Invega is an antipsychotic.
The mechanism of action
Paliperidone is a centrally acting antagonist of dopamine D2 receptors, which also has high antagonism to serotonin 5-NT2 receptors. In addition, paliperidone is an antagonist of α1– and α2-adrenergic receptors and H1-histamine receptors. Paliperidone has no affinity for cholinergic, muscarinic, and β1– and β2-adrenergic receptors. The pharmacological activity of the (+) and (-)-enantiomers of paliperidone is the same qualitatively and quantitatively.
The antipsychotic action is due to blockade of D2-dopaminergic receptors in the mesolimbic and mesocortical system. Causes less suppression of motor activity and is less likely to induce catalepsy than classical antipsychotics (neuroleptics).
The balanced central antagonism to serotonin and dopamine may reduce the propensity for extrapyramidal side effects and extend the therapeutic effects of the drug to include negative and productive symptoms of schizophrenia.
Paliperidone has effects on sleep patterns: decreases the latent period before falling asleep, decreases the number of awakenings after falling asleep, increases total sleep duration, increases sleep time, and increases the sleep quality index. It has an antiemetic effect, and may cause an increase in plasma prolactin concentrations.
Unless otherwise stated, the pharmacokinetic data presented in this section are based on data obtained for adult patients. The pharmacokinetic characteristics of paliperidone after oral administration are proportional to the dose taken in the recommended therapeutic range (3-12 mg once daily).
After a single dose of the drug, plasma concentrations of paliperidone increased steadily, and Cmax was reached after 24 h. In most patients, equilibrium concentrations of paliperidone were reached after 4-5 days of taking the drug once daily. Paliperidone is the active metabolite of risperidone. Peculiarities of the active substance release from the drug Invega® ensured less fluctuations of maximum and minimum concentrations of paliperidone than those observed with conventional dosage forms (concentration fluctuation index – 38% compared to 125% for conventional dosage forms).
The (+) and (-) enantiomers are mutually converted after taking paliperidone tablets, and the AUC – AUC (+)/AUC (-) ratio at equilibrium 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 of paliperidone as a sustained-release tablet together with a high-fat, high-calorie diet, 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, after a single administration of 12 mg of paliperidone as a sustained-release tablet together with a fatty, high-calorie food, Cmax and AUC increased by an average of 60 and 54%, respectively, relative to those same values when the tablet was taken on an empty stomach. Thus, the presence or absence of food in the stomach during paliperidone administration may alter the plasma concentration of paliperidone.
Paliperidone is rapidly distributed in tissues and body fluids. The apparent Vd is 487 l. The degree of binding to plasma proteins is 74%. Paliperidone binds predominantly to α1-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 detected in the urine and about 11% in the feces. Four pathways of paliperidone metabolism in vivo are known, none of which covers more than 6.5% of the dose: dealkylation, hydroxylation, dehydrogenation and benzisoxazole cleavage. In vitro studies have shown that the cytochrome P450 isoenzymes CYP2D6 and CYP3A4 may play a role in paliperidone metabolism, but evidence that they play a significant role in paliperidone metabolism in vivo was not available. Although CYP2D6 isoenzyme activity varies significantly in the general population, population pharmacokinetic studies have found no significant differences in apparent clearance of paliperidone in patients with active CYP2D6 isoenzyme substrate metabolism and in patients with poor CYP2D6 isoenzyme substrate metabolism. In vitro studies using heterologous microsomal preparations showed that CYP1A2, CYP2A6, CYP2C9,CYP2C19 and CYP3A5 isoenzymes are not involved in paliperidone metabolism.
The final T1/2 of paliperidone is approximately 23 h.
In vitro studies have shown that paliperidone is a substrate of P-glycoprotein and in high concentrations weakly inhibits it. There are no in vivo data and the clinical relevance is unknown.
Patients with impaired liver function. 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 hepatic impairment (class B according to Child-Pugh classification) has shown that in these patients plasma concentrations of unbound paliperidone were similar to those in healthy subjects. The use of Invega® in patients with severe hepatic impairment has not been studied.
Patients with impaired renal function. The dose of paliperidone should be reduced in patients with moderate to severe renal dysfunction. Paliperidone excretion has been studied in patients with varying degrees of renal dysfunction. It was found that paliperidone elimination decreased as creatinine clearance decreased. Total paliperidone clearance was reduced by 32% in patients with mild renal impairment (creatinine Cl 50 to1/2 of paliperidone was 24, 40 and 51 h in patients with mild, moderate and severe renal impairment, respectively; in those with normal renal function (creatinine Cl >80 ml/min) the figure was 23 h.
Adolescents. The systemic effects of paliperidone in adolescents were comparable to those in adults. Plasma concentrations of paliperidone in adolescents with body weight
Elderly patients. It is not recommended to change the dose of paliperidone depending on the patient’s age. The results of a pharmacokinetic study involving elderly patients aged 65 years and older showed that the apparent clearance of paliperidone at equilibrium after administration of Invega® in this group was 20% lower than in adult patients aged 18-45 years. However, after adjusting for age-related decreases in creatinine clearance, population-based analyses showed no effect of age of schizophrenic patients on paliperidone pharmacokinetics.
Raciality. No dose modification is required for patients of different racial backgrounds. Population pharmacokinetic analysis showed no racial differences in paliperidone pharmacokinetics with Invega®. No differences in pharmacokinetics were found in studies of Japanese and Caucasians.
Paul. The recommended doses of paliperidone are the same for men and women. The apparent clearance of paliperidone after taking the drug is about 19% lower in women than in men. This difference is mainly due to differences in the fat-free component of body weight and creatinine clearance between men and women, since population-based studies, after adjusting for the fat-free component of body weight and creatinine clearance, have found no clinically significant differences in the pharmacokinetics of paliperidone in men and women taking the drug.
Smoking. It is not recommended to modify doses of paliperidone in smokers. In vitro studies using human liver enzymes have shown that paliperidone is not a substrate of CYP1A2 isoenzyme and therefore smoking should not affect the pharmacokinetics of paliperidone. Consistent with in vitro studies, population-based studies showed no differences in paliperidone pharmacokinetics between smokers and nonsmokers.
- chizophrenia, 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;
- Therapy of schizoaffective disorders: as monotherapy or as part of combination therapy with antidepressants and/or normotimics in adult patients.
Paliperidone 3 mg;
iron oxide red;
iron oxide yellow;
Cellulose acetate (398-10);
Colorant dark yellow (hypromellose, titanium dioxide, polyethylene glycol 400, iron oxide yellow);
How to take, the dosage
Over the mouth, tablets should be swallowed whole with liquid and should not be chewed, crushed or split.
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, lower or higher doses within the recommended range of 3-12 mg once daily have a therapeutic effect. There is a general tendency to increase the effect when using higher doses of the drug. If an increase in dose is necessary, it is recommended that the dose be increased by 3 mg per day at intervals of more than 5 days.
Adolescents (12-17 years of age). 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, higher doses within the recommended range of 6-12 mg once daily have a therapeutic effect. Increasing the dose is possible only after clinical reassessment, with dose increases of 3 mg per day at intervals of more than 5 days.
Adults (over 18 years of age). 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, lower or higher doses within the recommended range of 6-12 mg once daily have a therapeutic effect. Increasing the dose, if necessary, should be done only after evaluation of the clinical condition of the patient. If a dose increase is necessary, it is recommended that the dose be increased by 3 mg/day at intervals of more than 4 days. Maintenance therapy in patients with schizoaffective disorder has not been studied.
Patients with hepatic dysfunction. No dose reduction is required in patients with mild to moderate hepatic impairment. The use of Invega® in patients with severe hepatic impairment has not been studied.
Patients with impaired renal function. For patients with mild renal dysfunction (Cl creatinine ≥50, but® in patients with Cl creatinine
Elderly patients. For elderly patients with normal renal function (creatinine Cl ≥80 ml/min) the same doses of the drug as for adult patients with normal renal function are recommended. However, in elderly patients, renal function may be reduced, in which case the drug dose should be adjusted to the renal function of the particular patient (see “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 efficacy and safety of Invega® in patients over 65 years of age in schizoaffective disorder have not been studied.
Children and adolescents. The efficacy and safety of the drug Invega® for the treatment of schizophrenia in children younger than 12 years has not been studied. The efficacy and safety of the drug Invega® for the treatment of schizoaffective disorder in patients younger than 18 years has not been studied.
Patient special groups
It is not recommended to change the dose of paliperidone depending on gender, age and whether or not the patient smokes.
Transfer patients to treatment with other antipsychotics
There are currently no systematically collected data on the transfer of patients from treatment with paliperidone to treatment with other antipsychotics. The pharmacodynamics and pharmacokinetics of different antipsychotic medications are not the same, and therefore physicians should monitor patients carefully when transferring them from one antipsychotic medication to another.
MNS. It is known that antipsychotic drugs, including paliperidone, may cause MNS, which is characterized by hyperthermia, muscle rigidity, instability of autonomic nervous system function, depressed consciousness, and increased serum concentrations of CPK. Myoglobinuria (rhabdomyolysis) and acute renal failure may also occur in patients with MNS. If a patient has objective or subjective symptoms of MNS, all antipsychotic drugs, including paliperidone, should be immediately withdrawn.
Late dyskinesia. Drugs that have the properties of dopamine receptor antagonists may cause tardive dyskinesia, which is characterized by rhythmic involuntary movements, primarily of the tongue and/or facial muscles. If a patient presents with objective or subjective symptoms suggestive of tardive dyskinesia, withdrawal of all antipsychotic medications, including paliperidone, should be considered.
QT interval prolongation. 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 co-administration with QT interval prolongers.
Hyperglycemia and diabetes mellitus. When treated with Invega®, hyperglycemia, diabetes mellitus and exacerbation of preexisting diabetes mellitus were observed. Establishing a relationship between the use of atypical antipsychotic drugs and impaired glucose metabolism is complicated by the increased risk of 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 adverse events associated with hyperglycemia has not been fully established. In patients diagnosed with diabetes mellitus, glucose levels should be monitored regularly. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) should have their fasting blood glucose 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 during treatment with atypical neuroleptics should have their blood glucose levels monitored. In some cases, symptoms of hyperglycemia have disappeared with discontinuation of atypical antipsychotics, but some patients require antidiabetic treatment despite discontinuation of the drug.
The increase in body weight. Significant increases in body weight have been observed with treatment with atypical antipsychotics. Patients’ body weight should be monitored.
Hyperprolactinemia. Like other D2 dopamine receptor antagonists, paliperidone increases prolactin levels, and this increase persists throughout the duration of the drug. The effects of paliperidone are comparable to those of risperidone, the drug with the greatest effect on prolactin levels among other antipsychotics. Hyperprolactinemia, regardless of etiology, may inhibit hypothalamic GnRH expression, resulting in decreased gonadotropin secretion by the pituitary gland. This, in turn, can suppress reproductive function by impairing sexual steroidogenesis in women and men. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients taking drugs that increase prolactin levels. Prolonged hyperprolactinemia associated with hypogonadism can lead to decreased bone density in women and men.
In vitro studies on tissue cultures have shown 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 diagnosed breast cancer. Clinical and epidemiological studies to date have not shown an association between taking atypical antipsychotic drugs and tumor formation in humans. However, the available data are too limited to draw definitive conclusions.
Orthostatic hypotension. Paliperidone has α-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, cardiac conduction disorders), cerebrovascular disease, and with conditions contributing to arterial hypotension (e.g., dehydration, hypovolemia and therapy with antihypertensive drugs).
The regulation of body temperature. An undesirable effect attributed to antipsychotic drugs is impairment 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 internal body temperature, these include intense physical activity, dehydration of the body, exposure to high external temperatures, or concurrent use of drugs with anticholinergic activity.
The antiemetic effect. In preclinical studies, an antiemetic effect of paliperidone was found. This effect, if produced in humans, may mask the objective and subjective symptoms of overdose of certain drugs, as well as diseases such as intestinal obstruction, Reye’s syndrome and brain tumors.
Priapism. Drugs with α-adrenoblocking effects can cause priapism. In post-marketing studies of paliperidone, the development of priapism has been reported.
Suicidal attempts. The possibility of suicide attempts is characteristic of mental illness, so therapy for high-risk patients should be closely monitored. In these 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 antipsychotic agents, including Invega®. Agranulocytosis was observed very rarely during post-marketing observations. In patients with a history of clinically significant decrease in leukocyte counts or drug-dependent leukopenia/neutropenia, a complete blood count during the first months of therapy is recommended; discontinuation of treatment with Invega® should be considered at the first clinically significant decrease in leukocyte count in the absence of other possible causes. Patients with clinically significant neutropenia should be monitored for fever or symptoms of infection and treatment should be started immediately if such symptoms occur. Patients with severe neutropenia (absolute neutrophil counts less than 1-109/L) should discontinue Invega® until the white blood cell count normalizes.
Venous thromboembolism. Cases of venous thromboembolism have been reported with antipsychotic medications. Because patients taking antipsychotic medications are often at risk for venous thromboembolism, all possible risk factors should be identified before and during treatment with Invega® and preventive measures should be taken.
Intraoperative flabby iris syndrome (ISDR). ISDR has been observed during cataract surgery in patients receiving therapy with α1-adrenoreceptor antagonists. ISDR increases the risk of vision-related complications during and after the surgical intervention. The physician performing such surgery should be informed in advance that the patient has taken or is currently taking medications with α1-adrenoreceptor antagonist activity. The potential benefit of withdrawal of therapy with α1-adrenoceptor antagonists prior to surgery has not been established, and should be evaluated in light of the risks associated with withdrawal of antipsychotic therapy.
Pregnancy and child care. Patients should notify their physician if they are pregnant or planning to become pregnant during treatment with Invega®. Caution should be exercised when prescribing Invega® to nursing mothers (see “Use in pregnancy and lactation”).
The use of 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 lead to decreased gastrointestinal retention of the drug, such as diseases associated with chronic diarrhea, may cause decreased absorption of paliperidone.
Invega tablets® are manufactured using osmotic release technology in which osmotic pressure allows the release of paliperidone at a controlled rate. The system, which resembles a capsule-like 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 drug layers containing the drug substance and excipients, as well as an expulsion layer containing osmotically active components. On the dome side of the drug layers there are two laser-assisted exit holes. In the GI tract, the color coating quickly dissolves and water begins to enter the inside of the tablet through a semi-permeable controlling membrane. The membrane controls the level of water entry, which in turn controls the level of drug release.
The hydrophilic polymers of the tablet’s core absorb water and swell to form a gel containing paliperidone, which is then expelled through holes in the dome. The insoluble components of the tablet are eliminated from the body with stools. Patients should not worry if they notice something that looks like a pill in the stool.
The effect on driving and operating machinery. Paliperidone may impair 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 determined.
It is contraindicated in patients with hypersensitivity to paliperidone, risperidone, and any excipient 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 conditions 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 GI tract, and therefore they should not be prescribed to patients with severe GI lumen narrowing (pathological or iatrogenic) or to patients who have dysphagia or who have difficulty swallowing tablets. There are rare reports of symptoms of gastrointestinal obstruction associated with ingestion of non-deformable dosage forms with controlled release of the active substance. Paliperidone is also one of these dosage forms and should therefore only be prescribed to patients who can swallow the 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 who received atypical antipsychotics such as risperidone, aripiprazole, olanzapine and quetiapine had higher mortality rates than patients who received placebo. Placebo-controlled studies involving elderly patients with dementia demonstrated an increased incidence of cerebrovascular adverse events (strokes and transient ischemic attacks), including death, in patients receiving some atypical antipsychotics that included risperidone, aripiprazole and olanzapine, compared with patients who received placebo.
Parkinson’s disease and dementia with Levi’s corpuscles. Physicians should carefully weigh the possible risks and potential benefits of prescribing antipsychotics, including paliperidone, to patients with Parkinson’s disease or dementia with Levi’s corpuscles, as these patients may have an increased risk of malignant neuroleptic syndrome (MNS) or increased sensitivity to antipsychotics. Manifestations of this hypersensitivity include, in addition to extrapyramidal symptoms, confusion, blunted reactions and postural hypotension with frequent falls.
Infections: often – upper respiratory tract infections, nasopharyngitis; infrequent – urinary tract infections, acrodermatitis, bronchitis, subcutaneous fatty tissue inflammation, cystitis, ear infections, influenza, onychomycosis, pneumonia, respiratory tract infections, sinusitis, tonsillitis.
Immune system disorders: infrequent anaphylactic reaction and hypersensitivity.
Hematopoietic and lymphatic system: infrequent anemia, decrease of hematocrit, neutropenia, decreased number of leukocytes; rarely – thrombocytopenia; very rare – agranulocytosis.
Endocrine system: infrequent hyperprolactinemia; very rare – inadequate secretion of ADH.
Metabolism and nutrition: infrequent – increased CPK activity, anorexia, hyperglycemia; rare – diabetes mellitus, hypoglycemia, water intoxication; very rare – diabetic ketoacidosis.
Mental disorders: frequently – insomnia (including initial and intermediate insomnia), mania; infrequently – nightmares, sleep disorders, depression.
Nervous system disorders: very often – headache; often – akathisia, dystonia, dysarthria, increased muscle tone, parkinsonism, sedation, somnolence, tremor, salivation; infrequent – cerebrovascular disorders, postural dizziness, dyskinesia, seizures, syncope, attention disorders, hypoesthesia, loss of consciousness, paresthesia, psychomotor hyperactivity, tardive dyskinesia, hypokinesia, opisthotonus.
It is known that antipsychotics, including paliperidone, can cause MNS, which is characterized by hyperthermia, muscle rigidity, instability of autonomic nervous system function, depressed consciousness, increased CPK activity, myoglobinuria, rhabdomyolysis, acute renal failure.
A visual organs: infrequent – conjunctivitis, dry eyes, photophobia, lacrimation; with unknown frequency – flabby iris syndrome (intraoperative).
Hearing organ and labyrinth disorders: infrequent – ear pain, vertigo, tinnitus.
Particularly: infrequent bradycardia, palpitations, AV blockade, abnormal conduction, changes on ECG, prolongation of QT interval, ischemia, hot flashes, increased blood pressure, decreased blood pressure; rarely – atrial fibrillation; very rare – deep vein thrombosis, pulmonary embolism.
Gastrointestinal disorders: frequently – nausea, diarrhea, constipation, upper abdominal discomfort, dyspepsia, increased appetite; infrequently – decreased appetite, lip inflammation, dysphagia, fecal incontinence, small bowel obstruction, flatulence, gastroenteritis, tongue swelling, toothache, dysgeusia; very rarely – pancreatitis, bowel obstruction.
Hepatic and biliary tract disorders: very rarely – jaundice.
Respiratory system disorders: infrequent – pain in the pharyngeopharynx, stuffy nose, cough, shortness of breath, hyperventilation of the lungs, wheezing; rarely – sleep apnea syndrome.
Muscular and connective tissue disorders: often – myalgia, musculoskeletal pain; infrequent – muscle cramps, back pain, arthralgia, stiffness in joints, joint swelling, muscle weakness, neck pain.
Skin and subcutaneous tissue disorders: infrequent – rash, itching, acne, dry skin, eczema, erythema, seborrheic dermatitis, skin discoloration; rarely – Quincke’s edema, alopecia.
Recreational and urinary tract disorders: infrequent – dysuria, semilakiuria, urinary incontinence, urinary retention.
Gender and mammary glands: infrequent – decreased libido, anorgasmia, nipple discharge, erectile dysfunction, gynecomastia, menstrual cycle changes, sexual dysfunction, vaginal discharge, ejaculation disorders, breast engorgement; very rare – priapism.
Influence on the course of pregnancy, postpartum and perinatal conditions: very rare – withdrawal syndrome in newborns.
Others: frequent – weight gain; infrequent – weight loss, chills, facial edema, gait disturbance, edema (including generalized, peripheral, mild), increased body temperature, fever, thirst; very rare – hypothermia.
Laboratory tests: infrequent – increased GGT activity, increased liver enzyme activity, increased transaminase activity, increased blood cholesterol concentration, increased blood triglyceride concentration.
Symptoms: in general, objective and subjective symptoms of paliperidone overdose represent the enhanced pharmacological effects of this drug, i.e. drowsiness and sedation, tachycardia and arterial hypotension, QT interval prolongation and extrapyramidal symptoms. Bidirectional tachycardia and ventricular fibrillation have been observed in oral paliperidone overdose. In acute overdose, the possibility of toxic effects of multiple drugs should be considered.
When evaluating a patient’s therapeutic needs and the effectiveness of overdose management, keep in mind that Invega® is a drug with prolonged release of the active substance.
Treatment: Generally accepted supportive measures should be implemented. Good airway patency and adequate oxygenation and ventilation should be ensured and maintained. Cardiovascular monitoring (ECG monitoring to detect possible arrhythmias) should be arranged immediately.
Arterial hypotension and collaptoid states are treated by IV administration of plasma substitute solutions and/or sympathomimetic agents. In certain situations gastric lavage is indicated (after intubation if the patient is unconscious), administration of activated charcoal and laxatives.
In case of severe extrapyramidal symptoms, m-cholinoblockers should be administered. Observation of the patient’s condition and monitoring of basic physiological functions should be continued until the effects of overdose are completely eliminated. There is no specific antidote for paliperidone.
|Conditions of storage|
At 15-30 °C
Janssen Pharmaceuticals N.V., Belgium
Janssen Pharmaceuticals N.V.
Buy Invega, 3 mg 28 pcs. with delivery to USA, UK, Europe and over 120 other countries.