Paliperidone (injection)

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# Black Box Warning

# Overview
Paliperidone (injection) is an atypical antipsychotic that is FDA approved for the treatment of schizophrenia. There is a Black Box Warning for this drug as shown here.  Common adverse reactions include injection site reactions, somnolence/sedation, dizziness, akathisia, and extrapyramidal disorder.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)

## Indications
- Paliperidone is indicated for the treatment of:
- Schizophrenia.
- Schizoaffective disorder as monotherapy and as an adjunct to mood stabilizers or antidepressants.

## Dosage

### Administration Instructions
- Each injection must be administered only by a health care professional.
- Parenteral drug products should be inspected visually for foreign matter and discoloration prior to administration, whenever product and container permit.
- Paliperidone (injection) is intended for intramuscular use only. Do not administer by any other route. Avoid inadvertent injection into a blood vessel. Administer the dose in a single injection; do not administer the dose in divided injections. Inject slowly, deep into the muscle.
- The recommended needle size for administration of Paliperidone (injection) into the deltoid muscle is determined by the patient's weight:
- For patients weighing less than 90 kg, the 1-inch, 23 gauge needle is recommended.
- For patients weighing 90 kg or more, the 112-inch, 22 gauge needle is recommended.
- Deltoid injections should be alternated between the two deltoid muscles.
- The recommended needle size for administration of paliperidone (injection) into the gluteal muscle is the 112-inch, 22 gauge needle regardless of patient weight.
- Administer into the upper-outer quadrant of the gluteal muscle. Gluteal injections should be alternated between the two gluteal muscles.

### Schizophrenia and Schizoaffective Disorder
- For patients who have never taken oral paliperidone or oral or injectable risperidone, it is recommended to establish tolerability with oral paliperidone or oral risperidone prior to initiating treatment with paliperidone (injection).
- The recommended dosing of paliperidone (injection) for each approved indication is displayed in Table 1. The recommended initiation of paliperidone (injection) is with a dose of 234 mg on treatment day 1 and 156 mg one week later, both administered in the deltoid muscle. Following the second initiation dose, monthly maintenance doses can be administered in either the deltoid or gluteal muscle.
- Adjustment of the maintenance dose may be made monthly. When making dose adjustments, the prolonged-release characteristics of paliperidone (injection) should be considered, as the full effect of the dose adjustment may not be evident for several months.

### Missed Doses
- Avoiding Missed Doses
- It is recommended that the second initiation dose of paliperidone (injection) be given one week after the first dose. To avoid a missed dose, patients may be given the second dose 4 days before or after the one-week time point. Similarly, the third and subsequent injections after the initiation regimen are recommended to be given monthly. To avoid a missed monthly dose, patients may be given the injection up to 7 days before or after the monthly time point.
- Management of a Missed Second Initiation Dose
- If the target date for the second paliperidone (injection) (one week  4 days) is missed, the recommended reinitiation depends on the length of time which has elapsed since the patient's first injection. In case of a missed second initiation dose follow the dosing instructions provided in Table 2.

### Use with Oral Paliperidone or with Risperidone
- Concomitant use of paliperidone (injection) with oral paliperidone or oral or injectable risperidone has not been studied. Since paliperidone is the major active metabolite of risperidone, consideration should be given to the additive paliperidone exposure if any of these medications are coadministered with paliperidone (injection).

### Dosage Adjustments
- Renal Impairment
- Paliperidone (injection) has not been systematically studied in patients with renal impairment. For patients with mild renal impairment (creatinine clearance  50 mL/min to < 80 mL/min ), initiate paliperidone (injection) with a dose of 156 mg on treatment day 1 and 117 mg one week later. Administer both doses in the deltoid muscle. Thereafter, follow with monthly injections of 78 mg in either the deltoid or gluteal muscle.
- Paliperidone (injection) is not recommended in patients with moderate or severe renal impairment (creatinine clearance < 50 mL/min).
- Coadministration with Strong CYP3A4/P-glycoprotein (P-gp) Inducers
- It may be necessary to increase the dose of paliperidone (injection) when a strong inducer of both CYP3A4 and P-gp (e.g., carbamazepine, rifampin, St John's wort) is co-administered. Conversely, on discontinuation of the strong inducer, it may be necessary to decrease the dose of paliperidone (injection).

### Switching from Other Antipsychotics
- There are no systematically collected data to specifically address switching patients with schizophrenia or schizoaffective disorder from other antipsychotics to paliperidone (injection), or concerning concomitant administration with other antipsychotics.
- Switching from Oral Antipsychotics
- For patients who have never taken oral paliperidone or oral or injectable risperidone, tolerability should be established with oral paliperidone or oral risperidone prior to initiating treatment with paliperidone (injection).
- Previous oral antipsychotics can be discontinued at the time of initiation of treatment with paliperidone (injection). Recommended initiation of paliperidone (injection) is with a dose of 234 mg on treatment day 1 and 156 mg one week later, both administered in the deltoid muscle. Patients previously stabilized on different doses of INVEGA Extended-Release tablets can attain similar paliperidone steady-state exposure during maintenance treatment with paliperidone (injection) monthly doses as depicted in Table 4.
- Switching from Long-Acting Injectable Antipsychotics
- For patients who have never taken oral paliperidone or oral or injectable risperidone, tolerability should be established with oral paliperidone or oral risperidone prior to initiating treatment with paliperidone (injection).
- When switching patients currently at steady-state on a long-acting injectable antipsychotic, initiate paliperidone (injection) therapy in place of the next scheduled injection. paliperidone (injection) should then be continued at monthly intervals. The one-week initiation dosing regimen as described in Section 2.2 is not required. See TABLE 1 above for recommended monthly maintenance dosing. Based on previous clinical history of tolerability and/or efficacy, some patients may benefit from lower or higher maintenance doses within the available strengths (39 mg, 78 mg, 117 mg, 156 mg, and 234 mg). The 39 mg strength was not studied in the long-term schizoaffective disorder study. Monthly maintenance doses can be administered in either the deltoid or gluteal muscle.
- If paliperidone (injection) is discontinued, its prolonged-release characteristics must be considered. As recommended with other antipsychotic medications, the need for continuing existing extrapyramidal symptoms (EPS) medication should be re-evaluated periodically.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Paliperidone (injection) in adult patients.

### NonGuideline-Supported Use
- There is limited information regarding Off-Label NonGuideline-Supported Use of Paliperidone (injection) in adult patients.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
- Safety and effectiveness of paliperidone (injection) in patients < 18 years of age have not been established.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Paliperidone (injection) in pediatric patients.

### NonGuideline-Supported Use
- There is limited information regarding Off-Label NonGuideline-Supported Use of Paliperidone (injection) in pediatric patients.

# Contraindications
- Paliperidone (injection) is contraindicated in patients with a known hypersensitivity to either paliperidone or risperidone, or to any of the excipients in the paliperidone (injection) formulation. Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been observed in patients treated with risperidone and paliperidone. Paliperidone palmitate is converted to paliperidone, which is a metabolite of risperidone.

# Warnings

## 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 (injection) is not approved for the treatment of patients with dementia-related psychosis.

## 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. Oral paliperidone and paliperidone (injection) were not marketed at the time these studies were performed and are not approved for the treatment of patients with dementia-related psychosis.

## 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 (injection).
- 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.

## 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 Torsades 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 oral 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 (Cmax ss = 113 ng/mL) was more than 2-fold the exposure observed with the maximum recommended 234 mg dose of paliperidone (injection) administered in the deltoid muscle (predicted median Cmax ss = 50 ng/mL). 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.
- In the three fixed-dose efficacy studies of oral paliperidone extended release in subjects with schizophrenia, electrocardiogram (ECG) measurements taken at various time points showed only one subject in the oral paliperidone 12 mg group had a change exceeding 60 msec at one time-point on Day 6 (increase of 62 msec).
- In the four fixed-dose efficacy studies of paliperidone (injection) in subjects with schizophrenia and in the long-term study in subjects with schizoaffective disorder, no subject experienced a change in QTcLD exceeding 60 msec and no subject had a QTcLD value of > 500 msec at any time point. In the maintenance study in subjects with schizophrenia, no subject had a QTcLD change > 60 msec, and one subject had a QTcLD value of 507 msec (Bazett's QT corrected interval  value of 483 msec); this latter subject also had a heart rate of 45 beats per minute.

## 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, paliperidone (injection) should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that is known to respond to antipsychotic drugs. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.
- If signs and symptoms of tardive dyskinesia appear in a patient treated with paliperidone (injection), drug discontinuation should be considered. However, some patients may require treatment with paliperidone (injection) despite the presence of the syndrome.

## 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 (injection). 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 reactions is not completely understood. However, epidemiological studies suggest an increased risk of hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics. Because paliperidone (injection) was not marketed at the time these studies were performed, it is not known if paliperidone (injection) is associated with this 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 four placebo-controlled (one 9-week and three 13-week), fixed-dose studies in subjects with schizophrenia are presented in Table 5.
- In a long-term open-label pharmacokinetic and safety study in subjects with schizophrenia in which the highest dose available (234 mg) was evaluated, paliperidone (injection) was associated with a mean change in glucose of -0.4 mg/dL at Week 29 (n=109) and +6.8 mg/dL at Week 53 (n=100).
- During the initial 25-week open-label period of a long-term study in subjects with schizoaffective disorder, paliperidone (injection) was associated with mean change in glucose of +5.3 mg/dL (n=518). At the endpoint of the subsequent 15-month double-blind period of the study, paliperidone (injection) was associated with a mean change in glucose of +0.3 mg/dL (n=131) compared with a mean change of +4.0 mg/dL in the placebo group (n=120).

### Dyslipidemia
- Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.
- Pooled data from the four placebo-controlled (one 9-week and three 13-week), fixed-dose studies in subjects with schizophrenia are presented in Table 6.
- In a long-term open-label pharmacokinetic and safety study in subjects with schizophrenia in which the highest dose available (234 mg) was evaluated, the mean changes from baseline in lipid values are presented in Table 7.
- The mean changes from baseline in lipid values during the initial 25-week open-label period and at the endpoint of the subsequent 15-month double-blind period in a long-term study in subjects with schizoaffective disorder are presented in Table 8.

### Weight Gain
- Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.
- Data on mean changes in body weight and the proportion of subjects meeting a weight gain criterion of  7% of body weight from the four placebo-controlled (one 9-week and three 13-week), fixed-dose studies in subjects with schizophrenia are presented in Table 9.
- In a long-term open-label pharmacokinetic and safety study in which the highest dose available (234 mg) was evaluated, paliperidone (injection) was associated with a mean change in weight of +2.4 kg at Week 29 (n=134) and +4.3 kg at Week 53 (n=113).
- During the initial 25-week open-label period of a long-term study in subjects with schizoaffective disorder, paliperidone (injection) was associated with a mean change in weight of +2.2 kg and 18.4% of subjects had an increase in body weight of  7% (n=653). At the endpoint of the subsequent 15-month double-blind period of the study, paliperidone (injection) was associated with a mean change in weight of -0.2 kg and 13.0% of subjects had an increase in body weight of  7% (n=161); the placebo group had a mean change in weight of -0.8 kg and 6.0% of subjects had an increase in body weight of  7% (n=168).

## Orthostatic Hypotension and Syncope
- Paliperidone can induce orthostatic hypotension and syncope in some patients because of its alpha-blocking activity. Syncope was reported in < 1% (4/1293) of subjects treated with paliperidone (injection) in the recommended dose range of 39 mg to 234 mg in the four fixed-dose, double-blind, placebo-controlled trials compared with 0% (0/510) of subjects treated with placebo. In the four fixed-dose efficacy studies in subjects with schizophrenia, orthostatic hypotension was reported as an adverse event by < 1% (2/1293) of paliperidone (injection)-treated subjects compared to 0% (0/510) with placebo. Incidences of orthostatic hypotension and syncope in the long-term studies in subjects with schizophrenia and schizoaffective disorder were similar to those observed in the short-term studies.
- Paliperidone (injection) 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.

## Leukopenia, Neutropenia, and Agranulocytosis
- In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents, including INVEGA, an oral form of paliperidone. Agranulocytosis has also been reported.
- Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug-induced leukopenia/neutropenia. Patients with a history of a clinically significant low WBC or a drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of paliperidone (injection) should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors.
- Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue paliperidone (injection) and have their WBC followed until recovery.

## 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. 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.

## Potential for Cognitive and Motor Impairment
- Somnolence, sedation, and dizziness were reported as adverse reactions in subjects treated with paliperidone (injection). Antipsychotics, including paliperidone (injection), 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.

## Seizures
- In the four fixed-dose double-blind placebo-controlled studies in subjects with schizophrenia, <1% (1/1293) of subjects treated with paliperidone (injection) in the recommended dose range of 39 mg to 234 mg experienced an adverse event of convulsion compared with <1% (1/510) of placebo-treated subjects who experienced an adverse event of grand mal convulsion.
- Like other antipsychotic drugs, paliperidone (injection) 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.

## 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 (injection) and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.

## Priapism
- Drugs with alpha-adrenergic blocking effects have been reported to induce priapism. Although no cases of priapism have been reported in clinical trials with paliperidone (injection), priapism has been reported with oral paliperidone during postmarketing surveillance. Severe priapism may require surgical intervention.

## Disruption of 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 (injection) 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.

# Adverse Reactions

## Clinical Trials Experience
- The most common (at least 5% in any paliperidone (injection) group) and likely drug-related (adverse events for which the drug rate is at least twice the placebo rate) adverse reactions from the double-blind, placebo-controlled trials in subjects with schizophrenia were injection site reactions, somnolence/sedation, dizziness, akathisia, and extrapyramidal disorder. No occurrences of adverse events reached this threshold in the long-term double-blind, placebo-controlled study in subjects with schizoaffective disorder.
- The data described in this section are derived from a clinical trial database consisting of a total of 3817 subjects (approximately 1705 patient-years exposure) with schizophrenia who received at least one dose of paliperidone (injection) in the recommended dose range of 39 mg to 234 mg and a total of 510 subjects with schizophrenia who received placebo. Among the 3817 paliperidone (injection)-treated subjects, 1293 received paliperidone (injection) in four fixed-dose, double-blind, placebo-controlled trials (one 9-week and three 13-week studies), 849 received paliperidone (injection) in the maintenance trial (median exposure 229 days during the initial 33-week open-label phase of this study, of whom 205 continued to receive paliperidone (injection) during the double-blind placebo-controlled phase of this study ), and 1675 received paliperidone (injection) in five non-placebo controlled trials (three noninferiority active-comparator trials, one long-term open-label pharmacokinetic and safety study, and an injection site  cross-over trial). One of the 13-week studies included a 234 mg paliperidone (injection) initiation dose followed by treatment with either 39 mg, 156 mg, or 234 mg every 4 weeks.
- The safety of paliperidone (injection) was also evaluated in a long-term study in adult subjects with schizoaffective disorder. A total of 667 subjects received paliperidone (injection) during the initial 25-week open-label period of this study (median exposure 147 days); 164 subjects continued to receive paliperidone (injection) during the 15-month double-blind placebo-controlled period of this study (median exposure 446 days). Adverse reactions that occurred more frequently in the paliperidone (injection) than the placebo group (a 2% difference or more between groups) were weight increased, nasopharyngitis, headache, hyperprolactinemia, and pyrexia.
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
- Commonly Reported Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials
- Table 10 lists the adverse reactions reported in 2% or more of paliperidone (injection)-treated subjects and at a greater proportion than in the placebo group with schizophrenia in the four fixed-dose, double-blind, placebo-controlled trials.

### Other Adverse Reactions Observed During the Clinical Trial Evaluation of Paliperidone (injection)
- The following list does not include reactions: 1) already listed in previous tables or elsewhere in labeling, 2) for which a drug cause was remote, 3) which were so general as to be uninformative, or 4) which were not considered to have significant clinical implications.
- Cardiac disorders: atrioventricular block first degree, bradycardia, bundle branch block, palpitations, postural orthostatic tachycardia syndrome, tachycardia
- Ear and labyrinth disorders: vertigo
- Eye disorders: eye movement disorder, eye rolling, oculogyric crisis, vision blurred
- Gastrointestinal disorders: constipation, dyspepsia, flatulence, salivary hypersecretion
- Immune system disorders: hypersensitivity
- Investigations: alanine aminotransferase increased, aspartate aminotransferase increased, electrocardiogram abnormal
- Metabolism and nutrition disorders: decreased appetite, hyperinsulinemia, increased appetite
- Musculoskeletal and connective tissue disorders: arthralgia, joint stiffness, muscle rigidity, muscle spasms, muscle tightness, muscle twitching, nuchal rigidity
- Nervous system disorders: bradykinesia, cerebrovascular accident, convulsion, dizziness postural, drooling, dysarthria, dyskinesia, dystonia, hypertonia, lethargy, oromandibular dystonia, parkinsonism, psychomotor hyperactivity, syncope
- Psychiatric disorders: insomnia, restlessness
- Reproductive system and breast disorders: amenorrhea, breast discharge, erectile dysfunction, galactorrhea, gynecomastia, menstrual disorder, menstruation delayed, menstruation irregular, sexual dysfunction
- Respiratory, thoracic and mediastinal disorders: nasal congestion
- Skin and subcutaneous tissue disorders: drug eruption, pruritus, pruritus generalized, rash, urticaria

### Discontinuations Due to Adverse Events
- The percentage of subjects who discontinued due to adverse events in the four fixed-dose, double-blind, placebo-controlled schizophrenia trials were similar for paliperidone (injection)- and placebo-treated subjects.
- The percentage of subjects who discontinued due to adverse events in the open-label period of the long-term study in subjects with schizoaffective disorder was 7.5%. During the double-blind, placebo-controlled period of that study, the percentages of subjects who discontinued due to adverse events were 5.5% and 1.8% in paliperidone (injection)- and placebo-treated subjects, respectively.

### Dose-Related Adverse Reactions
- Based on the pooled data from the four fixed-dose, double-blind, placebo-controlled trials in subjects with schizophrenia, among the adverse reactions that occurred at  2% incidence in the subjects treated with paliperidone (injection), only akathisia increased with dose. Hyperprolactinemia also exhibited a dose relationship, but did not occur at  2% incidence in paliperidone (injection)-treated subjects from the four fixed-dose studies.

### Demographic Differences
- An examination of population subgroups in the double-blind placebo-controlled trials did not reveal any evidence of differences in safety on the basis of age, gender, or race alone; however, there were few subjects  65 years of age.

### Extrapyramidal Symptoms (EPS)
- Pooled data from the two double-blind, placebo-controlled, 13-week, fixed-dose trials in adult subjects with schizophrenia provided information regarding EPS. Several methods were used to measure EPS: (1) the Simpson-Angus global score (mean change from baseline or score at the end of trial) which broadly evaluates Parkinsonism, (2) the Barnes Akathisia Rating Scale global clinical rating score (mean change from baseline or score at the end of trial) which evaluates akathisia, (3) use of anticholinergic medications to treat EPS, (4) the Abnormal Involuntary Movement Scale scores (mean change from baseline or scores at the end of trial) (Table 11), and (5) incidence of spontaneous reports of EPS (Table 12).
- The results across all phases of the maintenance trial in subjects with schizophrenia exhibited comparable findings. In the 9-week, fixed-dose, double-blind, placebo-controlled trial, the proportions of Parkinsonism and akathisia assessed by incidence of rating scales were higher in the paliperidone (injection) 156 mg group (18% and 11%, respectively) than in the paliperidone (injection) 78 mg group (9% and 5%, respectively) and placebo group (7% and 4%, respectively).
- In the 13-week study in subjects with schizophrenia involving 234 mg initiation dosing, the incidence of any EPS was similar to that of the placebo group (8%), but exhibited a dose-related pattern with 6%, 10%, and 11% in the paliperidone (injection) 234/39 mg, 234/156 mg, and 234/234 mg groups, respectively. Hyperkinesia was the most frequent category of EPS-related adverse events in this study, and was reported at a similar rate between the placebo (4.9%) and paliperidone (injection) 234/156 mg (4.8%) and 234/234 mg (5.5%) groups, but at a lower rate in the 234/39 mg group (1.3%).
- In the long-term study in subjects with schizoaffective disorder, the EPS during the 25-week open-label paliperidone (injection) treatment were hyperkinesia (12.3%), parkinsonism (8.7%), tremor (3.4%), dyskinesia (2.5%), and dystonia (2.1%). During the 15-month double-blind treatment, the incidence of any EPS was similar to that of the placebo group (8.5% and 7.1% respectively). The most commonly reported treatment-emergent EPS-related adverse events (>2%) in any treatment group in the double-blind phase of the study (paliperidone (injection) versus placebo) were hyperkinesia (3.7% vs. 2.9%), parkinsonism (3.0% vs. 1.8%), and tremor (1.2% vs. 2.4%).

### Dystonia
- Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.

### Laboratory Test Abnormalities
- In the pooled data from the two double-blind, placebo-controlled, 13-week, fixed-dose trials in subjects with schizophrenia, a between-group comparison revealed no medically important differences between paliperidone (injection) and placebo in the proportions of subjects experiencing potentially clinically significant changes in routine serum chemistry, hematology, or urinalysis parameters. Similarly, there were no differences between paliperidone (injection) 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, triglycerides, HDL, LDL, and total cholesterol measurements. However, paliperidone (injection) was associated with increases in serum prolactin. The results from the 13-week study involving 234 mg initiation dosing, the 9-week, fixed-dose, double-blind, placebo-controlled trial, and the double-blind phase of the maintenance trial in subjects with schizophrenia exhibited comparable findings.

### Pain Assessment and Local Injection Site Reactions
- In the pooled data from the two 13-week, fixed-dose, double-blind, placebo-controlled trials in subjects with schizophrenia, the mean intensity of injection pain reported by subjects using a visual analog scale (0 = no pain to 100 = unbearably painful) decreased in all treatment groups from the first to the last injection (placebo: 10.9 to 9.8; 39 mg: 10.3 to 7.7; 78 mg: 10.0 to 9.2; 156 mg: 11.1 to 8.8). The results from both the 9-week, fixed-dose, double-blind, placebo-controlled trial and the double-blind phase of the maintenance trial exhibited comparable findings.
- In the 13-week study involving 234 mg initiation dosing in subjects with schizophrenia, occurrences of induration, redness, or swelling, as assessed by blinded study personnel, were infrequent, generally mild, decreased over time, and similar in incidence between the paliperidone (injection) and placebo groups. Investigator ratings of injection pain were similar for the placebo and paliperidone (injection) groups. Investigator evaluations of the injection site after the first injection for redness, swelling, induration, and pain were rated as absent for 69100% of subjects in both the paliperidone (injection) and placebo groups. At Day 92, investigators rated absence of redness, swelling, induration, and pain in 95100% of subjects in both the paliperidone (injection) and placebo groups.

### Adverse Reactions Reported in Clinical Trials with Oral Paliperidone
- The following is a list of additional adverse reactions that have been reported in clinical trials with oral paliperidone:
- Cardiac disorders: bundle branch block left, sinus arrhythmia
- Gastrointestinal disorders: abdominal pain, small intestinal obstruction
- General disorders and administration site conditions: edema, edema peripheral
- Immune system disorders: anaphylactic reaction
- Infections and infestations: rhinitis
- Musculoskeletal and connective tissue disorders: musculoskeletal pain, torticollis, trismus
- Nervous system disorders: cogwheel rigidity, grand mal convulsion, parkinsonian gait, transient ischemic attack
- Psychiatric disorders: sleep disorder
- Reproductive system and breast disorders: breast engorgement, breast tenderness/breast pain, retrograde ejaculation
- Respiratory, thoracic and mediastinal disorders: pharyngolaryngeal pain, aspiration pneumonia
- Skin and subcutaneous tissue disorders: rash papular
- Vascular disorders: hypotension, ischemia

### Adverse Reactions Reported With Risperidone
- Paliperidone is the major active metabolite of risperidone. Adverse reactions reported with oral risperidone and risperidone long-acting injection can be found in the ADVERSE REACTIONS sections of the package inserts for those products.

## Postmarketing Experience
- The following adverse reactions have been identified during postapproval use of paliperidone; because these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Reactions already listed in other parts of ADVERSE REACTIONS (6), or those considered in WARNINGS AND PRECAUTIONS (5) are not listed here.
- Blood disorders: thrombotic thrombocytopenic purpura
- Gastrointestinal disorders: ileus
- Genitourinary disorders: urinary incontinence, urinary retention
- Immune system disorders: angioedema, swollen tongue
- Cases of anaphylactic reaction after injection with paliperidone (injection) have been reported during postmarketing experience in patients who have previously tolerated oral risperidone or oral paliperidone.

# Drug Interactions

## Potential for Paliperidone (injection) to Affect Other Drugs
- Paliperidone may antagonize the effect of levodopa and other dopamine agonists.
- Because of its potential for inducing orthostatic hypotension, an additive effect may occur when paliperidone (injection) is administered with other therapeutic agents that have this potential.
- No dose adjustment is necessary for lithium when it is coadministered with paliperidone (injection). Pharmacokinetic interaction between paliperidone (injection) and lithium is unlikely.
- No dose adjustment is necessary for valproate when paliperidone (injection) is added to the therapy. Steady-state pharmacokinetics of valproate was not affected when patients were coadministered oral paliperidone extended-release tablets.
- Paliperidone is not expected to cause clinically important pharmacokinetic interactions with drugs that are metabolized by cytochrome P450 isozymes.

## Potential for Other Drugs to Affect Paliperidone (injection)
- On initiation of strong inducers of both CYP3A4 and P-gp (e.g., carbamazepine, rifampin, or St John's wort), it may be necessary to increase the dose of paliperidone (injection). Conversely, on discontinuation of the strong inducer, it may be necessary to decrease the dose of paliperidone (injection).
- No dose adjustment is necessary for paliperidone (injection) when valproate is added to treatment.
- No dose adjustment is necessary for paliperidone (injection) when it is coadministered with lithium. Pharmacokinetic interaction between paliperidone (injection) and lithium is unlikely.
- In vitro studies indicate that CYP2D6 and CYP3A4 may be involved in paliperidone metabolism; however, there is no evidence in vivo that inhibitors of these enzymes significantly affect the metabolism of paliperidone. Paliperidone is not a substrate of CYP1A2, CYP2A6, CYP2C9, and CYP2C19; an interaction with inhibitors or inducers of these isozymes is unlikely.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): C

### Risk Summary
- Adequate and well controlled studies with paliperidone (injection) have not been conducted in pregnant women. Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. Paliperidone (injection) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

### Clinical Considerations
- Fetal/Neonatal Adverse Reactions
- Monitor neonates exhibiting extrapyramidal or withdrawal symptoms. Some neonates recover within hours or days without specific treatment; others may require prolonged hospitalization.
- Data
- Human Data
- There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder in neonates following in utero exposure to antipsychotics in the third trimester. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization.
- Animal Data
- There were no treatment-related effects on the offspring when pregnant rats were injected intramuscularly with paliperidone palmitate during the period of organogenesis at doses up to 250 mg/kg, which is 10 times the maximum recommended human 234 mg dose of paliperidone (injection) on a mg/m2 body surface area basis.
- In studies in pregnant rats and rabbits in which paliperidone was given orally during the period of organogenesis, there were no increases in fetal abnormalities up to the highest doses tested (10 mg/kg/day in rats and 5 mg/kg/day in rabbits, which are each 8 times the maximum recommended human dose of 12 mg/day of orally administered paliperidone  on a mg/m2 body surface area basis).
- In rat reproduction studies with risperidone, which is extensively converted to paliperidone in rats and humans, increases in pup deaths were seen at oral doses which are less than the maximum recommended human dose of risperidone on a mg/m2 body surface area basis (see RISPERDAL package insert).
Pregnancy Category (AUS): 
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Paliperidone (injection) in women who are pregnant.

### Labor and Delivery
- The effect of paliperidone (injection) on labor and delivery in humans is unknown.

### Nursing Mothers
- In animal studies with paliperidone and in human studies with risperidone, paliperidone was excreted in the milk. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

### Pediatric Use
- Safety and effectiveness of paliperidone (injection) in patients < 18 years of age have not been established.
- In a study in which juvenile rats were treated with oral paliperidone from days 24 to 73 of age, a reversible impairment of performance in a test of learning and memory was seen, in females only, with a no-effect dose of 0.63 mg/kg/day, which produced plasma levels (AUC) of paliperidone similar to those in adolescents. No other consistent effects on neurobehavioral or reproductive development were seen up to the highest dose tested (2.5 mg/kg/day), which produced plasma levels of paliperidone 23 times those in adolescents.
- Juvenile dogs were treated for 40 weeks with oral risperidone, which is extensively metabolized to paliperidone in animals and humans, at doses of 0.31, 1.25, or 5 mg/kg/day. Decreased bone length and density were seen with a no-effect dose of 0.31 mg/kg/day, which produced plasma levels (AUC) of risperidone plus paliperidone which were similar to those in children and adolescents receiving the maximum recommended human dose of risperidone. In addition, a delay in sexual maturation was seen at all doses in both males and females. The above effects showed little or no reversibility in females after a 12-week drug-free recovery period.
- The long-term effects of paliperidone on growth and sexual maturation have not been fully evaluated in children and adolescents.

### Geriatic Use
- Clinical studies of paliperidone (injection) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.
- This drug is known to be substantially excreted by the kidney and clearance is decreased in patients with renal impairment, who should be given reduced doses. Because elderly patients are more likely to have decreased renal function, adjust dose based on renal function.

### Gender
There is no FDA guidance on the use of Paliperidone (injection) with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Paliperidone (injection) with respect to specific racial populations.

### Renal Impairment
- Use of paliperidone (injection) is not recommended in patients with moderate or severe renal impairment (creatinine clearance < 50 mL/min). Dose reduction is recommended for patients with mild renal impairment (creatinine clearance  50 mL/min to < 80 mL/min).

### Hepatic Impairment
- Paliperidone (injection) has not been studied in patients with hepatic impairment. Based on a study with oral paliperidone, no dose adjustment is required in patients with mild or moderate hepatic impairment. Paliperidone has not been studied in patients with severe hepatic impairment.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Paliperidone (injection) in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Paliperidone (injection) in patients who are immunocompromised.

### 8.8 Patients with Parkinson's Disease or Lewy Body Dementia
- Patients with Parkinson's Disease or Dementia with Lewy Bodies can experience increased sensitivity to paliperidone (injection). Manifestations can include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinical features consistent with neuroleptic malignant syndrome.

# Administration and Monitoring

### Administration
- Intramuscular.

### Instructions for Use

### Monitoring
There is limited information regarding Paliperidone (injection) Monitoring in the drug label.

# IV Compatibility
There is limited information regarding the compatibility of Paliperidone (injection) and IV administrations.

# Overdosage

## Human Experience
- No cases of overdose were reported in premarketing studies with paliperidone (injection). Because paliperidone (injection) is to be administered by health care professionals, the potential for overdosage by patients is low.
- While experience with paliperidone overdose is limited, among the few cases of overdose reported in premarketing trials with oral paliperidone, the highest estimated ingestion 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 sedation, tachycardia and hypotension, and QT prolongation. Torsades de pointes and ventricular fibrillation have been reported in a patient in the setting of overdose with oral paliperidone.
- 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.

## Management of Overdosage
- Contact a Certified Poison Control Center for the most up to date information on the management of paliperidone (injection) overdosage (1-800-222-1222 or www.poison.org). Provide supportive care, including close medical supervision and monitoring. Treatment should consist of general measures employed in the management of overdosage with any drug. Consider the possibility of multiple drug overdosage. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. Use supportive and symptomatic measures. There is no specific antidote to paliperidone.
- Consider the prolonged-release characteristics of paliperidone (injection) and the long apparent half-life of paliperidone when assessing treatment needs and recovery.

# Pharmacology

## Mechanism of Action
- Paliperidone palmitate is hydrolyzed to paliperidone. Paliperidone is the major active metabolite of risperidone. The mechanism of action of paliperidone is unknown. However, 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.

## Structure
- Paliperidone (injection) is an atypical antipsychotic. Paliperidone (injection) contains paliperidone palmitate. The active ingredient, paliperidone palmitate, is a psychotropic agent belonging to the chemical class of benzisoxazole derivatives. Paliperidone (injection) contains a racemic mixture of (+)- and (-)- paliperidone palmitate. The chemical name is (9RS)-3-ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyridopyrimadin-9-yl hexadecanoate. Its molecular formula is C39H57FN4O4 and its molecular weight is 664.89. The structural formula is:
- Paliperidone palmitate is very slightly soluble in ethanol and methanol, practically insoluble in polyethylene glycol 400 and propylene glycol, and slightly soluble in ethyl acetate.
- Paliperidone (injection) is available as a white to off-white sterile aqueous extended-release suspension for intramuscular injection in the following dose strengths of paliperidone palmitate (and deliverable volumes of the prefilled syringes): 39 mg (0.25 mL), 78 mg (0.5 mL), 117 mg (0.75 mL), 156 mg (1.0 mL), and 234 mg (1.5 mL). The drug product hydrolyzes to the active moiety, paliperidone, resulting in dose strengths of 25 mg, 50 mg, 75 mg, 100 mg, and 150 mg of paliperidone, respectively. The inactive ingredients are polysorbate 20 (12 mg/mL), polyethylene glycol 4000 (30 mg/mL), citric acid monohydrate (5 mg/mL), disodium hydrogen phosphate anhydrous, sodium dihydrogen phosphate monohydrate, sodium hydroxide, and water for injection.
- Paliperidone (injection) is provided in a prefilled syringe (cyclic-olefin-copolymer) with a plunger stopper and tip cap (bromobutyl rubber). The kit also contains 2 safety needles (a 1 12-inch 22 gauge safety needle and a 1-inch 23 gauge safety needle).

## Pharmacodynamics
- Paliperidone is a centrally active dopamine Type 2 (D2) receptor antagonist and a serotonin Type 2 (5HT2A) receptor antagonist. Paliperidone is also active as an antagonist at 1 and 2 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 1- and 2-adrenergic receptors. The pharmacological activity of the (+)- and (-)- paliperidone enantiomers is qualitatively and quantitatively similar in vitro.

## Pharmacokinetics
- Absorption and Distribution
- Due to its extremely low water solubility, paliperidone palmitate dissolves slowly after intramuscular injection before being hydrolyzed to paliperidone and absorbed into the systemic circulation. Following a single intramuscular dose, the plasma concentrations of paliperidone gradually rise to reach maximum plasma concentrations at a median Tmax of 13 days. The release of the drug starts as early as day 1 and lasts for as long as 126 days.
- Following intramuscular injection of single doses (39 mg  234 mg) in the deltoid muscle, on average, a 28% higher Cmax was observed compared with injection in the gluteal muscle. The two initial deltoid intramuscular injections of 234 mg on day 1 and 156 mg on day 8 help attain therapeutic concentrations rapidly. The release profile and dosing regimen of paliperidone (injection) results in sustained therapeutic concentrations. The AUC of paliperidone following paliperidone (injection) administration was dose-proportional over a 39 mg234 mg dose range, and less than dose-proportional for Cmax for doses exceeding 78 mg. The mean steady-state peak:trough ratio for an paliperidone (injection) dose of 156 mg was 1.8 following gluteal administration and 2.2 following deltoid administration.
- Following administration of paliperidone palmitate the (+) and (-) enantiomers of paliperidone interconvert, reaching an AUC (+) to (-) ratio of approximately 1.61.8.
- Based on a population analysis, the apparent volume of distribution of paliperidone is 391 L. The plasma protein binding of racemic paliperidone is 74%.
- Metabolism and Elimination
- In a study with oral immediate-release 14C-paliperidone, one week following administration of a single oral dose of 1 mg immediate-release 14C-paliperidone, 59% of the dose was excreted unchanged into urine, indicating that paliperidone is not extensively metabolized in the liver. Approximately 80% of the administered radioactivity was recovered in urine and 11% in the feces. Four metabolic pathways have been identified in vivo, none of which accounted for more than 10% of the dose: dealkylation, hydroxylation, dehydrogenation, and benzisoxazole scission. Although in vitro studies suggested a role for CYP2D6 and CYP3A4 in the metabolism of paliperidone, there is no evidence in vivo that these isozymes play a significant role in the metabolism of paliperidone. Population pharmacokinetics analyses indicated no discernible difference on the apparent clearance of paliperidone after administration of oral paliperidone between extensive metabolizers and poor metabolizers of CYP2D6 substrates.
- The median apparent half-life of paliperidone following paliperidone (injection) single-dose administration over the dose range of 39 mg  234 mg ranged from 25 days  49 days.
- Long-Acting Paliperidone Palmitate Injection versus Oral Extended-Release Paliperidone
- Paliperidone (injection) is designed to deliver paliperidone over a monthly period while extended-release oral paliperidone is administered on a daily basis. The initiation regimen for paliperidone (injection) (234 mg/156 mg in the deltoid muscle on Day 1/Day 8) was designed to rapidly attain steady-state paliperidone concentrations when initiating therapy without the use of oral supplementation.
- In general, overall initiation plasma levels with paliperidone (injection) were within the exposure range observed with 612 mg extended-release oral paliperidone. The use of the paliperidone (injection) initiation regimen allowed patients to stay in this exposure window of 612 mg extended-release oral paliperidone even on trough pre-dose days (Day 8 and Day 36). The intersubject variability for paliperidone pharmacokinetics following delivery from paliperidone (injection) was lower relative to the variability determined from extended-release oral paliperidone tablets. Because of the difference in median pharmacokinetic profiles between the two products, caution should be exercised when making a direct comparison of their pharmacokinetic properties.
- Drug Interaction Studies
- Potential for paliperidone (injection) to Affect Other Drugs
- In vitro studies in human liver microsomes demonstrated 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.
- In a drug interaction study, co-administration of oral paliperidone extended-release tablets (12 mg once daily for 5 days) with divalproex sodium extended-release tablets (500 mg to 2000 mg once daily) did not affect the steady-state pharmacokinetics (AUC24h and Cmax,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 oral paliperidone extended-release tablets 315 mg/day was added to their existing valproate treatment.
- Potential for Other Drugs to Affect paliperidone (injection)
- While in vitro studies indicate that CYP2D6 and CYP3A4 may be minimally involved in paliperidone metabolism, in vivo studies did not demonstrate decreased elimination by these isozymes; they contribute to only a small fraction of total body clearance. In vitro studies demonstrated that paliperidone is a P-gp substrate.
- Co-administration of oral paliperidone extended-release 6 mg once daily with carbamazepine, a strong inducer of both CYP3A4 and P-gp, at 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.
- Co-administration of a single dose of oral paliperidone extended-release 12 mg tablet with divalproex sodium extended-release tablets (two 500 mg tablets once daily at steady-state) resulted in an increase of approximately 50% in the Cmax and AUC of paliperidone. Although this interaction has not been studied with paliperidone (injection), a clinically significant interaction would not be expected between divalproex sodium and paliperidone (injection) intramuscular injection.
- Paliperidone is metabolized to a limited extent by CYP2D6. In an interaction study in healthy subjects in which a single 3 mg dose of oral paliperidone extended-release 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.
- Specific Populations
- Renal Impairment
- Paliperidone (injection) has not been systematically studied in patients with renal impairment. Based on a limited number of observations with paliperidone (injection) in subjects with mild renal impairment and pharmacokinetic simulations, the dose of paliperidone (injection) should be reduced in patients with mild renal impairment; paliperidone (injection) is not recommended in patients with moderate or severe renal impairment. Although paliperidone (injection) was not studied in patients with moderate or severe renal impairment, the disposition of a single oral dose paliperidone 3 mg extended-release tablet was studied in subjects with varying degrees of renal function. Elimination of paliperidone decreased with decreasing estimated creatinine clearance. Total clearance of paliperidone was reduced in subjects with impaired renal function by 32% on average in mild (CrCl = 50 mL/min to < 80 mL/min), 64% in moderate (CrCl = 30 mL/min to < 50 mL/min), and 71% in severe (CrCl = 10 mL/min to < 30 mL/min) renal impairment, corresponding to an average increase in exposure (AUCinf) of 1.5 fold, 2.6 fold, and 4.8 fold, respectively, compared to healthy subjects.
- Hepatic Impairment
- Paliperidone (injection) has not been studied in patients with hepatic impairment. Based on a study with oral paliperidone in subjects with moderate hepatic impairment (Child-Pugh class B), no dose adjustment is required in patients with mild or moderate hepatic impairment. In the study with oral paliperidone in subjects with moderate hepatic impairment (Child-Pugh class B), the plasma concentrations of free paliperidone were similar to those of healthy subjects, although total paliperidone exposure decreased because of a decrease in protein binding. Paliperidone has not been studied in patients with severe hepatic impairment.
- Elderly
- No dosage adjustment is recommended based on age alone. However, dose adjustment may be required because of age-related decreases in creatinine clearance.
- Race
- No dosage adjustment is recommended based on race. No differences in pharmacokinetics were observed between Japanese and Caucasians.
- Gender
- No dosage adjustment is recommended based on gender, although slower absorption was observed in females in a population pharmacokinetic analysis.
- Smoking
- No dosage adjustment is recommended based on smoking status. Based on in vitro studies utilizing human liver enzymes, paliperidone is not a substrate for CYP1A2; smoking should, therefore, not have an effect on the pharmacokinetics of paliperidone.

## Nonclinical Toxicology

### Carcinogenesis, Mutagenesis, Impairment of Fertility
- Carcinogenesis
- The carcinogenic potential of intramuscularly injected paliperidone palmitate was assessed in rats. There was an increase in mammary gland adenocarcinomas in female rats at 16, 47, and 94 mg/kg/month, which is 0.6, 2, and 4 times, respectively, the maximum recommended human 234 mg dose of paliperidone (injection) on a mg/m2 body surface area basis. A no-effect dose was not established. Male rats showed an increase in mammary gland adenomas, fibroadenomas, and carcinomas at 47 mg and 94 mg/kg/month. A carcinogenicity study in mice has not been conducted with paliperidone palmitate.
- Carcinogenicity studies of risperidone, which is extensively converted to paliperidone in rats, mice, and humans, were conducted in Swiss albino mice and Wistar rats. Risperidone was administered in the diet at daily doses of 0.63, 2.5, and 10 mg/kg for 18 months to mice and for 25 months to rats. A maximum tolerated dose was not achieved in male mice. There were statistically significant increases in pituitary gland adenomas, endocrine pancreas adenomas, and mammary gland adenocarcinomas. The no-effect dose for these tumors was less than or equal to the maximum recommended human dose of risperidone on a mg/m2 body surface area basis (see RISPERDAL package insert). An increase in mammary, pituitary, and endocrine pancreas neoplasms has been found in rodents after chronic administration of other antipsychotic drugs and is considered to be mediated by prolonged dopamine D2-receptor antagonism and hyperprolactinemia. The relevance of these tumor findings in rodents in terms of human risk is unknown.
- Mutagenesis
- Paliperidone palmitate showed no genotoxic potential in the Ames reverse mutation test or the mouse lymphoma assay. No evidence of genotoxic potential for paliperidone was found in the Ames reverse mutation test, the mouse lymphoma assay, or the in vivo rat micronucleus test.
- Impairment of Fertility
- Fertility studies of paliperidone palmitate have not been performed.
- In a study of fertility conducted with orally administered paliperidone, the percentage of treated female rats that became pregnant was not affected at doses of paliperidone of up to 2.5 mg/kg/day. However, pre- and post-implantation loss were increased, and the number of live embryos was slightly decreased, at 2.5 mg/kg, a dose that also caused slight maternal toxicity. These parameters were not affected at a dose of 0.63 mg/kg, which is half of the maximum recommended human dose (12 mg/day) of orally administered paliperidone (INVEGA) on a mg/m2 body surface area basis.
- The fertility of male rats was not affected at oral doses of paliperidone of up to 2.5 mg/kg/day, although sperm count and sperm viability studies were not conducted with paliperidone. In a subchronic study in Beagle dogs with risperidone, which is extensively converted to paliperidone in dogs and humans, all doses tested (0.31 mg/kg  5.0 mg/kg) resulted in decreases in serum testosterone and in sperm motility and concentration. Serum testosterone and sperm parameters partially recovered, but remained decreased after the last observation (two months after treatment was discontinued).

# Clinical Studies

## Schizophrenia

### Short-Term Monotherapy (Studies 1, 2, 3, 4)
- The efficacy of paliperidone (injection) in the acute treatment of schizophrenia was evaluated in four short-term (one 9-week and three 13-week) double-blind, randomized, placebo-controlled, fixed-dose studies of acutely relapsed adult inpatients who met DSM-IV criteria for schizophrenia. The fixed doses of paliperidone (injection) in these studies were given on days 1, 8, and 36 in the 9-week study, and additionally on day 64 of the 13-week studies, i.e., at a weekly interval for the initial two doses and then every 4 weeks for maintenance.
- Efficacy was evaluated using the total score on the Positive and Negative Syndrome Scale (PANSS). The PANSS is a 30 item scale that measures positive symptoms of schizophrenia (7 items), negative symptoms of schizophrenia (7 items), and general psychopathology (16 items), each rated on a scale of 1 (absent) to 7 (extreme); total PANSS scores range from 30 to 210.
- In Study 1 (PSY-3007), a 13-week study (n=636) comparing three fixed doses of paliperidone (injection) (initial deltoid injection of 234 mg followed by 3 gluteal or deltoid doses of either 39 mg/4 weeks, 156 mg/4 weeks or 234 mg/4 weeks) to placebo, all three doses of paliperidone (injection) were superior to placebo in improving the PANSS total score.
- In Study 2 (PSY-3003), another 13-week study (n=349) comparing three fixed doses of paliperidone (injection) (78 mg/4 weeks, 156 mg/4 weeks, and 234 mg/4 weeks) to placebo, only 156 mg/4 weeks of paliperidone (injection) was superior to placebo in improving the PANSS total score.
- In Study 3 (PSY-3004), a third 13-week study (n=513) comparing three fixed doses of paliperidone (injection) (39 mg/4 weeks, 78 mg/4 weeks, and 156 mg/4 weeks) to placebo, all three doses of paliperidone (injection) were superior to placebo in improving the PANSS total score.
- In Study 4 (SCH-201), the 9-week study (n=197) comparing two fixed doses of paliperidone (injection) (78 mg/4 weeks and 156 mg/4 weeks) to placebo, both doses of paliperidone (injection) were superior to placebo in improving PANSS total score.
- A summary of the mean baseline PANSS scores along with the mean changes from baseline in the four short-term acute schizophrenia studies are provided in Table 13.

### Maintenance Monotherapy Treatment (Study 5: PSY-3001)
- The efficacy of paliperidone (injection) in maintaining symptomatic control in schizophrenia was established in a longer-term double-blind, placebo-controlled, flexible-dose study involving adult subjects who met DSM-IV criteria for schizophrenia. This study included a minimum 12-week, fixed-dose stabilization phase, and a randomized, placebo-controlled phase to observe for relapse. During the double-blind phase, patients were randomized to either the same dose of paliperidone (injection) they received during the stabilization phase, i.e., 39 mg, 78 mg, or 156 mg administered every 4 weeks, or to placebo. A total of 410 stabilized patients were randomized to either paliperidone (injection) or to placebo until they experienced a relapse of schizophrenia symptoms. Relapse was pre-defined as time to first emergence of one or more of the following: psychiatric hospitalization,  25% increase (if the baseline score was > 40) or a 10-point increase (if the baseline score was  40) in total PANSS score on two consecutive assessments, deliberate self-injury, violent behavior, suicidal/homicidal ideation, or a score of  5 (if the maximum baseline score was  3) or  6 (if the maximum baseline score was 4) on two consecutive assessments of the specific PANSS items. The primary efficacy variable was time to relapse. A pre-planned interim analysis showed a statistically significantly longer time to relapse in patients treated with paliperidone (injection) compared to placebo, and the study was stopped early because maintenance of efficacy was demonstrated. Thirty-four percent (34%) of subjects in the placebo group and 10% of subjects in the paliperidone (injection) group experienced a relapse event. There was a statistically significant difference between the treatment groups in favor of paliperidone (injection). A Kaplan-Meier plot of time to relapse by treatment group is shown in Figure 1. The time to relapse for subjects in the placebo group was statistically significantly shorter than for the paliperidone (injection) group. An examination of population subgroups did not reveal any clinically significant differences in responsiveness on the basis of gender, age, or race.

## Schizoaffective Disorder

### Maintenance Treatment  Monotherapy and as Adjunct to Mood Stabilizer or Antidepressant (SAff Study 1: SCA-3004)
- The efficacy of paliperidone (injection) in maintaining symptom control in schizoaffective disorder was established in a long-term double-blind, placebo-controlled, flexible-dose randomized-withdrawal study designed to delay relapse in adult subjects who met DSM-IV criteria for schizoaffective disorder, as confirmed by the Structured Clinical Interview for DSM-IV Disorders. The population included subjects with schizoaffective bipolar and depressive types. Subjects received paliperidone (injection) either as monotherapy or as an adjunct to stable doses of antidepressant or mood stabilizers.
- This study included a 13-week, open-label, flexible-dose (paliperidone (injection) 78 mg, 117 mg, 156 mg, or 234 mg) lead-in period which enrolled a total of 667 subjects who had 1) acute exacerbation of psychotic symptoms; 2) score 4 on 3 PANSS items of delusions, conceptual disorganization, hallucinatory behavior, excitement, suspiciousness/persecution, hostility, uncooperativeness, tension, and poor impulse control; and 3) prominent mood symptoms 16 on the Young Mania Rating Scale (YMRS) and/or the Hamilton Rating Scale for Depression, 21-item version (HAM-D-21). Subjects were 19 to 66 years old (mean 39.5 years) and 53.5% were male. The mean scores at open-label enrollment of PANSS total was 85.8 (range 42 to 128), HAM-D-21 was 20.4 (range 3 to 43), YMRS was 18.6 (range 0 to 50), and CGI-S-SCA was 4.4 (range 2 to 6).
- After the 13-week open-label flexible-dose paliperidone (injection) treatment, 432 subjects met stabilization criteria (PANSS total score 70, YMRS 12, and HAM-D-21 12) and continued into the 12-week open-label fixed-dose stabilization period.
- A total of 334 subjects who met stabilization criteria for 12 consecutive weeks were randomized (1:1) to continue the same dose of paliperidone (injection) or to placebo in the 15-month, double-blind, maintenance period. For the 164 subjects who were randomized to paliperidone (injection), dose distribution was 78 mg (4.9%), 117 mg (9.8%), 156 mg (47.0%), and 234 mg (38.4%). The primary efficacy variable was time to relapse. Relapse was defined as the first occurrence of one or more of the following: 1) psychiatric hospitalization; 2) intervention employed to avert hospitalization; 3) clinically significant self-injury, suicidal or homicidal ideation or violent behavior; 4) a score of 6 (if the score was 4 at randomization) of any of the individual PANSS items: delusions, conceptual disorganization, hallucinatory behavior, excitement, suspiciousness/persecution, hostility, uncooperativeness, or poor impulse control; 5) on two consecutive assessments within 7 days: 25% increase (if the score at randomization was >45) or 10-point increase (if the score at randomization was 45) in total PANSS score; a score of 5 (if the score was 3 at randomization) of any of the individual PANSS items: delusions, conceptual disorganization, hallucinatory behavior, excitement, suspiciousness/persecution, hostility, uncooperativeness, or poor impulse control; an increase of 2 points (if the score was 1  to 3  at randomization) or increase of 1 point (if the score was 4  at randomization) in CGI-S-SCA overall score.
- There was a statistically significant difference in time to relapse between the treatment groups in favor of paliperidone (injection). A Kaplan-Meier plot of time to relapse by treatment group is shown in Figure 2.

# How Supplied
- Paliperidone (injection) is available as a white to off-white sterile aqueous extended-release suspension for intramuscular injection in dose strengths of 39 mg, 78 mg, 117 mg, 156 mg, and 234 mg paliperidone palmitate. The kit contains a prefilled syringe and 2 safety needles (a 1 12-inch 22 gauge safety needle and a 1-inch 23 gauge safety needle).
- 39 mg paliperidone palmitate kit (NDC 50458-560-01)
- 78 mg paliperidone palmitate kit (NDC 50458-561-01)
- 117 mg paliperidone palmitate kit (NDC 50458-562-01)
- 156 mg paliperidone palmitate kit (NDC 50458-563-01)
- 234 mg paliperidone palmitate kit (NDC 50458-564-01)

## Storage
- Store at room temperature (25C, 77F); excursions between 15C and 30C (between 59F and 86F) are permitted.

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
- Physicians are advised to discuss the following issues with patients for whom they prescribe paliperidone (injection).

### 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.

### Interference with Cognitive and Motor Performance
- Patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that paliperidone (injection) therapy does not affect them adversely, as paliperidone (injection) has the potential to impair judgment, thinking, or motor skills.

### Pregnancy
- Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during treatment with INVEGA SUSTENNA.

### Nursing
- Inform patients and caregivers that INVEGA SUSTENNA is present in human breast milk; there is a potential for serious adverse reactions in nursing infants. Advise patients that the decision whether to discontinue nursing or to discontinue the drug should take into account the importance of the drug to the patient.

### 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.

### Heat Exposure and Dehydration
- Patients should be advised regarding appropriate care in avoiding overheating and dehydration.

### Patient Informations

# Precautions with Alcohol
Alcohol-Paliperidone (injection) interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
- INVEGA SUSTENNA 

# Look-Alike Drug Names
There is limited information regarding Paliperidone (injection) Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price