PALIPERIDONE- paliperidone_tablet, extended release

Paliperidone is the major active metabolite of risperidone. The mechanism of action of paliperidone in schizophrenia is unclear. However, the drug's therapeutic effect in schizophrenia could be mediated through a combination of central dopamine Type 2 (D 2 2A In vitro 2 2A 2 2A 1 2 1 1 2 in vitro Following a single dose, the plasma concentrations of paliperidone gradually rise to reach peak plasma concentration (C max Absorption and Distribution max [see Dosage and Administration (2. 3)] Metabolism and Elimination in vitro in vivo [see Drug Interactions (7)] 14 in vivo Special Populations Renal Impairment [see Dosage and Administration (2. 5)] Hepatic Impairment Adolescents (12 to 17 years of age) Elderly [see Renal Impairment above and Dosage and Administration ( 2. 5 Race Gender Smoking.

Paliperidone is an atypical antipsychotic agent indicated for Treatment of schizophrenia ( 1. 2 Paliperidone extended-release tablets are indicated for the treatment of schizophrenia [see Clinical Studies (14. 1 Paliperidone extended-release tablets are indicated for the treatment of schizoaffective disorder as monotherapy and an adjunct to mood stabilizers and/or antidepressant therapy [see Clinical Studies (14.

Initial Dose Recommended Dose Maximum Dose Schizophrenia - adults ( 2. 1 6 mg/day 3 to 12 mg/day 12 mg/day Schizophrenia-adolescents ( 2. 1 Weight < 51kg 3 mg/day 3 to 6 mg/day 6 mg/day Weight >= 51kg 3 mg/day 3 to 12 mg/day 12 mg/day Schizoaffective disorder - adults ( 2. 2 6 mg/day 3 to 12 mg/day 12 mg/day Tablet should be swallowed whole and should not be chewed, divided, or crushed. 3 Adults [see Clinical Studies (14)] The recommended dose of paliperidone extended-release tablets for the treatment of schizoaffective disorder in adults is 6 mg administered once daily. 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. This trend must be weighed against dose-related increase in adverse reactions. Dosage adjustment, if indicated, should occur only after clinical reassessment. Dose increases, if indicated, generally should occur at intervals of more than 4 days. When dose increases are indicated, increments of 3 mg/day are recommended. The maximum recommended dose is 12 mg/day. Paliperidone extended-release tablets can be taken with or without food. Concomitant use of paliperidone extended-release tablets with risperidone has not been studied. Since paliperidone is the major active metabolite of risperidone, consideration should be given to the additive paliperidone exposure if risperidone is coadministered with paliperidone extended-release tablets. Renal Impairment [See Clinical Pharmacology ( 12. 3 Hepatic Impairment [see Clinical Pharmacology ( 12. 3 Elderly [see Renal Impairment above].

The following adverse reactions are discussed in more detail in other sections of the labeling: Increased mortality in elderly patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5. 1)] Cerebrovascular adverse reactions, including stroke, in elderly patients with dementia-related psychosis [see Warnings and Precautions (5. 2)] Neuroleptic malignant syndrome [see Warnings and Precautions (5. 3)] QT prolongation [see Warnings and Precautions (5. 4)] Tardive dyskinesia [see Warnings and Precautions (5. 5)] Metabolic changes [see Warnings and Precautions (5. 6)] Hyperprolactinemia [see Warnings and Precautions (5. 7)] Potential for gastrointestinal obstruction [see Warnings and Precautions (5. 8)] Orthostatic hypotension and syncope [see Warnings and Precautions (5. 9)] Falls [see Warnings and Precautions (5. 10)] Leukopenia, neutropenia, and agranulocytosis [see Warnings and Precautions (5. 11)] Potential for cognitive and motor impairment [see Warnings and Precautions (5. 12)] Seizures [see Warnings and Precautions (5. 13)] Dysphagia [see Warnings and Precautions (5. 14)] Priapism [see Warnings and Precautions (5. 15)] Disruption of body temperature regulation [see Warnings and Precautions (5. 17)] Commonly observed adverse reactions (incidence >= 5% and at least twice that for placebo) were (6) Adults with schizophrenia: extrapyramidal symptoms, tachycardia, and akathisia. Adolescents with schizophrenia: somnolence, akathisia, tremor, dystonia, cogwheel rigidity, anxiety, weight increased, and tachycardia. Adults with schizoaffective disorder: extrapyramidal symptoms, somnolence, dyspepsia, constipation, weight increased, and nasopharyngitis. To report SUSPECTED ADVERSE REACTIONS, contact McKesson Corporation dba SKY Packaging at 1-888-243-4363 or FDA at 1-800-FDA-1088 or www. gov/medwatch. The most common adverse reactions in clinical trials in adult subjects with schizophrenia (reported in 5% or more of subjects treated with paliperidone and at least twice the placebo rate in any of the dose groups) were extrapyramidal symptoms, tachycardia, and akathisia. The most common adverse reactions in clinical trials in adult patients with schizoaffective disorder (reported in 5% or more of subjects treated with paliperidone and at least twice the placebo rate) were extrapyramidal symptoms, somnolence, dyspepsia, constipation, weight increased, and nasopharyngitis. [See Adverse Reactions (6. 4)] Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials en dash Schizophrenia in Adults and Adolescents Adult Patients with Schizophrenia Table 4 Table 4. Adverse Reactions Reported by >= 2% of Paliperidone-Treated Adult Subjects with Schizophrenia in Three Short-Term, Fixed-Dose, Placebo-Controlled Clinical Trials * Body System or Organ Class Percentage of Patients Paliperidone Placebo 3 mg once daily 6 mg once daily 9 mg once daily 12 mg once daily (N=355) (N=127) (N=235) (N=246) (N=242) Total percentage of subjects with adverse reactions 37 48 47 53 59 Cardiac disorders Atrioventricular block first degree 1 2 0 2 1 Bundle branch block 2 3 1 3 <1 Sinus arrhythmia 0 2 1 1 <1 Tachycardia 7 14 12 12 14 Gastrointestinal disorders Abdominal pain upper 1 1 3 2 2 Dry mouth 1 2 3 1 3 Salivary hypersecretion <1 0 <1 1 4 General disorders Asthenia 1 2 <1 2 2 Fatigue 1 2 1 2 2 Nervous system disorders Akathisia 4 4 3 8 10 Dizziness 4 6 5 4 5 Extrapyramidal symptoms 8 10 7 20 18 Headache 12 11 12 14 14 Somnolence 7 6 9 10 11 Vascular disorders Orthostatic hypotension 1 2 1 2 4 * Table includes adverse reactions that were reported in 2% or more of subjects in any of the paliperidone Adolescent Patients with Schizophrenia Table 5 Table 5. Adverse Reactions Reported by 2% of Paliperidone-Treated Adolescent Subjects with Schizophrenia in a Fixed-Dose, Placebo-Controlled Clinical Trial * Body System or Organ Class Percentage of Patients Paliperidone Placebo 1. 5 mg once daily 3 mg once daily 6 mg once daily 12 mg once daily (N=51) (N=54) (N=16) (N=45) (N=35) Total percentage of subjects with adverse reactions 43 37 50 58 74 Cardiac disorders Tachycardia 0 0 6 9 6 Eye disorders Vision blurred 0 0 0 0 3 Gastrointestinal disorders Dry mouth 2 0 0 0 3 Salivary hypersecretion 0 2 6 2 0 Swollen tongue 0 0 0 0 3 Vomiting 10 0 6 11 3 General disorders Asthenia 0 0 0 2 3 Fatigue 0 4 0 2 3 Infections and infestations Nasopharyngitis 2 4 0 4 0 Investigations Weight increased 0 7 6 2 3 Nervous system disorders Akathisia 0 4 6 11 17 Dizziness 0 2 6 2 3 Extrapyramidal symptoms 0 4 19 18 23 Headache 4 9 6 4 14 Lethargy 0 0 0 0 3 Somnolence 4 9 13 20 26 Tongue paralysis 0 0 0 0 3 Psychiatric disorders Anxiety 4 0 0 2 9 Reproductive system and breast disorders Amenorrhea 0 0 6 0 0 Galactorrhea 0 0 0 4 0 Gynecomastia 0 0 0 0 3 Respiratory, thoracic and mediastinal disorders Epistaxis 0 0 0 2 0 * Table includes adverse reactions that were reported in 2% or more of subjects in any of the paliperidone Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials en dash Schizoaffective Disorder in Adults Table 6 Table 6. Adverse Drug Reactions Reported by 2% of Paliperidone-Treated Adult Subjects with Schizoaffective Disorder in Two Double-Blind, Placebo-Controlled Clinical Trials Body System or Organ Class Percentage of Patients Placebo Paliperidone 3 to 6 mg once-daily fixed-dose range Paliperidone 9 to 12 mg once-daily fixed-dose range Paliperidone 3 to 12 mg once-daily flexible dose (N=202) (N=108) (N=98) (N=214) Total percentage of subjects with adverse reactions 32 48 50 43 Cardiac disorders Tachycardia 2 3 1 2 Gastrointestinal disorders Abdominal discomfort/Abdominal pain upper 1 1 0 3 Constipation 2 4 5 4 Dyspepsia 2 5 6 6 Nausea 6 8 8 5 Stomach discomfort 1 0 1 2 General disorders Asthenia 1 3 4 <1 Infections and Infestations Nasopharyngitis 1 2 5 3 Rhinitis 0 1 3 1 Upper respiratory tract infection 1 2 2 2 Investigations Weight increased 1 5 4 4 Metabolism and nutrition disorders Decreased appetite <1 1 0 2 Increased appetite <1 3 2 2 Musculoskeletal and connective tissue disorders Back pain 1 1 1 3 Myalgia <1 2 4 1 Nervous system disorders Akathisia 4 4 6 6 Dysarthria 0 1 4 2 Extrapyramidal symptoms 8 20 17 12 Somnolence 5 12 12 8 Psychiatric disorders Sleep disorder <1 2 3 0 Respiratory, thoracic and mediastinal disorders Cough 1 1 3 1 Pharyngolaryngeal pain <1 0 2 1 * Table includes adverse reactions that were reported in 2% or more of subjects in any of the paliperidone dose groups and which occurred at greater incidence than in the placebo group. Data are pooled from two studies. One study included once-daily paliperidone doses of 6 mg (with the option to reduce to 3 mg) and 12 mg (with the option to reduce to 9 mg). The second study included flexible once-daily doses of 3 to 12 mg. Among the 420 subjects treated with paliperidone, 230 (55%) received paliperidone as monotherapy and 190 (45%) received paliperidone as an adjunct to mood stabilizers and/or antidepressants. Extrapyramidal symptoms includes the terms bradykinesia, drooling, dyskinesia, dystonia, hypertonia, muscle rigidity, muscle twitching, oculogyration, parkinsonian gait, parkinsonism, restlessness, and tremor. Somnolence includes the terms sedation and somnolence. Tachycardia includes the terms tachycardia, sinus tachycardia, and heart rate increased. Monotherapy versus Adjunctive Therapy Discontinuations Due to Adverse Reactions Schizophrenia Trials Schizoaffective Disorder Trials Dose-Related Adverse Reactions Schizophrenia Trials Schizoaffective Disorder Trials Demographic Differences [see Use in Specific Populations (8. 5)] Extrapyramidal Symptoms (EPS) Table 7 Table 8 Table 7. Treatment-Emergent Extrapyramidal Symptoms (EPS) Assessed by Incidence of Ratings Scales and Use of Anticholinergic Medication en dash Schizophrenia Studies in Adults EPS Group Percentage of Patients Paliperidone Placebo 3 mg once daily 6 mg once daily 9 mg once daily 12 mg once daily (N=355) (N=127) (N=235) (N=246) (N=242) a b c a b c Table 8. Treatment-Emergent Extrapyramidal Symptoms (EPS)-Related Adverse Events by MedDRA Preferred Term en dash Schizophrenia Studies in Adults EPS Group Percentage of Patients Paliperidone Placebo 3 mg once daily 6 mg once daily 9 mg once daily 12 mg once daily (N=355) (N=127) (N=235) (N=246) (N=242) Dyskinesia group includes: Dyskinesia, extrapyramidal disorder, muscle twitching, tardive dyskinesia Table 9 Table 9. Treatment-Emergent Extrapyramidal Symptoms (EPS)-Related Adverse Events by MedDRA Preferred Term en dash Schizoaffective Disorder Studies in Adults EPS Group Percentage of Patients Paliperidone Placebo 3 to 6 mg once-daily fixed-dose range 9 to 12 mg once-daily fixed-dose range 3 to 12 mg once-daily flexible dose (N=202) (N=108) (N=98) (N=214) Dyskinesia group includes: Dyskinesia, muscle twitching (Table 10) Table 10. Treatment-Emergent Extrapyramidal Symptoms (EPS)-Related Adverse Events by MedDRA Preferred Term en dash Schizophrenia Studies in Adolescent Subjects Placebo EPS Group Percentage of Patients Paliperidone Placebo 1. 5 mg once daily 3 mg once daily 6 mg once daily 12 mg once daily (N=51) (N=54) (N=16) (N=45) (N=35) Hyperkinesia group includes: Akathisia Dystonia Class Effect: Laboratory Test Abnormalities [see Warnings and Precautions (5. Other Adverse Reactions Observed During Premarketing Evaluation of Paliperidone Cardiac disorders: Eye disorders: Gastrointestinal disorders: General disorders: Immune system disorders: Infections and infestations: Investigations: Musculoskeletal and connective tissue disorders: Nervous system disorders: Psychiatric disorders: Reproductive system and breast disorders: Respiratory, thoracic and mediastinal disorders: Skin and subcutaneous tissue disorders: Vascular disorders: The safety of paliperidone was also evaluated in a long-term trial designed to assess the maintenance of effect with paliperidone in adults with schizophrenia [see Clinical Studies (14)] The following adverse reactions have been identified during postapproval use of paliperidone; because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency: angioedema, catatonia, ileus, priapism, somnambulism, swollen tongue, tardive dyskinesia, thrombotic thrombocytopenic purpura, urinary incontinence, urinary retention. Paliperidone is the major active metabolite of risperidone. Adverse reactions reported with risperidone can be found in the ADVERSE REACTIONS section of the risperidone package insert.

Paliperidone is contraindicated in patients with a known hypersensitivity to either paliperidone or risperidone, or to any of the excipients in the paliperidone extended-release tablet formulation. Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been reported in patients treated with risperidone and in patients treated with paliperidone. Paliperidone is a metabolite of risperidone. Known hypersensitivity to paliperidone, risperidone, or to any excipients in paliperidone extended-release tablets.

Renal impairment: Dosing must be individualized according to renal function status. 5) Elderly: Same as for younger adults (adjust dose according to renal function status). 4) Pregnancy: May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure. 1) Pediatric Use: Safety and effectiveness in the treatment of schizophrenia not established in patients less than 12 years of age. Safety and effectiveness in the treatment of schizoaffective disorder not established in patients less than 18 years of age. 4) Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including paliperidone, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or online at http://womensmentalhealth. org/clinical-andresearch-programs/pregnancyregistry/. Risk Summary Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery ( see Clinical Considerations see Data see Clinical Considerations The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. In animal reproduction studies, there were no increases in fetal abnormalities when pregnant rats and rabbits were treated with paliperidone during the period of organogenesis with up to 8 times the maximum recommended human dose (MRHD) based on mg/m 2 Clinical Considerations Disease-associated maternal and/or embryo/fetal risk There is a risk to the mother from untreated schizophrenia, including increased risk of relapse, Fetal/Neonatal Adverse Reactions Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs, including paliperidone, during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Data Human Data Published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics during pregnancy do not report a clear association with antipsychotics and major birth defects. A prospective observational study including 6 women treated with risperidone, the parent compound of paliperidone, demonstrated placental passage of risperidone and paliperidone. A retrospective cohort study from a Medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects. There was a small increase in the risk of major birth defects (RR= 1. 26, 95% CI 1. 56) and of cardiac malformations (RR=1. 26, 95% CI 0. 81) in a subgroup of 1566 women exposed to the parent compound of paliperidone, risperidone, during the first trimester of pregnancy; however, there is no mechanism of action to explain the difference in malformation rates. Animal Data In animal reproduction studies, there were no increases in fetal abnormalities when pregnant rats and rabbits were treated with paliperidone during the period of organogenesis with up to 8 times the MRHD of 12 mg based on mg/m 2 Additional reproduction toxicity studies were conducted with orally administered risperidone, which is extensively converted to paliperidone. Cleft palate was observed in the offspring of pregnant mice treated with risperidone at 3 to 4 times the MRHD of 16 mg based on mg/m 2 2 2 In rat reproduction studies with risperidone, pup deaths occurred at oral doses which are less than the MRHD of risperidone based on mg/m 2 registered Risk Summary Limited data from published literature report the presence of paliperidone in human breast milk. There is no information on the effects on the breastfed infant, or the effects on milk production; however, there are reports of sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements) in breastfed infants exposed to paliperidone's parent compound, risperidone ( see Clinical Considerations Clinical Considerations Infants exposed to paliperidone through breastmilk should be monitored for excess sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements). Infertility Females Based on the pharmacologic action of paliperidone (D2 receptor antagonism), treatment with paliperidone extended-release tablets may result in an increase in serum prolactin levels, which may lead to a reversible reduction in fertility in females of reproductive potential [see Warnings and Precautions (5. Safety and effectiveness of paliperidone in the treatment of schizophrenia were evaluated in 150 adolescent subjects 12 to 17 years of age with schizophrenia who received paliperidone in the dose range of 1. 5 mg to 12 mg/day in a 6-week, double-blind, placebo-controlled trial. Safety and effectiveness of paliperidone for the treatment of schizophrenia in patients < 12 years of age have not been established. Safety and effectiveness of paliperidone for the treatment of schizoaffective disorder in patients < 18 years of age have not been studied. Juvenile Animal Studies In a study in which juvenile rats were treated with oral paliperidone from days 24 to 73 of age, a reversible impairment of performance in a test of learning and memory was seen, in females only, with a no-effect dose of 0. 63 mg/kg/day, which produced plasma levels (AUC) of paliperidone similar to those in adolescents at MRHD of 12 mg/day. No other consistent effects on neurobehavioral or reproductive development were seen up to the highest dose tested (2. 5 mg/kg/day), which produced plasma levels of paliperidone 2 to 3 times those in adolescents. Juvenile dogs were treated for 40 weeks with oral risperidone, which is extensively metabolized to paliperidone in animals and humans, at doses of 0. 25, or 5 mg/kg/day. Decreased bone length and density were seen with a no-effect dose of 0. 31 mg/kg/day, which produced plasma levels (AUC) of risperidone plus paliperidone which were similar to those in children and adolescents receiving the MRHD of risperidone. In addition, a delay in sexual maturation was seen at all doses in both males and females. The above effects showed little or no reversibility in females after a 12-week drug-free recovery period. The long-term effects of paliperidone on growth and sexual maturation have not been fully evaluated in children and adolescents. The safety, tolerability, and efficacy of paliperidone were evaluated in a 6-week placebo-controlled study of 114 elderly subjects with schizophrenia (65 years of age and older, of whom 21 were 75 years of age and older). In this study, subjects received flexible doses of paliperidone (3 mg to 12 mg once daily). In addition, a small number of subjects 65 years of age and older were included in the 6-week placebo-controlled studies in which adult schizophrenic subjects received fixed doses of paliperidone (3 mg to 15 mg once daily) [see Clinical Studies ( 14)] (n = 1796), including those who received paliperidone or placebo, 125 (7%) were 65 years of age and older and 22 (1. 2%) were 75 years of age and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. [see Clinical Pharmacology ( 12. 3 [see Dosage and Administration ( 2. 5 Dosing must be individualized according to the patient’s renal function status [see Dosage and Administration ( 2. 5 No dosage adjustment is required in patients with mild to moderate hepatic impairment. Paliperidone has not been studied in patients with severe hepatic impairment. Patients with Parkinson’s Disease or Dementia with Lewy Bodies can experience increased sensitivity to paliperidone. Manifestations can include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinical features consistent with neuroleptic malignant syndrome.

Centrally-acting drugs: Due to CNS effects, use caution in combination. Avoid alcohol. 1 Drugs that may cause orthostatic hypotension: An additive effect may be observed when coadministered with paliperidone. 1 Strong CYP3A4/P-glycoprotein (P-gp) inducers: It may be necessary to increase the dose of paliperidone when a strong inducer of both CYP3A4 and P-gp (e. , carbamazepine) is coadministered. Conversely, on discontinuation of the strong inducer, it may be necessary to decrease the dose of paliperidone. 2 Coadministration of divalproex sodium increased C max 7. 2 Given the primary CNS effects of paliperidone [see Adverse Reactions (6. 2)] 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. [see Warnings and Precautions (5. 9)] In vitro in vivo max Paliperidone is not a substrate of CYP1A2, CYP2A6, CYP2C9, and CYP2C19, so that an interaction with inhibitors or inducers of these isozymes is unlikely. While in vitro in vivo In vitro max [see Clinical Pharmacology (12.

OVERDOSAGE
While experience with paliperidone overdose is limited, among the few cases of overdose reported in pre-marketing trials, the highest estimated ingestion of paliperidone was 405 mg. Observed signs and symptoms included extrapyramidal symptoms and gait unsteadiness. Other potential signs and symptoms include those resulting from an exaggeration of paliperidone’s known pharmacological effects, i. , drowsiness and somnolence, tachycardia and hypotension, and QT prolongation. Torsade de pointes and ventricular fibrillation have been reported in a patient in the setting of overdose. There is no specific antidote to paliperidone, therefore, appropriate supportive measures should be instituted and close medical supervision and monitoring should continue until the patient recovers. Consideration should be given to the extended-release nature of the product when assessing treatment needs and recovery. Multiple drug involvement should also be considered. In case of acute overdose, establish and maintain an airway and ensure adequate oxygenation and ventilation. Administration of activated charcoal together with a laxative should be considered. The possibility of obtundation, seizures, or dystonic reaction of the head and neck following overdose may create a risk of aspiration with induced emesis. Cardiovascular monitoring should commence immediately, including continuous electrocardiographic monitoring for possible arrhythmias. If antiarrhythmic therapy is administered, disopyramide, procainamide, and quinidine carry a theoretical hazard of additive QT-prolonging effects when administered in patients with an acute overdose of paliperidone. Similarly, the alpha-blocking properties of bretylium might be additive to those of paliperidone, resulting in problematic hypotension. Hypotension and circulatory collapse should be treated with appropriate measures, such as intravenous fluids and/or sympathomimetic agents (epinephrine and dopamine should not be used, since beta stimulation may worsen hypotension in the setting of paliperidone-induced alpha blockade). In cases of severe extrapyramidal symptoms, anticholinergic medication should be administered.
NONCLINICAL TOXICOLOGY
Carcinogenesis Carcinogenicity studies with paliperidone administered orally have not been performed. Carcinogenicity studies with risperidone, which is extensively converted to paliperidone in rats, mice, and humans, were conducted in Swiss albino mice and Wistar rats. Risperidone was administered in the diet at daily doses of 0.63 mg/kg, 2.5 mg/kg, and 10 mg/kg for 18 months to mice and for 25 months to rats. A maximum tolerated dose was not achieved in male mice. There were statistically significant increases in pituitary gland adenomas, endocrine pancreas adenomas, and mammary gland adenocarcinomas. The no-effect dose for these tumors was less than or equal to the MRHD of risperidone based on mg/m 2 2 [see Warnings and Precautions ( 5.7 Mutagenesis No evidence of genotoxic potential for paliperidone was found in the Ames reverse mutation test, the mouse lymphoma assay, or the in vivo Impairment of Fertility In a study of fertility, the percentage of treated female rats that became pregnant was not affected at oral doses of paliperidone of up to 2.5 mg/kg/day which is 2 times the MRHD based on mg/m 2 2 The fertility of male rats was not affected at oral doses of paliperidone of up to 2 times the MRHD of 12 mg/day based on mg/m 2 2
CLINICAL STUDIES
Adults daily, and subjects weighing at least 51 kg at the baseline visit were randomly assigned to receive placebo or 1. 5 mg (Low dose), 6 mg (Medium dose), or 12 mg (High dose) of paliperidone daily. Dosing was in the morning without regard to meals.

McKesson Corporation dba SKY Packaging

PALIPERIDONE- paliperidone_tablet, extended release Product manual source documgent