PALIPERIDONE Drug Interactions: What You Need to Know

INTERACTIONS Centrally-acting drugs: Due to CNS effects, use caution in combination. Avoid alcohol. (7.1) Drugs that may cause orthostatic hypotension: An additive effect may be observed when co-administered with paliperidone. (7.1) Strong CYP3A4/P-glycoprotein (P-gp) inducers: It may be necessary to increase the dose of paliperidone when a strong inducer of both CYP3A4 and P-gp (e.g., carbamazepine) is co-administered. Conversely, on discontinuation of the strong inducer, it may be necessary to decrease the dose of paliperidone. (7.2) Co-administration of divalproex sodium increased C max and AUC of paliperidone by approximately 50%. Adjust dose of paliperidone if necessary based on clinical assessment. (7.2)

7.1 Potential for Paliperidone to Affect Other Drugs Given the primary CNS effects of paliperidone <span class="opacity-50 text-xs">[see Adverse Reactions (6.1, 6.2) ]</span> , 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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.9) ]</span>. Paliperidone is not expected to cause clinically important pharmacokinetic interactions with drugs that are metabolized by cytochrome P450 isozymes. In vitro studies in human liver microsomes showed that paliperidone does not substantially inhibit the metabolism of drugs metabolized by cytochrome P450 isozymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and CYP3A5. Therefore, paliperidone is not expected to inhibit clearance of drugs that are metabolized by these metabolic pathways in a clinically relevant manner. Paliperidone is also not expected to have enzyme inducing properties. Paliperidone is a weak inhibitor of P-glycoprotein (P-gp) at high concentrations. No in vivo data are available and the clinical relevance is unknown. Pharmacokinetic interaction between lithium and paliperidone is unlikely. In a drug interaction study, co-administration of paliperidone (12 mg once daily for 5 days) with divalproex sodium extended-release tablets (500 mg to 2000 mg once daily) did not affect the steady-state pharmacokinetics (AUC 24h 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. Co-administration 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 co-administration. On initiation of carbamazepine, the dose of paliperidone should be re-evaluated and increased if necessary. Conversely, on discontinuation of carbamazepine, the dose of paliperidone should be re-evaluated and decreased if necessary. Paliperidone is metabolized to a limited extent by CYP2D6 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . In an interaction study in healthy subjects in which a single 3 mg dose of paliperidone was administered concomitantly with 20 mg per day of paroxetine (a potent CYP2D6 inhibitor), paliperidone exposures were on average 16% (90% CI: 4, 30) higher in CYP2D6 extensive metabolizers. Higher doses of paroxetine have not been studied. The clinical relevance is unknown. Co-administration of a single dose of paliperidone 12 mg with divalproex sodium extended-release tablets (two 500 mg tablets once daily) resulted in an increase of approximately 50% in the C max and AUC of paliperidone. Dosage reduction for paliperidone should be considered when paliperidone is co-administered with valproate after clinical assessment. Pharmacokinetic interaction between lithium and paliperidone is unlikely.

7.1 Potential for Paliperidone to Affect Other Drugs Given the primary CNS effects of paliperidone <span class="opacity-50 text-xs">[see Adverse Reactions (6.1, 6.2) ]</span> , 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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.9) ]</span>. Paliperidone is not expected to cause clinically important pharmacokinetic interactions with drugs that are metabolized by cytochrome P450 isozymes. In vitro studies in human liver microsomes showed that paliperidone does not substantially inhibit the metabolism of drugs metabolized by cytochrome P450 isozymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and CYP3A5. Therefore, paliperidone is not expected to inhibit clearance of drugs that are metabolized by these metabolic pathways in a clinically relevant manner. Paliperidone is also not expected to have enzyme inducing properties. Paliperidone is a weak inhibitor of P-glycoprotein (P-gp) at high concentrations. No in vivo data are available and the clinical relevance is unknown. Pharmacokinetic interaction between lithium and paliperidone is unlikely. In a drug interaction study, co-administration of paliperidone (12 mg once daily for 5 days) with divalproex sodium extended-release tablets (500 mg to 2000 mg once daily) did not affect the steady-state pharmacokinetics (AUC 24h 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. Co-administration 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 co-administration. On initiation of carbamazepine, the dose of paliperidone should be re-evaluated and increased if necessary. Conversely, on discontinuation of carbamazepine, the dose of paliperidone should be re-evaluated and decreased if necessary. Paliperidone is metabolized to a limited extent by CYP2D6 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . In an interaction study in healthy subjects in which a single 3 mg dose of paliperidone was administered concomitantly with 20 mg per day of paroxetine (a potent CYP2D6 inhibitor), paliperidone exposures were on average 16% (90% CI: 4, 30) higher in CYP2D6 extensive metabolizers. Higher doses of paroxetine have not been studied. The clinical relevance is unknown. Co-administration of a single dose of paliperidone 12 mg with divalproex sodium extended-release tablets (two 500 mg tablets once daily) resulted in an increase of approximately 50% in the C max and AUC of paliperidone. Dosage reduction for paliperidone should be considered when paliperidone is co-administered with valproate after clinical assessment. Pharmacokinetic interaction between lithium and paliperidone is unlikely.

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. Known hypersensitivity to paliperidone, risperidone, or to any excipients in paliperidone extended-release tablets. ( 4 )

AND PRECAUTIONS Cerebrovascular Adverse Reactions: An increased incidence of cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack, including fatalities) has been seen in elderly patients with dementia-related psychoses treated with atypical antipsychotics. (5.2)

Neuroleptic Malignant

Syndrome: Manage with immediate discontinuation of drug and close monitoring. (5.3) QT Prolongation: Increase in QT interval, avoid use with drugs that also increase QT interval and in patients with risk factors for prolonged QT interval. (5.4)

Tardive

Dyskinesia: Discontinue drug if clinically appropriate. (5.5)

Metabolic

Changes: Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and weight gain. (5.6) Hyperglycemia and Diabetes Mellitus: Monitor patients for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Monitor glucose regularly in patients with diabetes or at risk for diabetes. (5.6) Dyslipidemia: Undesirable alterations have been observed in patients treated with atypical antipsychotics. (5.6)

Weight

Gain: Significant weight gain has been reported. Monitor weight gain. (5.6) Hyperprolactinemia: Prolactin elevations occur and persist during chronic administration. (5.7)

Gastrointestinal

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

Orthostatic

Hypotension and Syncope: Use with caution in patients with known cardiovascular or cerebrovascular disease and patients predisposed to hypotension. (5.9) Leukopenia, Neutropenia, and Agranulocytosis: has been reported with antipsychotics, including paliperidone. Patients with a history of a clinically significant low white blood cell count (WBC) or a drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of paliperidone should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors. (5.11) Potential for Cognitive and Motor Impairment: Use caution when operating machinery. (5.12) Seizures: Use cautiously in patients with a history of seizures or with conditions that lower the seizure threshold. (5.13)

5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. Paliperidone is not approved for the treatment of dementia-related psychosis <span class="opacity-50 text-xs">[see Boxed Warning ]</span>.

5.2 Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly subjects with dementia, there was a higher incidence of cerebrovascular adverse reactions (cerebrovascular accidents and transient ischemic attacks) including fatalities compared to placebo-treated subjects. Paliperidone was not marketed at the time these studies were performed. Paliperidone is not approved for the treatment of patients with dementia-related psychosis <span class="opacity-50 text-xs">[see also Boxed Warning and Warnings and Precautions (5.1) ]</span>.

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 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 (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 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 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, drug discontinuation should be considered. However, some patients may require treatment with paliperidone despite the presence of the syndrome.

5.6 Metabolic Changes Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile. Hyperglycemia and Diabetes Mellitus Hyperglycemia and diabetes mellitus, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, have been reported in patients treated with all atypical antipsychotics. These cases were, for the most part, seen in post-marketing clinical use and epidemiologic studies, not in clinical trials, and there have been few reports of hyperglycemia or diabetes in trial subjects treated with paliperidone. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Because paliperidone was not marketed at the time these studies were performed, it is not known if paliperidone is associated with this increased risk. Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug. Pooled data from the three placebo-controlled, 6-week, fixed-dose studies in adult subjects with schizophrenia are presented in Table 1a.

Table

1a. Change in Fasting Glucose from Three Placebo-Controlled, 6-Week, Fixed-Dose Studies in Adult Subjects with Schizophrenia Paliperidone 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% (&lt;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 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 Schizophrenia Paliperidone 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% (&lt;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 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 LDL n=322 n=116 n=210 n=231 n=225 Change from baseline -3.2 0.5 -0.8 -3.9 -2 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% (&lt;200 mg/dL to ≥240 mg/dL) (5/194) (2/71) (7/125) (6/147) (4/130)

Ldl

Normal to High 1.9% 0% 5% 3.7% 0% (<100 mg/dL to ≥160 mg/dL) (2/105) (0/44) (3/60) (3/81) (0/69)

Hdl

Normal to Low 22% 16.3% 29.1% 23.4% 20% (≥40 mg/dL to <40 mg/dL) (44/200) (13/80) (39/134) (32/137) (27/135)

Triglycerides

Normal to High 5.3% 11% 8.8% 8.7% 4.3% (<150 mg/dL to ≥200 mg/dL) (11/208) (9/82) (12/136) (13/150) (6/139) In the uncontrolled, longer-term open-label extension studies, paliperidone was associated with a mean change in (a) total cholesterol of -1.5 mg/dL at Week 24 (n=573) and -1.5 mg/dL at Week 52 (n=317), (b) triglycerides of -6.4 mg/dL at Week 24 (n=573) and -10.5 mg/dL at Week 52 (n=317); (c) LDL of -1.9 mg/dL at Week 24 (n=557) and -2.7 mg/dL at Week 52 (n=297); and (d) HDL of +2.2 mg/dL at Week 24 (n=568) and +3.6 mg/dL at Week 52 (n=302). Data from the placebo-controlled 6-week study in adolescent subjects (12 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 Schizophrenia Paliperidone 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% (&lt;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 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

1.1 Weight Gain ≥ 7% increase from baseline 5% 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 <span class="opacity-50 text-xs">[see Clinical Studies (14.1) ]</span> 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 Schizophrenia Paliperidone 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 with an increase in body weight of ≥ 7% from baseline was 33%. When treating adolescent patients with paliperidone, weight gain should be assessed against that expected with normal growth. When taking into consideration the median duration of exposure to paliperidone in the open-label study (182 days) along with expected normal growth in this population based on age and gender, an assessment of standardized scores relative to normative data provides a more clinically relevant measure of changes in weight. The mean change from open-label baseline to endpoint in standardized score for weight was 0.1 (4% above the median for normative data). Based on comparison to the normative data, these changes are not considered to be clinically significant.

Schizoaffective Disorder

Trials In the pooled data from the two placebo-controlled, 6-week studies in adult subjects with schizoaffective disorder, a higher percentage of paliperidone-treated subjects (5%) had an increase in body weight of ≥ 7% compared with placebo-treated subjects (1%). In the study that examined high- and low-dose groups, the increase in body weight of ≥ 7% was 3% in the low-dose group, 7% in the high-dose group, and 1% in the placebo group.

5.7 Hyperprolactinemia Like other drugs that antagonize dopamine D 2 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 <span class="opacity-50 text-xs">[see Nonclinical Toxicology (13.1) ]</span>. Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans, but the available evidence is too limited to be conclusive.

5.8 Potential for Gastrointestinal Obstruction Because the paliperidone extended-release 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 pseudo-obstruction, 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) and Patient Counseling Information (17) ]</span>. 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 In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents, including paliperidone. Agranulocytosis has also been reported. Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC)/absolute neutrophil count (ANC) and history of drug-induced leukopenia/neutropenia. In patients with a history of a clinically significant low WBC/ANC or a drug-induced leukopenia/neutropenia, perform a complete blood count (CBC) frequently during the first few months of therapy. In such patients, consider discontinuation of paliperidone at the first sign of a clinically significant decline in WBC in the absence of other causative factors. Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur. Discontinue paliperidone in patients with severe neutropenia (absolute neutrophil count &lt; 1000/mm 3 ) and follow their WBC until recovery.

5.12 Potential for Cognitive and Motor Impairment Somnolence, sedation, and dizziness were reported as adverse reactions in subjects treated with paliperidone <span class="opacity-50 text-xs">[see Adverse Reactions (6.2) ]</span>. 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 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.

5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. Paliperidone is not approved for the treatment of dementia-related psychosis <span class="opacity-50 text-xs">[see Boxed Warning ]</span>.

5.2 Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly subjects with dementia, there was a higher incidence of cerebrovascular adverse reactions (cerebrovascular accidents and transient ischemic attacks) including fatalities compared to placebo-treated subjects. Paliperidone was not marketed at the time these studies were performed. Paliperidone is not approved for the treatment of patients with dementia-related psychosis <span class="opacity-50 text-xs">[see also Boxed Warning and Warnings and Precautions (5.1) ]</span>.

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 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 (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 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 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, drug discontinuation should be considered. However, some patients may require treatment with paliperidone despite the presence of the syndrome.

5.6 Metabolic Changes Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile. Hyperglycemia and Diabetes Mellitus Hyperglycemia and diabetes mellitus, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, have been reported in patients treated with all atypical antipsychotics. These cases were, for the most part, seen in post-marketing clinical use and epidemiologic studies, not in clinical trials, and there have been few reports of hyperglycemia or diabetes in trial subjects treated with paliperidone. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Because paliperidone was not marketed at the time these studies were performed, it is not known if paliperidone is associated with this increased risk. Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug. Pooled data from the three placebo-controlled, 6-week, fixed-dose studies in adult subjects with schizophrenia are presented in Table 1a.

Table

1a. Change in Fasting Glucose from Three Placebo-Controlled, 6-Week, Fixed-Dose Studies in Adult Subjects with Schizophrenia Paliperidone 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% (&lt;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 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 Schizophrenia Paliperidone 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% (&lt;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 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 LDL n=322 n=116 n=210 n=231 n=225 Change from baseline -3.2 0.5 -0.8 -3.9 -2 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% (&lt;200 mg/dL to ≥240 mg/dL) (5/194) (2/71) (7/125) (6/147) (4/130)

Ldl

Normal to High 1.9% 0% 5% 3.7% 0% (<100 mg/dL to ≥160 mg/dL) (2/105) (0/44) (3/60) (3/81) (0/69)

Hdl

Normal to Low 22% 16.3% 29.1% 23.4% 20% (≥40 mg/dL to <40 mg/dL) (44/200) (13/80) (39/134) (32/137) (27/135)

Triglycerides

Normal to High 5.3% 11% 8.8% 8.7% 4.3% (<150 mg/dL to ≥200 mg/dL) (11/208) (9/82) (12/136) (13/150) (6/139) In the uncontrolled, longer-term open-label extension studies, paliperidone was associated with a mean change in (a) total cholesterol of -1.5 mg/dL at Week 24 (n=573) and -1.5 mg/dL at Week 52 (n=317), (b) triglycerides of -6.4 mg/dL at Week 24 (n=573) and -10.5 mg/dL at Week 52 (n=317); (c) LDL of -1.9 mg/dL at Week 24 (n=557) and -2.7 mg/dL at Week 52 (n=297); and (d) HDL of +2.2 mg/dL at Week 24 (n=568) and +3.6 mg/dL at Week 52 (n=302). Data from the placebo-controlled 6-week study in adolescent subjects (12 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 Schizophrenia Paliperidone 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% (&lt;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 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

1.1 Weight Gain ≥ 7% increase from baseline 5% 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 <span class="opacity-50 text-xs">[see Clinical Studies (14.1) ]</span> 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 Schizophrenia Paliperidone 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 with an increase in body weight of ≥ 7% from baseline was 33%. When treating adolescent patients with paliperidone, weight gain should be assessed against that expected with normal growth. When taking into consideration the median duration of exposure to paliperidone in the open-label study (182 days) along with expected normal growth in this population based on age and gender, an assessment of standardized scores relative to normative data provides a more clinically relevant measure of changes in weight. The mean change from open-label baseline to endpoint in standardized score for weight was 0.1 (4% above the median for normative data). Based on comparison to the normative data, these changes are not considered to be clinically significant.

Schizoaffective Disorder

Trials In the pooled data from the two placebo-controlled, 6-week studies in adult subjects with schizoaffective disorder, a higher percentage of paliperidone-treated subjects (5%) had an increase in body weight of ≥ 7% compared with placebo-treated subjects (1%). In the study that examined high- and low-dose groups, the increase in body weight of ≥ 7% was 3% in the low-dose group, 7% in the high-dose group, and 1% in the placebo group.

5.7 Hyperprolactinemia Like other drugs that antagonize dopamine D 2 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 <span class="opacity-50 text-xs">[see Nonclinical Toxicology (13.1) ]</span>. Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans, but the available evidence is too limited to be conclusive.

5.8 Potential for Gastrointestinal Obstruction Because the paliperidone extended-release 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 pseudo-obstruction, 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) and Patient Counseling Information (17) ]</span>. 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.

5.11 Leukopenia, Neutropenia, and Agranulocytosis In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents, including paliperidone. Agranulocytosis has also been reported. Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC)/absolute neutrophil count (ANC) and history of drug-induced leukopenia/neutropenia. In patients with a history of a clinically significant low WBC/ANC or a drug-induced leukopenia/neutropenia, perform a complete blood count (CBC) frequently during the first few months of therapy. In such patients, consider discontinuation of paliperidone at the first sign of a clinically significant decline in WBC in the absence of other causative factors. Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur. Discontinue paliperidone in patients with severe neutropenia (absolute neutrophil count &lt; 1000/mm 3 ) and follow their WBC until recovery.

5.12 Potential for Cognitive and Motor Impairment Somnolence, sedation, and dizziness were reported as adverse reactions in subjects treated with paliperidone <span class="opacity-50 text-xs">[see Adverse Reactions (6.2) ]</span>. 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 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.