NDC 60687-470 Paliperidone

Paliperidone

NDC Product Code 60687-470

NDC CODE: 60687-470

Proprietary Name: Paliperidone What is the Proprietary Name?
The proprietary name also known as the trade name is the name of the product chosen by the medication labeler for marketing purposes.

Non-Proprietary Name: Paliperidone What is the Non-Proprietary Name?
The non-proprietary name is sometimes called the generic name. The generic name usually includes the active ingredient(s) of the product.

Drug Use Information

Drug Use Information
The drug use information is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate. This information is not individual medical advice and does not substitute for the advice of a health care professional. Always ask a health care professional for complete information about this product and your specific health needs.

  • This medication is used to treat certain mental/mood disorders (such as schizophrenia, schizoaffective disorder). This medication can decrease hallucinations and help you to think more clearly and positively about yourself, feel less agitated, and take a more active part in everyday life. Paliperidone belongs to a class of drugs called atypical antipsychotics. It works by helping to restore the balance of certain natural substances in the brain.

Product Characteristics

Color(s):
WHITE (C48325 - WHITE TO OFF-WHITE)
YELLOW (C48330)
Shape: ROUND (C48348)
Size(s):
8 MM
Imprint(s):
765
766
Score: 1

NDC Code Structure

  • 60687 - American Health Packaging

NDC 60687-470-01

Package Description: 100 BLISTER PACK in 1 BOX, UNIT-DOSE > 1 TABLET, EXTENDED RELEASE in 1 BLISTER PACK (60687-470-11)

NDC Product Information

Paliperidone with NDC 60687-470 is a a human prescription drug product labeled by American Health Packaging. The generic name of Paliperidone is paliperidone. The product's dosage form is tablet, extended release and is administered via oral form.

Labeler Name: American Health Packaging

Dosage Form: Tablet, Extended Release - A solid dosage form containing a drug which allows at least a reduction in dosing frequency as compared to that drug presented in conventional dosage form.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Paliperidone Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • PALIPERIDONE 6 mg/1

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • POLYETHYLENE GLYCOL, UNSPECIFIED (UNII: 3WJQ0SDW1A)
  • HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO)
  • ANHYDROUS LACTOSE (UNII: 3SY5LH9PMK)
  • MAGNESIUM STEARATE (UNII: 70097M6I30)
  • ETHYLCELLULOSE, UNSPECIFIED (UNII: 7Z8S9VYZ4B)
  • TRIETHYL CITRATE (UNII: 8Z96QXD6UM)
  • TALC (UNII: 7SEV7J4R1U)
  • TITANIUM DIOXIDE (UNII: 15FIX9V2JP)
  • SHELLAC (UNII: 46N107B71O)
  • FERROSOFERRIC OXIDE (UNII: XM0M87F357)
  • BUTYL ALCOHOL (UNII: 8PJ61P6TS3)
  • PROPYLENE GLYCOL (UNII: 6DC9Q167V3)
  • AMMONIA (UNII: 5138Q19F1X)
  • POLYETHYLENE GLYCOL, UNSPECIFIED (UNII: 3WJQ0SDW1A)
  • HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO)
  • ANHYDROUS LACTOSE (UNII: 3SY5LH9PMK)
  • MAGNESIUM STEARATE (UNII: 70097M6I30)
  • ETHYLCELLULOSE, UNSPECIFIED (UNII: 7Z8S9VYZ4B)
  • TRIETHYL CITRATE (UNII: 8Z96QXD6UM)
  • TALC (UNII: 7SEV7J4R1U)
  • TITANIUM DIOXIDE (UNII: 15FIX9V2JP)
  • LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)
  • FERRIC OXIDE YELLOW (UNII: EX438O2MRT)
  • FERRIC OXIDE RED (UNII: 1K09F3G675)
  • SHELLAC (UNII: 46N107B71O)
  • FERROSOFERRIC OXIDE (UNII: XM0M87F357)
  • BUTYL ALCOHOL (UNII: 8PJ61P6TS3)
  • PROPYLENE GLYCOL (UNII: 6DC9Q167V3)
  • AMMONIA (UNII: 5138Q19F1X)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Oral - Administration to or by way of the mouth.
  • Oral - Administration to or by way of the mouth.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Atypical Antipsychotic - [EPC] (Established Pharmacologic Class)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: American Health Packaging
Labeler Code: 60687
FDA Application Number: ANDA205618 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: ANDA - A product marketed under an approved Abbreviated New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 11-11-2019 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2020 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA’s requests for correction to deficient or non-compliant submissions. Values = ‘Y’ or ‘N’.

* Please review the disclaimer below.

Paliperidone Product Label Images

Paliperidone Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

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)]

1.1 Schizophrenia

Paliperidone extended-release tablets are indicated for the treatment of schizophrenia
[see
Clinical Studies (14.1)].
The efficacy of paliperidone extended-release tablets in schizophrenia was established in three 6-week trials in adults and one 6-week trial in adolescents, as well as one maintenance trial in adults.

1.2 Schizoaffective Disorder

Paliperidone extended-release tablets are indicated for the treatment of schizoaffective disorder as monotherapy and an adjunct to mood stabilizers and/or antidepressant therapy


[see


Clinical Studies (14.2)].


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

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 extended-release tablets should be prescribed at the lowest effective dose for maintaining clinical stability and the physician should periodically reevaluate the long-term usefulness of the drug in individual patients.
Adolescents (12 to 17 years of age)
The recommended starting dose of paliperidone extended-release tablets for the treatment of schizophrenia in adolescents 12 to 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 extended-release tablets with risperidone has not been studied. Since paliperidone is the major active metabolite of risperidone, consideration should be given to the additive paliperidone exposure if risperidone is coadministered with paliperidone extended-release tablets.

2.5 Dosage In Special Populations

Renal Impairment
Dosing must be individualized according to the patient’s renal function status. For patients with mild renal impairment (creatinine clearance ≥ 50 mL/min to < 80 mL/min), the recommended initial dose of paliperidone extended-release tablets is 3 mg once daily. The dose may then be increased to a maximum of 6 mg once daily based on clinical response and tolerability. For patients with moderate to severe renal impairment (creatinine clearance ≥ 10 mL/min to < 50 mL/min), the recommended initial dose of paliperidone extended-release tablets is 1.5 mg once daily, which may be increased to a maximum of 3 mg once daily after clinical reassessment. As paliperidone 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 extended-release tablets 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 (brown), 3 mg (white to off-white), 6 mg (yellow), and 9 mg (pink). All tablets are circular shaped and are imprinted with either “744”, “765”, “766”, or “767”.

4 Contraindications

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

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].

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
max 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
max 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 postmarketing 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 SchizophreniaPaliperidonePlacebo3 mg/day6 mg/day9 mg/day12 mg/dayMean change from baseline (mg/dL)n=322n=122n=212n=234n=218Serum Glucose Change from baseline0.8-0.70.42.34.3Proportion of Patients with ShiftsSerum 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 to 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 to 17 years of age) with SchizophreniaPaliperidonePlacebo1.5 mg/day3 mg/day6 mg/day12 mg/dayMean change from baseline (mg/dL)n=41n=44n=11n=28n=32Serum Glucose Change from baseline0.8-1.4-1.8-0.15.2Proportion of Patients with ShiftsSerum Glucose Normal to High
(<100 mg/dL to ≥126 mg/dL)
3%

(1/32)
0%

(0/34)
0%

(0/9)
0%

(0/20)
11%

(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 SchizophreniaPaliperidonePlacebo3 mg/day6 mg/day9 mg/day12 mg/dayMean change from baseline (mg/dL)Cholesteroln=331n=120n=216n=236n=231Change from baseline-6.3-4.4-2.4-5.3-4LDLn=322n=116n=210n=231n=225Change from baseline-3.20.5-0.8-3.9-2HDLn=331n=119n=216n=234n=230Change from baseline0.3-0.40.50.81.2Triglyceridesn=331n=120n=216n=236n=231Change from baseline-22.3-18.3-12.6-10.6-15.4Proportion of Patients with ShiftsCholesterolNormal 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)
LDLNormal to High(<100 mg/dL to ≥160 mg/dL)1.9%

(2/105)
0%

(0/44)
5%

(3/60)
3.7%

(3/81)
0%

(0/69)
HDLNormal to Low( ≥40 mg/dL to <40 mg/dL)22%

(44/200)
16.3%

(13/80)
29.1%

(39/134)
23.4%

(32/137)
20%

(27/135)
TriglyceridesNormal to High(<150 mg/dL to ≥200 mg/dL)5.3%

(11/208)
11%

(9/82)
8.8%

(12/136)
8.7%

(13/150)
4.3%

(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 to 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 to 17 years of age) with SchizophreniaPaliperidonePlacebo1.5 mg/day3 mg/day6 mg/day12 mg/dayMean change from baseline (mg/dL)Cholesteroln=39n=45n=11n=28n=32Change from baseline-7.8-3.312.73-1.5LDLn=37n=40n=9n=27n=31Change from baseline-4.1-3.17.22.40.6HDLn=37n=41n=9n=27n=31Change from baseline-1.901.31.40Triglyceridesn=39n=44n=11n=28n=32Change from baseline-8.93.217.6-5.43.9Proportion of Patients with ShiftsCholesterolNormal to High(<170 mg/dL to ≥200 mg/dL)7%

(2/27)
4%

(1/26)
0%

(0/6)
6%

(1/18)
11%

(2/19)
LDLNormal to High(<110 mg/dL to ≥130 mg/dL)3%

(1/32)
4%

(1/25)
14%

(1/7)
0%

(0/22)
9%

(2/22)
HDLNormal to Low( ≥40 mg/dL to <40 mg/dL)14%

(4/28)
7%

(2/30)
29%

(2/7)
13%

(3/23)
23%

(5/22)
TriglyceridesNormal to High(<150 mg/dL to ≥200 mg/dL)3%

(1/34)
5%

(2/38)
13%

(1/8)
8%

(2/26)
7%

(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 SchizophreniaPaliperidonePlacebo3 mg/day6 mg/day9 mg/day12 mg/dayn=323n=112n=215n=235n=218Weight (kg)Change from baseline-0.40.60.611.1Weight Gain≥7% increase from baseline5%7%6%9%9%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 to 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 to 17 years of age) with SchizophreniaPaliperidonePlacebo1.5 mg/day3 mg/day6 mg/day12 mg/dayn=51n=54n=16n=45n=34Weight (kg)Change from baseline00.30.81.21.5Weight Gain≥7% increase from baseline2%6%19%7%18%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 D2 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 tablet is non-deformable and does not appreciably change in shape in the gastrointestinal tract, paliperidone should ordinarily not be administered to patients with pre‑existing 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 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 preexisting 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


3) 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)].

6.1 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 reactions, including stroke, in elderly patients with dementia-related psychosis
  • [see
  • Warnings and Precautions (5.2)]
  • Neuroleptic malignant syndrome
  • [see
  • Warnings and Precautions (5.3)]
  • QT prolongation
  • [see
  • Warnings and Precautions (5.4)]
  • Tardive dyskinesia
  • [see
  • Warnings and Precautions (5.5)]
  • Metabolic changes
  • [see
  • Warnings and Precautions (5.6)]
  • Hyperprolactinemia
  • [see
  • Warnings and Precautions (5.7)]
  • Potential for gastrointestinal obstruction
  • [see
  • Warnings and Precautions (5.8)]
  • Orthostatic hypotension and syncope
  • [see
  • Warnings and Precautions (5.9)]
  • Falls
  • [see
  • Warnings and Precautions (5.10)]
  • Leukopenia, neutropenia, and agranulocytosis
  • [see
  • Warnings and Precautions (5.11)]
  • Potential for cognitive and motor impairment
  • [see
  • Warnings and Precautions (5.12)]
  • Seizures
  • [see
  • Warnings and Precautions (5.13)]
  • Dysphagia
  • [see
  • Warnings and Precautions (5.14)]
  • Priapism
  • [see
  • Warnings and Precautions (5.15)]
  • 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 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 to 17 years of age with schizophrenia who received paliperidone in the dose range of 1.5 mg to 12 mg/day in a 6-week, double-blind, placebo-controlled trial.The safety of paliperidone was also evaluated in 622 adult subjects with schizoaffective disorder who participated in two placebo-controlled, 6-week, double-blind trials. In one of these trials, 206 subjects were assigned to one of two dose levels of paliperidone: 6 mg with the option to reduce to 3 mg (n = 108) or 12 mg with the option to reduce to 9 mg (n=98) once daily. In the other study, 214 subjects received flexible doses of paliperidone (3 to 12 mg once daily). Both studies included subjects who received paliperidone either as monotherapy or as an adjunct to mood stabilizers and/or antidepressants. Adverse events during exposure to study treatment were obtained by general inquiry and recorded by clinical investigators using their own terminology. Consequently, to provide a meaningful estimate of the proportion of individuals experiencing adverse events, events were grouped in standardized categories using MedDRA terminology.Throughout this section, adverse reactions are reported. Adverse reactions are adverse events that were considered to be reasonably associated with the use of paliperidone (adverse drug reactions) based on the comprehensive assessment of the available adverse event information. A causal association for paliperidone often cannot be reliably established in individual cases. Further, because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

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. Body System or Organ Class
Dictionary-Derived Term
Percentage of PatientsPaliperidonePlacebo3 mg once daily6 mg once daily9 mg once daily12 mg once daily(N=355)(N=127)(N=235)(N=246)(N=242)Total percentage of subjects with adverse reactions3748475359Cardiac disorders Atrioventricular block first degree12021 Bundle branch block2313<1 Sinus arrhythmia0211<1 Tachycardia714121214Gastrointestinal disorders Abdominal pain upper11322 Dry mouth12313 Salivary hypersecretion<10<114General disorders Asthenia12<122 Fatigue12122Nervous system disorders Akathisia443810 Dizziness46545 Extrapyramidal symptoms81072018 Headache1211121414 Somnolence7691011Vascular disorders Orthostatic hypotension12124Adolescent Patients with Schizophrenia
Table 5 lists the adverse reactions reported in a fixed-dose, placebo-controlled study in adolescent subjects 12 to 17 years of age with schizophrenia, listing those that occurred in 2% or more of subjects treated with paliperidone in any of the dose groups, and for which the incidence in paliperidone-treated subjects in any of the dose groups was greater than the incidence in subjects treated with placebo.
Table 5. Adverse Reactions Reported by ≥ 2% of Paliperidone-Treated Adolescent Subjects with Schizophrenia in a Fixed-Dose, Placebo-Controlled Clinical Trial
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.Body System or Organ Class
Dictionary-Derived Term
Percentage of PatientsPaliperidonePlacebo1.5 mg once daily3 mg once daily6 mg once daily12 mg once daily(N=51)(N=54)(N=16)(N=45)(N=35)Total percentage of subjects with adverse reactions4337505874Cardiac disorders Tachycardia00696Eye disorders Vision blurred00003Gastrointestinal disorders Dry mouth20003 Salivary hypersecretion02620 Swollen tongue00003 Vomiting1006113General disorders Asthenia00023 Fatigue04023Infections and infestations Nasopharyngitis24040Investigations Weight increased07623Nervous system disorders Akathisia0461117 Dizziness02623 Extrapyramidal symptoms04191823 Headache496414 Lethargy00003 Somnolence49132026 Tongue paralysis00003Psychiatric disorders Anxiety40029Reproductive system and breast disorders Amenorrhea00600 Galactorrhea00040 Gynecomastia00003Respiratory, thoracic and mediastinal disorders Epistaxis00020

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
Table includes adverse reactions that were reported in 2% or more of subjects in any of the paliperidone dose groups and which occurred at greater incidence than in the placebo group. Data are pooled from two studies. One study included once-daily paliperidone doses of 6 mg (with the option to reduce to 3 mg) and 12 mg (with the option to reduce to 9 mg). The second study included flexible once-daily doses of 3 to 12 mg. Among the 420 subjects treated with paliperidone, 230 (55%) received paliperidone as monotherapy and 190 (45%) received paliperidone as an adjunct to mood stabilizers and/or antidepressants. Extrapyramidal symptoms includes the terms bradykinesia, drooling, dyskinesia, dystonia, hypertonia, muscle rigidity, muscle twitching, oculogyration, parkinsonian gait, parkinsonism, restlessness, and tremor. Somnolence includes the terms sedation and somnolence. Tachycardia includes the terms tachycardia, sinus tachycardia, and heart rate increased.Body System or Organ Class
Dictionary-Derived Term
Percentage of PatientsPlaceboPaliperidone 3 to 6 mg once-daily fixed-dose rangePaliperidone 9 to 12 mg once-daily fixed-dose rangePaliperidone 3 to 12 mg once-daily flexible dose(N=202)(N=108)(N=98)(N=214)Total percentage of subjects with adverse reactions32485043Cardiac disorders Tachycardia2312Gastrointestinal disorders Abdominal discomfort/Abdominal pain upper1103 Constipation2454 Dyspepsia2566 Nausea6885 Stomach discomfort1012General disorders Asthenia134<1Infections and Infestations Nasopharyngitis1253 Rhinitis0131 Upper respiratory tract infection1222Investigations Weight increased1544Metabolism and nutrition disorders Decreased appetite<1102 Increased appetite<1322Musculoskeletal and connective tissue disorders Back pain1113 Myalgia<1241Nervous system disorders Akathisia4466 Dysarthria0142 Extrapyramidal symptoms8201712 Somnolence512128Psychiatric disorders Sleep disorder<1230Respiratory, thoracic and mediastinal disorders Cough1131 Pharyngolaryngeal pain<1021Monotherapy 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 in adults 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).

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 subjects with schizophrenia and in the two placebo-controlled, 6-week studies in adult 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 adult 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 AdultsEPS GroupPercentage of PatientsPaliperidonePlacebo3 mgonce daily6 mgonce daily9 mgonce daily12 mgonce daily(N=355)(N=127)(N=235)(N=246)(N=242)Parkinsonism
For Parkinsonism, percent of patients with Simpson-Angus global score > 0.3 (Global score defined as total sum of items score divided by the number of items)91131514Akathisia
For Akathisia, percent of patients with Barnes Akathisia Rating Scale global score ≥ 266479Use of anticholinergic medications
Percent of patients who received anticholinergic medications to treat emergent EPS101092222Table 8. Treatment-Emergent Extrapyramidal Symptoms (EPS)-Related Adverse Events by MedDRA Preferred Term – Schizophrenia Studies in AdultsEPS GroupPercentage of PatientsPaliperidonePlacebo3 mgonce daily6 mgonce daily9 mgonce daily12 mgonce daily(N=355)(N=127)(N=235)(N=246)(N=242)Overall percentage of patients with EPS- related AE1113102526Dyskinesia35389Dystonia11155Hyperkinesia443810Parkinsonism23376Tremor33343Dyskinesia 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
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 AdultsEPS GroupPercentage of PatientsPaliperidonePlacebo3 to 6 mg once-daily fixed-dose range9 to 12 mg once-daily fixed-dose range3 to 12 mg once-daily flexible dose(N=202)(N=108)(N=98)(N=214)Overall percentage of patients with EPS- related AE11232217Dyskinesia1311Dystonia1232Hyperkinesia5587Parkinsonism31477Tremor312115Dyskinesia 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
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 PlaceboEPS GroupPercentage of Patients PaliperidonePlacebo1.5 mg

once daily
3 mgonce daily6 mgonce daily12 mgonce daily(N=51)(N=54)(N=16)(N=45)(N=35)Overall percentage of patients with EPS- related AE06252240Hyperkinesia0461117Dystonia0201114Tremor026711Parkinsonism006214Dyskinesia02626Hyperkinesia 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
DystoniaClass 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 adult subjects with schizophrenia and from the two placebo-controlled, 6-week studies in adult 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 and schizoaffective disorder 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, ileus, 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.

7.1 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, coadministration 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 (AUC24h and C
max,ss) of valproate in 13 patients stabilized on valproate. In a clinical study, subjects on stable doses of valproate had comparable valproate average plasma concentrations when paliperidone 3 to 15 mg/day was added to their existing valproate treatment.

7.2 Potential For Other Drugs To Affect Paliperidone

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.
Coadministration of paliperidone 6 mg once daily with carbamazepine, a strong inducer of both CYP3A4 and P-glycoprotein (P-gp), at 200 mg twice daily caused a decrease of approximately 37% in the mean steady-state C
max 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 coadministration. 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.
Coadministration 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
max and AUC of paliperidone. Dosage reduction for paliperidone should be considered when paliperidone is coadministered with valproate after clinical assessment.
Pharmacokinetic interaction between lithium and paliperidone is unlikely.

8.1 Pregnancy

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 paliperidone, 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% to 4% and 15% to 20%, respectively.In animal reproduction studies, there were no increases in fetal abnormalities when pregnant rats and rabbits were treated with paliperidone during the period of organogenesis with up to 8 times the maximum recommended human dose (MRHD) based on mg/m
2 body surface area. Additional reproduction toxicity studies were conducted with orally administered risperidone, which is extensively converted to paliperidone
(see Animal Data).
Clinical ConsiderationsDisease-associated maternal and/or embryo/fetal risk
There is a risk to the mother from untreated schizophrenia, including increased risk of relapse, hospitalization, and suicide. Schizophrenia are associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is a direct result of the illness or other comorbid factors.
Fetal/Neonatal Adverse Reactions
Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs, including paliperidone, during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization.
DataHuman 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 to 1.56) and of cardiac malformations (RR=1.26, 95% CI 0.88 to 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
2 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
2 body surface area; maternal toxicity occurred at 4 times the MHRD. There was no evidence of teratogenicity in embryo-fetal developmental toxicity studies with risperidone in rats and rabbits at doses up to 6 times the MRHD of 16 mg/day risperidone based on mg/m
2 body surface area. When the offspring of pregnant rats, treated with risperidone at 0.6 times the MRHD based on mg/m
2 body surface area, reached adulthood, learning was impaired. Increased neuronal cell death occurred in the fetal brains of the offspring of pregnant rats treated at 0.5 to 1.2 times the MRHD; the postnatal development and growth of the offspring was delayed.
In rat reproduction studies with risperidone, pup deaths occurred at oral doses which are less than the MRHD of risperidone based on mg/m
2 body surface area; it is not known whether these deaths were due to a direct effect on the fetuses or pups or to effects on the dams (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 parent compound, 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

InfertilityFemales
Based on the pharmacologic action of paliperidone (D2 receptor antagonism), treatment with paliperidone extended-release tablets may result in an increase in serum prolactin levels, which may lead to a reversible reduction in fertility in females of reproductive potential
[see
Warnings and Precautions (5.7)].

8.4 Pediatric Use

Safety and effectiveness of paliperidone in the treatment of schizophrenia were evaluated in 150 adolescent subjects 12 to 17 years of age with schizophrenia who received paliperidone in the dose range of 1.5 mg to 12 mg/day in a 6-week, double-blind, placebo-controlled trial.Safety and effectiveness of paliperidone for the treatment of schizophrenia in patients < 12 years of age have not been established. Safety and effectiveness of paliperidone for the treatment of schizoaffective disorder in patients < 18 years of age have not been studied.Juvenile Animal Studies
In a study in which juvenile rats were treated with oral paliperidone from days 24 to 73 of age, a reversible impairment of performance in a test of learning and memory was seen, in females only, with a no-effect dose of 0.63 mg/kg/day, which produced plasma levels (AUC) of paliperidone similar to those in adolescents at MRHD of 12 mg/day. No other consistent effects on neurobehavioral or reproductive development were seen up to the highest dose tested (2.5 mg/kg/day), which produced plasma levels of paliperidone 2 to 3 times those in adolescents.
Juvenile dogs were treated for 40 weeks with oral risperidone, which is extensively metabolized to paliperidone in animals and humans, at doses of 0.31, 1.25, or 5 mg/kg/day. Decreased bone length and density were seen with a no-effect dose of 0.31 mg/kg/day, which produced plasma levels (AUC) of risperidone plus paliperidone which were similar to those in children and adolescents receiving the MRHD of risperidone. In addition, a delay in sexual maturation was seen at all doses in both males and females. The above effects showed little or no reversibility in females after a 12-week drug-free recovery period.The long-term effects of paliperidone on growth and sexual maturation have not been fully evaluated in children and adolescents.

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%) 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.

9.1 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.

10.1 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

Paliperidone extended-release tablet contains paliperidone USP, 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 C
23H
27FN
4O
3 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 intended for oral administration and are available in 1.5 mg (brown), 3 mg (white to off-white), 6 mg (yellow), and 9 mg (pink) strengths. Paliperidone extended-release tablets are formulated as a polymer matrix based once-a-day controlled release tablet for oral use.
[see
Description (11)].
Inactive ingredients are polyethylene oxide, hypromellose, anhydrous lactose, magnesium stearate, ethyl cellulose, triethyl citrate, talc, titanium dioxide and polyethylene glycol. The 1.5 mg and 6 mg tablets also contain lactose monohydrate, iron oxide yellow and iron oxide red. The 9 mg tablets also contain lactose monohydrate and iron oxide red.Imprinting ink contains shellac glaze, iron oxide black, N-butyl alcohol, propylene glycol and ammonium hydroxide.

Delivery System Components And Performance

Paliperidone extended release tablets employ a film-coated hydrophilic hydrogel matrix to deliver paliperidone at a controlled rate over 24 hours. The system comprises of: a core consists of the drug, rate-controlling polymer (forming hydrogel) and other excipients with pH independent coat surrounding core, comprising of water soluble and insoluble polymer and a film coat over it. Upon ingestion outer film coat dissolves exposing the coated tablet to the gastric fluids. Once the water soluble polymer from coat gets dissolved, pores are formed which allow penetration of fluid inside the membrane leading to hydration of core-forming hydrogel. Drug release occurs via slow diffusion out of the gel layer and subsequent gel erosion.

12.1 Mechanism Of Action

Paliperidone is the major active metabolite of risperidone. The mechanism of action of paliperidone in schizophrenia is unclear. However, the drug's therapeutic effect in schizophrenia could be mediated through a combination of central dopamine Type 2 (D
2) and serotonin Type 2 (5HT
2A) receptor antagonism.

12.2 Pharmacodynamics

In vitro, paliperidone acts as an antagonist at the central dopamine Type 2 (D
2) and serotonin Type 2 (5HT
2A) receptors, with binding affinities (Ki values) of 1.6 to 2.8 nM for D
2 and 0.8 to 1.2 nM for 5HT
2A receptors. Paliperidone is also active as an antagonist at the α
1 and α
2 adrenergic receptors and H
1 histaminergic receptors, which may explain some of the other effects of the drug. Paliperidone has no affinity for cholinergic muscarinic or β
1- and β
2-adrenergic receptors. The pharmacological activity of the (+)- and (-)- paliperidone enantiomers is qualitatively and quantitatively similar
in vitro.

12.3 Pharmacokinetics

Following a single dose, the plasma concentrations of paliperidone gradually rise to reach peak plasma concentration (C
max) approximately 24 hours after dosing. The pharmacokinetics of paliperidone following paliperidone administration are dose-proportional within the available dose range. The terminal elimination half-life of paliperidone is approximately 23 hours.
Steady-state concentrations of paliperidone are attained within 4 to 5 days of dosing with paliperidone in most subjects. The mean steady-state peak: trough ratio for an paliperidone dose of 9 mg was 1.7 with a range of 1.2 to 3.1.Following administration of paliperidone, the (+) and (-) enantiomers of paliperidone interconvert, reaching an AUC (+) to (-) ratio of approximately 1.6 at steady state.Absorption and Distribution
The absolute oral bioavailability of paliperidone following paliperidone administration is 28%.
Administration of a 12 mg paliperidone extended-release tablet to healthy ambulatory subjects with a standard high-fat/high-caloric meal gave mean C
max and AUC values of paliperidone that were increased by 60% and 54%, respectively, compared with administration under fasting conditions. Clinical trials establishing the safety and efficacy of paliperidone were carried out in subjects without regard to the timing of meals. While paliperidone 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
14C-paliperidone to 5 healthy volunteers, 59% (range 51% to 67%) of the dose was excreted unchanged into urine, 32% (26% to 41%) of the dose was recovered as metabolites, and 6% to 12% of the dose was not recovered. Approximately 80% of the administered radioactivity was recovered in urine and 11% in the feces. Four primary metabolic pathways have been identified
in vivo, none of which could be shown to account for more than 10% of the dose: dealkylation, hydroxylation, dehydrogenation, and benzisoxazole scission.
Population pharmacokinetic analyses found no difference in exposure or clearance of paliperidone between extensive metabolizers and poor metabolizers of CYP2D6 substrates.Special PopulationsRenal 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 adult subjects with varying degrees of renal function. Elimination of paliperidone decreased with decreasing estimated creatinine clearance. Total clearance of paliperidone was reduced in subjects with impaired renal function by 32% on average in mild (CrCl = 50 mL/min to < 80 mL/min), 64% in moderate (CrCl = 30 mL/min to < 50 mL/min), and 71% in severe (CrCl = 10 mL/min to < 30 mL/min) renal impairment, corresponding to an average increase in exposure (AUC
inf) of 1.5 fold, 2.6 fold, and 4.8 fold, respectively, compared to healthy subjects. The mean terminal elimination half-life of paliperidone was 24 hours, 40 hours, and 51 hours in subjects with mild, moderate, and severe renal impairment, respectively, compared with 23 hours in subjects with normal renal function (CrCl ≥ 80 mL/min).
Hepatic Impairment
In a study in adult subjects with moderate hepatic impairment (Child-Pugh class B), the plasma concentrations of free paliperidone were similar to those of healthy subjects, although total paliperidone exposure decreased because of a decrease in protein binding. Consequently, no dose adjustment is required in patients with mild or moderate hepatic impairment. Paliperidone has not been studied in patients with severe hepatic impairment.
Adolescents (12 to 17 years of age)
Paliperidone systemic exposure in adolescents weighing ≥ 51 kg (≥ 112 lbs) was similar to that in adults. In adolescents weighing < 51 kg (< 112 lbs), a 23% higher exposure was observed; this is considered not to be clinically significant. Age did not influence the paliperidone exposure.
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.

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis
Carcinogenicity studies with paliperidone administered orally have not been performed.
Carcinogenicity studies with risperidone, which is extensively converted to paliperidone in rats, mice, and humans, were conducted in Swiss albino mice and Wistar rats. Risperidone was administered in the diet at daily doses of 0.63 mg/kg, 2.5 mg/kg, and 10 mg/kg for 18 months to mice and for 25 months to rats. A maximum tolerated dose was not achieved in male mice. There were statistically significant increases in pituitary gland adenomas, endocrine pancreas adenomas, and mammary gland adenocarcinomas. The no-effect dose for these tumors was less than or equal to the MRHD of risperidone based on mg/m
2 body surface area (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 D
2 antagonism and hyperprolactinemia. The relevance of these tumor findings in rodents to 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
2 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 MRHD based on mg/m
2 body surface area.
The fertility of male rats was not affected at oral doses of paliperidone of up to 2 times the MRHD of 12 mg/day based on mg/m
2 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 to 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
2 body surface area). Serum testosterone and sperm parameters partially recovered, but remained decreased after the last observation (two months after treatment was discontinued).

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 U.S., India, Romania, Russia, and Ukraine, and involved subjects 12 to 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-SADS-PL).
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 to 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-D‑-21 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.3 mg tablets are white to off-white, circular, biconvex, beveled edged, film-coated tablets imprinted with “765” in black ink on one side and plain on the other side.

Unit dose packages of 100 (10 x 10) NDC 60687-459-01.
6 mg tablets are yellow, circular, biconvex, beveled edged, film-coated tablets imprinted with “766” in black ink on one side and plain on the other side.

Unit dose packages of 100 (10 x 10) NDC 60687-470-01.
Storage and Handling
Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F) [see USP Controlled Room Temperature]. Protect from moisture.
FOR YOUR PROTECTION: Do not use if blister is torn or broken.
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.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 (5.12)].
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 (5.18)].
Administration
Patients should be informed that paliperidone should be swallowed whole with the aid of liquids. Tablets should not be chewed, divided, or crushed
[see
Dosage and Administration (2.3)].
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
[see
Use in Specific Populations (8.1)].
Lactation
Advise breastfeeding women using paliperidone 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 paliperidone may impair fertility due to an increase in serum prolactin levels. The effects on fertility are reversible
[see
Use in Specific Populations (8.3)].

Packaging Information

American Health Packaging unit dose blisters (see How Supplied section) contain drug product from Sun Pharmaceutical Industries, Inc. as follows:

(3 mg / 100 UD) NDC 60687-459-01 packaged from NDC 47335-765

(6 mg / 100 UD) NDC 60687-470-01 packaged from NDC 47335-766
Distributed by:
American Health Packaging
Columbus, OH 43217
8445901/0519F

Package/Label Display Panel – Carton – 3 Mg

NDC 60687-
459-01
Paliperidone
Extended-Release Tablets
3 mg100 Tablets (10 x 10)               Rx OnlyEach Film-Coated Tablet Contains:
Paliperidone USP...................................................... 3 mg
Usual Dosage: See package insert for full prescribing

information.
Tablets should be swallowed whole. Do not divide,

crush or chew. Paliperidone extended-release tablets

should be taken once daily.
Store at 20° to 25°C (68° to 77°F); excursions permitted

between 15° to 30°C (59° to 86°F) [see USP Controlled

Room Temperature]. Protect from moisture.
Keep this and all drugs out of reach of children.FOR YOUR PROTECTION: Do not use if blister is torn

or broken.
The drug product contained in this package is from

NDC # 47335-765, Sun Pharmaceutical Industries, Inc.
Distributed by:

American Health Packaging

Columbus, Ohio 43217
745902

0445901/0519OS

Package/Label Display Panel – Carton – 6 Mg

NDC 60687-
470-01
Paliperidone
Extended-Release Tablets
6 mg100 Tablets (10 x 10)               Rx OnlyEach Film-Coated Tablet Contains:
Paliperidone USP......................................................6 mg
Usual Dosage: See package insert for full prescribing

information.
Tablets should be swallowed whole. Do not divide,

crush or chew. Paliperidone extended-release tablets

should be taken once daily.
Store at 20° to 25°C (68° to 77°F); excursions permitted

between 15° to 30°C (59° to 86°F) [see USP Controlled

Room Temperature]. Protect from moisture.
Keep this and all drugs out of reach of children.FOR YOUR PROTECTION: Do not use if blister is torn

or broken.
The drug product contained in this package is from

NDC # 47335-766, Sun Pharmaceutical Industries, Inc.
Distributed by:

American Health Packaging

Columbus, Ohio 43217
747002

0447001/0519OS

* Please review the disclaimer below.