PALIPERIDONE tablet, extended release

United States - English - NLM (National Library of Medicine)

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Active ingredient:
PALIPERIDONE (UNII: 838F01T721) (PALIPERIDONE - UNII:838F01T721)
Available from:
Inventia Healthcare Limited
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Paliperidone extended-release tablets are indicated for the treatment of schizophrenia [see Clinical Studies (14.1)]. The efficacy of paliperidone 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. 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 (14.2)]. The efficacy of paliperidone in schizoaffective disorder was established in two 6-week trials in adults. Paliperidoneis contraindicated in patients with a known hypersensitivity to either paliperidone or risperidone, or to any of the excipients in the Paliperidone 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. Pregnancy Exposure Reg
Product summary:
Paliperidone extended-release tablets are available in the following strengths and packages. All tablets are circular shaped. 1.5 mg tablets are orange-brown colored, circular shaped, biconvex, beveled edged, coated tablet plain on one side and "032" printed in black ink on other side, and are available in bottles of 30 (NDC 49252-032-10). 3 mg tablets are white to off-white colored, circular shaped, biconvex, beveled edged, coated tablet plain on one side and "033" printed in black ink on other side, and are available in bottles of 30 (NDC 49252-033-10). 6 mg tablets are beige colored, circular shaped, biconvex, beveled edged, coated tablet plain on one side and "034" printed in black ink on other side, and are available in bottles of 30 (NDC 49252-034-10). 9 mg tablets are pink colored, circular shaped, biconvex, beveled edged, coated tablet plain on one side and "035" printed in black ink on other side, and are available in bottles of 30 (NDC 49252-035-10). Storage and Handling Store at 20º to 25ºC (68º to 77ºF)[see USP Controlled Room Temperature] . Protect from moisture. Dispense in a tight container. Keep out of reach of children.
Authorization status:
Abbreviated New Drug Application
Authorization number:
49252-032-10, 49252-033-10, 49252-034-10, 49252-035-10

PALIPERIDONE- paliperidone tablet, extended release

Inventia Healthcare Limited

----------

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use PALIPERIDONE EXTENDED-RELEASE

TABLETS safely and effectively. See full prescribing information for PALIPERIDONE EXTENDED-RELEASE

TABLETS.

PALIPERIDONE extended-release tablets, for oral use

Initial U.S. Approval: 2006

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED

PSYCHOSIS

See full prescribing information for complete boxed warning.

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk

of death. Paliperidone is not approved for use in patients with dementia-related psychosis. (5.1)

RECENT MAJOR CHANGES

Warnings and Precautions (5.5) 07/2018

Warnings and Precautions, Suicide (5.15) Removed 07/2018

Warnings and Precautions, Monitoring: Laboratory Tests(5.21) Removed 07/2018

INDICATIONS AND USAGE

Paliperidone is an atypical antipsychotic agent indicated for

Treatment of schizophrenia (1.1)

Adults: Efficacy was established in three 6-week trials and one maintenance trial. (14.1)

Adolescents (ages 12-17): Efficacy was established in one 6-week trial. (14.1)

Treatment of schizoaffective disorder as monotherapy and as an adjunct to mood stabilizers and/or antidepressants (1.2)

Efficacy was established in two 6-week trials in adult patients (14.2)

DOSAGE AND ADMINISTRATION

Initial Dose

Recommended Dose

Maximum Dose

Schizophrenia - adults (2.1)

6 mg/day

3 - 12 mg/day

12 mg/day

Schizophrenia-

Weight < 51kg

3 mg/day

3 - 6 mg/day

6 mg/day

adolescents (2.1)

Weight ≥ 51kg

3 mg/day

3 - 12 mg/day

12 mg/day

Schizoaffective disorder - adults (2.2)

6 mg/day

3 - 12 mg/day

12 mg/day

Tablet should be swallowed whole and should not be chewed, divided, or crushed. (2.3)

DOSAGE FORMS AND STRENGTHS

Tablets: 1.5 mg, 3 mg, 6 mg, and 9 mg (3)

CONTRAINDICATIONS

Known hypersensitivity to paliperidone, risperidone, or to any excipients in Paliperidone. (4)

WARNINGS AND PRECAUTIONS

Cerebrovascular Adverse Reactions: An increased incidence of cerebrovascular adverse reactions (e.g. stroke, transient

ischemic attack, including fatalities) has been seen in elderly patients with dementia- related psychoses treated with atypical

antipsychotics. (5.2)

Neuroleptic Malignant Syndrome : Manage with immediate discontinuation of drug and close monitoring. (5.3)

QT Prolongation: Increase in QT interval, avoid use with drugs that also increase QT interval and in patients with risk

factors for prolonged QT interval. (5.4)

Tardive Dyskinesia: Discontinue drug if clinically appropriate. (5.5)

Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes that may increase

cardiovascular/ cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and weight gain. (5.6)

Hyperglycemia and Diabetes Mellitus: Monitor patients for symptoms of hyperglycemia including polydipsia,

polyuria, polyphagia, and weakness. Monitor glucose regularly in patients with diabetes or at risk for diabetes. (5.6)

Dyslipidemia: Undesirable alterations have been observed in patients treated with atypical antipsychotics. (5.6)

Weight Gain: Significant weight gain has been reported. Monitor weight gain. (5.6)

Hyperprolactinemia: Prolactin elevations occur and persist during chronic administration. (5.7)

Gastrointestinal Narrowing: Obstructive symptoms may result in patients with gastrointestinal disease. (5.8)

Orthostatic Hypotension and Syncope: Use with caution in patients with known cardiovascular or cerebrovascular

disease and patients predisposed to hypotension. (5.9)

Leukopenia, Neutropenia, and Agranulocytosis: has been reported with antipsychotics, including paliperidone. Patients

with a history of a clinically significant low white blood cell count (WBC) or a drug-induced leukopenia/neutropenia should

have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of

paliperidone should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative

factors. (5.10)

Potential for Cognitive and Motor Impairment : Use caution when operating machinery. (5.11)

Seizures: Use cautiously in patients with a history of seizures or with conditions that lower the seizure threshold. (5.12)

ADVERSE REACTIONS

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 Inventia Healthcare Ltd. at 1-855-642-2594 or FDA at

1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

Centrally-acting drugs: Due to CNS effects, use caution in combination. Avoid alcohol.(7.1)

Drugs that may cause orthostatic hypotension: An additive effect may be observed when co-administered with

paliperidone. (7.1)

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.g., carbamazepine) is co-administered. Conversely, on discontinuation of

the strong inducer, it may be necessary to decrease the dose of paliperidone. (7.2)

Co-administration of divalproex sodium increased C

and AUC of paliperidone by approximately 50%. Adjust dose of

paliperidone if necessary based on clinical assessment. (7.2)

USE IN SPECIFIC POPULATIONS

Renal impairment: Dosing must be individualized according to renal function status. (2.5)

Elderly: Same as for younger adults (adjust dose according to renal function status). (2.4)

Pregnancy: May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure. (8.1)

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. (8.4)

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 6/2019

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-

RELATED PSYCHOSIS

RECENT MAJOR CHANGES

1. INDICATIONS AND USAGE

1.1 Schizophrenia

1.2 Schizoaffective Disorder

m ax

2. DOSAGE AND ADMINISTRATION

2.1 Schizophrenia

2.2 Schizoaffective Disorder

2.3 Administration Instructions

2.4 Use with Risperidone

2.5 Dosage in Special Populations

3. DOSAGE FORMS AND STRENGTHS

4. CONTRAINDICATIONS

5. WARNINGS AND PRECAUTIONS

5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis

5.2 Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients With Dementia-

Related Psychosis

5.3 Neuroleptic Malignant Syndrome

5.4 QT Prolongation

5.5 Tardive Dyskinesia

5.6 Metabolic Changes

5.7 Hyperprolactinemia

5.8 Potential for Gastrointestinal Obstruction

5.9 Orthostatic Hypotension and Syncope

5.10 Falls

5.11 Leukopenia, Neutropenia, and Agranulocytosis

5.12 Potential for Cognitive and Motor Impairment

5.13 Seizures

5.14 Dysphagia

5.15 Priapism

5.16 Thrombotic Thrombocytopenic Purpura (TTP)

5.17 Body Temperature Regulation

5.18 Antiemetic Effect

5.19 Use in Patients with Concomitant Illness

6. ADVERSE REACTIONS

6.1 Overall Adverse Reaction Profile

6.2 Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials -

Schizophrenia in Adults and Adolescents

6.3 Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials –

Schizoaffective Disorder in Adults.

6.4 Discontinuations Due to Adverse Reactions

6.5 Dose-Related Adverse Reactions

6.6 Demographic Differences

6.7 Extrapyramidal Symptoms (EPS)

6.8 Laboratory Test Abnormalities

6.9 Other Adverse Reactions Observed During Premarketing Evaluation of Paliperidone

6.10 Postmarketing Experience

6.11 Adverse Reactions Reported With Risperidone

7. DRUG INTERACTIONS

7.1 Potential for Paliperidone to Affect Other Drugs

7.2 Potential for Other Drugs to Affect Paliperidopne

8. USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Renal Impairment

8.7 Hepatic Impairment

9. DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

9.2 Abuse

9.3 Dependence

10. OVERDOSAGE

10.1 Human Experience

10.2 Management of Overdosage

11. DESCRIPTION

12. CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13. NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14. CLINICAL STUDIES

14.1 Schizophrenia

14.2 Schizoaffective Disorder

16. HOW SUPPLIED/STORAGE AND HANDLING

17. PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH

DEMENTIA- RELATED PSYCHOSIS

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an

increased risk of death. Paliperidone extended-release tablets are not approved for the

treatment of patients with dementia-related psychosis. [see Warnings and Precautions (5.1)]

1. INDICATIONS AND USAGE

1.1 Schizophrenia

Paliperidone extended-release tablets are indicated for the treatment of schizophrenia [see Clinical

Studies (14.1)].

The efficacy of paliperidone 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

Sections or subsections omitted from the full prescribing information are not listed.

monotherapy and an adjunct to mood stabilizers and/or antidepressant therapy [see Clinical Studies (14.2)].

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

2. DOSAGE AND ADMINISTRATION

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 has been shown to be effective in delaying time to relapse in

patients with schizophrenia who were stabilized on paliperidone for 6 weeks [see Clinical Studies (14)].

Paliperidone 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 (12-17 years of age)

The recommended starting dose of paliperidone extended-release tablets for the treatment of

schizophrenia in adolescents 12-17 years of age is 3 mg administered once daily. Initial dose titration is

not required. 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. 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.

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.

2.4 Use with Risperidone

Concomitant use of paliperidone 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.

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 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 is 1.5

mg once daily, which may be increased to a maximum of 3 mg once daily after clinical reassessment. As

paliperidone has not been studied in patients with creatinine clearance below 10 mL/min, use is not

recommended in such patients. [See Clinical Pharmacology (12.3)]

Hepatic Impairment

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

adjustment is recommended [See Clinical Pharmacology (12.3)]. Paliperidone has not been studied in

patients with severe hepatic impairment.

Elderly

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 is 3 mg once daily [see Renal Impairment above].

3. DOSAGE FORMS AND STRENGTHS

Paliperidone extended-release tablets are available in the following strengths and colors: 1.5 mg

(orange-brown), 3 mg (white), 6 mg (beige), and 9 mg (pink). All tablets are circular shaped, biconvex,

beveled edged, coated tablet plain on one side and with either "032", "033", "034", or "035" printed in

black ink on other side.

4. CONTRAINDICATIONS

Paliperidoneis contraindicated in patients with a known hypersensitivity to either paliperidone or

risperidone, or to any of the excipients in the Paliperidone 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.

5. WARNINGS AND PRECAUTIONS

5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an

increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks),

largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated

patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course

of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%,

compared to a rate of about 2.6% in the placebo group. Although the causes of death were

varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death)

or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical

antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality.

The extent to which the findings of increased mortality in observational studies may be attributed

to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear.

Paliperidone is not approved for the treatment of dementia-related psychosis [see Boxed Warning].

5.2 Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients With Dementia-

Related Psychosis

In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly subjects with

dementia, there was a higher incidence of cerebrovascular adverse reactions (cerebrovascular

accidents and transient ischemic attacks) including fatalities compared to placebo-treated subjects.

Paliperidone was not marketed at the time these studies were performed. Paliperidone is not approved

for the treatment of patients with dementia-related psychosis [see also Boxed Warning and Warnings and

Precautions (5.1)].

5.3 Neuroleptic Malignant Syndrome

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS)

has been reported in association with antipsychotic drugs, including paliperidone. Clinical

manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of

autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac

dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria

(rhabdomyolysis), and acute renal failure.

The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is

important to identify cases in which the clinical presentation includes both serious medical illness (e.g.,

pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and

symptoms (EPS). Other important considerations in the differential diagnosis include central

anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology.

The management of NMS should include: (1) immediate discontinuation of antipsychotic drugs and other

drugs not essential to concurrent therapy; (2) intensive symptomatic treatment and medical monitoring;

and (3) treatment of any concomitant serious medical problems for which specific treatments are

available. There is no general agreement about specific pharmacological treatment regimens for

uncomplicated NMS.

If a patient appears to require antipsychotic drug treatment after recovery from NMS, reintroduction of

drug therapy should be closely monitored, since recurrences of NMS have been reported.

5.4 QT Prolongation

Paliperidone causes a modest increase in the corrected QT (QTc) interval. The use of paliperidone

should be avoided in combination with other drugs that are known to prolong QTc including Class 1A

(e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic medications,

antipsychotic medications (e.g., chlorpromazine, thioridazine), antibiotics (e.g., gatifloxacin,

moxifloxacin), or any other class of medications known to prolong the QTc interval. Paliperidone

should also be avoided in patients with congenital long QT syndrome and in patients with a history of

cardiac arrhythmias.

Certain circumstances may increase the risk of the occurrence of torsade de pointes and/or sudden death

in association with the use of drugs that prolong the QTc interval, including (1) bradycardia; (2)

hypokalemia or hypomagnesemia; (3) concomitant use of other drugs that prolong the QTc interval; and

(4) presence of congenital prolongation of the QT interval.

The effects of paliperidone on the QT interval were evaluated in a double-blind, active-controlled

(moxifloxacin 400 mg single dose), multicenter QT study in adults with schizophrenia and

schizoaffective disorder, and in three placebo- and active-controlled 6-week, fixed-dose efficacy trials

in adults with schizophrenia.

In the QT study (n = 141), the 8 mg dose of immediate-release oral paliperidone (n=50) showed a mean

placebo-subtracted increase from baseline in QTcLD of 12.3 msec (90% CI: 8.9; 15.6) on day 8 at 1.5

hours post-dose. The mean steady-state peak plasma concentration for this 8 mg dose of paliperidone

immediate-release was more than twice the exposure observed with the maximum recommended 12 mg

dose of paliperidone (C

ss = 113 ng/mL and 45 ng/mL, respectively, when administered with a

standard breakfast). In this same study, a 4 mg dose of the immediate-release oral formulation of

paliperidone, for which C

ss = 35 ng/mL, showed an increased placebo-subtracted QTcLD of 6.8

msec (90% CI: 3.6; 10.1) on day 2 at 1.5 hours post-dose. None of the subjects had a change exceeding

60 msec or a QTcLD exceeding 500 msec at any time during this study.

For the three fixed-dose efficacy studies in subjects with schizophrenia, electrocardiogram (ECG)

measurements taken at various time points showed only one subject in the paliperidone 12 mg group had

a change exceeding 60 msec at one time-point on Day 6 (increase of 62 msec). No subject receiving

paliperidone had a QTcLD exceeding 500 msec at any time in any of these three studies.

5.5 Tardive Dyskinesia

A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients

treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among

the elderly, especially elderly women, it is impossible to predict which patients will develop the

syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is

unknown.

The risk of developing tardive dyskinesia and the likelihood that it will become irreversible appear to

increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to

the patient increase, but the syndrome can develop after relatively brief treatment periods at low doses,

although this is uncommon.

The syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic

treatment itself may suppress (or partially suppress) the signs and symptoms of the syndrome and may

thus mask the underlying process. The effect of symptomatic suppression on the long-term course of

the syndrome is unknown.

Given these considerations, paliperidone should be prescribed in a manner that is most likely to

minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be

reserved for patients who suffer from a chronic illness that is known to respond to antipsychotic drugs.

In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment

producing a satisfactory clinical response should be sought. The need for continued treatment should

be reassessed periodically.

If signs and symptoms of tardive dyskinesia appear in a patient treated with paliperidone, drug

discontinuation should be considered. However, some patients may require treatment with paliperidone

despite the presence of the syndrome.

5.6 Metabolic Changes

Atypical antipsychotic drugs have been associated with metabolic changes that may increase

cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia,

and body weight gain. While all of the drugs in the class have been shown to produce some metabolic

changes, each drug has its own specific risk profile.

Hyperglycemia and Diabetes Mellitus

Hyperglycemia and diabetes mellitus, in some cases extreme and associated with ketoacidosis or

hyperosmolar coma or death, have been reported in patients treated with all atypical antipsychotics.

These cases were, for the most part, seen in post-marketing clinical use and epidemiologic studies, not

in clinical trials, and there have been few reports of hyperglycemia or diabetes in trial subjects treated

with paliperidone. Assessment of the relationship between atypical antipsychotic use and glucose

abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in

patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population.

Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-

related adverse events is not completely understood. However, epidemiological studies suggest an

increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the

atypical antipsychotics. Because paliperidone was not marketed at the time these studies were

performed, it is not known if paliperidone is associated with this increased risk.

Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics

should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes

mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics

should undergo fasting blood glucose testing at the beginning of treatment and periodically during

treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of

hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop

symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood

glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was

discontinued; however, some patients required continuation of anti-diabetic treatment despite

discontinuation of the suspect drug.

Pooled data from the three placebo-controlled, 6-week, fixed-dose studies in adult subjects with

schizophrenia are presented in Table 1a.

Table 1a. Change in Fasting Glucose from Three Placebo-Controlled, 6-Week, Fixed-Dose

Studies in Adult Subjects with Schizophrenia

Paliperidone extended-release Tablets

Placebo

3 mg/day

6 mg/day

9 mg/day

12 mg/day

Mean change from baseline (mg/dL)

n=322

n=122

n=212

n=234

n=218

Serum Glucose

Change from baseline

-0.7

Proportion of Patients with Shifts

Serum Glucose

Normal to High

(<100 mg/dL to ≥ 126 mg/dL)

5.1 %

(12/236)

3.2 %

(3/93)

4.5 %

(7/156)

4.8 %

(9/187)

3.8 %

(6/157)

In the uncontrolled, longer-term open-label extension studies, paliperidone was associated with a mean

change in glucose of +3.3 mg/dL at Week 24 (n=570) and +4.6 mg/dL at Week 52 (n=314).

Data from the placebo-controlled 6-week study in adolescent subjects (12-17 years of age) with

schizophrenia are presented in Table 1b.

Table 1b. Change in Fasting Glucose from a Placebo-Controlled 6-Week Study in Adolescent

Subjects (12-17 years of age) with Schizophrenia

Paliperidone extended-release tablets

Placebo

1.5 mg/day

3 mg/day

6 mg/day

12 mg/day

Mean change from baseline (mg/dL)

n=41

n=44

n=11

n=28

n=32

Serum Glucose

Change from baseline

-1.4

-1.8

-0.1

Proportion of Patients with Shifts

Serum Glucose

Normal to High

(<100 mg/dL to ≥126 mg/dL)

(1/32)

(0/34)

(0/9)

(0/20)

(3/27)

Dyslipidemia

Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.

Pooled data from the three placebo-controlled, 6-week, fixed-dose studies in adult subjects with

schizophrenia are presented in Table 2a.

Table 2a. Change in Fasting Lipids from Three Placebo-Controlled, 6-Week, Fixed-Dose Studies

in Adult Subjects with Schizophrenia

Paliperidone extended-release Tablets

Placebo

3 mg/day

6 mg/day

9 mg/day

12 mg/day

Mean change from baseline (mg/dL)

Cholesterol

n=331

n=120

n=216

n=236

n=231

Change from baseline

-6.3

-4.4

-2.4

-5.3

-4.0

LDL

n=322

n=116

n=210

n=231

n=225

Change from baseline

-3.2

-0.8

-3.9

-2.0

HDL

n=331

n=119

n=216

n=234

n=230

Change from baseline

-0.4

Triglycerides

n=331

n=120

n=216

n=236

n=231

Change from baseline

-22.3

-18.3

-12.6

-10.6

-15.4

Proportion of Patients with Shifts

Cholesterol

Normal to High

(<200 mg/dL to ≥ 240 mg/dL)

2.6%

(5/194)

2.8%

(2/71)

5.6%

(7/125)

4.1%

(6/147)

3.1%

(4/130)

LDL

Normal to High

1.9%

0.0%

5.0%

3.7%

0.0%

(<100 mg/dL to ≥ 160 mg/dL)

(2/105)

(0/44)

(3/60)

(3/81)

(0/69)

HDL

Normal to Low

22.0%

16.3%

29.1%

23.4%

20.0%

(≥ 40 mg/dL to <40 mg/dL)

(44/200)

(13/80)

(39/134)

(32/137)

(27/135)

Triglycerides

Normal to High

5.3%

11.0%

8.8%

8.7%

4.3%

(<150 mg/dL to ≥ 200 mg/dL)

(11/208)

(9/82)

(12/136)

(13/150)

(6/139)

In the uncontrolled, longer-term open-label extension studies, paliperidone was associated with a mean

change in (a) total cholesterol of -1.5 mg/dL at Week 24 (n=573) and -1.5 mg/dL at Week 52 (n=317), (b)

triglycerides of -6.4 mg/dL at Week 24 (n=573) and -10.5 mg/dL at Week 52 (n=317); (c) LDL of -1.9

mg/dL at Week 24 (n=557) and -2.7 mg/dL at Week 52 (n=297); and (d) HDL of +2.2 mg/dL at Week 24

(n=568) and +3.6 mg/dL at Week 52 (n=302).

Data from the placebo-controlled 6-week study in adolescent subjects (12-17 years of age) with

schizophrenia are presented in Table 2b.

Table 2b. Change in Fasting Lipids from a Placebo-Controlled 6-Week Study in Adolescent

Subjects (12-17 years of age) with Schizophrenia

Paliperidone extended-release tablets

Placebo

1.5 mg/day

3 mg/day

6 mg/day

12 mg/day

Mean change from baseline (mg/dL)

Cholesterol

n=39

n=45

n=11

n=28

n=32

Change from baseline

-7.8

-3.3

12.7

-1.5

LDL

n=37

n=40

n=9

n=27

n=31

Change from baseline

-4.1

-3.1

HDL

n=37

n=41

n=9

n=27

n=31

Change from baseline

-1.9

Triglycerides

n=39

n=44

n=11

n=28

n=32

Change from baseline

-8.9

3.2

17.6

-5.4

3.9

Proportion of Patients with Shifts

Cholesterol

Normal to High

7%

4%

0%

6%

11%

(<170 mg/dL to ≥200 mg/dL)

(2/27)

(1/26)

(0/6)

(1/18)

(2/19)

LDL

Normal to High

3%

4%

14%

0%

9%

(<110 mg/dL to ≥130 mg/dL)

(1/32)

(1/25)

(1/7)

(0/22)

(2/22)

HDL

Normal to Low

14%

( ≥40 mg/dL to <40 mg/dL)

(4/28)

(2/30)

(2/7)

(3/23)

(5/22)

Triglycerides

Normal to High

3%

(<150 mg/dL to ≥200 mg/dL)

(1/34)

(2/38)

(1/8)

(2/26)

(2/28)

Weight Gain

Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is

recommended.

Schizophrenia Trials

Data on mean changes in body weight and the proportion of subjects meeting a weight gain criterion of

≥ 7% of body weight from the three placebo-controlled, 6-week, fixed-dose studies in adult subjects

are presented in Table 3a.

Table 3a. Mean Change in Body Weight (kg) and the Proportion of Subjects with ≥ 7% Gain in

Body Weight from Three Placebo-Controlled, 6-Week, Fixed-Dose Studies in Adult Subjects

with Schizophrenia

Paliperidone extended-release Tablets

Placebo

3 mg/day

6 mg/day

9 mg/day

12 mg/day

n=323

n=112

n=215

n=235

n=218

Weight(kg)

Change from baseline

-0.4

Weight Gain

≥7% increase from baseline

In the uncontrolled, longer-term open-label extension studies, paliperidone was associated with a mean

change in weight of +1.4 kg at Week 24 (n=63) and +2.6 kg at Week 52 (n=302).

Weight gain in adolescent subjects with schizophrenia was assessed in a 6-week, double-blind,

placebo-controlled study and an open-label extension with a median duration of exposure to

paliperidone of 182 days. Data on mean changes in body weight and the proportion of subjects meeting a

weight gain criterion of ≥ 7% of body weight [see Clinical Studies (14.1)] from the placebo-controlled

6-week study in adolescent subjects (12-17 years of age) are presented in Table 3b.

Table 3b. Mean Change in Body Weight (kg) and the Proportion of Subjects with ≥ 7% Gain in

Body Weight from a Placebo-Controlled 6-Week Study in Adolescent Subjects (12-17 years of age)

with Schizophrenia

Paliperidone extended-release tablets

Placebo

1.5 mg/day

3 mg/day

6 mg/day

12 mg/day

n=51

n=54

n=16

n=45

n=34

Weight (kg)

Change from baseline

Weight Gain

≥ 7% increase from baseline

In the open-label long-term study the proportion of total subjects treated with paliperidone with an

increase in body weight of ≥ 7% from baseline was 33%. When treating adolescent patients with

paliperidone, weight gain should be assessed against that expected with normal growth. When taking

into consideration the median duration of exposure to paliperidone in the open-label study (182 days)

along with expected normal growth in this population based on age and gender, an assessment of

standardized scores relative to normative data provides a more clinically relevant measure of changes in

weight. The mean change from open-label baseline to endpoint in standardized score for weight was 0.1

(4% above the median for normative data). Based on comparison to the normative data, these changes are

not considered to be clinically significant.

Schizoaffective Disorder Trials

In the pooled data from the two placebo-controlled, 6-week studies in adult subjects with

schizoaffective disorder, a higher percentage of paliperidone-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.

5.7 Hyperprolactinemia

Like other drugs that antagonize dopamine D receptors, paliperidone elevates prolactin levels and the

elevation persists during chronic administration. Paliperidone has a prolactin-elevating effect similar to

that seen with risperidone, a drug that is associated with higher levels of prolactin than other

antipsychotic drugs.

Hyperprolactinemia, regardless of etiology, may suppress hypothalamic GnRH, resulting in reduced

pituitary gonadotrophin secretion. This, in turn, may inhibit reproductive function by impairing gonadal

steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and

impotence have been reported in patients receiving prolactin-elevating compounds. Long-standing

hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both

female and male subjects.

Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin

dependent in vitro, a factor of potential importance if the prescription of these drugs is considered in a

patient with previously detected breast cancer. An increase in the incidence of pituitary gland, mammary

gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and pancreatic adenomas)

was observed in the risperidone carcinogenicity studies conducted in mice and rats [see Nonclinical

Toxicology (13.1)]. Neither clinical studies nor epidemiologic studies conducted to date have shown an

association between chronic administration of this class of drugs and tumorigenesis in humans, but the

available evidence is too limited to be conclusive.

5.8 Potential for Gastrointestinal Obstruction

Because the paliperidone extended-release tablets is non-deformable and does not appreciably change

in shape in the gastrointestinal tract, paliperidone extended-release tablet should ordinarily not be

administered to patients with preexisting severe gastrointestinal narrowing (pathologic or iatrogenic,

for example: esophageal motility disorders, small bowel inflammatory disease, "short gut" syndrome

due to adhesions or decreased transit time, past history of peritonitis, cystic fibrosis, chronic intestinal

pseudoobstruction, or Meckel’s diverticulum). 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. Because of the controlled-release design of the tablet, paliperidone extended-

release tablets should only be used in patients who are able to swallow the tablet whole [see Dosage

and Administration (2.3) and Patient Counseling Information (17)].

A decrease in transit time, e.g., as seen with diarrhea, would be expected to decrease bioavailability and

an increase in transit time, e.g., as seen with gastrointestinal neuropathy, diabetic gastroparesis, or other

causes, would be expected to increase bioavailability. These changes in bioavailability are more likely

when the changes in transit time occur in the upper GI tract.

5.9 Orthostatic Hypotension and Syncope

Paliperidone can induce orthostatic hypotension and syncope in some patients because of its alpha-

blocking activity. In pooled results of the three placebo-controlled, 6-week, fixed-dose trials in

subjects with schizophrenia, syncope was reported in 0.8% (7/850) of subjects treated with

paliperidone (3 mg, 6 mg, 9 mg, 12 mg) compared to 0.3% (1/355) of subjects treated with placebo.

Paliperidone should be used with caution in patients with known cardiovascular disease (e.g., heart

failure, history of myocardial infarction or ischemia, conduction abnormalities), cerebrovascular

disease, or conditions that predispose the patient to hypotension (e.g., dehydration, hypovolemia, and

treatment with antihypertensive medications). Monitoring of orthostatic vital signs should be considered

in patients who are vulnerable to hypotension.

5.10 Falls

Somnolence, postural hypotension, motor and sensory instability have been reported with the use of

antipsychotics, including paliperidone, which may lead to falls and, consequently, fractures or other

fall-related injuries. For patients, particularly the elderly, with diseases, conditions, or medications that

could exacerbate these effects, assess the risk of falls when initiating antipsychotic treatment and

recurrently for patients on long-term antipsychotic therapy.

5.11 Leukopenia, Neutropenia, and Agranulocytosis

Class Effect: In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia have

been reported temporally related to antipsychotic agents, including paliperidone. Agranulocytosis has

also been reported.

Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count

(WBC) and history of drug-induced leukopenia/neutropenia. Patients with a history of a clinically

significant low WBC or a drug-induced leukopenia/neutropenia should have their complete blood count

(CBC) monitored frequently during the first few months of therapy and discontinuation of paliperidone

should be considered at the first sign of a clinically significant decline in WBC in the absence of other

causative factors.

Patients with clinically significant neutropenia should be carefully monitored for fever or other

symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with

severe neutropenia (absolute neutrophil count <1000/mm ) should discontinue paliperidone and have

their WBC followed until recovery.

5.12 Potential for Cognitive and Motor Impairment

Somnolence was reported in subjects treated with paliperidone [see Adverse Reactions (6.1, 6.2)].

Antipsychotics, including paliperidone, have the potential to impair judgment, thinking, or motor skills.

Patients should be cautioned about performing activities requiring mental alertness, such as operating

hazardous machinery or operating a motor vehicle, until they are reasonably certain that paliperidone

therapy does not adversely affect them.

5.13 Seizures

During premarketing clinical trials in subjects with schizophrenia (the three placebo-controlled, 6-

week, fixed-dose studies and a study conducted in elderly schizophrenic subjects), seizures occurred in

0.22% of subjects treated with paliperidone (3 mg, 6 mg, 9 mg, 12 mg) and 0.25% of subjects treated

with placebo. Like other antipsychotic drugs, paliperidone should be used cautiously in patients with a

history of seizures or other conditions that potentially lower the seizure threshold. Conditions that

lower the seizure threshold may be more prevalent in patients 65 years or older.

5.14 Dysphagia

Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration

pneumonia is a common cause of morbidity and mortality in patients with advanced Alzheimer’s

dementia. Paliperidone and other antipsychotic drugs should be used cautiously in patients at risk for

aspiration pneumonia.

5.15 Priapism

Drugs with alpha-adrenergic blocking effects have been reported to induce priapism. Priapism has been

reported with paliperidone during postmarketing surveillance. Severe priapism may require surgical

intervention.

5.16 Thrombotic Thrombocytopenic Purpura (TTP)

No cases of TTP were observed during clinical studies with paliperidone. Although cases of TTP

have been reported in association with risperidone administration, the relationship to risperidone

therapy is unknown.

5.17 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 paliperidone to patients who will be experiencing

conditions which may contribute to an elevation in core body temperature, e.g., exercising strenuously,

exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being

subject to dehydration.

5.18 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 of conditions such as

intestinal obstruction, Reye’s syndrome, and brain tumor.

5.19 Use in Patients with Concomitant Illness

Clinical experience with paliperidone in patients with certain concomitant illnesses is limited [see

Clinical Pharmacology (12.3)].

Patients with Parkinson’s Disease or Dementia with Lewy Bodies are reported to have an increased

sensitivity to antipsychotic medication. Manifestations of this increased sensitivity include confusion,

obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinical features

consistent with the neuroleptic malignant syndrome.

Paliperidone has not been evaluated or used to any appreciable extent in patients with a recent history of

myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from

premarketing clinical trials. Because of the risk of orthostatic hypotension with paliperidone, caution

should be observed in patients with known cardiovascular disease [see Warnings and Precautions (5.9)].

6. ADVERSE REACTIONS

6.1 Overall Adverse Reaction Profile

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 events, 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)]

Thrombotic thrombocytopenic purpura (TTP) [see Warnings and Precautions (5.16)]

Disruption of body temperature regulation [see Warnings and Precautions (5.17)]

Antiemetic effect [see Warnings and Precautions (5.18)]

Patients with Concomitant illness [see Warnings and Precautions(5.19)]

The most common adverse reactions in clinical trials in adult in 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. [See Adverse

Reactions (6.4)].

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 12-17 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 (3-12 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.

6.2 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. Adverse Reactions Reported by ≥ 2% of Paliperidone –Treated Adult Subjects with

Schizophrenia in Three Short-Term, Fixed-Dose,Placebo-Controlled Clinical Trials

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 [see Clinical Studies (14)]. 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.

Percentage of Patients

Paliperidone extended-release Tablets

Placebo

3 mg

once daily

6 mg

once daily

9 mg

once daily

12 mg

once daily

Body System or Organ Class

Dictionary-Derived Term

(N=355)

(N=127)

(N=235)

(N=246)

(N=242)

Total percentage of

subjects with adverse

reactions

Cardiac disorders

Atrioventricular block first degree

Bundle branch block

Sinus arrhythmia

Tachycardia

<1

<1

Gastrointestinal disorders

Abdominal pain upper

Dry mouth

Salivary hypersecretion

<1

<1

General disorders

Asthenia

Fatigue

<1

Nervous system disorders

Akathisia

Dizziness

Extrapyramidal symptoms

Headache

Somnolence

Vascular disorders

Orthostatic hypotension

Adolescent Patients with Schizophrenia

Table 5 lists the adverse reactions reported in a fixed-dose, placebo-controlled study in adolescent

subjects 12-17 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. Adverse Reactions Reported by ≥ 2% of Paliperidone-Treated Adolescent Subjects with Schizophrenia in a Fixed-Dose,

Placebo-Controlled Clinical Trial

Percentage of Patients

Paliperidone extended-release tablets

Body System or Organ Class

Dictionary-Derived Term

Placebo (N=51)

1.5 mg once daily

(N=54)

3 mg once daily

(N=16)

6 mg once daily

(N=45)

12 mg once daily

(N=35)

Total percentage of subjects with adverse reactions

37

50

58

74

Cardiac disorders

Tachycardia

Eye disorders

Vision blurred

Gastrointestinal disorders

Dry mouth

Salivary hypersecretion

Swollen tongue

Vomiting

General disorders

Asthenia

Fatigue

*

*

Infections and infestations

Nasopharyngitis

Investigations

Weight increased

Nervous system disorders

Akathisia

Dizziness

Extrapyramidal symptoms Headache

Lethargy

Somnolence

Tongue paralysis

Psychiatric disorders

Anxiety

Reproductive system and breast disorders

Amenorrhea

Galactorrhea

Gynecomastia

Respiratory, thoracic and mediastinal disorders

Epistaxis

6.3 Commonly-Observed Adverse Reactions in 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. Adverse Drug Reactions Reported by ≥ 2% of Paliperidone-Treated Adult Subjects with Schizoaffective Disorder

in Two Double-Blind, Placebo-Controlled Clinical Trials

Percentage of Patients

Placebo Paliperidone 3-6 mg

once-daily

fixed-dose range

Paliperidone 9-12 mg

once-daily

fixed-dose range

Paliperidone 3-12 mg

once-daily

flexible dose range

Body System or Organ Class

Dictionary-Derived Term

(N=202)

(N=108)

(N=98)

(N=214)

Total percentage of subjects with adverse reactions

Cardiac disorders

Tachycardia

Gastrointestinal disorders

Abdominal

Discomfort/Abdominal pain

upper

Constipation

Dyspepsia

Nausea

Stomach discomfort

General disorders

Asthenia

<1

Infections and Infestations

Nasopharyngitis

Rhinitis

Upper respiratory tract infection

Investigations

Weight increased

Metabolism and nutrition disorders

Decreased appetite

<1

Increased appetite

<1

Musculoskeletal and connective tissue disorders

Back pain

Myalgia

<1

Nervous system disorders

Akathisia

Dysarthria

Extrapyramidal symptoms

Somnolence

Psychiatric disorders

Sleep disorder

<1

Respiratory, thoracic and mediastinal disorders

Cough

Pharyngolargeal pain

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

blood pressure increased. Gynecomastia includes the terms gynecomastia and breast swelling.

*

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 4 20 subjects treated with paliperidone, 230 (55%) received paliperidone as monotherapy and 190 (4 5%) received paliperidone as an

adjunct to mood stabilizers and/or antidepressants. Extrapyramidal symptoms includes the terms bradykinesia, drooling, dyskinesia, dystonia,

Monotherapy versus Adjunctive Therapy

The designs of the two placebo-controlled, 6-week, double-blind trials in adult subjects with

schizoaffective disorder included the option for subjects to receive antidepressants (except monoamine

oxidase inhibitors) and/or mood stabilizers (lithium, valproate, or lamotrigine). In the subject population

evaluated for safety, 230 (55%) subjects received paliperidone as monotherapy and 190 (45%) subjects

received paliperidone as an adjunct to mood stabilizers and/or antidepressants. When comparing these 2

subpopulations, only nausea occurred at a greater frequency (≥ 3% difference) in subjects receiving

paliperidone as monotherapy.

6.4 Discontinuations Due to Adverse Reactions

Schizophrenia Trials

The percentages of subjects who discontinued due to adverse reactions in the three schizophrenia

placebo-controlled, 6-week, fixed-dose studies were 3% and 1% in paliperidone-and placebo-treated

subjects, respectively. The most common reasons for discontinuation were nervous system disorders

(2% and 0% in paliperidone-and placebo-treated subjects, respectively).

Among the adverse reactions in the 6-week, fixed-dose, placebo-controlled study in adolescents with

schizophrenia, only dystonia led to discontinuation (<1% of paliperidone-treated subjects).

Schizoaffective Disorder Trials

The percentages of subjects who discontinued due to adverse reactions in the two schizoaffective

disorder placebo-controlled 6-week studies in adults were 1% and <1% in paliperidone - and placebo-

treated subjects, respectively. The most common reasons for discontinuation were gastrointestinal

disorders (1% and 0% in paliperidone- and placebo-treated subjects, respectively).

6.5 Dose-Related Adverse Reactions

Schizophrenia Trials

Based on the pooled data from the three placebo-controlled, 6-week, fixed-dose studies in adult

subjects with schizophrenia, among the adverse reactions that occurred with a greater than 2%

incidence in the subjects treated with paliperidone, the incidences of the following adverse reactions

increased with dose: somnolence, orthostatic hypotension, akathisia, dystonia, extrapyramidal disorder,

hypertonia, parkinsonism, and salivary hypersecretion. For most of these, the increased incidence was

seen primarily at the 12 mg dose, and, in some cases, the 9 mg dose.

In the 6-week, fixed-dose, placebo-controlled study in adolescents with schizophrenia, among the

adverse reactions that occurred with >2% incidence in the subjects treated with paliperidone, the

incidences of the following adverse reactions increased with dose: tachycardia, akathisia,

extrapyramidal symptoms, somnolence, and headache.

Schizoaffective Disorder Trials

In a placebo-controlled, 6-week, high- and low-dose study in adult subjects with schizoaffective

disorder, akathisia, dystonia, dysarthria, myalgia, nasopharyngitis, rhinitis, cough, and

pharyngolaryngeal pain occurred more frequently (i.e., a difference of at least 2%) in subjects who

received higher doses of paliperidone compared with subjects who received lower doses.

6.6 Demographic Differences

An examination of population subgroups in the three placebo-controlled, 6-week, fixed-dose studies in

adult in subjects with schizophrenia and in the two placebo-controlled, 6-week studies in subjects with

schizoaffective disorder did not reveal any evidence of clinically relevant differences in safety on the

basis of gender or race alone; there was also no difference on the basis of age [see Use in Specific

Populations (8.5)].

6.7 Extrapyramidal Symptoms (EPS)

Pooled data from the three placebo-controlled, 6-week, fixed-dose studies in subjects with

schizophrenia provided information regarding treatment-emergent EPS. Several methods were used to

measure EPS: (1) the Simpson-Angus global score (mean change from baseline) which broadly

evaluates Parkinsonism, (2) the Barnes Akathisia Rating Scale global clinical rating score (mean change

from baseline) which evaluates akathisia, (3) use of anticholinergic medications to treat emergent EPS

(Table 7), and (4) incidence of spontaneous reports of EPS (Table 8). For the Simpson-Angus Scale,

spontaneous EPS reports and use of anticholinergic medications, there was a dose-related increase

observed for the 9 mg and 12 mg doses. There was no difference observed between placebo and

paliperidone 3 mg and 6 mg doses for any of these EPS measures.

Table 7. Treatment-Emergent Extrapyramidal Symptoms (EPS) Assessed by Incidence of Ratings Scales and Use of Anticholinergic Medication – Schizophrenia Studies in Adults

Percentage of Patients

Paliperidone extended-release tablets

Placebo

3 mg

once

daily

6 mg

once

daily

9 mg

once

daily

12 mg

once

daily

EPS Group

(N=355)

(N=127)

(N=235)

(N=246)

(N=242)

Parkinsonism

Akathisia

Use of

Anticholinergic

medications

Table 8. Treatment-Emergent Extrapyramidal Symptoms (EPS)-Related Adverse Events by

MedDRA Preferred Term – Schizophrenia Studies in Adults

Percentage of Patients

Paliperidone extended-release Tablets

Placebo

3 mg

once daily

6 mg

once daily

9 mg

once daily

12 mg

once daily

EPS Group

(N=355)

(N=127)

(N=235)

(N=246)

(N=242)

Overall percentage of

patients with EPS-

related AE

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.

For Parkinsonism, percent of patients with Simpson-Angus global score > 0.3

For Akathisia, percent of patients with Barnes Akathisia Rating Scale global score ≥ 2

Percent of patients who received anticholinergic medications to treat emergent EPS

Dyskinesia group includes: Dyskinesia, extrapyramidal disorder, muscle twitching, tardive dyskinesia

Dystonia group includes: Dystonia, muscle spasms, oculogyration, trismus

Hyperkinesia group includes: Akathisia, hyperkinesia

Parkinsonism group includes: Bradykinesia, cogwheel rigidity, drooling, hypertonia, hypokinesia,

muscle rigidity, musculoskeletal stiffness, parkinsonism

Tremor group includes: Tremor

Hyperkinesia

Parkinsonism

Tremor

Compared to data from the studies in adults subjects with schizophrenia, pooled data from the two

placebo-controlled 6-week studies in adult subjects with schizoaffective disorder showed similar types

and frequencies of EPS as measured by rating scales, anticholinergic medication use, and spontaneous

reports of EPS-related adverse events. For subjects with schizoaffective disorder, there was no dose-

related increase in EPS observed for parkinsonism with the Simpson-Angus scale or akathisia with the

Barnes Akathisia Rating Scale. There was a dose-related increase observed with spontaneous EPS

reports of hyperkinesia and dystonia and in the use of anticholinergic medications.

Table 9 shows the EPS data from the pooled schizoaffective disorder trials.

Table 9.Treatment-Emergent Extrapyramidal Symptoms (EPS)-Related Adverse Events by MedDRA Preferred Term –

Schizoaffective Disorder Studies in Adults

Dyskinesia group includes: Dyskinesia, muscle twitching

Dystonia group includes: Dystonia, muscle spasms, oculogyration

Hyperkinesia group includes: Akathisia, hyperkinesia, restlessness

Parkinsonism group includes: Bradykinesia, drooling, hypertonia, muscle rigidity, muscle

tightness, musculoskeletal stiffness, parkinsonian gait, parkinsonism

Tremor group includes: Tremor

Percentage of Patients

Paliperidone

Placebo

3-6 mg

once-daily fixed-dose range

9-12 mg once-daily fixed-dose range

3-12 mg

once-daily

flexible dose

EPS Group

(N=202)

(N=108)

(N=98)

(N=214)

Overall percentage of patients with EPS-

related AE

Dyskinesia

Dystonia

Hyperkinesia

Parkinsonism

Tremor

The incidences of EPS-related adverse events in the adolescent schizophrenia studies showed a similar

dose-related pattern to those in the adult studies. There were notably higher incidences of dystonia,

hyperkinesia, tremor, and parkinsonism in the adolescent population as compared to the adult studies

(Table 10).

Table 10. Treatment-Emergent Extrapyramidal Symptoms (EPS)-Related Adverse Events by

MedDRA Preferred Term – Schizophrenia Studies in Adolescent Subjects

Hyperkinesia group includes: Akathisia

Dystonia group includes: Dystonia, muscle contracture, oculogyric crisis, tongue paralysis, torticollis

Tremor group includes: Tremor

Parkinsonism group includes: Cogwheel rigidity, extrapyramidal disorder, muscle rigidity

Dyskinesia group includes: Dyskinesia, muscle contractions involuntary

Percentage of Patients

Paliperidone extended-release tablets

EPS Group

Placebo

(N=51)

1.5 mg

once daily

(N=54)

3 mg

once daily

(N=16)

6 mg

once daily

(N=45)

12 mg

once daily

(N=35)

Overall percentage of patients with EPS -

related AE

Hyperkinesia

Dystonia

Tremor

Parkinsonism

Dyskinesia

Dystonia

Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in

susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the

neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty

breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur

more frequently and with greater severity with high potency and at higher doses of first generation

antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.

6.8 Laboratory Test Abnormalities

In the pooled data from the three placebo-controlled, 6-week, fixed-dose studies in subjects with

schizophrenia and from the two placebo-controlled, 6-week studies in subjects with schizoaffective

disorder, between-group comparisons revealed no medically important differences between

paliperidone and placebo in the proportions of subjects experiencing potentially clinically significant

changes in routine serum chemistry, hematology, or urinalysis parameters. Similarly, there were no

differences between paliperidone and placebo in the incidence of discontinuations due to changes in

hematology, urinalysis, or serum chemistry, including mean changes from baseline in fasting glucose,

insulin, c-peptide, triglyceride, HDL, LDL, and total cholesterol measurements. However, paliperidone

was associated with increases in serum prolactin [see Warnings and Precautions (5.7)].

6.9 Other Adverse Reactions Observed During Premarketing Evaluation of Paliperidone

The following additional adverse reactions occurred in < 2% of Paliperidone-treated subjects in the

above schizophrenia clinical trial datasets. The following also includes additional adverse reactions

reported at any frequency by paliperidone-treated subjects who participated in other clinical studies.

Cardiac disorders: bradycardia, palpitations

Eye disorders: eye movement disorder

Gastrointestinal disorders: flatulence

General disorders: edema

Immune system disorders: anaphylactic reaction

Infections and infestations: urinary tract infection

Investigations: alanine aminotransferase increased, aspartate aminotransferase increased

Musculoskeletal and connective tissue disorders: arthralgia, pain in extremity

Nervous system disorders: opisthotonus

Psychiatric disorders: agitation, insomnia, nightmare

Reproductive system and breast disorders: breast discomfort, menstruation irregular, retrograde

ejaculation

Respiratory, thoracic and mediastinal disorders: nasal congestion

Skin and subcutaneous tissue disorders: pruritus, rash

Vascular disorders: hypertension

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)]. In general, adverse

reaction types, frequencies, and severities during the initial 14-week open-label phase of this study

were comparable to those observed in the 6-week, placebo-controlled, fixed-dose studies. Adverse

reactions 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.

6.10 Postmarketing Experience

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, priapism, somnambulism, swollen tongue, tardive

dyskinesia, urinary incontinence, urinary retention.

6.11 Adverse Reactions Reported With Risperidone

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.

7. DRUG INTERACTIONS

7.1 Potential for Paliperidone to Affect Other Drugs

Given the primary CNS effects of paliperidone [see Adverse Reactions (6.1, 6.2)], paliperidone 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, an additive effect may be observed when

paliperidone is administered with other therapeutic agents that have this potential [see Warnings and

Precautions (5.9)].

Paliperidone is not expected to cause clinically important pharmacokinetic interactions with drugs that

are metabolized by cytochrome P450 isozymes. In vitro studies in human liver microsomes showed that

paliperidone does not substantially inhibit the metabolism of drugs metabolized by cytochrome P450

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. Paliperidone is also not expected to have enzyme

inducing properties.

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.

Pharmacokinetic interaction between lithium and paliperidone is unlikely.

In a drug interaction study, co-administration of paliperidone (12 mg once daily for 5 days) with

divalproex sodium extended-release tablets (500 mg to 2000 mg once daily) did not affect the steady-

state pharmacokinetics (AUC

and C

) of valproate in 13 patients stabilized on valproate. In a

clinical study, subjects on a stable dose of valproate showed comparable valproate average plasma

concentrations when paliperidone 3-15 mg of paliperidone was added to their existing valproate

treatment.

7.2 Potential for Other Drugs to Affect Paliperidopne

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 studies indicate that CYP2D6

and CYP3A4 may be minimally involved in paliperidone metabolism, in vivo studies do not show

decreased elimination by these isozymes and they contribute to only a small fraction of total body

clearance. In vitro studies have shown that paliperidone is a P-gp substrate.

Co-administration of paliperidone 6 mg once daily with carbamazepine 200 mg twice daily caused a

decrease of approximately 37% in the mean steady-state C

and AUC of paliperidone. This decrease

is caused, to a substantial degree, by a 35% increase in renal clearance of paliperidone. 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 paliperidone should be re-evaluated and increased if necessary.

Conversely, on discontinuation of carbamazepine, the dose of paliperidone should be re-evaluated and

decreased if necessary.

Paliperidone is metabolized to a limited extent by CYP2D6 [see Clinical Pharmacology (12.3)]. In an

interaction study in healthy subjects in which a single 3 mg dose of paliperidone was administered

concomitantly with 20 mg per day of paroxetine (a potent CYP2D6 inhibitor), paliperidone exposures

were on average 16% (90% CI: 4, 30) higher in CYP2D6 extensive metabolizers. Higher doses of

paroxetine have not been studied. The clinical relevance is unknown.

Co-administration of a single dose of paliperidone 12 mg with divalproex sodium extended-release

tablets (two 500 mg tablets once daily) resulted in an increase of approximately 50% in the C

AUC of paliperidone. Dosage reduction for paliperidone should be considered when paliperidone is

co-administered with valproate after clinical assessment.

Pharmacokinetic interaction between lithium and paliperidone is unlikely.

8. USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

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

max ss

to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-

961-2388 or online at http://womensmentalhealth.org/clinical-and-research-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).

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 (see DATA). There are risks to the mother associated with untreated

schizophrenia and with exposure to antipsychotics, including INVEGA , during pregnancy (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. In the U.S. general population, the estimated background risk

of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%,

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/m2 body surface area. Additional

reproduction toxicity studies were conducted with orally administered risperidone, which is

extensively converted to paliperidone (see ANIMAL DATA).

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,

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 INVEGA®, 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 1.02–1.56) 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.

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 body surface area.

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 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 body surface area. When the offspring of pregnant rats, treated

with risperidone at 0.6 times the MRHD based on mg/m 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 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 (see RISPERDAL package

insert).

8.2 Lactation

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 parentcompound,risperidone

(see CLINICAL CONSIDERATIONS). The developmental and health benefits of breastfeeding should

be considered along with the mother's clinical need for paliperidone and any potential adverse effects

on the breastfed child from paliperidone or from the mother's underlying condition.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).

8.3 Females and Males of Reproductive Potential

Infertility

Females

Based on the pharmacologic action of paliperidone (D2 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[see WARNINGS AND PRECAUTIONS (5.7)].

8.4 Pediatric Use

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

adolescent subjects 12-17 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 studied.

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. 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 2-3

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

maximum recommended human dose 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.

8.5 Geriatric Use

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)]. 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 (7.0%) 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 [see Clinical Pharmacology (12.3)], 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 [see Dosage and Administration (2.5)].

8.6 Renal Impairment

Dosing must be individualized according to the patient’s renal function status [see Dosage and

Administration (2.5)].

8.7 Hepatic Impairment

No dosage adjustment is required in patients with mild to moderate hepatic impairment. Paliperidone has

not been studied in patients with severe hepatic impairment.

9. DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

Paliperidone is not a controlled substance.

9.2 Abuse

Paliperidone has not been systematically studied in animals or humans for its potential for abuse. It is not

possible to predict the extent to which a CNS-active drug will be misused, diverted, and/or abused once

marketed. Consequently, patients should be evaluated carefully for a history of drug abuse, and such

patients should be observed closely for signs of paliperidone misuse or abuse (e.g., development of

tolerance, increases in dose, drug-seeking behavior).

9.3 Dependence

Paliperidone has not been systematically studied in animals or humans for its potential for tolerance or

physical dependence.

10. OVERDOSAGE

10.1 Human Experience

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.

11. DESCRIPTION

11. DESCRIPTION

Paliperidone extended-release tablets contains paliperidone, an atypical antipsychotic belonging to the

chemical class of benzisoxazole derivatives. Paliperidone contains a racemic mixture of (+)- and (-)-

paliperidone. 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

H FN O and its molecular weight is 426.49. The structural formula is:

Paliperidone 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 available in 1.5 mg (orange-brown), 3 mg (white), 6 mg

(beige), and 9 mg (pink) strengths. Paliperidone extended-release tablets utilize coated matrix drug-

release technology [see Description (11)].

Inactive ingredients are butylated hydroxytoluene, carbomer homopolymer, colloidal silicon dioxide,

dibutyl sebacate, ethyl cellulose, hypromellose phthalate, magnesium stearate, microcrystalline

cellulose, polyethylene oxides, talc, titanium dioxide. The 1.5 mg and 6 mg tablets also contain ferric

oxide yellow and ferric oxide red. The 9 mg tablets contain ferric oxide red.

Paliperidone extended-release tablets uses coated matrix formulation to deliver paliperidone at a

controlled rate. The delivery system which resembles the round shape tablet in appearance consists of

active in a core surrounded by a semipermeable membrane. The matrix core is composed of the drug,

release controlling polymers and excipients. The semipermiable membrane surrounding the core

consists of polymers. Each tablet strength has a different colorant and printing markings. In an aqueous

environment, such as the gastrointestinal tract, aqueous fluid enters the tablets core through

semipermeable membrane that controls the rate at which aqueous medium enters the tablet core, which

intern determine the lag of drug delivery. The hydrophilic polymers of the core hydrates, swells,

creating a gel containing paliperidone which intern determine the rate of drug delivery.

12. CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Paliperidone is the major active metabolite of risperidone. The mechanism of action of paliperidone, as

with other drugs having efficacy in schizophrenia, is unknown, but it has been proposed that the drug's

therapeutic activity in schizophrenia is mediated through a combination of central dopamine Type 2 (D2)

and serotonin Type 2 (5HT2A) receptor antagonism.

12.2 Pharmacodynamics

In vitro, paliperidone acts as an antagonist at the central dopamine Type 2 (D ) and serotonin Type 2

(5HT

) receptors, with binding affinities (Ki values) of 1.6–2.8 nM for D and 0.8–1.2 nM for 5HT

receptors. Paliperidone is also active as an antagonist at α and α adrenergic receptors and H

histaminergic receptors, which may explain some of the other effects of the drug. Paliperidone has no

affinity for cholinergic muscarinic or β - and β -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

) approximately 24 hours after dosing. The pharmacokinetics of paliperidone

following paliperidone extended-release tablets 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 4-5 days of dosing with paliperidone

extended release tablets in most subjects. The mean steady-state peak: trough ratio for an paliperidone

extended release tablets dose of 9 mg was 1.7 with a range of 1.2-3.1.

Following administration of paliperidone extended-release tablets, the (+) and (-) enantiomers of

paliperidone interconvert, reaching an AUC (+) to (-) ratio of approximately 1.6 at steady state.

Absorption and Distribution

The absolute oral bioavailability of paliperidone following paliperidone extended-release tablets

administration is 28%.

Administration of a 12 mg paliperidone extended-release tablets to healthy ambulatory subjects with a

standard high-fat/high-caloric meal gave mean C

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 can be taken without regard to food, the presence of

food at the time of paliperidone administration may increase exposure to paliperidone [see Dosage and

Administration (2.3)].

Based on a population analysis, the apparent volume of distribution of paliperidone is 487 L. The

plasma protein binding of racemic paliperidone is 74%.

Metabolism and Elimination

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

[see Drug Interactions (7)].

One week following administration of a single oral dose of 1 mg immediate-release

C-paliperidone

to 5 healthy volunteers, 59% (range 51% - 67%) of the dose was excreted unchanged into urine, 32%

(26% - 41%) of the dose was recovered as metabolites, and 6% - 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.

Special Populations

Renal Impairment

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

Dosage and Administration (2.5)]. The disposition of a single dose paliperidone 3 mg extended-release

tablet was studied in 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 (AUCinf) 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).

Hepatic Impairment

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, 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 (12-17 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.

Elderly

No dosage adjustment is recommended based on age alone. However, dose adjustment may be required

because of age-related decreases in creatinine clearance [see Renal Impairment above and Dosage and

Administration (2.1, 2.5)].

Race

No dosage adjustment is recommended based on race. No differences in pharmacokinetics were

observed in a pharmacokinetic study conducted in Japanese and Caucasians.

Gender

No dosage adjustment is recommended based on gender. No differences in pharmacokinetics were

observed in a pharmacokinetic study conducted in men and women.

Smoking

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.

13. NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Carcinogenicity studies of paliperidone administered orally have not been performed.

Carcinogenicity studies of 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 maximum

recommended human dose of risperidone on a mg/m2 basis (see risperidone package insert). An

increase in mammary, pituitary, and endocrine pancreas neoplasms has been found in rodents after

chronic administration of other antipsychotic drugs and is considered to be mediated by prolonged

dopamine D2 antagonism and hyperprolactinemia. The relevance of these tumor findings in rodents in

terms of human risk is unclear [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 rat micronucleus test.

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 body surface

area. However, pre- and post-implantation loss was increased, and the number of live embryos was

slightly decreased, at 2.5 mg/kg, a dose that also caused slight maternal toxicity. These parameters were

not affected at a dose of 0.63 mg/kg, which is half of the maximum recommended human dose on a

mg/m basis.

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 body surface area, although sperm count and sperm viability studies were not

conducted with paliperidone. In a subchronic study in Beagle dogs with risperidone, which is

extensively converted to paliperidone in dogs and humans, all doses tested (0.31 mg/kg - 5.0 mg/kg)

resulted in decreases in serum testosterone and in sperm motility and concentration (0.6 to 10 times the

MRHD of 16 mg/day for risperidone, based on mg/m body surface area). Serum testosterone and sperm

parameters partially recovered, but remained decreased after the last observation (two months after

treatment was discontinued).

14. CLINICAL STUDIES

14.1 Schizophrenia

Adults

The acute efficacy of paliperidone (3 mg to 15 mg once daily) was established in three placebo-

controlled and active-controlled (olanzapine), 6-week, fixed-dose trials in non-elderly adult subjects

(mean age of 37) who met DSM-IV criteria for schizophrenia. Studies were carried out in North

America, Eastern Europe, Western Europe, and Asia. The doses studied among these three trials

included 3 mg/day, 6 mg/day, 9 mg/day, 12 mg/day, and 15 mg/day. Dosing was in the morning without

regard to meals.

Efficacy was evaluated using the Positive and Negative Syndrome Scale (PANSS), a validated multi-

item inventory composed of five factors to evaluate positive symptoms, negative symptoms,

disorganized thoughts, uncontrolled hostility/excitement, and anxiety/depression. Efficacy was also

evaluated using the Personal and Social Performance (PSP) scale. The PSP is a validated clinician-rated

scale that measures personal and social functioning in the domains of socially useful activities (e.g.,

work and study), personal and social relationships, self-care, and disturbing and aggressive behaviors.

In all 3 studies (n = 1665), paliperidone was superior to placebo on the PANSS at all doses. Mean

effects at all doses were fairly similar, although the higher doses in all studies were numerically

superior. Paliperidone was also superior to placebo on the PSP in these trials.

An examination of population subgroups did not reveal any evidence of differential responsiveness on

the basis of gender, age (there were few patients over 65), or geographic region. There were

insufficient data to explore differential effects based on race.

In a longer-term trial, adult outpatients meeting DSM-IV criteria for schizophrenia who had clinically

responded (defined as PANSS score ≤ 70 or ≤ 4 on pre-defined PANSS subscales, as well as having

been on a stable fixed dose of paliperidone for the last two weeks of an 8-week run-in phase) were

entered into a 6-week open-label stabilization phase where they received paliperidone (doses ranging

from 3 mg to 15 mg once daily). After the stabilization phase, patients were randomized in a double-

blind manner to either continue on paliperidone at their achieved stable dose, or to placebo, until they

experienced a relapse of schizophrenia symptoms. Relapse was pre-defined as significant increase in

PANSS (or pre-defined PANSS subscales), hospitalization, clinically significant suicidal or homicidal

ideation, or deliberate injury to self or others. An interim analysis of the data showed a significantly

longer time to relapse in patients treated with paliperidone compared to placebo, and the trial was

stopped early because maintenance of efficacy was demonstrated.

Adolescents

The efficacy of paliperidone in adolescent subjects with schizophrenia was established in a

randomized, double-blind, parallel-group, placebo-controlled, 6-week study using a fixed-dose weight-

based treatment group design over the dose range of 1.5 to 12 mg/day. The study was carried out in the

US, India, Romania, Russia, and Ukraine, and involved subjects 12-17 years of age meeting DSM-IV

criteria for schizophrenia, with diagnosis confirmation using the Kiddie Schedule for Affective

Disorders and Schizophrenia-Present and Lifetime Version (K-SADSPL).

Eligible subjects were randomly assigned to 1 of 4 treatment groups: a placebo group or paliperidone

Low, Medium, or High dose groups. Doses were administered based on body weight to minimize the

risk of exposing lower-weight adolescents to high doses of paliperidone. Subjects weighing between

29 kg and less than 51 kg at the baseline visit were randomly assigned to receive placebo or 1.5 mg

(Low dose), 3 mg (Medium dose), or 6 mg (High dose) of paliperidone 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.Efficacy was evaluated using PANSS. Overall, this study demonstrated the efficacy of

paliperidone in adolescents with schizophrenia in the dose range of 3 to 12 mg/day. Doses within this

broad range were shown to be effective, however, 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. Although paliperidone was adequately tolerated within the dose range of 3 to 12 mg/day,

adverse events were dose related.

14.2 Schizoaffective Disorder

Adults

The acute efficacy of paliperidone (3 mg to 12 mg once daily) in the treatment of schizoaffective

disorder was established in two placebo-controlled, 6-week trials in non-elderly adult subjects.

Enrolled subjects 1) met DSM-IV criteria for schizoaffective disorder, as confirmed by the Structured

Clinical Interview for DSM-IV Disorders, 2) had a Positive and Negative Syndrome Scale (PANSS)

total score of at least 60, and 3) had prominent mood symptoms as confirmed by a score of at least 16 on

the Young Mania Rating Scale and/or Hamilton Rating Scale for Depression. The population included

subjects with schizoaffective bipolar and depressive types. In one of these trials, efficacy was assessed

in 211 subjects who received flexible doses of paliperidone (3-12 mg once daily). In the other study,

efficacy was assessed in 203 subjects who were assigned to one of two 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. Both studies included subjects who received paliperidone either as monotherapy [no mood

stabilizers and/or antidepressants (55%)] or as an adjunct to mood stabilizers and/or antidepressants

(45%). The most commonly used mood stabilizers were valproate and lithium. The most commonly used

antidepressants were SSRIs and SNRIs. Paliperidone was dosed 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 PANSS, a validated multi-item inventory composed of five factors to

evaluate positive symptoms, negative symptoms, disorganized thoughts, uncontrolled

hostility/excitement, and anxiety/depression. As secondary outcomes, mood symptoms were evaluated

using the Hamilton Depression Rating Scale (HAM-D-21) and the Young Mania Rating Scale (YMRS).

The paliperidone group in the flexible-dose study (dosed between 3 and 12 mg/day, mean modal dose of

8.6 mg/day) and the higher dose group of paliperidone in the 2 dose-level study (12 mg/day with option

to reduce to 9 mg/day) were each superior to placebo in the PANSS. Numerical improvements in mood

symptoms were also observed, as measured by the HAM-D21 and YMRS. 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 as an adjunct to

mood stabilizers and/or antidepressants. 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 differential effects based on race.

16. HOW SUPPLIED/STORAGE AND HANDLING

Paliperidone extended-release tablets are available in the following strengths and packages. All tablets

are circular shaped.

1.5 mg tablets are orange-brown colored, circular shaped, biconvex, beveled edged, coated tablet plain

on one side and "032" printed in black ink on other side, and are available in bottles of 30 (NDC 49252-

032-10).

3 mg tablets are white to off-white colored, circular shaped, biconvex, beveled edged, coated tablet

plain on one side and "033" printed in black ink on other side, and are available in bottles of 30 (NDC

49252-033-10).

6 mg tablets are beige colored, circular shaped, biconvex, beveled edged, coated tablet plain on one

side and "034" printed in black ink on other side, and are available in bottles of 30 (NDC 49252-034-

10).

9 mg tablets are pink colored, circular shaped, biconvex, beveled edged, coated tablet plain on one side

and "035" printed in black ink on other side, and are available in bottles of 30 (NDC 49252-035-10).

Storage and Handling

Store at 20º to 25ºC (68º to 77ºF)[see USP Controlled Room Temperature]. Protect from moisture.

Dispense in a tight container. Keep out of reach of children.

17. PATIENT COUNSELING INFORMATION

Physicians are advised to discuss the following issues with patients for whom they prescribe

paliperidone extended-release tablets.

Orthostatic Hypotension

Patients should be advised that there is risk of orthostatic hypotension, particularly at the time of

initiating treatment, re-initiating treatment, or increasing the dose [see Warnings and Precautions (5.9)].

Interference with Cognitive and Motor Performance

As paliperidone has the potential to impair judgment, thinking, or motor skills, patients should be

cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain

that paliperidone therapy does not affect them adversely [see Warnings and Precautions (5.11)].

Concomitant Medication

Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription

or over-the-counter drugs, as there is a potential for interactions [see Drug Interactions (7)].

Alcohol

Patients should be advised to avoid alcohol while taking paliperidone [see Drug Interactions (7.1)].

Heat Exposure and Dehydration

Patients should be advised regarding appropriate care in avoiding overheating and dehydration [see

Warnings and Precautions (5.17)].

Adminis tration

Patients should be informed that paliperidone extended-release tablets should be swallowed whole with

the aid of liquids. Tablets should not be chewed, divided, or crushed. [see Dosage and Administration

(2.3)].

Paliperidone extended-release tablets

Pregnancy

Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant

during treatment with paliperidone. Advise patients that paliperidone may cause extrapyramidal and/or

withdrawal symptoms in a neonate. Advise patients that there is a pregnancy registry that monitors

pregnancy outcomes in women exposed to paliperidone during pregnancy [see USE IN SPECIFIC

POPULATIONS (8.1)].

Lactation

Advise breastfeeding women using palipeirdone to monitor infants for somnolence, failure to thrive,

jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements) and to seek medical

care if they notice these signs [see USE IN SPECIFIC POPULATIONS (8.2)].

Infertility

Advise females of reproductive potential that INVEGA® may impair fertility due to an increase in

serum prolactin levels. The effects on fertility are reversible [see USE IN SPECIFIC POPULATIONS

(8.3)].

Paliperidone extended-release tablets

Product of India

Manufactured By:

Inventia Healthcare Limited

Plot No.F1 & F-1/1, Additional Ambernath M.I.D.C.,

Ambernath (East)-421506,

Dist. Thane, Maharashtra, India

Revised: March 2019

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

PALIPERIDONE EXTENDED RELEASE TABELETS

NDC 49252-032-10

1.5 mg

Rx only

30 Tablets

PALIPERIDONE EXTENDED RELEASE TABELETS

NDC 49252-033-10

3 mg

Rx only

30 Tablets

PALIPERIDONE EXTENDED RELEASE TABELETS

NDC 49252-034-10

6 mg

Rx only

30 Tablets

PALIPERIDONE EXTENDED RELEASE TABELETS

NDC 49252-035-10

9 mg

Rx only

30 Tablets

PALIPERIDONE

paliperidone tablet, extended release

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:49 252-0 32

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

PALIPERIDO NE (UNII: 8 38 F0 1T721) (PALIPERIDONE - UNII:8 38 F0 1T721)

PALIPERIDONE

1.5 mg

Inactive Ingredients

Ingredient Name

Stre ng th

PO LYETHYLENE GLYCO L (UNII: 3WJQ0 SDW1A)

CARBO MER HO MO PO LYMER TYPE A ( ALLYL PENTAERYTHRITO L CRO SSLINKED) (UNII: F6 8 VH75CJC)

CELLULO SE, MICRO CRYSTALLINE (UNII: OP1R32D6 1U)

BUTYLATED HYDRO XYTO LUENE (UNII: 1P9 D0 Z171K)

SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

FERRIC O XIDE YELLO W (UNII: EX438 O2MRT)

FERRIC O XIDE RED (UNII: 1K0 9 F3G6 75)

HYPRO MELLO SE PHTHALATE ( 3 1% PHTHALATE, 4 0 CST) (UNII: G4U0 24CQK6 )

ETHYLCELLULO SES (UNII: 7Z8 S9 VYZ4B)

DIBUTYL SEBACATE (UNII: 4W5IH7FLNY)

TALC (UNII: 7SEV7J4R1U)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

Product Characteristics

Color

ORANGE (Orange-bro wn)

S core

no sco re

S hap e

ROUND (CIRCULAR)

S iz e

Flavor

Imprint Code

0 32

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:49 252-0 32-10

30 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 9 /0 1/20 19

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA20 4452

0 9 /0 1/20 19

PALIPERIDONE

paliperidone tablet, extended release

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:49 252-0 33

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

PALIPERIDO NE (UNII: 8 38 F0 1T721) (PALIPERIDONE - UNII:8 38 F0 1T721)

PALIPERIDONE

3 mg

Inactive Ingredients

Ingredient Name

Stre ng th

PO LYETHYLENE GLYCO L (UNII: 3WJQ0 SDW1A)

CARBO MER HO MO PO LYMER TYPE A ( ALLYL PENTAERYTHRITO L CRO SSLINKED) (UNII: F6 8 VH75CJC)

CELLULO SE, MICRO CRYSTALLINE (UNII: OP1R32D6 1U)

BUTYLATED HYDRO XYTO LUENE (UNII: 1P9 D0 Z171K)

SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

HYPRO MELLO SE PHTHALATE ( 3 1% PHTHALATE, 4 0 CST) (UNII: G4U0 24CQK6 )

ETHYLCELLULO SES (UNII: 7Z8 S9 VYZ4B)

DIBUTYL SEBACATE (UNII: 4W5IH7FLNY)

TALC (UNII: 7SEV7J4R1U)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

Product Characteristics

Color

WHITE (white)

S core

no sco re

S hap e

ROUND (circular)

S iz e

Flavor

Imprint Code

0 33

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:49 252-0 33-10

30 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 9 /0 1/20 19

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA20 4452

0 9 /0 1/20 19

PALIPERIDONE

paliperidone tablet, extended release

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:49 252-0 34

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

PALIPERIDO NE (UNII: 8 38 F0 1T721) (PALIPERIDONE - UNII:8 38 F0 1T721)

PALIPERIDONE

6 mg

Inactive Ingredients

Ingredient Name

Stre ng th

PO LYETHYLENE GLYCO L (UNII: 3WJQ0 SDW1A)

CARBO MER HO MO PO LYMER TYPE A ( ALLYL PENTAERYTHRITO L CRO SSLINKED) (UNII: F6 8 VH75CJC)

CELLULO SE, MICRO CRYSTALLINE (UNII: OP1R32D6 1U)

BUTYLATED HYDRO XYTO LUENE (UNII: 1P9 D0 Z171K)

SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

FERRIC O XIDE YELLO W (UNII: EX438 O2MRT)

FERRIC O XIDE RED (UNII: 1K0 9 F3G6 75)

HYPRO MELLO SE PHTHALATE ( 3 1% PHTHALATE, 4 0 CST) (UNII: G4U0 24CQK6 )

ETHYLCELLULO SES (UNII: 7Z8 S9 VYZ4B)

DIBUTYL SEBACATE (UNII: 4W5IH7FLNY)

TALC (UNII: 7SEV7J4R1U)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

Product Characteristics

Color

BROWN (Beige)

S core

no sco re

S hap e

ROUND (Circular)

S iz e

Flavor

Imprint Code

0 34

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:49 252-0 34-10

30 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 9 /0 1/20 19

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA20 4452

0 9 /0 1/20 19

PALIPERIDONE

paliperidone tablet, extended release

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:49 252-0 35

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

PALIPERIDO NE (UNII: 8 38 F0 1T721) (PALIPERIDONE - UNII:8 38 F0 1T721)

PALIPERIDONE

9 mg

Inactive Ingredients

Ingredient Name

Stre ng th

PO LYETHYLENE GLYCO L (UNII: 3WJQ0 SDW1A)

CARBO MER HO MO PO LYMER TYPE A ( ALLYL PENTAERYTHRITO L CRO SSLINKED) (UNII: F6 8 VH75CJC)

CELLULO SE, MICRO CRYSTALLINE (UNII: OP1R32D6 1U)

BUTYLATED HYDRO XYTO LUENE (UNII: 1P9 D0 Z171K)

SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

FERRIC O XIDE RED (UNII: 1K0 9 F3G6 75)

HYPRO MELLO SE PHTHALATE ( 3 1% PHTHALATE, 4 0 CST) (UNII: G4U0 24CQK6 )

ETHYLCELLULO SES (UNII: 7Z8 S9 VYZ4B)

DIBUTYL SEBACATE (UNII: 4W5IH7FLNY)

TALC (UNII: 7SEV7J4R1U)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

Product Characteristics

Color

PINK (Pink)

S core

no sco re

S hap e

ROUND (Circular)

S iz e

Flavor

Imprint Code

0 35

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:49 252-0 35-10

30 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 9 /0 1/20 19

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA20 4452

0 9 /0 1/20 19

Inventia Healthcare Limited

Labeler -

Inventia Healthcare Limited (677604412)

Registrant -

Inventia Healthcare Limited. (650452522)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Inventia Healthcare Limited

6 776 0 4412

manufacture(49 252-0 32, 49 252-0 33, 49 252-0 34, 49 252-0 35)

Revised: 6/2019

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