XEPLION

Paliperidone extended-release tablets contains paliperidone

USP, an atypical antipsychotic belonging to the chemical class of benzisoxazole derivatives.

Paliperidone, USP contains a racemic mixture of (+).

• and (-).

The chemical name is (±)-3-[2-[4-(6-fluoro-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.

Its molecular formula is

C 23 H 27 FN 4 O and its molecular weight is 426.49.

The structural formula is

Paliperidone, USP is sparingly soluble in 0.1N HCl and methylene chloride; practically insoluble in water, 0.1N NaOH, and hexane; and slightly soluble in N,N-dimethylformamide.

Paliperidone extended-release tablets are intended for oral administration and are available in 1.5 mg (brown), 3 mg (white), 6 mg (light beige), and 9 mg (pink) strengths.

Inactive ingredients are colloidal silicon dioxide, fumaric acid, hypromellose, lactose monohydrate, macrogol, magnesium stearate, methacrylic acid copolymer, microcrystalline cellulose, polyethylene oxides, povidone, talc and triethyl citrate.

The 1.5 mg tablets also contain iron oxide black, iron oxide red and iron oxide yellow.

The 6 mg tablets also contain iron oxide red and iron oxide yellow.

The 9 mg tablets also contain iron oxide black, iron oxide red and iron oxide yellow. chem structure.

Paliperidone extended-release tablets are an atypical antipsychotic agent indicated for Treatment of schizophrenia Adults: Efficacy was established in three 6-week trials and one maintenance trial.

Adolescents (ages to 17): Efficacy was established in one 6-week trial.

Treatment of schizoaffective disorder as monotherapy and as an adjunct to mood stabilizers and/or antidepressants.

Efficacy was established in two 6-week trials in adult patients. 1.1 Schizophrenia Paliperidone extended-release tablets are indicated for the treatment of schizophrenia.

The efficacy of paliperidone extended-release tablets in schizophrenia was established in three 6-week trials in adults and one 6-week trial in adolescents, as well as one maintenance trial in adults. 1.2 Schizoaffective Disorder Paliperidone extended-release tablets are indicated for the treatment of schizoaffective disorder as monotherapy and an adjunct to mood stabilizers and/or antidepressant therapy.

The efficacy of paliperidone in schizoaffective disorder was established in two 6-week trials in adults.

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 ) and serotonin Type 2 (5HT 2A ) receptor antagonism. 12.2 Pharmacodynamics In vitro, paliperidone acts as an antagonist at the central dopamine Type 2 (D 2 ) and serotonin Type 2 (5HT 2A ) receptors, with binding affinities (Ki values) of 1.6-2.8 nM for D and 0.8-1.2 nM for 5HT 2A receptors.

Paliperidone is also active as an antagonist at the α 1 and α 2 adrenergic receptors and H 1 histaminergic receptors, which may explain some of the other effects of the drug.

Paliperidone has no affinity for cholinergic muscarinic or β 1.

• and β 2 -adrenergic receptors.

The pharmacological activity of the (+).

• and (-).

• paliperidone enantiomers is qualitatively and quantitatively similar in vitro. 12.3 Pharmacokinetics Following a single dose, the plasma concentrations of paliperidone gradually rise to reach peak plasma concentration (C max ) approximately 24 hours after dosing.

The pharmacokinetics of paliperidone following paliperidone administration are dose-proportional within the available dose range.

The terminal elimination half-life of paliperidone is approximately 23 hours.

Steady-state concentrations of paliperidone are attained within to 5 days of dosing with paliperidone in most subjects.

The mean steady-state peak:trough ratio for a paliperidone dose of 9 mg was 1.7 with a range of 1.2 to 3.1.

Following administration of paliperidone, 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 paliperidone extended-release tablet administration is 28%.

Administration of a 12 mg paliperidone extended-release tablet to healthy ambulatory subjects with a standard high-fat/high-caloric meal gave mean C max and AUC values of paliperidone that were increased by 60% and 54%, respectively, compared with administration under fasting conditions.

Clinical trials establishing the safety and efficacy of paliperidone were carried out in subjects without regard to the timing of meals.

While paliperidone extended-release tablets can be taken without regard to food, the presence of food at the time of paliperidone extended-release tablet administration may increase exposure to paliperidone.

Based on a population analysis, the apparent volume of distribution of paliperidone is 487 L. The plasma protein binding of racemic paliperidone is 74%.

Although in vitro studies suggested a role for CYP2D6 and CYP3A4 in the metabolism of paliperidone, in vivo results indicate that these isozymes play a limited role in the overall elimination of paliperidone.

One week following administration of a single oral dose of 1 mg immediate-release 14 C-paliperidone to 5 healthy volunteers, 59% (range 51% to 67%) of the dose was excreted unchanged into urine, 32% (26% to 41%) of the dose was recovered as metabolites, and 6% to 12% of the dose was not recovered.

Approximately 80% of the administered radioactivity was recovered in urine and 11% in the feces.

Four primary metabolic pathways have been identified in vivo, none of which could be shown to account for more than 10% of the dose: dealkylation, hydroxylation, dehydrogenation, and benzisoxazole scission.

Population pharmacokinetic analyses found no difference in exposure or clearance of paliperidone between extensive metabolizers and poor metabolizers of CYP2D6 substrates.

The dose of paliperidone should be reduced in patients with moderate or severe renal impairment.

The disposition of a single dose paliperidone 3 mg extended-release tablet was studied in adult subjects with varying degrees of renal function.

Elimination of paliperidone decreased with decreasing estimated creatinine clearance.

Total clearance of paliperidone was reduced in subjects with impaired renal function by 32% on average in mild (CrCl = 50 mL/min to < 80 mL/min), 64% in moderate (CrCl = 30 mL/min to < 50 mL/min), and 71% in severe (CrCl = 10 mL/min to < 30 mL/min) renal impairment, corresponding to an average increase in exposure (AUC inf ) of 1.5 fold, 2.6 fold, and 4.8 fold, respectively, compared to healthy subjects.

The mean terminal elimination half-life of paliperidone was 24 hours, 40 hours, and 51 hours in subjects with mild, moderate, and severe renal impairment, respectively, compared with 23 hours in subjects with normal renal function (CrCl ≥ 80 mL/min).

In a study in adult subjects with moderate hepatic impairment (Child-Pugh class B), the plasma concentrations of free paliperidone were similar to those of healthy subjects, although total paliperidone exposure decreased because of a decrease in protein binding.

Consequently, no dose adjustment is required in patients with mild or moderate hepatic impairment.

Paliperidone has not been studied in patients with severe hepatic impairment.

Adolescents (12 to 17 years of age) Paliperidone systemic exposure in adolescents weighing ≥ 51 kg (≥ 112 lbs) was similar to that in adults.

In adolescents weighing < 51 kg (< 112 lbs), a 23% higher exposure was observed; this is considered not to be clinically significant.

Age did not influence the paliperidone exposure.

No dosage adjustment is recommended based on age alone.

However, dose adjustment may be required because of age-related decreases in creatinine clearance.

No dosage adjustment is recommended based on race.

No differences in pharmacokinetics were observed in a pharmacokinetic study conducted in Japanese and Caucasians.

No dosage adjustment is recommended based on gender.

No differences in pharmacokinetics were observed in a pharmacokinetic study conducted in men and women.

No dosage adjustment is recommended based on 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.

The following adverse reactions are discussed in more detail in other sections of the labeling: Increased mortality in elderly patients with dementia-related psychosis Cerebrovascular adverse reactions, including stroke, in elderly patients with dementia-related psychosis Neuroleptic malignant syndrome QT prolongation Tardive dyskinesia Metabolic changes Hyperprolactinemia Potential for gastrointestinal obstruction Orthostatic hypotension and syncope Falls Leukopenia, neutropenia, and agranulocytosis Potential for cognitive and motor impairment Seizures Dysphagia Priapism Disruption of body temperature regulation Commonly observed adverse reactions (incidence ≥ 5% and at least twice that for placebo) were 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.fda.gov/medwatch 6.1 Clinical Trials Experience 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.

The most common adverse reactions that were associated with discontinuation from clinical trials in adult subjects with schizophrenia (causing discontinuation in 2% of paliperidone-treated subjects) were nervous system disorders.

The most common adverse reactions that were associated with discontinuation from clinical trials in adult subjects with schizoaffective disorder were gastrointestinal disorders, which resulted in discontinuation in 1% of paliperidone-treated subjects.

The safety of paliperidone was evaluated in 1205 adult subjects with schizophrenia who participated in three placebo-controlled, 6-week, double-blind trials, of whom 850 subjects received paliperidone at fixed doses ranging from 3 mg to 12 mg once daily.

The information presented in this section was derived from pooled data from these three trials.

Additional safety information from the placebo-controlled phase of the long-term maintenance study, in which subjects received paliperidone at daily doses within the range of 3 mg to 15 mg (n=104), is also included.

The safety of paliperidone was evaluated in 150 adolescent subjects 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.

The safety of paliperidone was also evaluated in 622 adult subjects with schizoaffective disorder who participated in two placebo-controlled, 6-week, double-blind trials.

In one of these trials, 206 subjects were assigned to one of two dose levels of paliperidone: 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 paliperidone (3 to 12 mg once daily).

Both studies included subjects who received paliperidone either as monotherapy or as an adjunct to mood stabilizers and/or antidepressants.

Adverse events during exposure to study treatment were obtained by general inquiry and recorded by clinical investigators using their own terminology.

Consequently, to provide a meaningful estimate of the proportion of individuals experiencing adverse events, events were grouped in standardized categories using MedDRA terminology.

Throughout this section, adverse reactions are reported.

Adverse reactions are adverse events that were considered to be reasonably associated with the use of paliperidone (adverse drug reactions) based on the comprehensive assessment of the available adverse event information.

A causal association for paliperidone often cannot be reliably established in individual cases.

Further, because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Commonly-Observed Adverse Reactions in

Double-Blind, Placebo-Controlled Clinical Trials – Schizophrenia in Adults and Adolescents Adult Patients with Schizophrenia Table 4 enumerates the pooled incidences of adverse reactions reported in the three placebo-controlled, 6-week, fixed-dose studies in adults, listing those that occurred in 2% or more of subjects treated with paliperidone in any of the dose groups, and for which the incidence in paliperidone-treated subjects in any of the dose groups was greater than the incidence in subjects treated with placebo.

Table 4.

Reported by ≥ 2% of Paliperidone-Treated Adult Subjects with Schizophrenia in Three Short-Term, Fixed-Dose, Placebo-Controlled Clinical Trials Percentage of Patients Paliperidone Placebo 3 mg once daily 6 mg once daily 9 mg once daily 12 mg once daily Body System or Organ Class (N=355) (N=127) (N=235) (N=246) (N=242) Dictionary-Derived Term 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 dose groups and which occurred at greater incidence than in the placebo group.

Data are pooled from three studies; one study included once-daily paliperidone doses of 3 mg and 9 mg, the second study included 6 mg, 9 mg, and 12 mg, and the third study included 6 mg and 12 mg.

Extrapyramidal symptoms includes the terms dyskinesia, dystonia, extrapyramidal disorder, hypertonia, muscle rigidity, oculogyration, parkinsonism, and tremor.

Somnolence includes the terms sedation and somnolence.

Tachycardia includes the terms tachycardia, sinus tachycardia, and heart rate increased.

Adverse reactions for which the paliperidone incidence was equal to or less than placebo are not listed in the table, but included the following: vomiting.

Table 5 lists the adverse reactions reported in a fixed-dose, placebo-controlled study in adolescent subjects to 17 years of age with schizophrenia, listing those that occurred in 2% or more of subjects treated with paliperidone in any of the dose groups, and for which the incidence in paliperidone-treated subjects in any of the dose groups was greater than the incidence in subjects treated with placebo.

Table 5.

Reported by ≥ 2% of Paliperidone-Treated Adolescent Subjects with Schizophrenia in a Fixed-Dose, Placebo-Controlled Clinical Trial * Percentage of Patients Paliperidone Placebo 1.5 mg once daily 3 mg once daily 6 mg once daily 12 mg once daily Body System or Organ Class (N=51) (N=54) (N=16) (N=45) (N=35) Dictionary-Derived Term 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 dose groups and which occurred at greater incidence than in the placebo group.

Extrapyramidal symptoms includes the terms oculogyric crisis, muscle rigidity, musculoskeletal stiffness, nuchal rigidity, torticollis, trismus, bradykinesia, cogwheel rigidity, dyskinesia, dystonia, extrapyramidal disorder, hypertonia, hypokinesia, muscle contractions involuntary, parkinsonian gait, parkinsonism, tremor, and restlessness.

Somnolence includes the terms somnolence, sedation, and hypersomnia.

Insomnia includes the terms insomnia and initial insomnia.

Hypertension includes the terms hypertension and blood pressure increased.

Gynecomastia includes the terms gynecomastia and breast swelling.

Double-Blind, Placebo-Controlled Clinical Trials – Schizoaffective Disorder in Adults Table 6 enumerates the pooled incidences of adverse reactions reported in the two placebo-controlled 6-week studies in adult subjects, listing those that occurred in 2% or more of subjects treated with paliperidone and for which the incidence in paliperidone-treated subjects was greater than the incidence in subjects treated with placebo.

Table 6.

Reported by > 2% of Paliperidone-Treated Adult Subjects with Schizoaffective Disorder in Two Double-Blind, Placebo-Controlled Clinical Trials * Percentage of Patients Placebo Paliperidone to 6 mg once-daily fixed-dose range Paliperidone to 12 mg once-daily fixed-dose range Paliperidone to 12 mg once-daily flexible dose Body System or Organ Class (N=202) (N=108) (N=98) (N=214) Dictionary-Derived Term 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.

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.e., 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.

Paliperidone is the major active metabolite of risperidone.

Overdose experience reported with risperidone can be found in the OVERDOSAGE section of the risperidone package insert. 10.2 Management of Overdosage 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.

Paliperidone extended-release tablets are 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.

• adults 6 mg/day to 12 mg/day 12 mg/day Schizophrenia-adolescents Weight < 51 kg 3 mg/day to 6 mg/day 6 mg/day Weight ≥ 51 kg 3 mg/day to 12 mg/day 12 mg/day Schizoaffective disorder.

• adults 6 mg/day to 12 mg/day 12 mg/day Tablet should be swallowed whole and should not be chewed, divided, or crushed. 2.1 Schizophrenia Adults The recommended dose of paliperidone extended-release tablets for the treatment of schizophrenia in adults is 6 mg administered once daily.

Initial dose titration is not required.

Although it has not been systematically established that doses above 6 mg have additional benefit, there was a general trend for greater effects with higher doses.

This must be weighed against the dose-related increase in adverse reactions.

Thus, some patients may benefit from higher doses, up to 12 mg/day, and for some patients, a lower dose of 3 mg/day may be sufficient.

Dose increases above 6 mg/day should be made only after clinical reassessment and generally should occur at intervals of more than 5 days.

When dose increases are indicated, increments of 3 mg/day are recommended.

The maximum recommended dose is 12 mg/day. In a longer-term study, paliperidone extended-release tablets have been shown to be effective in delaying time to relapse in patients with schizophrenia who were stabilized on paliperidone extended-release tablets for 6 weeks.

Paliperidone extended-release tablets should be prescribed at the lowest effective dose for maintaining clinical stability and the physician should periodically reevaluate the long-term usefulness of the drug in individual patients.

Adolescents (12 to 17 years of age) The recommended starting dose of paliperidone extended-release tablets for the treatment of schizophrenia in adolescents to 17 years of age is 3 mg administered once daily.

Dose increases, if considered necessary, should be made only after clinical reassessment and should occur at increments of 3 mg/day at intervals of more than 5 days.

Prescribers should be mindful that, in the adolescent schizophrenia study, there was no clear enhancement to efficacy at the higher doses, i.e., 6 mg for subjects weighing less than 51 kg and 12 mg for subjects weighing 51 kg or greater, while adverse events were dose-related. 2.2 Schizoaffective Disorder The recommended dose of paliperidone extended-release tablets for the treatment of schizoaffective disorder in adults is 6 mg administered once daily.

Some patients may benefit from lower or higher doses within the recommended dose range of 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.

The maximum recommended dose is 12 mg/day. 2.3 Administration Instructions Paliperidone extended-release tablets can be taken with or without food.

Paliperidone extended-release tablets must be swallowed whole with the aid of liquids.

Tablets should 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. 2.4 Use with Risperidone 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 co-administered with paliperidone extended-release tablets. 2.5 Dosage in Special Populations Renal Impairment Dosing must be individualized according to the patient’s renal function status.

For patients with mild renal impairment (creatinine clearance ≥ 50 mL/min to < 80 mL/min), the recommended initial dose of paliperidone extended-release tablets is 3 mg once daily.

The dose may then be increased to a maximum of 6 mg once daily based on clinical response and tolerability.

For patients with moderate to severe renal impairment (creatinine clearance ≥ 10 mL/min to < 50 mL/min), the recommended initial dose of paliperidone extended-release tablets is 1.5 mg once daily, which may be increased to a maximum of 3 mg once daily after clinical reassessment.

As paliperidone extended-release tablets have not been studied in patients with creatinine clearance below 10 mL/min, use is not recommended in such patients.

For patients with mild to moderate hepatic impairment, (Child-Pugh Classification A and B), no dose adjustment is recommended.

Paliperidone extended-release tablets have not been studied in patients with severe hepatic impairment.

Because elderly patients may have diminished renal function, dose adjustments may be required according to their renal function status.

In general, recommended dosing for elderly patients with normal renal function is the same as for younger adult patients with normal renal function.

For patients with moderate to severe renal impairment (creatinine clearance 10 mL/min to < 50 mL/min), the maximum recommended dose of paliperidone extended-release tablets are 3 mg once daily.

Paliperidone extended-release tablets, 1.5 mg, are supplied as brown, round, biconvex tablets, debossed “AN” over “80” on one side and plain on the other side.

They are available as follows

Bottles of 30: NDC 42291-915-30 Paliperidone extended-release tablets, 3 mg, are supplied as white, round, biconvex tablets, debossed “AN” over “81” on one side and plain on the other side.

Bottles of 30: NDC 42291-916-30 Paliperidone extended-release tablets, 6 mg, are supplied as light beige, round, biconvex tablets, debossed “AN” over “82” on one side and plain on the other side.

Bottles of 30: NDC 42291-917-30 Paliperidone extended-release tablets, 9 mg, are supplied as pink, round, biconvex tablets, debossed “AN” over “83” on one side and plain on the other side.

Bottles of 30: NDC 42291-918-30 Storage and Handling Store at 20° to 25ºC (68° to 77ºF); excursions permitted between 15° to 30ºC (59° to 86ºF) .

Protect from moisture.

Keep out of reach of children.

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.

Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery.

Overall, available data from published epidemiologic studies of pregnant women exposed to paliperidone have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

There are risks to the mother associated with untreated schizophrenia and with exposure to antipsychotics, including paliperidone, during pregnancy.

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.

In the

U.S. 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 body surface area.

Additional reproduction toxicity studies were conducted with orally administered risperidone, which is extensively converted to paliperidone.

Disease-associated maternal and/or embryo/fetal risk There is a risk to the mother from untreated schizophrenia, including increased risk of relapse, hospitalization, and suicide.

Schizophrenia are associated with increased adverse perinatal outcomes, including preterm birth.

It is not known if this is a direct result of the illness or other comorbid factors.

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.

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 1.02-1.56) and of cardiac malformations (RR=1.26, 95% CI 0.88-1.81) 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.

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 body surface area.

Cleft palate was observed in the offspring of pregnant mice treated with risperidone at to 4 times the MRHD of 16 mg based on mg/m 2 body surface area; maternal toxicity occurred at 4 times the MHRD.

There was no evidence of teratogenicity in embryo-fetal developmental toxicity studies with risperidone in rats and rabbits at doses up to 6 times the MRHD of 16 mg/day risperidone based on mg/m 2 body surface area.

When the offspring of pregnant rats, treated with risperidone at 0.6 times the MRHD based on mg/m 2 body surface area, reached adulthood, learning was impaired.

Increased neuronal cell death occurred in the fetal brains of the offspring of pregnant rats treated at 0.5 to 1.2 times the MRHD; the postnatal development and growth of the offspring was delayed.

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 body surface area; it is not known whether these deaths were due to a direct effect on the fetuses or pups or to effects on the dams.

Females and Males of Reproductive Potential Infertility Females Based on the pharmacologic action of paliperidone (D 2 receptor antagonism), treatment with paliperidone may result in an increase in serum prolactin levels, which may lead to a reversible reduction in fertility in females of reproductive potential.

Safety and effectiveness of paliperidone in the treatment of schizophrenia were evaluated in 150 adolescent subjects 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.

In a study in which juvenile rats were treated with oral paliperidone from days 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 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 0.31, 1.25, 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 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) .

There were no subjects ≥ 65 years of age in the schizoaffective disorder studies.

Overall, of the total number of subjects in schizophrenia clinical studies of paliperidone (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.

This drug is known to be substantially excreted by the kidney and clearance is decreased in patients with moderate to severe renal impairment, who should be given reduced doses.

Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.