Invega

Paliperidone.

Each extended-release tablet contains 6, or 9 mg of paliperidone. Paliperidone (Invega) 6 mg extended-release tablets are beige capsule-shaped tablets imprinted with "PAL 6". Paliperidone (Invega) 9 mg extended-release tablets are pink capsule-shaped tablets imprinted with "PAL 9". The chemical name is (±)-3-[2-[4-(6-fl uoro-1,2-benzisoxazol-3-yl)-1-piperidinyl] ethyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one. Inactive ingredients are butyl hydroxytoluene, carnauba wax, cellulose acetate, hydroxyethyl cellulose, hypromellose, iron oxides, polyethylene glycol, polyethylene oxides, povidone, propylene glycol, sodium chloride, stearic acid, and titanium dioxide.
Paliperidone (Invega) utilizes osmotic drug-release technology, whereby osmotic pressure delivers paliperidone from the dosage form at a controlled rate. The system, which resembles a capsule-shaped tablet in appearance, comprises an osmotically active trilayer core surrounded by a subcoat and semipermeable membrane. The trilayer core is composed of two drug layers containing the drug and excipients, and a push layer containing osmotically active components. There are two precision laser-drilled orifices on the drug-layer dome of the tablet. Each strength is identified by a unique color overcoat and print markings. In an aqueous environment, such as the gastrointestinal tract, the water-dispersible color overcoat erodes quickly. Water is then imbibed through the semipermeable, rate-controlling membrane. The membrane controls the rate at which water enters the tablet core, which, in turn, controls drug delivery. The hydrophilic polymers of the core hydrate and swell, creating a gel containing paliperidone that is then pushed out through the tablet orifices. The biologically inert components of the tablet remain intact during gastrointestinal transit and are eliminated in the stool as a tablet shell, along with insoluble core components.

Pharmacology: Pharmacodynamics: Paliperidone, the active ingredient of Invega, is a psychotropic agent belonging to the chemical class of benzisoxazole derivatives (atypical neuroleptic antipsychotic). Invega contains a racemic mixture of (+)- and (-)-paliperidone.
Mechanism of Action: Paliperidone is a centrally active dopamine D₂-antagonist with predominant serotonergic 5-HT_2A antagonistic activity. Invega is also active as an antagonist at α₁ and α₂ adrenergic receptors and H₁ histaminergic receptors. Paliperidone has no affinity for cholinergic muscarinic or β₁- and β₂-adrenergic receptors. The pharmacological activity of the (+)- and (-)- paliperidone enantiomers is qualitatively and quantitatively similar.
The mechanism of action of paliperidone, as with other drugs having efficacy in schizophrenia, is unknown. However, it has been proposed that the drug's therapeutic activity in schizophrenia is mediated through a combination of dopamine type 2 (D₂) and serotonin type 2 (5-HT_2A) receptor antagonism. Antagonism at receptors other than D₂ and 5-HT_2A may explain some of the other effects of paliperidone.
Polysomnography: Centrally-acting medications through their mechanism of action, drug-release profile, and/or time of dose administration may affect sleep. To evaluate the impact of morning dosing of paliperidone on sleep architecture and continuity, a placebo-controlled study was conducted in 36 subjects with schizophrenia in which paliperidone 9 mg or placebo was administered once for 14 days. The following observations were made (mean data compared with placebo): Reduced latency to persistent sleep by 41 (SE 18.7) min, decreased sleep onset latency by 35.2 (SE 14.99) min, decreased number of awakenings after sleep onset by 7 (SE 3.88) events, increased total sleep time by 52.8 (SE 24.01) min, increased sleep period time by 41.7 (SE 18.75) min and increased sleep efficiency index by 11% (SE 5). There was also a statistically significant decrease (relative to placebo) in stage 1 sleep of 11.9 (SE 4.44) min and increase in stage 2 sleep of 50.7 (SE 17.67) min. No clinically relevant effect on REM sleep was observed.
Electrophysiology: The effects of paliperidone on the QT interval were evaluated in 2 randomized, double-blind, multicenter, phase 1 studies in adults with schizophrenia and schizoaffective disorder, and in 3 placebo- and active-controlled 6-week, fixed-dose efficacy trials in adults with schizophrenia.
In the 1st phase 1 study (n=141), subjects were randomized to receive either 7 days of immediate-release oral paliperidone once daily (titrated from 4-8 mg) or a single dose of moxifloxacin (400 mg). The 8-mg once daily dose of immediate-release oral paliperidone (n=44) achieved a mean steady-state peak plasma concentration >2 times the exposure observed with the maximum recommended paliperidone dose of 12 mg (C_{max ss}=113 and 45 ng/mL, respectively). In the model-adjusted day-averaged linear-derived QT correction (QTcLD), there was a mean increase of 5.5 msec (90% CI: 3.66; 7.25) in the paliperidone treatment group (n=44).
In the 2nd phase 1 study (n=109), subjects were randomized to receive either placebo, the maximum recommended paliperidone dose (12 mg once daily), subsequently titrated to a dose above the recommended range (18 mg once daily), or an active control from the same pharmacologic class of drugs (quetiapine 400 mg twice daily). The primary comparison in this 10-day noninferiority study was between paliperidone 12 mg and quetiapine. The least squares mean change from baseline in QTcLD at each individual's observed t_max was estimated to be 5.1 ms lower for paliperidone 12 mg (mean C_max 34 ng/mL) compared with quetiapine 400 mg twice daily (mean C_max 1183 ng/mL) (90% CI: -9.2; -0.9), meeting the prespecified noninferiority criterion of 10 msec. The mean change from baseline in QTcLD at each individual's observed t_max was estimated to be 2.3 msec lower for paliperidone 18 mg (mean C_max 53 ng/mL) compared with quetiapine 400 mg twice daily (mean C_max 1183 ng/mL) (90% CI: -6.8; 2.3).
The mean change from baseline in QTcLD at each individual's observed t_max was estimated to be 1.5 msec higher (90% CI: -3.3; 6.2) for paliperidone 12 mg and 8 msec higher (90% CI: 3.1; 12.9) for quetiapine 400 mg twice daily compared with the mean change from baseline in QTcLD at median observed t_max (of the active drug in the comparison) in the concurrent placebo arm. The mean change from baseline in QTcLD at each individual's observed t_max was estimated to be 4.9 msec higher (90% CI: -0.5; 10.3) for paliperidone ER 18 mg and 7.5 msec higher (90% CI: 2.5; 12.5) for quetiapine 400 mg twice daily compared with the mean change baseline in QTcLD at median observed t_max (of the active drug in the comparison) in the concurrent placebo arm.
None of the subjects had a change from baseline exceeding 60 msec or a QTcLD exceeding 500 msec at any time during either of these studies.
For the 3 fixed-dose efficacy studies, extensive electrocardiography (ECG) measurements were taken at 15-time points on specified days (including the times of expected C_max) using a standardized methodology. Mean QTcLD increase did not exceed 5 msec in any treatment group at any time point, based on pooled data from, 836 subjects treated with paliperidone, 357 subjects treated with olanzapine, and 350 subjects treated with placebo. One subject each in the paliperidone 12 mg and olanzapine groups had a change >60 msec at 1 time-point during these studies (increases of 62 and 110 msec, respectively).
Clinical Efficacy: Schizophrenia: The efficacy of Invega was established in 3 placebo-controlled, double-blind, 6-week trials in subjects who met DSM-IV criteria for schizophrenia. An active control (olanzapine) was included for assay sensitivity purposes. Invega doses, which varied across the 3 studies, ranged from 3-15 mg once daily. Efficacy was evaluated using the Positive and Negative Syndrome Scale (PANSS); the primary endpoint was decrease in total PANSS scores. An examination of population subgroups did not reveal any evidence of differential responsiveness on the basis of age, race, or gender. Secondary endpoints were also assessed, including Personal and Social Performance (PSP) and the Clinical Global Impression-Severity (CGI-S) scale.
The PSP is a validated clinician-rated scale that measures 4 areas of personal and social functioning (socially useful activities including work and study, personal and social relationships, self-care, and disturbing and aggressive behaviors). The CGI-S is an independent investigator-rated assessment of overall severity of illness. In a pooled analysis of these 3 studies, each dose of paliperidone was superior to placebo on the PSP and CGI-S. In addition, the effect on PSP was distinct from the improvement in symptoms as measured by the primary endpoint, total PANSS. Further evaluation of the open-label extensions of these 3 studies showed that flexibly-dosed paliperidone (3-15 mg once daily) up to 52 weeks was associated with continued improvement on PSP.
In a long-term trial designed to assess the maintenance of effect, paliperidone was significantly more effective than placebo in maintaining symptom control and delaying recurrence of schizophrenia. In this study, adults who met DSM-IV criteria for schizophrenia and who remained clinically stable on an established dose of paliperidone during an 8-week period of open-label treatment (doses ranging 3-15 mg once daily) after having been treated for an acute episode for the previous 6 weeks with paliperidone (doses ranging 3-15 mg once daily) were then randomized in a double-blind manner to either continue on paliperidone at their achieved stable dose or to placebo until they experienced a recurrence of schizophrenia symptoms. The trial was stopped early for efficacy reasons based on an interim analysis that achieved predefined criteria by showing a significantly longer time to recurrence in patients treated with paliperidone compared to placebo (p=0.0053). Based on final analysis (including also those patients included after the cut-off point for the interim analysis), the rate of recurrence events was 22.1% in the paliperidone group compared with 51.5% in the placebo group. A significant improvement in symptoms was achieved at the end of the open-label stabilization phase [decrease in PANSS total scores of 38 (SD±16.03) points], but after randomization to double-blind treatment, the patients receiving placebo deteriorated significantly more than those on paliperidone (p<0.001). Paliperidone was also significantly more effective than placebo in maintaining personal and social performance. During the double-blind phase of this study as measured by the CGI-S scale, there was worsening on the overall severity of psychosis in the placebo group, while patients treated with paliperidone remained clinically stable.
Bipolar Disorder: The efficacy of paliperidone in the treatment of acute manic episodes was established in 2 multicenter, placebo-controlled, double-blind trials in subjects who met DSM-IV criteria for Bipolar l Disorder, most recent episode manic or mixed. One study evaluated the efficacy and safety of paliperidone over a flexible dose range of 3-12 mg relative to placebo and quetiapine over a 12-week period, while the other study evaluated the efficacy and safety of fixed doses of paliperidone (3, 6, and 12 mg) relative to placebo over a 3-week period.
Paliperidone over a flexible dose range of 3-12 mg and at a fixed dose of 12 mg was superior to placebo with regard to the primary efficacy variable, change in YMRS total score from baseline at the 3-week endpoint. Superiority to placebo was established as early as day 2, and antimanic efficacy compared to placebo was maintained at every subsequent assessment for up to 3 weeks. After 3 weeks of treatment, >½ of subjects treated with paliperidone were rated as treatment responders. Flexibly dosed paliperidone was statistically superior to placebo with regard to both the rate of response and remission at week 3. The efficacy observed for the primary efficacy variable was supported by improvements in secondary efficacy variables eg global measures of disease severity (CGI-BP-S) and function (GAF), as well as psychotic symptoms (PANSS).
Over the 12-week double-blind treatment period of the flexible-dose study, paliperidone was shown noninferior to quetiapine in the authorized dose range for the primary efficacy variable using a predefined noninferiority margin.
In a separate multicenter, placebo-controlled, double-blind trial in subjects with bipolar l disorder, most recent episode manic or mixed, paliperidone was shown to be well-tolerated when used in combination with the mood stabilizers, lithium or valproate, over a period of 6 weeks, while the incremental benefit of paliperidone as adjunctive therapy was not demonstrated in this study.
Schizoaffective Disorder: The efficacy of paliperidone (3-12 mg once daily) in the treatment of schizoaffective disorder was established in 2 placebo-controlled, 6-week trials in non-elderly adult subjects who met DSM-IV criteria for schizoaffective disorder, as confirmed by the Structured Clinical Interview for DSM-IV Disorders. In one of these trials, efficacy was assessed in 203 subjects who were assigned to 1 of 2 dose levels of paliperidone 6 mg with the option to reduce to 3 mg (n=105) or 12 mg with the option to reduce to 9 mg (n=98) once daily. In the other study, efficacy was assessed in 211 subjects who received flexible doses of paliperidone (3-12 mg once daily). Both studies included subjects who received paliperidone either as monotherapy or in combination with antidepressants and/or mood stabilizers. Dosing was in the morning without regard to meals. Studies were carried out in the United States, Eastern Europe, Russia and Asia. Efficacy was evaluated using the Positive and Negative Syndrome Scale (PANSS), a validated multi-item inventory composed of 5 factors to evaluate positive, negative symptoms, disorganized thoughts, uncontrolled hostility/excitement and anxiety/depression. The higher dose group of paliperidone in the 2 dose-level study (12 mg/day with option to reduce dose to 9 mg/day) and the paliperidone group in the flexible-dose study (dosed 3-12 mg/day, mean modal dose of 8.6 mg/day) were each superior to placebo in the PANSS. In the lower dose group of the 2 dose-level study (6 mg/day with option to reduce to 3 mg/day), paliperidone was not significantly different from placebo as measured by the PANSS. Taking the results of both studies together, paliperidone improved the symptoms of schizoaffective disorder at endpoint relative to placebo when administered either as monotherapy or in combination with antidepressants and/or mood stabilizers. An examination of population subgroups did not reveal any evidence of differential responsiveness on the basis of gender, age or geographic region. There were insufficient data to explore different effects based on race.
Pharmacokinetics: The pharmacokinetics of paliperidone following Invega administration are dose-proportional within the recommended clinical dose range (3-12 mg).
Absorption: Following a single dose of Invega, the plasma concentrations of paliperidone steadily rise to reach peak plasma concentration (C_max) in approximately 24 hrs after dosing. With once-daily dosing of Invega, steady-state concentrations of paliperidone are attained within 4-5 days of dosing in most subjects.
The release characteristics of Invega result in minimal peak-trough fluctuations as compared to those observed with immediate-release risperidone. In a study comparing the steady-state pharmacokinetics following once-daily administration of paliperidone 12 mg (administered as extended-release tablet) with immediate-release risperidone 4 mg in schizophrenic subjects, the fluctuation indexes were 38% for paliperidone extended-release compared to 125% for risperidone immediate-release (see figure).

Click on icon to see table/diagram/image

Following administration of Invega, the (+) and (-) enantiomers of paliperidone interconvert, reaching an AUC (+) to (-) ratio of approximately 1.6 at steady state. The absolute oral bioavailability of paliperidone following Invega administration is 28%.
Following administration of a single paliperidone 15 mg extended-release tablet to healthy subjects, confined to bed for 36 hrs, with a standard high-fat/high-caloric meal, the C_max and AUC values increased by 42% and 46%, respectively, compared with administration under fasting conditions. In another study involving healthy ambulatory subjects, the C_max and AUC of paliperidone following administration of a single paliperidone 12 mg prolonged-release tablet with a standard high-fat/high-caloric meal resulted in increases of 60% and 54%, respectively, compared with administration under fasting conditions. Although the presence or absence of food at the time of Invega administration may increase or decrease exposure to paliperidone, these changes are not considered clinically relevant. Clinical trials establishing the safety and efficacy of Invega were carried-out in subjects without regard to the timing of meals. (See Dosage & Administration.)
In the phase 3 studies of Invega tablet in bipolar I disorder, median dose-normalized paliperidone plasma concentrations at 8 hrs post-dose after 6 days of treatment were comparable between fasted subjects and subjects who had consumed a standard continental or high-caloric breakfast between 2 hrs before and 1 hr after their medication intake.
Distribution: Paliperidone is rapidly distributed. The apparent volume of distribution is 487 L. The plasma protein-binding of paliperidone is 74%. It binds primarily to α₁-acid glycoprotein and albumin. In vitro, high therapeutic concentrations of diazepam (3 mcg/mL), sulfamethazine (100 mcg/mL), warfarin (10 mcg/mL), and carbamazepine (10 mcg/mL) caused a slight increase in the free fraction of paliperidone at 50 ng/mL. These changes are not expected to be of clinical significance.
Metabolism and Elimination: One week following administration of a single oral dose of ¹⁴C-paliperidone 1 mg immediate-release, 59% of the dose was excreted unchanged into urine, indicating that paliperidone is not extensively metabolized in the liver. Approximately 80% of the administered radioactivity was recovered in urine and 11% in the feces. Four metabolic pathways have been identified in vivo, none of which accounted for >6.5% of the dose: Dealkylation, hydroxylation, dehydrogenation, and benzisoxazole scission. Although in vitro studies suggested a role for CYP2D6 and CYP3A4 in the metabolism of paliperidone, there is no evidence in vivo that these isozymes play a significant role in the metabolism of paliperidone. Despite the large variation in the general population with regard to the ability to metabolize CYP2D6 substrates, population pharmacokinetics analyses indicated no discernable difference on the apparent clearance of paliperidone after administration of Invega between extensive metabolizers and poor metabolizers of CYP2D6 substrates. In vitro studies using microsomal preparations of heterologous systems indicate that CYP1A2, CYP2A6, CYP2C9, CYP2C19 and CYP3A5 are not involved in the metabolism of paliperidone. The terminal elimination t_½ of paliperidone is about 23 hrs.
Special Populations: Hepatic Impairment: Paliperidone is not extensively metabolized in the liver. In a study in subjects with moderate hepatic impairment (Child-Pugh class B), the plasma concentrations of free paliperidone were similar to those of healthy subjects. Paliperidone has not been studied in patients with severe hepatic impairment.
Renal Impairment: The dose should be reduced in patients with moderate and severe renal impairment (See Dosage & Administration). The disposition of paliperidone was studied in subjects with varying degrees of renal function. Elimination of paliperidone decreased with decreasing CrCl. Total clearance of paliperidone was reduced in subjects with impaired renal function by 32% in mild (CrCl = 50 to <80 mL/min), 64% in moderate (CrCl = 30 to <50 mL/min), and 71% in severe (CrCl = 10 to <30 mL/min) renal impairment. The mean terminal elimination t_½ of paliperidone was 24, 40, and 51 hrs in subjects with mild, moderate, and severe renal impairment, respectively, compared with 23 hrs in subjects with normal renal function (CrCl=80 mL/min).
Elderly: Data from a pharmacokinetic study in elderly subjects (≥65 years, n=26) indicated that the apparent steady-state clearance of paliperidone following Invega administration was 20% lower compared to that of adult subjects (18-45 years, n=28). However, there was no discernable effect of age in the population pharmacokinetic analysis involving schizophrenia subjects after correction of age-related decreases in CrCl.
Race: No dosage adjustment is recommended based on race. Population pharmacokinetics analysis revealed no evidence of race-related differences in the pharmacokinetics of paliperidone following Invega administration. No differences in pharmacokinetics were observed in a pharmacokinetics study conducted in Japanese and Caucasian subjects.
Gender: The apparent clearance of paliperidone following Invega administration is approximately 19% lower in women than men. This difference is largely explained by differences in lean body mass and CrCl between men and women, as a population pharmacokinetics evaluation revealed no evidence of clinically significant gender-related differences in the pharmacokinetics of paliperidone following Invega administration after correction for lean body mass and CrCl.
Smoking Status: Based on in vitro studies utilizing human liver enzymes, paliperidone is not a substrate for CYP1A2; smoking should, therefore, not have an effect on the pharmacokinetics of paliperidone. Consistent with these in vitro results, population pharmacokinetic evaluation has not revealed any differences between smokers and non-smokers.
Toxicology: Preclinical Safety Data: As with other drugs that antagonize dopamine (D₂) receptors, paliperidone elevated serum prolactin levels in repeat-dose toxicity studies.
Carcinogenicity, Mutagenicity & Impairment of Fertility: The carcinogenic potential of paliperidone, an active metabolite of risperidone, was assessed based on studies with risperidone conducted in mice and rats. Risperidone was administered at doses up to 10 mg/kg/day for 18 months to mice and for 25 months to rats. There were statistically significant increases in pituitary gland adenomas, endocrine pancreas adenomas and mammary gland adenocarcinomas. An increase in mammary, pituitary, and endocrine pancreas tumors has been found in rodents after chronic administration of other antipsychotic drugs and is considered to be mediated by prolonged dopamine D₂ antagonism. The relevance of these tumor findings in rodents in terms of human risk is unknown.
No evidence of mutagenic potential for paliperidone was found in the Ames reverse mutation test, the mouse lymphoma assay, or the rat micronucleus test.
Impairment of Fertility: Although paliperidone treatment resulted in prolactin- and CNS-mediated effects, the fertility of male and female rats was not affected. At a maternally toxic dose, female rat showed a slightly lower number of live embryos.

Paliperidone (Invega) is indicated for the treatment of schizophrenia in adults, including acute treatment and recurrence prevention. Paliperidone (Invega) is indicated for the treatment of schizophrenia in adolescents 12-17 years of age. Paliperidone (Invega) is indicated for the treatment of acute manic and mixed episodes associated with bipolar I disorder in adults. Paliperidone (Invega) is indicated for the treatment of schizoaffective disorder as monotherapy and in combination with antidepressants and/or mood stabilizers in adults.

Schizophrenia: Adults (≥ 18 years of age): The recommended dose of paliperidone (Invega) for the treatment of schizophrenia in adults is 6 mg once daily, administered in the morning. Initial dose titration is not required. Some patients may benefit from lower or higher doses within the recommended range of 3 to 12 mg once daily. Dosage adjustment, if indicated, should occur only after clinical reassessment. When dose increases are indicated, increments of 3 mg/day are recommended and generally should occur at intervals of more than 5 days.
Adolescents (12-17 years of age): The recommended dose of paliperidone (Invega) for the treatment of schizophrenia in adolescents 12-17 years of age is 3 mg once daily, administered in the morning. Initial dose titration is not required. Some patients may benefit from a higher dose of 6 mg to 12 mg/day. Dose increases should be made only after clinical reassessment and should occur at increments of 3 mg/day at intervals of more than 5 days.
Bipolar Disorder: Adults (≥ 18 years of age): The recommended dose of paliperidone (Invega) for the treatment of acute manic and mixed episodes associated with bipolar I disorder in adults is 9 mg once daily, administered in the morning. Initial dose titration is not required. Some patients may benefit from lower or higher doses within the recommended range of 3 to 12 mg once daily. Dosage adjustment, if indicated, should occur only after clinical reassessment. A dose increase to 12 mg/day, if indicated, should occur at an interval of 2 days or more.
Schizoaffective Disorder: Adults (≥ 18 years of age): The recommended dose of paliperidone (Invega) for the treatment of schizoaffective disorder in adults is 6 mg once daily, administered in the morning. Initial dose titration is not required. Some patients may benefit from lower or higher doses within the recommended dose range of 3 to 12 mg once daily. A general trend for greater effects was seen with higher doses. Dosage adjustment, if indicated, should occur only after clinical reassessment. When dose increases are indicated, increments of 3 mg/day are recommended and generally should occur at intervals of more than 4 days.
Special populations: Adolescents and Children: Safety and effectiveness of paliperidone (Invega) for the treatment of schizophrenia in patients < 12 years of age have not been established. Safety and effectiveness of paliperidone (Invega) for the treatment of bipolar disorder or schizoaffective disorder in patients < 18 years of age have not been studied.
Elderly: Dosing recommendations for elderly patients with normal renal function (≥ 80 mL/min) are the same as for adults with normal renal function (see previously mentioned). However, because elderly patients may have diminished renal function, dose adjustments may be required according to their renal function status (see Renal Impairment as follows).
Renal Impairment: For patients with mild renal impairment (creatinine clearance ≥ 50 to < 80 mL/min), the recommended initial dose is 3 mg once daily. The dose may be increased to 6 mg once daily based on clinical response and tolerability. For patients with moderate to severe renal impairment (creatinine clearance ≥ 10 to < 50 mL/min), the recommended dose of paliperidone (Invega) is 3 mg every other day, which may then be increased to 3 mg once daily after clinical reassessment. As paliperidone (Invega) has not been studied in patients with creatinine clearance < 10 mL/min, use is not recommended in such patients.
Hepatic Impairment: No dose adjustment is required in patients with mild to moderate hepatic impairment. Paliperidone (Invega) has not been studied in patients with severe hepatic impairment.
Other Populations: No dose adjustment for paliperidone (Invega) is recommended based on gender, race, or smoking status. (For pregnant women and nursing mothers see Precautions).
Switching to other antipsychotic agents: There are no systematically collected data to specifically address switching patients from paliperidone (Invega) to other antipsychotic agents. Due to different pharmacodynamic and pharmacokinetic profiles among antipsychotic products, supervision by a clinician is needed when switching to another antipsychotic product is considered medically appropriate.
Administration: Paliperidone (Invega) is for oral administration and can be administered with or without food. Paliperidone (Invega) must be swallowed whole with the aid of liquids, and must not be chewed, divided, or crushed. The medication is contained within a nonabsorbable shell designed to release the drug at a controlled rate. The tablet shell, along with insoluble core components, is eliminated from the body; patients should not be concerned if they occasionally notice in their stool something that looks like a tablet.

Symptoms: Generally, expected signs and symptoms are those resulting from an exaggeration of paliperidone's known pharmacological effects ie, drowsiness and sedation, tachycardia and hypotension, QT prolongation and extrapyramidal symptoms. Torsades de pointes and ventricular fibrillation have been reported in a patient in the setting of overdose. In the case of acute overdosage, the possibility of multiple drug involvement should be considered.
Treatment: Consideration should be given to the extended-release nature of Invega when assessing treatment needs and recovery. There is no specific antidote to paliperidone. General supportive measures should be employed. Clear airway must be established and maintained. Adequate oxygenation and ventilation must be ensured. Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring for possible arrhythmias. Hypotension and circulatory collapse should be treated with appropriate measures eg IV fluid and/or sympathomimetic agents. Gastric lavage (after intubation of the patient if unconscious) and administration of activated charcoal together with a laxative should be considered. In case of severe extrapyramidal symptoms, anticholinergic agents should be administered. Close supervision and monitoring should continue until the patient recovers.

Known hypersensitivity to paliperidone or to any components of Invega including its active metabolite, risperidone.

Neuroleptic Malignant Syndrome: Neuroleptic malignant syndrome (NMS), characterized by hyperthermia, muscle rigidity, autonomic instability, altered consciousness and elevated serum creatinine phosphokinase levels has been reported to occur with antipsycotic drugs, including paliperidone. Additional clinical signs may include myoglobinuria (rhabdomyolysis) and acute renal failure. If a patient develops signs or symptoms indicative of NMS, all antipsychotic drugs, including Invega, should be discontinued.
Tardive Dyskinesia: Drugs with dopamine receptor antagonistic properties have been associated with the induction of tardive dyskinesia characterized by rhythmical, involuntary movements, predominantly of the tongue and/or face. If signs and symptoms of tardive dyskinesia appear, the discontinuation of all antipsychotic drugs, including Invega, should be considered.
QT Interval: As with other atipsychotics, caution should be exercised when Invega is prescribed in patients with a history or cardiac arrhythmias, in patients with congenital long QT syndrome and in concomitant use with drugs known to prolong QT interval.
Hyperglycemia: Rare cases of glucose-related adverse events have been reported in clinical trials with Invega. Appropriate clinical monitoring is advisable in diabetic patients and in patients with risk factors for the development of diabetes mellitus.
Orthostatic Hypotension: Paliperidone may induce orthostatic hypotension in some patients based on its α-blocking activity. Invega should be used with caution in patients with known cardiovascular disease (eg, heart failure, myocardial infarction or ischemia, conduction abnormalities), cerebrovascular disease or conditions that predispose the patient to hypotension (eg, dehydration, hypovolemia and treatment with antihypertensive medications).
Seizures: As with other antipsychotic drugs, Invega should be used cautiously in patients with a history of seizures or other conditions that potentially lower the seizure threshold.
Potential for Gastrointestinal Obstruction: Because the Invega tablet is non-deformable and does not appreciably change shape in the gastrointestinal tract, Invega should not ordinarily be administered to patients with preexisting severe gastrointestinal narrowing (pathologic or iatrogenic) or in patients with dysphagia or significant difficulty in swallowing tablets. There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of drugs in non-deformable controlled-release formulations. Due to the controlled-release design of the dosage form, Invega should only be used in patients who are able to swallow the tablet whole. (See also Dosage & Administration.)
Elderly Patients with Dementia: Invega has not been studied in elderly patients with dementia.
Overall Mortality: In a meta-analysis of 17 controlled clinical trials, elderly patients with dementia treated with other atypical antipsychotic drugs including risperidone, aripiprazole, olanzapine and quetiapine, had an increased risk of mortality compared to placebo.
Cerebrovascular Adverse Events: In placebo-controlled trials in elderly patients with dementia treated with some atypical antipsychotic drugs including risperidone, aripiprazole and olanzapine, there was a higher incidence of cerebrovascular adverse events (cerebrovascular accidents and transient ischemic attacks) including fatalities, compared to placebo.
Parkinson's Disease and Dementia with Lewy Bodies (DLB): Physicians should weigh the risks versus the benefits when prescribing antipsychotic drugs, including Invega, to patients with Parkinson's disease or DLB since both groups may be at increased risk of neuroleptic malignant syndrome as well as having an increased sensitivity to antipsychotic medications. Manifestations of this increased sensitivity can include confusion, obtundation, postural instability with frequent falls, in addition to extrapyramidal symptoms.
Priapism: Drugs with α-adrenergic blocking effects have been reported to induce priapism. Priapism has been reported with Invega during post-marketing surveillance (see Adverse Reactions).
Body Temperature Regulation: Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing Invega to patients who will be experiencing conditions which may contribute to an elevation in core body temperature eg, exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity or being subject to dehydration.
Antiemetic Effect: An antiemetic effect was observed in preclinical studies with paliperidone. This effect, if it occurs in humans, may mask the signs and symptoms of overdosage with certain drugs or conditions eg, intestinal obstruction, Reye's syndrome and brain tumor.
Effects in the Ability to Drive or Operate Machinery: Invega may interfere with activities requiring mental alertness and may have visual effects (see Adverse Reactions). Therefore, patients should be advised not to drive or operate machinery until their individual susceptibility is known.
Use in pregnancy: The safety of paliperidone for use during human pregnancy has not been established. No teratogenic effect was noted in any animal study. Laboratory animals treated with a high dose of paliperidone showed a slight increase in fetal deaths. This high dose was toxic to the mothers. The offspring was not affect ed at exposures 20- to 34-fold the maximum human exposure. Invega should only be used during pregnancy if the benefits outweighs the risk. The effect of Invega on labor and delivery in humans is unknown.
Use of antipsychotic drugs during the last trimester of pregnancy has been associated with reversible extrapyramidal symptoms in the neonate.
Use in lactation: In animal studies with paliperidone and in human studies with risperidone, paliperidone was excreted in the milk. Therefore, women receiving Invega should not breastfeed infants.

Use in pregnancy: The safety of paliperidone for use during human pregnancy has not been established. No teratogenic effect was noted in any animal study. Laboratory animals treated with a high dose of paliperidone showed a slight increase in fetal deaths. This high dose was toxic to the mothers. The offspring was not affect ed at exposures 20- to 34-fold the maximum human exposure. Invega should only be used during pregnancy if the benefits outweighs the risk. The effect of Invega on labor and delivery in humans is unknown.
Use of antipsychotic drugs during the last trimester of pregnancy has been associated with reversible extrapyramidal symptoms in the neonate.
Use in lactation: In animal studies with paliperidone and in human studies with risperidone, paliperidone was excreted in the milk. Therefore, women receiving Invega should not breastfeed infants.

Clinical Trials Data: The safety of Invega in the treatment of schizophrenia was evaluated in 1205 adult subjects with schizophrenia who participated in 3 double-blind, placebo-controlled 6-week trials, of whom 850 subjects received Invega at fixed doses ranging from 3-12 mg once daily.
The safety of Invega in the treatment of acute manic and mixed episodes associated with bipolar I disorder was evaluated in a total of 3 clinical trials (n=1257). The conditions and duration of treatment with Invega varied across these studies and included (in overlapping categories) placebo- and active-controlled, double-blind and fixed- and flexible-dose studies. Of the 1257 adult subjects, 739 subjects received Invega in the dose range of 3-12 mg once daily and 376 subjects received placebo.
The safety of Invega was also evaluated in 622 subjects with schizoaffective disorder who participated in 2 double-blind, placebo-controlled, three 6-week trials. In 1 of these trials, 206 subjects were assigned to 1 of 2 dose levels of Invega: 6 mg with the option to reduce to 3 mg (n=108) or 12 mg with the option to reduce to 9 mg (n=98) once daily. In the other study, 214 subjects received flexible doses of Invega (3-12 mg once daily). Both studies included subjects who received Invega either as monotherapy or in combination with antidepressants and/or mood stabilizers. The information in this section was derived from pooled data. The majority of adverse drug reactions (ADRs) were mild to moderate in severity.
Double-Blind, Placebo-Controlled Data: Schizophrenia: ADRs reported by ≥2% of Invega-treated subjects in the three 6-week double-blind, placebo-controlled, fixed-dose schizophrenia trials are shown in Table 1.

Click on icon to see table/diagram/image

Double-Blind, Placebo-Controlled Data: Bipolar Disorder: ADRs reported by ≥2% of Invega-treated subjects in the 3 double-blind, placebo-controlled bipolar disorder trials are shown in Table 2.

Click on icon to see table/diagram/image

Double-Blind, Placebo-Controlled Data: Schizoaffective Disorder: ADRs reported by ≥2% of Invega-treated subjects in the 2 placebo-controlled schizoaffective disorder trials are shown in Table 3.

Click on icon to see table/diagram/image

Monotherapy versus Combination Therapy: The designs of the 2 placebo-controlled, 6-week, double-blind trials in subjects with schizoaffective disorder included the option for subjects to receive antidepressants (except MAOIs) and/or mood stabilizers (lithium, valproate or lamotrigine). In the subject population evaluated for safety, 230 (55%) subjects received Invega as monotherapy and 190 (45%) subjects received Invega in combination with antidepressants and/or mood stabilizers. When comparing these 2 subpopulations, only nausea occurred at a greater frequency (≥3% difference) in subjects receiving Invega as monotherapy.
Dose-Related Adverse Reactions: In the placebo-controlled, 6-week, high- and low-dose study in subjects with schizoaffective disorder, dystonia, dysarthria and nasopharyngitis occurred more frequently (ie, a difference of at least 3%) in subjects who received higher doses of Invega compared with subjects who received lower doses. Hypertonia occurred more frequently in subjects who received lower doses of Invega compared with subjects who received higher doses.
Other Clinical Trial Data: Additional ADRs reported <2% of Invega-treated subjects in the previously mentioned schizophrenia, bipolar disorder and schizoaffective disorder clinical trial datasets are listed as follows. Also listed are ADRs reported at any frequency in other clinical trials.
Infections and Infestations: Urinary tract infection (UTI), upper respiratory tract infection, rhinitis.
Immune System Disorders: Anaphylactic reaction.
Endocrine Disorders: Hyperprolactinemia.
Metabolism and Nutritional Disorders: Decreased appetite.
Psychiatric Disorders: Sleep disorders, restlessness, nightmare.
Nervous System Disorders: Cerebrovascular accident, grand mal convulsion, convulsion, transient ischemic attack, syncope, dyskinesia, bradykinesia, lethargy, Parkinsonian gait, cogwheel rigidity, postural dizziness.
Cardiac Disorders: Palpitations, bradycardia, left bundle branch block.
Vascular Disorders: Ischemia, hypotension.
Respiratory, Thoracic and Mediastinal Disorders: Aspiration pneumonia, pharyngolaryngeal pain, nasal congestion, cough.
Gastrointestinal Disorders: Small intestinal obstruction, stomach discomfort, flatulence.
Skin and Subcutaneous Tissue Disorders: Rash, papular rash, pruritus.
Musculoskeletal and Connective Tissue Disorders: Muscle spasms, back and extremity pain, arthralgia, trismus, torticollis, muscle rigidity and twitching, musculoskeletal pain.
Reproductive System and Breast Disorders: Galactorrhea, amenorrhea, gynecomastia, erectile dysfunction, irregular menstruation, breast engorgement and discharge, retrograde ejaculation, breast tenderness and pain.
General Disorders: Edema, peripheral edema.
Investigations: Abnormal electrocardiogram.
Elderly: The safety of Invega was evaluated in 81 elderly subjects with schizophrenia (≥65 years) who received either flexible doses (n=76) or fixed doses (n=5) of Invega in a range of 3-12 mg once daily for a duration of up to 6 weeks during double-blind, placebo-controlled trials. Although this dataset does not allow for a systemic direct comparison between elderly and non-elderly subjects, the safety profile was similar in the 2 populations. However, based on these limited data and consistent general clinical practice, a greater sensitivity of older individuals to ADRs cannot be ruled out.
Extrapyramidal Symptoms (EPS): Pooled data form the three 6-week double-blind, placebo-controlled, fixed-dose schizophrenia studies (see Clinical Efficacy in Pharmacodynamics under Actions) showed no differences in treatment-emergent EPS between placebo (11%) and Invega 3 and 6 mg doses (13% and 10%, respectively). Dose-relatedness for EPS was seen with the 2 higher doses of Invega (25% and 26% for the 9 and 12 mg doses, respectively). EPS included a pooled analysis of the following terms: Dyskinesia, dystonia, hyperkinesia, Parkinsonism and tremor. Pooled data from the two 6-week, double-blind, placebo-controlled studies in subjects with schizoaffective disorder (see Clinical Efficacy in Pharmacodynamics under Actions) showed similar results. Weight Gain: In the pooled data from the 3 placebo-controlled, 6-week, fixed dose schizophrenia studies (see Clinical Efficacy in Pharmacodynamics under Actions), the proportions of subjects meeting a weight gain criterion of ≥7% of body weight were compared, revealing a similar incidence of weight gain for Invega 3 mg and 6 mg (7% and 6%, respectively) compared with placebo (5%) and a higher incidence of weight gain for Invega 9 mg and 12 mg (9% and 9%, respectively).
In the pooled data from the 2 placebo-controlled, 6-week studies in subjects with schizoaffective disorder (see Clinical Efficacy in Pharmacodynamics under Actions), a higher percentage of Invega-treated subjects (5%) had an increase in body weight of ≥7% compared with placebo-treated subjects (1%). In the study that examined high- and low-dose groups, the increase in body weight of ≥7% was 3% in the low-dose group, 7% in the high-dose group and 1% in the placebo group.
Laboratory Tests: Serum Prolactin: Based on pooled data from the three 6-week double-blind, placebo-controlled, fixed-dose schizophrenia studies (see Clinical Efficacy in Pharmacodynamics under Actions), increases in serum prolactin were observed in subjects of both genders who received Invega. Maximum mean increases of serum prolactin concentrations were generally observed on day 15 of treatment, but remained above baseline levels at study endpoint.
Clinical Trials: ADRs in a Long-Term, Placebo-Controlled Study: The safety of Invega was also evaluated in a long-term trial designed to assess the maintenance of effect with Invega in adults with schizophrenia (see Clinical Efficacy in Pharmacodynamics under Actions). In general, the types, frequencies and severities of ADRs reported during the initial 14-week open-label phase of the study were comparable to those reported in the 6-week, placebo-controlled, fixed-dose studies. The ADRs reported during the long-term double-blind phase of this study were similar in type and severity to those observed in the initial 14-week open-label phase, but occurred at generally lower frequencies.
Post-Marketing Data: Adverse events first identified as ADRs during post-marketing experience with Invega are listed as follows. The frequencies are provided according to the following convention: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/10,000, including isolated reports).
Immune System Disorders: Rare: Angioedema.
Nervous System Disorders: Very Rare: Tardive dyskinesia.
Gastrointestinal Disorders: Very Rare: Swollen tongue.
Renal and Urinary Disorders: Very Rare: Urinary incontinence and retention.
Reproductive System and Breast Disorders: Very Rare: Priaprism.
Safety Information Reported with Risperidone: Paliperidone is an active metabolite of risperidone. The release profile and pharmacokinetic characteristics of paliperidone are considerably different than those observed with oral immediate-release risperidone formulations. Safety information reported with clinical trials and post-marketing experience can be found in local labeling with risperidone.

Caution is advised when prescribing Invega with drugs known to prolong the QT interval.
Potential for Invega to Affect Other Drugs: Paliperidone is not expected to cause clinically important pharmacokinetic interactions with drugs that are metabolized by cytochrome P-450 isozymes. In vitro studies in human liver microsomes showed that paliperidone does not substantially inhibit the metabolism of drugs metabolized by cytochrome P-450 isozymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4 and CYP3A5. Therefore, paliperidone is not expected to inhibit clearance of drugs that are metabolized by these metabolic pathways in a clinically relevant manner. In vitro studies indicated that paliperidone is not an inducer of CYP1A2, 2C19 or 3A4 activity.
Paliperidone is a weak inhibitor of P-glycoprotein (P-gp) at high concentrations. No in vivo data are available and the clinical relevance is unknown.
Given the primary central nervous system effects of paliperidone (see Adverse Reactions), Invega should be used with caution in combination with other centrally acting drugs and alcohol. Paliperidone may antagonize the effect of levodopa and other dopamine agonists.
Because of its potential for inducing orthostatic hypotension (see Precautions), an additive effect may be observed when Invega is administered with other therapeutic agents that have this potential.
Co-administration of Invega at steady state (12 mg once daily) with divalproex sodium extended-release tablets (500-2000 mg once daily) did not affect the steady-state pharmacokinetics of valproate.
Potential for Other Drugs to Affect Invega: Paliperidone is not a substrate of CYP1A2, CYP2A6, CYP2C9, CYP2C19 and CYP3A5. This suggests that an interaction with inhibitors or inducers of these isoenzymes is unlikely. While in vitro studies indicate that CYP2D6 and CYP3A4 may be minimally involved in paliperidone metabolism, there are no indications in vitro nor in vivo that these isoenzymes play a significant role in the metabolism of paliperidone. In vitro studies have shown that paliperidone is a P-gp substrate. Paliperidone is metabolized to a limited extent by CYP2D6 (see Metabolism and Elimination in Pharmacokinetics under Actions). In an interaction study in healthy subjects in which Invega was administered concomitantly with paroxetine, a potent CYP2D6 inhibitor, no clinically relevant effects on the pharmacokinetics of paliperidone were observed.
Co-administration of Invega once daily with carbamazepine 200 mg twice daily caused a decrease of approximately 37% in the mean steady-state C_max and AUC of paliperidone. This decreased is caused, to a substantial degree, by a 35% increase in renal clearance of paliperidone likely as a result of induction of renal P-gp by carbamazepine. A minor decrease in the amount of drug excreted unchanged in the urine suggests that there was little effect on the CYP metabolism or bioavailability of paliperidone during carbamazepine co-administration. On initiation of carbamazepine, the dose of Invega should be re-evaluated and increased if necessary. Conversely, on discontinuation of carbamazepine, the dose of Invega should be re-evaluated and decreased if necessary. Paliperidone, a cation under physiological pH, is primarily excreted unchanged by the kidneys, approximately ½ via filtration and ½ via active secretion. Concomitant administration of trimethoprim, a drug known to inhibit active renal cation drug transport, did not influence the pharmacokinetics of paliperidone.
Co-administration of a single dose of Invega 12 mg with divalproex sodium extended-release tablets (two 500 mg tablets once daily) resulted in an increase of approximately 50% in the C_max and AUC of paliperidone. Dosage reduction for Invega should be considered when Invega is co-administered with valproate after clinical assessment. Pharmacokinetic interaction between lithium and paliperidone is unlikely. Concomitant Use of Invega with Risperidone: Concomitant use of Invega with risperidone has not been studied. Since paliperidone is an active metabolite of risperidone, consideration should be given to the additive paliperidone exposure if risperidone is co-administered with Invega.

Store at temperatures not exceeding 30°C. Protect from moisture.

Antipsychotics

N05AX13 - paliperidone ; Belongs to the class of other antipsychotics.

Rx

Extentab 3 mg x 28's. 6 mg x 28's. 9 mg x 28's.