.

Endocrine system disorders uncommon – hyperprolactinemia; very rare – inappropriate antidiuretic hormone secretion.

Metabolism and nutrition disorders : uncommon – increased creatine phosphokinase activity, anorexia, hyperglycemia; rare – diabetes mellitus, hypoglycemia, water intoxication; very rare – diabetic ketoacidosis.

Psychiatric disorders : common – insomnia (including initial and middle insomnia), mania; uncommon – “nightmare” dreams, sleep disorders, depression.

Nervous system disorders : very common – headache; common – akathisia, dystonia, dysarthria, increased muscle tone, parkinsonism, sedative effect, somnolence, tremor, drooling; uncommon – cerebrovascular disorders, postural dizziness, dyskinesia, seizures, syncope, attention disturbance, hypoesthesia, loss of consciousness, paresthesia, psychomotor hyperactivity, tardive dyskinesia, hypokinesia, opisthotonus.

It is known that antipsychotic drugs, including Paliperidone, can cause neuroleptic malignant syndrome (NMS), which is characterized by hyperthermia, muscle rigidity, autonomic instability, impaired consciousness, increased creatine phosphokinase activity, myoglobinuria, rhabdomyolysis, acute renal failure.

Eye disorders : uncommon – conjunctivitis, dry eye, photophobia, lacrimation; frequency not known: intraoperative floppy iris syndrome.

Ear and labyrinth disorders : uncommon – ear pain, vertigo, tinnitus.

Cardiac disorders : uncommon – bradycardia, palpitations, atrioventricular block, conduction disorder, ECG changes, QT interval prolongation, ischemia, “hot flushes”, increased blood pressure, decreased blood pressure; rare – atrial fibrillation; very rare – deep vein thrombosis, pulmonary embolism.

Gastrointestinal disorders : common – nausea, diarrhea, constipation, upper abdominal discomfort, dyspepsia, increased appetite; uncommon – decreased appetite, lip inflammation, dysphagia, fecal incontinence, small intestinal obstruction, flatulence, gastroenteritis, tongue edema, toothache, dysgeusia; very rare – pancreatitis, intestinal obstruction.

Hepatobiliary disorders very rare – jaundice.

Respiratory, thoracic and mediastinal disorders: uncommon – oropharyngeal pain, nasal congestion, cough, dyspnea, hyperventilation, wheezing; rare – sleep apnea syndrome.

Musculoskeletal and connective tissue disorders: common – myalgia, musculoskeletal pain; uncommon – muscle spasms, back pain, arthralgia, joint stiffness, joint swelling, muscle weakness, neck pain.

Skin and subcutaneous tissue disorders uncommon – rash, pruritus, acne, dry skin, eczema, erythema, seborrheic dermatitis, skin discoloration; rare – angioedema, alopecia.

Renal and urinary disorders uncommon – dysuria, pollakiuria, urinary incontinence, urinary retention.

Reproductive system and breast disorders : uncommon – decreased libido, anorgasmia, nipple discharge, erectile dysfunction, gynecomastia, menstrual cycle changes, breast discomfort, sexual dysfunction, vaginal discharge, ejaculation disorder, breast engorgement; very rare – priapism.

Pregnancy, puerperium and perinatal conditions : very rare – neonatal withdrawal syndrome.

General disorders and administration site conditions : common – weight increased; uncommon – weight decreased, chills, facial edema, gait disturbance, edema (including generalized edema, peripheral edema, pitting edema), increased body temperature, pyrexia, thirst, chest discomfort; very rare – hypothermia.

Investigations uncommon – increased gamma-glutamyltransferase activity, increased liver enzymes, increased transaminases, increased blood cholesterol, increased blood triglycerides.

Information on dose-dependent adverse effects is provided in Table 1.

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

Table 2. Adverse effects reported in ≥2% of adolescents (12-17 years) with schizophrenia receiving Invega^® in clinical studies.

* Extrapyramidal disorders include: oculogyric crisis, muscle rigidity, musculoskeletal rigidity, nuchal rigidity, torticollis, trismus, bradykinesia, cogwheel rigidity, dyskinesia, dystonia, extrapyramidal disorder, hypertonia, hypokinesia, involuntary muscle contractions, parkinsonian gait, parkinsonism, tremor, and restlessness. Somnolence includes somnolence, sedation, and hypersomnia. Insomnia includes insomnia and initial insomnia. Tachycardia includes tachycardia, sinus tachycardia, and increased heart rate. Hypertension includes hypertension and increased blood pressure. Gynecomastia includes gynecomastia and breast swelling.

Paliperidone is an active metabolite of risperidone; however, due to its release profile and pharmacokinetic characteristics, Invega^® is significantly different from immediate-release oral formulations of risperidone. Adverse effects reported with risperidone may occur with paliperidone.

Elderly patients

In clinical studies involving elderly patients with schizophrenia, the safety profile of the drug was the same as for younger patients. Invega^® has not been studied in patients with dementia. Studies with other antipsychotic drugs have noted an increased risk of death and cerebrovascular disorders. Elderly patients with dementia have an increased risk of stroke.

Other reported findings

Extrapyramidal symptom

In the conducted clinical studies, there was no difference compared to placebo for the 3 mg and 6 mg doses. Dose-dependent extrapyramidal symptoms were reported at higher doses of Invega^® (9 mg and 12 mg). In clinical studies of schizoaffective disorder, cases of extrapyramidal syndrome were identified at higher doses of Invega^® compared to placebo across all patient groups without a clear dose relationship. Extrapyramidal disorders included a pooled analysis of the following symptoms: dyskinesia, dystonia, hyperkinesia, parkinsonism, and tremor.

Weight increased

In clinical studies in patients with schizophrenia, the proportion of patients with a weight increase of more than 7% from baseline body weight was compared. Approximately the same proportion was found for Invega^® 3 mg and 6 mg compared to placebo, and a higher likelihood of weight increase was found for Invega^® 9 mg and 12 mg compared to placebo.

In clinical studies in patients with schizoaffective disorder, a higher percentage of patients taking Invega^® (5%) experienced a weight increase of more than 7% compared to patients taking placebo (1%). In this study, 27 patients were divided into 2 groups; the weight increase of more than 7% for low doses of Invega^® (3 mg and 6 mg) was 3%, for patients taking high doses of Invega^® (9 mg and 12 mg) it was 7%, and 1% in the placebo group.

Laboratory findings

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

Class effects

When taking antipsychotic drugs, the following adverse events may occur: QT interval prolongation, ventricular arrhythmia (atrial fibrillation, ventricular tachycardia), sudden unexplained death, cardiac arrest, and torsades de pointes. Cases of venous thromboembolism, including cases of pulmonary embolism and deep vein thrombosis, have been identified with the use of antipsychotic drugs.

Contraindications

• Hypersensitivity to paliperidone, risperidone, or to any excipient of the drug.

With caution

History of seizures and conditions that may lower the seizure threshold

Like other antipsychotics, Paliperidone should be used with caution in patients with a history of seizures or other conditions that may lower the seizure threshold.

Dysphagia and gastrointestinal narrowing (risk of obstruction)

Invega^® tablets do not deform and change their shape very little in the gastrointestinal tract, and therefore they should not be prescribed to patients with severe gastrointestinal narrowing (pathological or iatrogenic), or to patients who suffer from dysphagia or 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 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 showed that elderly patients with dementia treated with atypical antipsychotic drugs such as risperidone, aripiprazole, olanzapine, and quetiapine had a higher mortality rate compared to patients receiving placebo. Placebo-controlled studies involving elderly patients with dementia demonstrated an increased incidence of cerebrovascular adverse effects (strokes and transient ischemic attacks), including fatal ones, in patients receiving some atypical antipsychotic drugs, including risperidone, aripiprazole, and olanzapine, compared to patients receiving placebo.

Parkinson’s disease and dementia with Lewy bodies

Physicians should carefully weigh the possible risks and potential benefits when prescribing antipsychotic drugs, including Paliperidone, to patients suffering from Parkinson’s disease or dementia with Lewy bodies, as such patients may have an increased risk of developing neuroleptic malignant syndrome or increased sensitivity to antipsychotic drugs. Manifestations of this increased sensitivity include, in addition to extrapyramidal symptoms, confusion, dulled reactions, and postural hypotension with frequent falls.

Use in Pregnancy and Lactation

Currently, there are no data on the safety of paliperidone for pregnant women and fetal development. The drug can be used in pregnant women only in case of absolute necessity, when the potential benefit to the mother outweighs the possible risk to the fetus. The effect of paliperidone on labor is not known.

If a woman has taken antipsychotic drugs (including Paliperidone) in the third trimester of pregnancy, there is a risk of extrapyramidal disorders and/or withdrawal syndrome of varying severity in newborns. These symptoms may include agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding difficulties. Therefore, special monitoring of newborns is necessary. If treatment discontinuation during pregnancy is necessary, the dose should be reduced gradually.

Lactation

Paliperidone penetrates into breast milk in clinically significant amounts; therefore, the drug should not be prescribed during lactation.

Use in Hepatic Impairment

Patients with impaired liver function do not require a dose reduction.

Use in Renal Impairment

For patients with moderate or severe renal impairment (CrCl < 50 ml/min) the recommended dose of the drug is 3 mg once daily.

Pediatric Use

The efficacy and safety of Invega^® for the treatment of schizophrenia in children under 12 years of age have not been studied. The efficacy and safety of Invega^® for the treatment of schizoaffective disorder in patients under 18 years of age have not been studied.

Geriatric Use

For elderly patients with normal renal function (CrCl ≥80 ml/min), the same drug doses are recommended as for adult patients with normal renal function. However, renal function may be impaired in elderly patients, and in this case, the drug dose should be adjusted according to the patient’s renal function.

Special Precautions

Neuroleptic Malignant Syndrome

Antipsychotic drugs, including Paliperidone, are known to cause Neuroleptic Malignant Syndrome (NMS), which is characterized by hyperthermia, muscle rigidity, instability of autonomic nervous system function, impaired consciousness, and increased serum creatine phosphokinase levels. Patients with NMS may also experience myoglobinuria (rhabdomyolysis) and acute renal failure. If a patient develops objective or subjective symptoms of NMS, all antipsychotic drugs, including Paliperidone, must be discontinued immediately.

Tardive Dyskinesia

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

QT Interval Prolongation

As with other antipsychotic agents, caution should be exercised when prescribing Invega^® to patients with a history of cardiac arrhythmias, congenital long QT syndrome, and when co-administered with drugs that prolong the QT interval.

Hyperglycemia and Diabetes Mellitus

Hyperglycemia, diabetes mellitus, and exacerbation of pre-existing diabetes have been observed during treatment with Invega^®. Establishing a relationship between the use of atypical antipsychotic drugs and glucose metabolism disorders is complicated by the increased risk of developing diabetes in patients with schizophrenia and the prevalence of diabetes in the general population. Given these factors, the relationship between the use of atypical antipsychotic drugs and the development of adverse events related to hyperglycemia is not fully established. In patients with an established diagnosis of diabetes, blood glucose levels should be regularly monitored. Patients with risk factors for developing diabetes (e.g., obesity, family history of diabetes) should undergo fasting blood glucose testing at the start of treatment and periodically during treatment. All patients should be clinically monitored for symptoms of hyperglycemia and diabetes. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo blood glucose testing. In some cases, symptoms of hyperglycemia resolved upon discontinuation of the atypical antipsychotic drug; however, some patients require antidiabetic treatment despite discontinuation of the suspected drug.

Weight Gain

Significant weight gain has been observed during treatment with atypical antipsychotics. Patient body weight should be monitored.

Hyperprolactinemia

Like other D₂ dopamine receptor antagonists, Paliperidone increases prolactin levels, and this increase persists throughout treatment. The effect of paliperidone is comparable to that of risperidone, the antipsychotic drug with the greatest effect on prolactin levels.

Hyperprolactinemia, regardless of etiology, can suppress the expression of hypothalamic GnRH (gonadotropin-releasing hormone), leading to reduced pituitary secretion of gonadotropins. This, in turn, can suppress reproductive function by impairing gonadal steroidogenesis in both women and men. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients taking drugs that increase prolactin levels. Long-term hyperprolactinemia associated with hypogonadism may lead to decreased bone mineral density in both women and men.

In vitro tissue culture studies indicate that approximately one-third of human breast cancers are prolactin-dependent. This should be considered when prescribing drugs that increase prolactin levels to patients with previously detected breast cancer. Clinical and epidemiological studies conducted to date have not shown an association between the 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 therefore may cause orthostatic hypotension in some patients. Paliperidone should be used with caution in patients with cardiovascular diseases (e.g., heart failure, myocardial infarction or ischemia, conduction abnormalities), cerebrovascular diseases, as well as conditions that may predispose to hypotension (e.g., dehydration, hypovolemia, and treatment with antihypertensive drugs).

Body Temperature Regulation

Antipsychotic drugs are attributed with the undesirable effect of impairing 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, which include strenuous exercise, dehydration, exposure to extreme heat, or concomitant use of drugs with anticholinergic activity.

Antiemetic Effect

An antiemetic effect was observed in preclinical studies of paliperidone. This effect, if it occurs in humans, could mask the signs and symptoms of overdose with certain drugs or of conditions such as intestinal obstruction, Reye’s syndrome, and brain tumors.

Priapism

Drugs with alpha-adrenergic blocking effects may cause priapism. Cases of priapism have been reported during post-marketing experience with paliperidone.

Suicidal Attempts

The possibility of suicide attempts is inherent in mental illness; therefore, therapy for patients at high risk should be conducted under close supervision. In such cases, Invega^® should be prescribed in the minimum number of tablets to reduce the risk of overdose.

Leukopenia, Neutropenia, Agranulocytosis

Leukopenia, neutropenia, and agranulocytosis have been reported with the use of antipsychotic agents, including with the use of Invega^®. Agranulocytosis has been reported very rarely during post-marketing observation. Patients with a history of clinically significant decrease in white blood cell count or drug-induced leukopenia/neutropenia are advised to have a complete blood count during the first few months of therapy; discontinuation of Invega^® treatment should be considered at the first clinically significant decrease in white blood cell count in the absence of other possible causes. Patients with clinically significant neutropenia should be monitored for fever or other symptoms of infection and treated promptly if such symptoms occur. Patients with severe neutropenia (absolute neutrophil count less than 1×10⁹/L) should discontinue Invega^® until the white blood cell count returns to normal.

Venous Thromboembolism

Cases of venous thromboembolism have been reported with the use of antipsychotic drugs. Since patients taking antipsychotic drugs often have risk factors for 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 (IFIS)

IFIS has been observed during cataract surgery in patients receiving therapy with drugs of the α₁-adrenergic antagonist class.

IFIS increases the risk of eye-related complications during and after surgery. The operating surgeon should be informed in advance that the patient is taking or has taken drugs with α₁-adrenergic antagonist activity. The potential benefit of discontinuing α₁-adrenergic antagonist therapy prior to surgery has not been established and should be weighed against the risks associated with discontinuing antipsychotic therapy.

Pregnancy and Childcare

The patient should notify their doctor of pregnancy or planned pregnancy during treatment with Invega^®. Caution should be exercised when prescribing Invega^® to nursing mothers.

Alcohol Consumption

Patients should avoid consuming alcohol during treatment with Invega^®.

Conditions Leading to Decreased Gastrointestinal Transit Time

Conditions leading to decreased gastrointestinal transit time, for example, diseases associated with chronic diarrhea, may cause decreased absorption of paliperidone.

Invega^® tablets are manufactured using an osmotic controlled-release oral delivery system, where osmotic pressure provides controlled release of paliperidone. The system, which externally resembles a capsule-shaped tablet, consists of an osmotically active trilayer core surrounded by a subcoat and a semipermeable membrane. The trilayer core consists of two drug layers containing the active substance and excipients, and a push layer containing osmotically active components. There are two release orifices on the dome side of the drug layers, created by laser drilling. In the gastrointestinal tract, the colored coating dissolves quickly, and water begins to enter the tablet through the semipermeable controlled-release membrane. The membrane controls the rate of water influx, which in turn controls the rate of drug release.

The hydrophilic polymers of the tablet core absorb water and swell, forming a gel containing Paliperidone, which is then pushed out through the orifices in the dome. The insoluble components of the tablet are excreted in the stool. Patients should not be concerned if they notice something resembling a tablet in their stool.

Effect on Ability to Drive and Operate Machinery

Paliperidone may impair activities requiring rapid mental reaction and may have visual effects; therefore, patients should refrain from driving vehicles and operating machinery until their individual sensitivity to paliperidone is established.

Overdose

In general, the signs and symptoms of paliperidone overdose represent an exaggeration of its pharmacological effects, i.e., drowsiness and sedation, tachycardia and arterial hypotension, QT interval prolongation, and extrapyramidal symptoms. Bidirectional tachycardia and ventricular fibrillation have been observed with oral paliperidone overdose. In cases of acute overdose, the possibility of multiple drug involvement should be considered.

When assessing the patient’s therapeutic needs and the effectiveness of overdose management, it should be remembered that Invega^® is an extended-release drug. There is no specific antidote for paliperidone. General supportive measures should be instituted. Ensure and maintain a patent airway and adequate oxygenation and ventilation. Cardiovascular monitoring should be instituted immediately (ECG monitoring to detect possible arrhythmias). Arterial hypotension and circulatory collapse should be treated with intravenous plasma expanders and/or sympathomimetic agents. Gastric lavage (after intubation if the patient is unconscious), administration of activated charcoal, and a laxative may be indicated in certain situations. Severe extrapyramidal symptoms should be treated with anticholinergic agents. Patient observation and monitoring of vital functions should continue until the overdose effects have resolved completely.

Drug Interactions

Caution should be exercised when co-administering Invega^® with drugs that prolong the QT interval.

Effect of Paliperidone on Other Drugs

Paliperidone is unlikely to participate in clinically significant pharmacokinetic interactions with drugs metabolized by cytochrome P450 isoenzymes. In vitro studies using human liver microsomes showed that Paliperidone does not substantially inhibit the biotransformation of drugs metabolized by cytochrome P450 isoenzymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and CYP3A5. Therefore, there is little reason to expect that Paliperidone will inhibit the clearance of drugs metabolized by these enzymes to a clinically significant extent. In in vitro studies, Paliperidone did not induce the activity of CYP1A2, CYP2C19, or CYP3A4 isoenzymes.

At high concentrations, Paliperidone is a weak inhibitor of P-glycoprotein. In vivo data are lacking, and the clinical significance is unknown.

Given that Paliperidone acts primarily on the CNS, it should be used cautiously in combination with other centrally acting drugs and with alcohol. Paliperidone may antagonize the effect of levodopa and other dopamine agonists. Due to paliperidone’s potential to induce orthostatic hypotension, an additive effect may occur when the drug is used concurrently with other drugs that cause orthostatic hypotension.

A pharmacokinetic interaction between paliperidone and lithium is unlikely.

Concomitant administration of Invega^® 12 mg once daily and divalproex sodium extended-release tablets (at a dose of 500-2000 mg once daily) did not affect the pharmacokinetics of valproate. In clinical studies in patients taking a stable dose of valproate, plasma valproate concentrations were no different from those in patients taking valproate concomitantly with Invega^® 3-15 mg.

Ability of Other Drugs to Affect Paliperidone

Paliperidone is not a substrate for CYP1A2, CYP2A6, CYP2C9, CYP2C19, or CYP3A5 isoenzymes. This suggests a low likelihood of interaction with inhibitors or inducers of these enzymes. In vitro studies revealed minimal involvement of CYP2D6 and CYP3A4 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 for P-glycoprotein.

Paliperidone is metabolized to a limited extent by the CYP2D6 isoenzyme. In a drug interaction study in healthy adult volunteers, co-administration of paliperidone with paroxetine, a potential inhibitor of the CYP2D6 isoenzyme, did not result in clinically significant changes in the pharmacokinetics of paliperidone.

Co-administration of paliperidone with carbamazepine 200 mg twice daily resulted in a decrease in the C_max and AUC of paliperidone by approximately 37%. This decrease is caused by a 35% increase in the renal clearance of paliperidone due to induction of renal P-glycoprotein by carbamazepine. The small decrease in the amount of drug excreted unchanged suggests that carbamazepine has a minor effect on the CYP metabolism or bioavailability of paliperidone when co-administered. When carbamazepine is initiated, the dose of paliperidone should be re-evaluated and increased if necessary. Conversely, upon discontinuation of carbamazepine, the dose of paliperidone should be re-evaluated and decreased if necessary.

Paliperidone, being a cation at physiological pH, is excreted largely unchanged by the kidneys; approximately half of the excretion is via filtration and about half via active secretion. Concomitant use of paliperidone with trimethoprim, which is known to inhibit the active renal transport of cationic drugs, did not affect the pharmacokinetics of paliperidone.

Concomitant administration of Invega^® 12 mg once daily and divalproex sodium extended-release tablets (2 tablets of 500 mg once daily) resulted in an increase in C_max and AUC of paliperidone by 50%. A dose reduction of Invega^® should be considered when co-administered with valproate based on clinical assessment of the patient.

Concomitant use of paliperidone and risperidone has not been the subject of scientific studies. Paliperidone is an active metabolite of risperidone, and therefore, concomitant use of paliperidone and risperidone may lead to increased blood levels of paliperidone.

Storage Conditions

The drug should be stored at a temperature between 15°C (59°F) and 30°C (86°F) in a place inaccessible to children.

Shelf Life

The shelf life is 2 years. Do not use after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.