Paliperidone: Package Insert and Label Information

PALIPERIDONE — paliperidone tablet, extended release
Lupin Pharmaceuticals, Inc.

1 INDICATIONS AND USAGE

1.1 Schizophrenia

Paliperidone extended-release tablets are indicated for the treatment of schizophrenia [see CLINICAL STUDIES (14.1)].

The efficacy of paliperidone 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 DOSAGE AND ADMINISTRATION

2.1 Schizophrenia

Adults

The recommended dose of paliperidone extended-release tablets for the treatment of schizophrenia in adults is 6 mg administered once daily. Initial dose titration is not required. Although it has not been systematically established that doses above 6 mg have additional benefit, there was a general trend for greater effects with higher doses. This must be weighed against the dose-related increase in adverse reactions. Thus, some patients may benefit from higher doses, up to 12 mg/day, and for some patients, a lower dose of 3 mg/day may be sufficient. Dose increases above 6 mg/day should be made only after clinical reassessment and generally should occur at intervals of more than 5 days. When dose increases are indicated, increments of 3 mg/day are recommended. The maximum recommended dose is 12 mg/day.

In a longer-term study, paliperidone extended-release tablets have been shown to be effective in delaying time to relapse in patients with schizophrenia who were stabilized on paliperidone extended-release tablets for 6 weeks [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 years to 17 years of age)

The recommended starting dose of paliperidone extended-release tablets for the treatment of schizophrenia in adolescents 12 years 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 mg 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. The medication is contained within a nonabsorbable shell designed to release the drug at a controlled rate. The tablet shell, along with insoluble core components, is eliminated from the body; patients should not be concerned if they occasionally notice in their stool something that looks like a tablet.

2.4 Use with Risperidone

Concomitant use of paliperidone extended-release tablets with risperidone has not been studied. Since paliperidone is the major active metabolite of risperidone, consideration should be given to the additive paliperidone exposure if risperidone is 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 extended-release tablet 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 extended-release tablet 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), 6 mg (beige), and 9 mg (pink). All tablets are round shaped, biconvex and are imprinted with either “LP1”, “LP2”, “LP3”, or “LP4” on one side and plain on other side.

4 CONTRAINDICATIONS

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

5 WARNINGS AND PRECAUTIONS

5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. Paliperidone extended-release tablets are not approved for the treatment of dementia-related psychosis [see BOXED WARNING].

5.2 Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis

In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly subjects with dementia, there was a higher incidence of cerebrovascular adverse reactions (cerebrovascular accidents and transient ischemic attacks) including fatalities compared to placebo-treated subjects. Paliperidone extended-release tablets were not marketed at the time these studies were performed. Paliperidone extended-release tablets are 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

Neuroleptic Malignant Syndrome (NMS), a potentially fatal symptom complex, has been reported in association with antipsychotic drugs, including paliperidone. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status including delirium, and 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.

If NMS is suspected, immediately discontinue paliperidone extended-release tablets and provide symptomatic treatment and monitoring.

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 extended-release tablets (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 extended-release tablets 12 mg group had a change exceeding 60 msec at one time-point on Day 6 (increase of 62 msec). No subject receiving paliperidone extended-release tablets had a QTcLD exceeding 500 msec at any time in any of these three studies.

5.5 Tardive Dyskinesia

Tardive dyskinesia, a syndrome consisting 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 with duration of treatment and the cumulative dose. The syndrome can develop after relatively brief treatment periods, even at low doses. It may also occur after discontinuation of treatment.

Tardive dyskinesia may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.

Given these considerations, paliperidone extended-release tablets 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: (1) who suffer from a chronic illness that is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, use the lowest dose and the shortest duration of treatment producing a satisfactory clinical response. Periodically reassess the need for continued treatment.

If signs and symptoms of tardive dyskinesia appear in a patient on paliperidone extended-release tablets, drug discontinuation should be considered. However, some patients may require treatment with paliperidone extended-release tablets despite the presence of the syndrome.

5.6 Metabolic Changes

Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.

Hyperglycemia and Diabetes Mellitus

Hyperglycemia and diabetes mellitus, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, have been reported in patients treated with all atypical antipsychotics. These cases were, for the most part, seen in post-marketing clinical use and epidemiologic studies, not in clinical trials, and there have been few reports of hyperglycemia or diabetes in trial subjects treated with paliperidone extended-release tablets. 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 extended-release tablets were not marketed at the time these studies were performed, it is not known if paliperidone extended-release tablets are associated with this increased risk.

Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.

Pooled data from the three placebo-controlled, 6-week, fixed-dose studies in adult subjects with schizophrenia are presented in Table 1a.

Table 1a. Change in Fasting Glucose from Three Placebo-Controlled, 6-Week, Fixed-Dose Studies in Adult Subjects with Schizophrenia

	Paliperidone Extended – Release Tablets
	Placebo	3 mg / day	6 mg / day	9 mg / day	12 mg / day
	Mean change from baseline ( mg / dL )
	n = 322	n = 122	n = 212	n = 234	n = 218
Serum Glucose Change from baseline	0.8	-0.7	0.4	2.3	4.3
	Proportion of Patients with Shifts
Serum Glucose Normal to High	5.1%	3.2%	4.5%	4.8%	3.8%
(<100 mg/dL to ≥ 126 mg/dL)	(12/236)	(3/93)	(7/156)	(9/187)	(6/157)

In the uncontrolled, longer-term open-label extension studies, paliperidone extended-release tablets were 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 years 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 years to 17 years of age) with Schizophrenia

	Paliperidone Extended-Release Tablets
	Placebo	1.5 mg/day	3 mg/day	6 mg/day	12 mg/day
	Mean change from baseline (mg/dL)
	n = 41	n = 44	n = 11	n = 28	n = 32
Serum Glucose Change from baseline	0.8	-1.4	-1.8	-0.1	5.2
	Proportion of Patients with Shifts
Serum Glucose Normal to High	3%	0%	0%	0%	11%
(<100 mg/dL to ≥ 126 mg/dL)	(1/32)	(0/34)	(0/9)	(0/20)	(3/27)

Dyslipidemia

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

Pooled data from the three placebo-controlled, 6-week, fixed-dose studies in adult subjects with schizophrenia are presented in Table 2a.

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

	Paliperidone Extended – Release Tablets
	Placebo	3 mg / day	6 mg / day	9 mg / day	12 mg / day
	Mean change from baseline ( mg / dL )
Cholesterol	n = 331	n = 120	n = 216	n = 236	n = 231
Change from baseline	-6.3	-4.4	-2.4	-5.3	-4.0
LDL	n = 322	n = 116	n = 210	n = 231	n = 225
Change from baseline	-3.2	0.5	-0.8	-3.9	-2.0
HDL	n = 331	n = 119	n = 216	n = 234	n = 230
Change from baseline	0.3	-0.4	0.5	0.8	1.2
Triglycerides	n = 331	n = 120	n = 216	n = 236	n = 231
Change from baseline	-22.3	-18.3	-12.6	-10.6	-15.4
	Proportion of Patients with Shifts
Cholesterol
Normal to High	2.6%	2.8%	5.6%	4.1%	3.1%
(< 200 mg / dL to ≥ 240 mg / dL )	(5/194)	(2/71)	(7/125)	(6/147)	(4/130)
LDL
Normal to High	1.9%	0.0%	5.0%	3.7%	0.0%
(< 100 mg / dL to ≥ 160 mg / dL )	(2/105)	(0/44)	(3/60)	(3/81)	(0/69)
HDL
Normal to Low	22.0%	16.3%	29.1%	23.4%	20.0%
( ≥ 40 mg / dL to < 40 mg / dL )	(44/200)	(13/80)	(39/134)	(32/137)	(27/135)
Triglycerides
Normal to High	5.3%	11.0%	8.8%	8.7%	4.3%
(< 150 mg / dL to ≥ 200 mg / dL )	(11/208)	(9/82)	(12/136)	(13/150)	(6/139)

In the uncontrolled, longer-term open-label extension studies, paliperidone extended-release tablets were 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 years 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 years to 17 years of age) with Schizophrenia

	Paliperidone Extended – Release Tablets
	Placebo	1 . 5 mg / day	3 mg / day	6 mg / day	12 mg / day
	Mean change from baseline ( mg / dL )
Cholesterol	n = 39	n = 45	n = 11	n = 28	n = 32
Change from baseline	-7.8	-3.3	12.7	3.0	-1.5
LDL	n = 37	n = 40	n = 9	n = 27	n = 31
Change from baseline	-4.1	-3.1	7.2	2.4	0.6
HDL	n = 37	n = 41	n = 9	n = 27	n = 31
Change from baseline	-1.9	0.0	1.3	1.4	0.0
Triglycerides	n = 39	n = 44	n = 11	n = 28	n = 32
Change from baseline	-8.9	3.2	17.6	-5.4	3.9
	Proportion of Patients with Shifts
Cholesterol
Normal to High	7%	4%	0%	6%	11%
(< 170 mg / dL to ≥ 200 mg / dL )	(2/27)	(1/26)	(0/6)	(1/18)	(2/19)
LDL
Normal to High	3%	4%	14%	0%	9%
(< 110 mg / dL to ≥ 130 mg / dL )	(1/32)	(1/25)	(1/7)	(0/22)	(2/22)
HDL
Normal to Low	14%	7%	29%	13%	23%
( ≥ 40 mg / dL to < 40 mg / dL )	(4/28)	(2/30)	(2/7)	(3/23)	(5/22)
Triglycerides
Normal to High	3%	5%	13%	8%	7%
(< 150 mg / dL to ≥ 200 mg / dL )	(1/34)	(2/38)	(1/8)	(2/26)	(2/28)

Weight Gain

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

Schizophrenia Trials:

Data on mean changes in body weight and the proportion of subjects meeting a weight gain criterion of ≥ 7% of body weight from the three placebo-controlled, 6-week, fixed-dose studies in adult subjects are presented in Table 3a.

Table 3a. Mean Change in Body Weight (kg) and the Proportion of Subjects with ≥ 7% Gain in Body Weight from Three Placebo-Controlled, 6-Week, Fixed-Dose Studies in Adult Subjects with Schizophrenia

	Paliperidone Extended – Release Tablets
	Placebo	3 mg / day	6 mg / day	9 mg / day	12 mg / day
	n = 323	n = 112	n = 215	n = 235	n = 218
Weight ( kg )
Change from baseline	-0.4	0.6	0.6	1.0	1.1
Weight Gain
≥ 7 % increase from baseline	5%	7%	6%	9%	9%

In the uncontrolled, longer-term open-label extension studies, paliperidone extended-release tablets were 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 extended-release tablets 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 years 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 years to 17 years of age) with Schizophrenia

	Paliperidone Extended – Release Tablets
	Placebo	1 . 5 mg / day	3 mg / day	6 mg / day	12 mg / day
	n = 51	n = 54	n = 16	n = 45	n = 34
Weight ( kg )
Change from baseline	0.0	0.3	0.8	1.2	1.5
Weight Gain
≥ 7 % increase from baseline	2%	6%	19%	7%	18%

In the open-label long-term study the proportion of total subjects treated with paliperidone extended-release tablets with an increase in body weight of ≥ 7% from baseline was 33%. When treating adolescent patients with paliperidone extended-release tablets, weight gain should be assessed against that expected with normal growth. When taking into consideration the median duration of exposure to paliperidone extended-release tablets 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 extended-release tablets-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.