1.1 Schizophrenia

INVEGA® (paliperidone) Extended-Release Tablets are indicated for the acute and maintenance treatment of schizophrenia [see Clinical Studies (14)].

1.2 Schizoaffective Disorder

2.1 Schizophrenia

The recommended dose of INVEGA® (paliperidone) Extended-Release Tablets for the treatment of schizophrenia is 6 mg once daily, administered in the morning. 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, INVEGA® has been shown to be effective in delaying time to relapse in patients with schizophrenia who were stabilized on INVEGA® for 6 weeks [see Clinical Studies (14)]. INVEGA® 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.

2.2 Schizoaffective Disorder

The recommended dose of INVEGA® (paliperidone) Extended-Release Tablets for the treatment of schizoaffective disorder is 6 mg once daily, administered in the morning. 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

INVEGA® can be taken with or without food. Clinical trials establishing the safety and efficacy of INVEGA® were carried out in patients without regard to food intake.

INVEGA® 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 INVEGA® 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 INVEGA®.

2.5 Dosage in Special Populations

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. INVEGA® (paliperidone) is not approved for the treatment of dementia-related psychosis [see Boxed Warning].

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

In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly subjects with dementia, there was a higher incidence of cerebrovascular adverse reactions (cerebrovascular accidents and transient ischemic attacks) including fatalities compared to placebo-treated subjects. INVEGA® was not marketed at the time these studies were performed. INVEGA® 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 INVEGA® (Cmax 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 Cmax 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 INVEGA® 12 mg group had a change exceeding 60 msec at one time-point on Day 6 (increase of 62 msec). No subject receiving INVEGA® 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.

There is no known treatment for established tardive dyskinesia, although 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, INVEGA® 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 INVEGA®, drug discontinuation should be considered. However, some patients may require treatment with INVEGA® despite the presence of the syndrome.

5.6 Hyperglycemia and Diabetes Mellitus

Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has 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 INVEGA®. 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 INVEGA® was not marketed at the time these studies were performed, it is not known if INVEGA® 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.

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 INVEGA® tablet is non-deformable and does not appreciably change in shape in the gastrointestinal tract, INVEGA® 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, INVEGA® should only be used in patients who are able to swallow the tablet whole [see Dosage and Administration (2.3) and Patient Counseling Information (17.8)].

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 INVEGA® (3 mg, 6 mg, 9 mg, 12 mg) compared to 0.3% (1/355) of subjects treated with placebo. INVEGA® 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 Leukopenia, Neutropenia, and Agranulocytosis

5.11 Potential for Cognitive and Motor Impairment

Somnolence was reported in subjects treated with INVEGA® [see Adverse Reactions (6.1, 6.2)]. Antipsychotics, including INVEGA®, 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.

5.12 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 INVEGA® (3 mg, 6 mg, 9 mg, 12 mg) and 0.25% of subjects treated with placebo. Like other antipsychotic drugs, INVEGA® 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.

5.13 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. INVEGA® and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.

5.14 Suicide

The possibility of suicide attempt is inherent in psychotic illnesses, and close supervision of high-risk patients should accompany drug therapy. Prescriptions for INVEGA® should be written for the smallest quantity of tablets consistent with good patient management in order to reduce the risk of overdose.

5.15 Priapism

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

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

5.20 Monitoring: Laboratory Tests

No specific laboratory tests are recommended.

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

Table 1 enumerates the pooled incidences of adverse reactions reported in the three placebo-controlled, 6-week, fixed-dose studies, listing those that occurred in 2% or more of subjects treated with INVEGA® in any of the dose groups, and for which the incidence in INVEGA®-treated subjects in any of the dose groups was greater than the incidence in subjects treated with placebo.

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

Table 2 enumerates the pooled incidences of adverse reactions reported in the two placebo-controlled 6-week studies, listing those that occurred in 2% or more of subjects treated with INVEGA® and for which the incidence in INVEGA®-treated subjects was greater than the incidence in subjects treated with placebo.

6.3 Other Adverse Reactions Observed During Premarketing Evaluation of INVEGA®

The following additional adverse reactions occurred in < 2% of INVEGA®-treated subjects in the above schizophrenia and schizoaffective disorder clinical trial datasets. The following also includes additional adverse reactions reported at any frequency by INVEGA®-treated subjects who participated in other clinical studies.

Cardiac disorders: bradycardia, bundle branch block left, palpitations

Endocrine disorders: hyperprolactinemia

Eye disorders: vision blurred

Gastrointestinal disorders: abdominal pain, flatulence, small intestinal obstruction, swollen tongue

General disorders: edema, edema peripheral

Immune system disorders: anaphylactic reaction

Infections and infestations: urinary tract infection

Investigations: electrocardiogram abnormal

Musculoskeletal and connective tissue disorders: arthralgia, pain in extremity

Nervous system disorders: cerebrovascular accident, convulsion, dizziness postural, grand mal convulsion, lethargy, syncope, transient ischemic attack, additional extrapyramidal symptoms (cogwheel rigidity, muscle spasms, musculoskeletal pain, torticollis, trismus)

Psychiatric disorders: agitation, nightmare

Reproductive system and breast disorders: amenorrhea, breast discharge, breast engorgement, breast tenderness, breast pain, erectile dysfunction, galactorrhea, gynecomastia, menstruation irregular, retrograde ejaculation

Respiratory, thoracic and mediastinal disorders: nasal congestion, pneumonia aspiration

Skin and subcutaneous tissue disorders: pruritus, rash, rash papular

Vascular disorders: hypotension, ischemia

6.4 Discontinuations Due to Adverse Reactions

6.5 Dose-Related Adverse Reactions

6.6 Demographic Differences

An examination of population subgroups in the three placebo-controlled, 6-week, fixed-dose studies in subjects with schizophrenia and in the two placebo-controlled, 6-week studies in subjects with schizoaffective disorder did not reveal any evidence of clinically relevant differences in safety on the basis of gender or race alone; there was also no difference on the basis of age [see Use in Specific Populations (8.5)].

6.7 Extrapyramidal Symptoms (EPS)

Pooled data from the three placebo-controlled, 6-week, fixed-dose studies in subjects with schizophrenia provided information regarding treatment-emergent EPS. Several methods were used to measure EPS: (1) the Simpson-Angus global score (mean change from baseline) which broadly evaluates Parkinsonism, (2) the Barnes Akathisia Rating Scale global clinical rating score (mean change from baseline) which evaluates akathisia, (3) use of anticholinergic medications to treat emergent EPS (Table 3), and (4) incidence of spontaneous reports of EPS (Table 4). 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 INVEGA® 3 mg and 6 mg doses for any of these EPS measures.

Compared to data from the studies in schizophrenia, pooled data from the two placebo-controlled 6-week studies in 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 5 shows the EPS data from the pooled schizoaffective disorder trials.

6.8 Laboratory Test Abnormalities

In the pooled data from the three placebo-controlled, 6-week, fixed-dose studies in subjects with schizophrenia and from the two placebo-controlled, 6-week studies in subjects with schizoaffective disorder, between-group comparisons revealed no medically important differences between INVEGA® 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 INVEGA® 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, INVEGA® was associated with increases in serum prolactin [see Warnings and Precautions (5.7)].

6.9 Weight Gain

6.10 Other Findings Observed During Clinical Trials

The safety of INVEGA® was also evaluated in a long-term trial designed to assess the maintenance of effect with INVEGA® 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.

6.11 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of INVEGA®; because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency: angioedema, priapism, swollen tongue, tardive dyskinesia, urinary incontinence, urinary retention.

6.12 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 INVEGA® to Affect Other Drugs

Given the primary CNS effects of paliperidone [see Adverse Reactions (6.1, 6.2)], INVEGA® 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 INVEGA® 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 INVEGA® is unlikely.

In a clinical study, subjects on a stable dose of valproate showed comparable valproate average plasma concentrations when 3–15 mg of INVEGA® was added to their existing valproate treatment.

7.2 Potential for Other Drugs to Affect INVEGA®

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 INVEGA® 6 mg once daily with carbamazepine 200 mg twice daily caused a decrease of approximately 37% in the mean steady-state Cmax 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 INVEGA® should be re-evaluated and increased if necessary. Conversely, on discontinuation of carbamazepine, the dose of INVEGA® 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 INVEGA® 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 INVEGA® 12 mg with divalproex sodium extended-release tablets (two 500 mg tablets once daily) resulted in an increase of approximately 50% in the Cmax and AUC of paliperidone. Dosage reduction for INVEGA® should be considered when INVEGA® is co-administered with valproate after clinical assessment.

Pharmacokinetic interaction between lithium and INVEGA® is unlikely.

8.1 Pregnancy

8.3 Nursing Mothers

Paliperidone is 9-hydroxyrisperidone, the active metabolite of risperidone. In animal studies, risperidone and 9-hydroxyrisperidone were excreted in milk. Risperidone and 9-hydroxyrisperidone are also excreted in human breast milk. Caution should be exercised when INVEGA® is administered to a nursing woman. The known benefits of breastfeeding should be weighed against the unknown risks of infant exposure to paliperidone.

8.4 Pediatric Use

Safety and effectiveness of INVEGA® in patients < 18 years of age have not been established.

8.5 Geriatric Use

The safety, tolerability, and efficacy of INVEGA® 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 INVEGA® (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 INVEGA® (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 INVEGA® (n = 1796), including those who received INVEGA® or placebo, 125 (7.0%) were 65 years of age and older and 22 (1.2%) were 75 years of age and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

This drug is known to be substantially excreted by the kidney and clearance is decreased in patients with moderate to severe renal impairment [see Clinical Pharmacology (12.3)], who should be given reduced doses. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [see Dosage and Administration (2.5)].

8.6 Renal Impairment

Dosing must be individualized according to the patient's renal function status [see Dosage and Administration (2.5)].

8.7 Hepatic Impairment

No dosage adjustment is required in patients with mild to moderate hepatic impairment. INVEGA® has not been studied in patients with severe hepatic impairment.

9.1 Controlled Substance

INVEGA® (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 INVEGA® 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 INVEGA® 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. Gastric lavage (after intubation if patient is unconscious) and 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.

11.1 Delivery System Components and Performance

INVEGA® uses osmotic pressure to deliver paliperidone at a controlled rate. The delivery system, which resembles a capsule-shaped tablet in appearance, consists of an osmotically active trilayer core surrounded by a subcoat and semipermeable membrane. The trilayer core is composed of two drug layers containing the drug and excipients, and a push layer containing osmotically active components. There are two precision laser-drilled orifices on the drug-layer dome of the tablet. Each tablet strength has a different colored water-dispersible overcoat and print markings. In an aqueous environment, such as the gastrointestinal tract, the water-dispersible color overcoat erodes quickly. Water then enters the tablet through the semipermeable membrane that controls the rate at which water enters the tablet core, which, in turn, determines the rate of drug delivery. The hydrophilic polymers of the core hydrate and swell, creating a gel containing paliperidone that is then pushed out through the tablet orifices. The biologically inert components of the tablet remain intact during gastrointestinal transit and are eliminated in the stool as a tablet shell, along with insoluble core components.

12.1 Mechanism of Action

Paliperidone is the major active metabolite of risperidone. The mechanism of action of paliperidone, as with other drugs having efficacy in schizophrenia, is unknown, but it has been proposed that the drug's therapeutic activity in schizophrenia is mediated through a combination of central dopamine Type 2 (D2) and serotonin Type 2 (5HT2A) receptor antagonism.

12.2 Pharmacodynamics

Paliperidone is a centrally active dopamine Type 2 (D2) antagonist and with predominant serotonin Type 2 (5HT2A) activity. Paliperidone is also active as an antagonist at α1 and α2 adrenergic receptors and H1 histaminergic receptors, which may explain some of the other effects of the drug. Paliperidone has no affinity for cholinergic muscarinic or β1- and β2-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 (Cmax) approximately 24 hours after dosing. The pharmacokinetics of paliperidone following INVEGA® administration are dose-proportional within the available dose range. The terminal elimination half-life of paliperidone is approximately 23 hours.

Steady-state concentrations of paliperidone are attained within 4–5 days of dosing with INVEGA® in most subjects. The mean steady-state peak:trough ratio for an INVEGA® dose of 9 mg was 1.7 with a range of 1.2–3.1.

Following administration of INVEGA®, the (+) and (-) enantiomers of paliperidone interconvert, reaching an AUC (+) to (-) ratio of approximately 1.6 at steady state.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14.1 Schizophrenia

The acute efficacy of INVEGA® (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), INVEGA® 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. INVEGA® 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 INVEGA® 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 INVEGA® (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 INVEGA® 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 INVEGA® compared to placebo, and the trial was stopped early because maintenance of efficacy was demonstrated.

14.2 Schizoaffective Disorder

The acute efficacy of INVEGA® (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 INVEGA® (3-12 mg once daily). In the other study, efficacy was assessed in 203 subjects who were assigned to one of two dose levels of INVEGA®: 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 INVEGA® 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. INVEGA® 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 INVEGA® 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 INVEGA® 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), INVEGA® was not significantly different from placebo as measured by the PANSS.

Taking the results of both studies together, INVEGA® 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.

Storage and Handling

Store up to 25ºC (77ºF); excursions permitted to 15 – 30ºC (59 – 86ºF) [see USP Controlled Room Temperature]. Protect from moisture.

Keep out of reach of children.

17.1 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)].

17.2 Interference with Cognitive and Motor Performance

As INVEGA® 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 INVEGA® therapy does not affect them adversely [see Warnings and Precautions (5.11)].

17.3 Pregnancy

Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during treatment with INVEGA® [see Use in Specific Populations (8.1)].

17.4 Nursing

Caution should be exercised when INVEGA® is administered to a nursing woman. The known benefits of breastfeeding should be weighed against the unknown risks of infant exposure to paliperidone. [See Use in Specific Populations (8.3)].

17.5 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)].

17.6 Alcohol

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

17.7 Heat Exposure and Dehydration

Patients should be advised regarding appropriate care in avoiding overheating and dehydration [see Warnings and Precautions (5.17)].

17.8 Administration

Patients should be informed that INVEGA® should 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 something that looks like a tablet in their stool [see Dosage and Administration (2.3)].