VA Class:CN709

AHFS Class:

• Atypical Antipsychotics 28:16.08.04

Generic Name(s):

• Paliperidone

Chemical Name:

• (±)-3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidyl]ethyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one

Molecular Formula:

• C₂₃H₂₇FN₄O₃

Paliperidone is considered an atypical or second-generation antipsychotic agent.1,2,3,4,5,6,7,8,12,39,41

Psychotic Disorders

Paliperidone is used for the symptomatic management of psychotic disorders (e.g., schizophrenia).1,2,3,4,6,7,8,12,39,41 Drug therapy is integral to the management of acute psychotic episodes in patients with schizophrenia and generally is required for long-term stabilization to sustain symptom remission or control and to minimize the risk of relapse.2 Antipsychotic agents are the principal class of drugs used for the management of all phases of schizophrenia.2 Patient response and tolerance to antipsychotic agents are variable, and patients who do not respond to or tolerate one drug may be successfully treated with an agent from a different class or with a different adverse effect profile.2

Schizophrenia

Paliperidone is used orally for the acute and maintenance treatment of schizophrenia in adults and adolescents 12-17 years of age.1,3,4,6,7,8,39,41,45,49 Schizophrenia is a major psychotic disorder that frequently has devastating effects on various aspects of the patient's life and carries a high risk of suicide and other life-threatening behaviors.2,10 Manifestations of schizophrenia involve multiple psychologic processes, including perception (e.g., hallucinations), ideation, reality testing (e.g., delusions), emotion (e.g., flatness, inappropriate affect), thought processes (e.g., loose associations), behavior (e.g., catatonia, disorganization), attention, concentration, motivation (e.g., avolition, impaired intention and planning), and judgment.2,10 The principal manifestations of this disorder usually are described in terms of positive and negative (deficit) symptoms, and more recently, disorganized symptoms.2 Positive symptoms include hallucinations, delusions, bizarre behavior, hostility, uncooperativeness, and paranoid ideation, while negative symptoms include restricted range and intensity of emotional expression (affective flattening), reduced thought and speech productivity (alogia), anhedonia, apathy, and decreased initiation of goal-directed behavior (avolition).2 Disorganized symptoms include disorganized speech (thought disorder) and behavior and poor attention.2

The short-term efficacy of paliperidone in the acute treatment of schizophrenia in adults was established in 3 placebo-controlled and active comparator (olanzapine)-controlled, fixed-dose clinical trials of 6 weeks' duration in 1665 adult patients with schizophrenia.1,3,6,7,8,39,41,43 In these 3 studies, patients receiving paliperidone (3-15 mg daily as extended-release tablets) demonstrated substantially greater improvement in the Positive and Negative Syndrome Scale (PANSS) than did patients receiving placebo.1,3,6,7,8,39,41 The mean effects at all dosages (3, 6, 9, 12, and 15 mg daily) were fairly similar, although higher dosages produced numerically superior results.1,3,6,7,8,41 Paliperidone also was found to be superior to placebo in improving scores on the Personal and Social Performance (PSP) scale in these trials.1,3,6,7,41

In a longer-term study, adult outpatients with schizophrenia who had clinically responded to oral paliperidone and who had received a stable fixed dosage of the drug for 2 weeks entered a 6-week, open-label, stabilization phase where they received a paliperidone dosage from 3-15 mg once daily as extended-release tablets.1,4,39,41 After the stabilization phase, patients were randomized in a double-blind manner to either continue receiving paliperidone at their stable dosage or to receive placebo until they experienced a relapse of schizophrenia symptoms.1,4,39,41 The median treatment exposure during this double-blind phase was 45 days for extended-release paliperidone and 29 days for placebo; the mean paliperidone dosage was approximately 11 mg daily throughout the phases of this trial.4,39 An interim analysis of the data showed a significantly longer time to relapse in the paliperidone-treated patients compared with those receiving placebo.1,4,39,41 In addition, 25% of the paliperidone-treated patients experienced a relapse of schizophrenia symptoms compared with 53% of those receiving placebo.4 The study was stopped early because maintenance of efficacy was demonstrated.1,4,39,41 If paliperidone is used for extended periods, the need for continued therapy should be reassessed periodically on an individualized basis.1,22 (See Dosage and Administration: Dosage.)

Short-term efficacy and safety of oral paliperidone in the acute treatment of schizophrenia in adolescents 12-17 years of age were established in a double-blind, placebo-controlled trial of 6 weeks' duration in 201 patients who met DSM-IV criteria for schizophrenia.45,49 The trial used a fixed-dosage, weight-based treatment group design over a dosage range of 1.5-12 mg once daily given as extended-release tablets.45,49 Patients were randomized to one of 4 treatment groups: a placebo group or a low-dosage (1.5 mg daily for all body weights), medium-dosage (3 or 6 mg daily depending on body weight), or high-dosage group (6 or 12 mg daily depending on body weight).45,49 Efficacy was evaluated using the PANSS.45,49 The study demonstrated the overall efficacy of paliperidone in adolescents with schizophrenia receiving dosages ranging from 3-12 mg once daily.45,49 However, no clear improvement in efficacy was observed at the higher dosages studied (i.e., 6 mg daily for adolescents weighing less than 51 kg and 12 mg daily for adolescents weighing 51 kg or more).45,49 Tolerability was adequate within the 3-12 mg daily dosage ran however, adverse effects were dose related.45,49 Longer-term efficacy and safety of extended-release paliperidone in adolescent patients with schizophrenia are currently being evaluated in clinical studies.49

The American Psychiatric Association (APA) considers most atypical antipsychotic agents first-line drugs for the management of the acute phase of schizophrenia (including first psychotic episodes), principally because of the decreased risk of adverse extrapyramidal effects and tardive dyskinesia, with the understanding that the relative advantages, disadvantages, and cost-effectiveness of conventional and atypical antipsychotic agents remain controversial.2 The APA states that, with the possible exception of clozapine for the management of treatment-resistant symptoms, there currently is no definitive evidence that one atypical antipsychotic agent will have superior efficacy compared with another agent in the class, although meaningful differences in response may be observed in individual patients.2 Conventional antipsychotic agents may be considered first-line therapy in patients who have been treated successfully in the past with or who prefer conventional agents.2 The choice of an antipsychotic agent should be individualized, considering past response to therapy, adverse effect profile (including the patient's experience of subjective effects such as dysphoria), and the patient's preference for a specific drug, including route of administration.2

For additional information on the symptomatic management of schizophrenia, including treatment recommendations and results of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) research program, see Schizophrenia and Other Psychotic Disorders under Uses: Psychotic Disorders, in the Phenothiazines General Statement 28:16.08.24.

Schizoaffective Disorder

Paliperidone is used orally for the treatment of schizoaffective disorder as monotherapy and as an adjunct to mood stabilizers and/or antidepressant therapy in adults.45,54,55,56

The acute efficacy of paliperidone in the treatment of schizoaffective disorder was principally established in 2 international, double-blind, placebo-controlled trials of 6 weeks' duration in nonelderly adults.45,54,55,56 Patients enrolled in these trials met DSM-IV criteria for schizoaffective disorder, had a PANSS total score of at least 60, and had prominent mood symptoms (confirmed by a score of at least 16 on the Young Mania Rating Scale [YMRS] and/or Hamilton Rating Scale for Depression [HRSD]).45,54,55,56 The patients in these trials included individuals with schizoaffective disorder bipolar and depressive types.45,54,55,56 In the first trial, efficacy was assessed in 211 patients who received flexible dosages of paliperidone (3-12 mg once daily as extended-release tablets).45,54,56 In the second trial, efficacy was assessed in 203 patients who were assigned to one of two different dosages of paliperidone: 6 mg with the option to reduce to 3 mg once daily or 12 mg with the option to reduce to 9 mg once daily.45,54,55 In both studies, patients received paliperidone either as monotherapy (55%) or as an adjunct to mood stabilizers and/or antidepressants (45%).45,54 The most commonly used mood stabilizers in the studies were valproic acid and lithium and the most commonly used antidepressants were selective serotonin-reuptake inhibitors and selective serotonin- and norepinephrine-reuptake inhibitors.45,54 Efficacy was principally evaluated using the PANSS; as secondary outcomes, mood symptoms were evaluated using the Hamilton Depression Rating Scale (HAM-D-21) and YMRS.45,54,55,56 The paliperidone-treated patients in the flexible-dose study (mean modal dosage of 8.6 mg daily) and the higher dosage group of paliperidone in the 2-dosage-level study were each found to be superior to placebo (as measured by the PANSS).45 The lower dosage group of paliperidone in the 2-dosage-level study (6 mg with option to reduce to 3 mg once daily) was not found to be substantially different from placebo (as measured by the PANSS).45 Improvements in mood symptoms (as measured by the HAM-D-21 and YMRS) also were observed in the studies.45

In an analysis of both placebo-controlled studies in schizoaffective disorder, paliperidone improved the symptoms of schizoaffective disorder at the study end points when administered either as monotherapy or as an adjunct to mood stabilizers and/or antidepressants.45 An examination of population subgroups did not reveal evidence of differential responsiveness based on gender, age, or geographic region.45 There were insufficient data to explore differential effects based on race.45

Administration

Paliperidone extended-release tablets are administered orally once daily, usually in the morning, with or without food.1,12,39,41

Paliperidone extended-release tablets should be swallowed whole with fluids and should not be chewed, divided, or crushed.1,12 Patients should be advised not to become concerned if they notice a tablet-like substance in their stools; this is normal since the tablet is designed to remain intact and slowly release the drug from a nonabsorbable shell during passage through the GI tract.1,5,12

Dosage

Schizophrenia

For the management of schizophrenia in adults, the usual recommended initial dosage of paliperidone is 6 mg orally once daily in the morning; initial dosage titration is not required.1,5,41 Although it remains to be systematically evaluated whether dosages exceeding 6 mg once daily provide additional clinical benefit, a general trend for greater clinical effects with higher dosages has been observed.1,3,6,7,8 However, the potential for increased clinical efficacy at higher dosages must be weighed against the potential for a dose-related increase in adverse effects.1 Some patients may benefit from higher dosages of up to 12 mg once daily, while a lower dosage of 3 mg once daily may be sufficient for other patients.1 The manufacturer states that increases beyond a dosage level of 6 mg once daily should be made only after clinical reassessment and generally should be made at intervals of more than 5 days.1 When dosage increases are necessary, increments of 3 mg daily are recommended.1 The maximum recommended dosage in adults is 12 mg once daily.1

For the management of schizophrenia in adolescents 12-17 years of age, the usual recommended initial dosage of paliperidone is 3 mg (regardless of body weight) orally once daily in the morning; initial dosage titration is not required.45 The manufacturer states that dosage increases, if considered necessary, should be made only after clinical reassessment and should made in increments of 3 mg daily at intervals of more than 5 days.45 The recommended adolescent dosage range for patients weighing less than 51 kg is 3-6 mg once daily and for those weighing 51 kg or more is 3-12 mg once daily.45 However, clinicians should consider that, in the adolescent schizophrenia study, there was no clear improvement in efficacy at the higher paliperidone dosage studied (i.e., 6 mg once daily for adolescents weighing less than 51 kg and 12 mg once daily for adolescents weighing 51 kg or more) while adverse effects were found to be dose related.45,49 The maximum recommended adolescent dosage is 6 mg once daily for adolescents weighing less than 51 kg and 12 mg once daily for adolescents weighing 51 kg or more.45

The optimum duration of oral paliperidone therapy in patients with schizophrenia currently is not known, but maintenance therapy with paliperidone 3-15 mg daily as extended-release tablets has been shown to be effective in preventing relapse in adults.1,4 Patients responding to paliperidone therapy should continue to receive the drug as long as clinically necessary and tolerated but at the lowest possible effective dosage, and the need for continued therapy with the drug should be reassessed periodically.1,2 The American Psychiatric Association (APA) states that prudent long-term treatment options in patients with schizophrenia with remitted first- or multiple-episodes include either indefinite maintenance therapy or gradual discontinuance of the antipsychotic agent with close follow-up and a plan to reinstitute treatment upon symptom recurrence.2 Discontinuance of antipsychotic therapy should be considered only after a period of at least 1 year of symptom remission or optimal response while receiving the antipsychotic agent.2 In patients who have had multiple previous psychotic episodes or 2 psychotic episodes within 5 years, indefinite maintenance antipsychotic treatment is recommended.2

Schizoaffective Disorder

The recommended initial and target dosage of paliperidone for the treatment of schizoaffective disorder in adults in 6 mg orally once daily.45 Initial dosage titration is not required.45 However, some patients may benefit from lower or higher dosages within the recommended dosage range of 3-12 mg once daily.45 Although a general trend for greater clinical effects with higher dosages has been observed, the potential for increased clinical efficacy must be weighed against the potential for a dose-related increase in adverse effects.45 Dosage adjustment, if necessary, should occur only after clinical reassessment and generally should be made at intervals of more than 4 days.45 When dosage increases are necessary, increments of 3 mg daily are recommended.45 The maximum recommended adult dosage is 12 mg once daily.45

Special Populations

The manufacturer states that the dosage of paliperidone must be individualized according to the patient's renal function status.45 In patients with mild renal impairment (creatinine clearance of 50-79 mL/minute), the recommended initial oral dosage of paliperidone is 3 mg once daily.45 The dosage may then be increased up to a maximum of 6 mg once daily based on clinical response and tolerability.45 In patients with moderate to severe renal impairment (creatinine clearance of 10-49 mL/minute), the recommended initial dosage of paliperidone is 1.5 mg once daily, which may be increased up to a maximum of 3 mg once daily after clinical reassessment.45 Use in patients with a creatinine clearance below 10 mL/minute is not recommended since paliperidone has not been studied in such patients.45 (See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Dosage adjustment is not necessary in patients with mild to moderate hepatic impairment (Child-Pugh class A and B).39,41,45 Paliperidone has not been studied in patients with severe hepatic impairment.45 (See Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Because geriatric patients may have reduced renal function, dosage adjustment may be required based on renal function status.1,39,41 Geriatric patients with normal renal function generally may receive the same dosage recommended for younger adults with normal renal function.1,39 In geriatric patients with moderate or severe renal impairment, the maximum recommended paliperidone dosage is 3 mg once daily.1,39 (See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

No dosage adjustment is necessary based on race, gender, or smoking status (see Drug Interactions: Smoking).39,45

Contraindications

Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been observed in patients receiving risperidone or paliperidone.45 Paliperidone is therefore contraindicated in patients with a known hypersensitivity to paliperidone, risperidone, or any ingredient in the paliperidone formulation.12,45

Warnings/Precautions

Warnings

Increased Mortality in Geriatric Patients with Dementia-related Psychosis

Geriatric patients with dementia-related psychosis treated with antipsychotic drugs appear to be at an increased risk of death.11,45,51 Analysis of 17 placebo-controlled trials (modal duration of 10 weeks) revealed an approximate 1.6- to 1.7-fold increase in mortality among geriatric patients receiving atypical antipsychotic drugs (i.e., aripiprazole, olanzapine, quetiapine, risperidone) compared with that observed in patients receiving placebo.11,45 Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5% compared with a rate of about 2.6% in the placebo group.11,45 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.11,45 Observational studies suggest that, similar to atypical antipsychotics, treatment with conventional (first-generation) antipsychotics 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 remains unclear.45,51 The manufacturer states that paliperidone is not approved for the treatment of patients with dementia-related psychosis.45 (See Adverse Cerebrovascular Events, including Stroke, in Geriatric Patients with Dementia-related Psychosis under Warnings/Precautions: Other Warnings and Precautions, in Cautions, Dysphagia under Warnings/Precautions: Other Warnings and Precautions, in Cautions, and also see Geriatric Use under Warnings/Precautions: Specific Populations, in Cautions.)

Sensitivity Reactions

Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been observed in patients receiving risperidone or paliperidone.45 (See Contraindications under Cautions.)

Other Warnings and Precautions

Adverse Cerebrovascular Events, including Stroke, in Geriatric Patients with Dementia-related Psychosis

An increased incidence of adverse cerebrovascular events (cerebrovascular accidents and transient ischemic attacks), including fatalities, has been observed in geriatric patients with dementia-related psychosis treated with certain atypical antipsychotic agents (aripiprazole, olanzapine, risperidone) in placebo-controlled studies.45 The manufacturer states that paliperidone is not approved for the treatment of patients with dementia-related psychosis.45 (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis under Warnings/Precautions: Warnings and also see Geriatric Use under Warnings/Precautions: Specific Populations, in Cautions.)

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome requiring immediate discontinuance of the drug and intensive symptomatic treatment, has been reported in patients receiving antipsychotic agents, including paliperidone.1,2,4 (See Advice to Patients.) For additional information on NMS, see Neuroleptic Malignant Syndrome under Cautions: Nervous System Effects, in the Phenothiazines General Statement 28:16.08.24.

Prolongation of QT Interval

Paliperidone causes a modest increase in the corrected QT (QT_c) interval.1,7,44 The risk of torsades de pointes in association with drugs that prolong the QT_c interval may be increased in patients with bradycardia, hypokalemia, or hypomagnesemia; patients receiving other drugs that prolong the QT_c interval; and in those with congenital prolongation of the QT interval.1 Therefore, the manufacturer states that paliperidone should be avoided in patients concurrently receiving other drugs known to prolong the QT_c interval, patients with congenital long QT syndrome, and those with a history of cardiac arrhythmias.1 (See Drug Interactions: Drugs that Prolong QT Interval.)

Tardive Dyskinesia

Because use of antipsychotic agents may be associated with tardive dyskinesia (a syndrome of potentially irreversible, involuntary, dyskinetic movements),1,2 paliperidone should be prescribed in a manner that is most likely to minimize the occurrence of this syndrome.1 Chronic antipsychotic treatment generally should be reserved for patients who suffer from a chronic illness that is known to respond to antipsychotic agents, and for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate.1 In patients who do require chronic treatment, the lowest dosage and the shortest duration of treatment producing a satisfactory clinical response should be sought, and the need for continued treatment should be reassessed periodically.1

The American Psychiatric Association (APA) currently recommends that patients receiving atypical antipsychotic agents be assessed clinically for abnormal involuntary movements every 12 months and that patients considered to be at increased risk for tardive dyskinesia be assessed every 6 months.2 If signs and symptoms of tardive dyskinesia appear in a paliperidone-treated patient, paliperidone discontinuance should be considered; however, some patients may require continued treatment with the drug despite the presence of the syndrome.45 For additional information on tardive dyskinesia, see Tardive Dyskinesia under Cautions: Nervous System Effects, in the Phenothiazines General Statement 28:16.08.24.

Metabolic Changes

Atypical antipsychotic agents have been associated with metabolic changes that may increase cardiovascular and cerebrovascular risk, including hyperglycemia, dyslipidemia, and body weight gain.45 While all of these drugs produce some metabolic changes, each drug has its own specific risk profile.45 (See Hyperglycemia and Diabetes Mellitus, see Dyslipidemia, and also see Weight Gain under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Hyperglycemia and Diabetes Mellitus

Hyperglycemia and diabetes mellitus, sometimes severe and associated with ketoacidosis, hyperosmolar coma, or death, have been reported in patients treated with all atypical antipsychotic agents.2,13,14,15,16,17,18,19,24,25,26,27,28,29,30,31,32,33,34,35,36,39,45 These cases were mainly seen in postmarketing clinical use and epidemiologic studies, not in clinical trials, and there have been few reports of hyperglycemia or diabetes mellitus in paliperidone-treated patients to date.7,45 While confounding factors such as an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population make it difficult to establish with certainty the relationship between use of agents in this drug class and glucose abnormalities, epidemiologic studies (which did not include paliperidone) suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with atypical antipsychotic agents.2,20,21,22,23,45 It remains to be determined whether paliperidone also is associated with this increased risk.45

The manufacturers of atypical antipsychotic agents state that patients with preexisting diabetes mellitus in whom therapy with an atypical antipsychotic is initiated should be closely monitored for worsening of glucose control; those with risk factors for diabetes (e.g., obesity, family history of diabetes) should undergo fasting blood glucose testing upon therapy initiation and periodically throughout treatment.24,25,26,27,28,29,30,31,32,33,34,35,36,45 Any patient who develops manifestations of hyperglycemia (including polydipsia, polyuria, polyphagia, and weakness) during treatment with an atypical antipsychotic should undergo fasting blood glucose testing.24,25,26,27,28,29,30,31,32,33,34,35,36,45 (See Advice to Patients.) In some cases, patients who developed hyperglycemia while receiving an atypical antipsychotic have required continuance of antidiabetic treatment despite discontinuance of the suspect drug; in other cases, hyperglycemia resolved with discontinuance of the antipsychotic.18,25,26,27,28,29,30,31,32,33,34,35,36,45

For further information on managing the risk of hyperglycemia and diabetes mellitus associated with atypical antipsychotic agents, see Hyperglycemia and Diabetes Mellitus under Cautions: Precautions and Contraindications, in Clozapine 28:16.08.04.

Dyslipidemia

Undesirable changes in lipid parameters have been observed in patients treated with some atypical antipsychotics.45 Data from short- and longer-term clinical studies suggest that the risk of developing clinically important dyslipidemia during paliperidone therapy is minimal.45

Weight Gain

Weight gain has been observed with atypical antipsychotic therapy.45 Monitoring of weight is recommended in patients receiving paliperidone and other atypical antipsychotic agents.45 (See Pediatric Use under Warnings/Precautions: Specific Populations, in Cautions.)

Hyperprolactinemia

Similar to other antipsychotic agents and drugs with dopamine D₂ antagonistic activity, paliperidone can elevate serum prolactin concentrations.2,4,6,37,38,39,41,42,45 Paliperidone's prolactin-elevating effect is similar to that seen with risperidone, which appears to be associated with a higher level of prolactin elevation than other currently available antipsychotic agents.2,37,38,42,45 Clinical disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been associated with prolactin-elevating drugs.2,42,45 In addition, chronic hyperprolactinemia associated with hypogonadism may lead to decreased bone density in both female and male patients.45

If paliperidone therapy is considered in a patient with previously detected breast cancer, clinicians should consider that approximately one-third of human breast cancers are prolactin-dependent in vitro.45

Potential for GI Obstruction

As with other nondeformable material, extended-release paliperidone tablets do not appreciably change in shape in the GI tract.1 Therefore, extended-release tablets of the drug generally should not be administered to patients with severe, preexisting GI narrowing (either pathologic or iatrogenic).1 Rare cases of obstructive symptoms in patients with known strictures have been reported in association with the ingestion of drugs in nondeformable, controlled-release formulations.1 Because of the extended-release design of paliperidone tablets, the drug should only be used in patients who are able to swallow the tablet whole.1

Decreased bioavailability of paliperidone extended-release tablets would be expected in patients with a decreased GI transit time (e.g., those with diarrhea) while an increased bioavailability would be expected in patients with an increased GI transit time (e.g., those with GI neuropathy, diabetic gastroparesis, or due to other causes).1 Such changes in bioavailability are more likely when changes in transit time occur in the upper GI tract.1

Orthostatic Hypotension and Syncope

Orthostatic hypotension and syncope may occur during paliperidone therapy in some patients, particularly early in treatment, perhaps because of the drug's α₁-adrenergic blocking activity.2,4,45 Syncope occurred in about 0.8% of patients receiving paliperidone in controlled clinical trials.45

Paliperidone should be used with caution in patients with known cardiovascular disease (e.g., heart failure, history of myocardial infarction, ischemic heart disease, conduction abnormalities), cerebrovascular disease, or conditions that would predispose patients to hypotension (e.g., dehydration, hypovolemia, concomitant antihypertensive therapy) and in antipsychotic-naive patients.45 Consideration should be given to monitoring orthostatic vital signs in paliperidone-treated patients who are susceptible to hypotension (e.g., geriatric patients).2,45

Leukopenia, Neutropenia, and Agranulocytosis

In clinical trial and/or postmarketing experience, leukopenia and neutropenia have been temporally related to antipsychotic agents, including paliperidone.45,52,53 Agranulocytosis also has been reported with antipsychotic agents.45

Possible risk factors for leukopenia and neutropenia include preexisting low leukocyte count and a history of drug-induced leukopenia and neutropenia.45,52 Patients with a preexisting low leukocyte count or a history of drug-induced leukopenia or neutropenia should have their complete blood count monitored frequently during the first few months of therapy.45 Paliperidone should be discontinued at the first sign of a decline in leukocyte count in the absence of other causative factors.45

Patients with clinically important neutropenia should be carefully monitored for fever or other signs or symptoms of infection and promptly treated if such signs and symptoms occur.45 In patients with severe neutropenia (absolute neutrophil count [ANC] less than 1000/mm³), paliperidone should be discontinued and the leukocyte count monitored until recovery occurs.45 Lithium reportedly has been used successfully in the treatment of several cases of leukopenia associated with aripiprazole, clozapine, and some other drugs; however, further clinical experience is needed to confirm these anecdotal findings.52

Cognitive and Motor Impairment

Like other antipsychotic agents, paliperidone potentially may impair judgment, thinking, or motor skills.7,45 In short-term, placebo-controlled trials in adults with schizophrenia, somnolence (including hypersomnia, hypersomnolence, and sedation) was reported in 6-11% of patients receiving the drug.7,45 The frequency of somnolence appears to be dose related.45 (See Advice to Patients.)

Seizures

Seizures have occurred in approximately 0.2% of patients with schizophrenia receiving paliperidone in premarketing clinical studies.45 As with other antipsychotic agents, paliperidone should be used with caution in patients with a history of seizures or with other conditions that may lower the seizure threshold (e.g., dementia of the Alzheimer's type); conditions that lower the seizure threshold may be more prevalent in patients 65 years of age or older.45

Dysphagia

Esophageal dysmotility and aspiration have been associated with the use of antipsychotic agents.45 Aspiration pneumonia is a common cause of morbidity and mortality in geriatric patients, particularly in those with advanced Alzheimer's dementia.45 Paliperidone is not approved for the treatment of patients with dementia-related psychosis and should be used with caution in patients at risk for aspiration pneumonia.45 (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis under Warnings/Precautions: Warnings, in Cautions.)

Suicide

There is an attendant risk of suicide in patients with psychotic illnesses; high-risk patients should be closely supervised.45 Paliperidone should be prescribed in the smallest quantity consistent with good patient management to reduce the risk of overdosage.45

Priapism

Drugs possessing α-adrenergic blocking activity have been reported to cause priapism.45 Priapism has been reported in paliperidone-treated patients during postmarketing surveillance.45 Severe priapism may require surgical intervention.45

Thrombotic Thrombocytopenic Purpura

Thrombotic thrombocytopenic purpura (TTP) has not been reported in clinical trials of paliperidone.1 TTP has been reported in association with risperidone therapy; however, the relationship of this adverse event to risperidone is unknown.1

Body Temperature Regulation

Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents.1 The manufacturer recommends appropriate caution when paliperidone is used in patients who will be experiencing conditions that may contribute to an elevation in core body temperature (e.g., strenuous exercise, extreme heat, concomitant use of agents with anticholinergic activity, dehydration).1

Antiemetic Effect

Antiemetic effects were observed in preclinical studies with paliperidone; these effects also may occur in humans and mask signs of overdosage of other drugs or obscure cause of vomiting in various disorders (e.g., intestinal obstruction, Reye's syndrome, brain tumor).1

Concomitant Illnesses

Clinical experience with paliperidone in patients with certain concomitant illnesses is limited.1

Patients with parkinsonian syndrome or dementia with Lewy bodies who receive antipsychotics reportedly have an increased sensitivity to antipsychotic agents.1 Clinical manifestations of this increased sensitivity have been reported to include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and features consistent with NMS.1 For additional information on extrapyramidal adverse effects and NMS, see Cautions: Nervous System Effects, in the Phenothiazines General Statement 28:16.08.24.

Paliperidone has not been adequately evaluated in patients with a recent history of myocardial infarction or unstable cardiovascular disease to date and patients with these conditions were excluded from premarketing clinical trials.45 Because of the risk of orthostatic hypotension associated with paliperidone, the manufacturer states that the drug should be used with caution in patients with known cardiovascular disease.45 (See Orthostatic Hypotension and Syncope under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Laboratory Test Monitoring

No specific laboratory tests are recommended in patients receiving paliperidone.45

Specific Populations

Pregnancy

Category C.1 (See Users Guide.)

Neonates exposed to antipsychotic agents during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery.45,46,47,48 Symptoms reported to date have included agitation, hypertonia, hypotonia, tardive dyskinetic-like symptoms, tremor, somnolence, respiratory distress, and feeding disorder.45,46,47,48 Neonates exhibiting such symptoms should be monitored.48 The complications have varied in severity; some neonates recovered within hours to days without specific treatment while others have required intensive care unit support and prolonged hospitalization.45,46,47,48 For further information on extrapyramidal and withdrawal symptoms in neonates, see Cautions: Pregnancy, Fertility, and Lactation, in the Phenothiazines General Statement 28:16.08.24.

Lactation

Paliperidone is distributed into milk in humans.39,40,45 The benefits of breastfeeding should be weighed against the unknown risks of infant exposure to the drug.45

Pediatric Use

Safety and efficacy of oral paliperidone in the treatment of schizophrenia in adolescents 12-17 years of age have been established in a double-blind, placebo-controlled study of 6 weeks' duration.45,49

Safety and efficacy of oral paliperidone in the treatment of schizophrenia have not been established in pediatric patients younger than 12 years of age.45

Safety and efficacy of oral paliperidone in the treatment of schizoaffective disorder have not been established in pediatric patients younger than 18 years of age.45

Weight gain has been associated with atypical antipsychotic use and monitoring of weight is recommended.45 However, in paliperidone-treated adolescents, weight gain should be assessed against that expected with normal growth.45 Weight gain in adolescents receiving paliperidone in an open-label, long-term study was not considered clinically substantial when compared with normative data.45

The manufacturer states that the long-term effects of paliperidone on growth and sexual maturation have not been fully evaluated in children and adolescents.45

Geriatric Use

In clinical studies, approximately 7% of nearly 1800 patients were 65 years of age or older.1,39 In addition, the short-term efficacy and safety of paliperidone have been demonstrated in a placebo-controlled trial of 6 weeks' duration in 114 geriatric patients with schizophrenia.1 While no substantial differences in efficacy or safety relative to younger adults were observed in these studies or in other clinical experience with the drug, increased sensitivity cannot be ruled out.1,39

Because geriatric patients may have reduced renal function, dosage adjustment may be required based on renal function status; consider monitoring renal function.1,41 (See Dosage and Administration: Special Populations.)

Geriatric patients with dementia-related psychosis treated with atypical antipsychotic drugs appear to be at an increased risk of death compared with that among patients receiving placebo.1 Paliperidone is not approved for the treatment of dementia-related psychosis.1 (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis under Warnings/Precautions: Warnings, in Cautions.)

Hepatic Impairment

Patients with moderate hepatic impairment (Child-Pugh class B) exhibited similar plasma concentrations of free paliperidone as healthy individuals, although total paliperidone exposure decreased because of decreased protein binding.1,41 Dosage adjustment is not necessary in patients with mild to moderate hepatic impairment (Child-Pugh class A and B).1,41 The effect of severe hepatic impairment on paliperidone pharmacokinetics is not known.1,41 (See Dosage and Administration: Special Populations.)

Renal Impairment

Clearance decreased by an average of 32, 64, and 71% in patients with mild, moderate, and severe renal impairment, respectively.41,45 Dosage adjustment is recommended in patients with renal impairment.41,45 (See Dosage and Administration: Special Populations.)

Common Adverse Effects

Adverse effects reported in 5% or more of adults receiving paliperidone for schizophrenia and at a frequency at least twice that reported with placebo include extrapyramidal symptoms,4,7,39,41,45 tachycardia,4,7,39,41,44,45 and akathisia.6,39,44,45

Adverse effects reported in 5% or more of adolescents receiving paliperidone for schizophrenia and at a frequency at least twice that reported with placebo include somnolence,45,49 extrapyramidal symptoms (e.g., akathisia, tremor, dystonia, cogwheel rigidity),45,49 anxiety,45,49 increased weight,45,49 and tachycardia.45,49

Adverse effects reported in 5% or more of adults receiving paliperidone for schizoaffective disorder and at a frequency at least twice that reported with placebo include extrapyramidal symptoms,45 somnolence,45 dyspepsia,45 constipation,45 increased weight,45 and nasopharyngitis.45

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors or inducers of cytochrome P-450 (CYP) isoenzymes 2D6, 3A4, 1A2, 2A6, 2C9, and 2C19: pharmacokinetic interaction unlikely.1,9,41

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, or CYP3A5: pharmacokinetic interaction unlikely.1,9,41

Drugs Inhibiting P-glycoprotein Transport System

At therapeutic concentrations, paliperidone did not inhibit P-glycoprotein; clinically relevant interactions unlikely.1

Drugs that Prolong QT Interval

Potential pharmacologic interaction (additive effect on QT-interval prolongation); avoid concomitant use of other drugs known to prolong the QT interval (e.g., amiodarone, quinidine, procainamide, sotalol, other Class Ia and III antiarrhythmics, chlorpromazine, thioridazine, gatifloxacin, moxifloxacin).1 (See Prolongation of QT Interval under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Alcohol

Potential pharmacologic interaction (additive CNS effects).1 Avoid alcoholic beverages during paliperidone therapy.1,12

Other CNS Agents

Potential pharmacologic interaction (additive CNS effects).1 Use with caution.1

Anticholinergic Agents

Potential pharmacologic interaction (possible disruption of body temperature regulation); use paliperidone with caution in patients concurrently receiving drugs with anticholinergic activity.1 (See Body Temperature Regulation under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Carbamazepine

Concurrent administration of carbamazepine and paliperidone decreased mean steady-state peak plasma concentrations and area under the concentration-time curves (AUCs) of paliperidone by approximately 37%.45 The manufacturer recommends reevaluating the dosage of paliperidone upon initiation of carbamazepine and increasing it, if necessary, based on clinical assessment.45 Upon discontinuance of carbamazepine, the dosage of paliperidone should also be reevaluated and decreased, if necessary.45

Hypotensive Agents

Because of its α₁-adrenergic blocking activity and potential to cause hypotension, the manufacturer recommends that paliperidone be used with caution in patients receiving antihypertensive agents; monitoring of orthostatic vital signs should be considered in such patients.12,45 (See Orthostatic Hypotension and Syncope under Warnings/Precautions: Other Warnings and Precautions, in Cautions and also see Advice to Patients.)

Levodopa and Dopamine Agonists

Potential pharmacologic interaction (antagonistic effects).1,12

Lithium

A pharmacokinetic interaction between paliperidone and lithium is unlikely.45

Paroxetine

Concomitant administration of paroxetine (20 mg daily) and a single dose of paliperidone (3 mg as extended-release tablets) caused a small, clinically insignificant increase in paliperidone AUCs compared with paliperidone administration alone.9 Therefore, dosage adjustment of paliperidone is not necessary.9

Protein-bound Drugs

Pharmacokinetic interaction unlikely.1,41

Risperidone

Concurrent use of paliperidone with risperidone has not been studied to date.1,39 However, because paliperidone is the principal active metabolite of risperidone, consideration should be given to additive paliperidone exposure if risperidone and paliperidone are concomitantly administered.1,39

Valproate

Concurrent administration of a single dose of paliperidone (12 mg) and divalproex sodium extended-release tablets (two 500-mg tablets once daily) resulted in an approximate 50% increase in peak plasma concentrations and AUCs of paliperidone.45 The manufacturer states that paliperidone dosage reduction should be considered when valproate is concomitantly administered with paliperidone.45

Smoking

Pharmacokinetic interaction unlikely.1,36 Dosage adjustment in patients who smoke is not necessary.1

Description

Paliperidone is a benzisoxazole-derivative antipsychotic agent that differs chemically from other currently available first-generation (typical) antipsychotic agents (e.g., butyrophenones, phenothiazines) and has been referred to as an atypical or second-generation antipsychotic agent.1,2,3,4,5,6,7,8,12,39,41 The drug is the major active metabolite of risperidone, another atypical antipsychotic agent.1,39,41

The exact mechanism of paliperidone's antipsychotic action, like that of other antipsychotic agents, has not been fully elucidated, but may involve antagonism of central dopamine type 2 (D₂) and serotonin type 2 (5-hydroxytryptamine [5-HT_2A]) receptors.1,39,41 Antagonism at α₁- and α₂-adrenergic and histamine (H₁) receptors may contribute to other therapeutic and adverse effects observed with the drug.1,2,39 Paliperidone possesses no affinity for cholinergic muscarinic and β₁- and β₂-adrenergic receptors.1,39

In vitro studies have suggested a role for cytochrome P-450 (CYP) isoenzymes 2D6 and 3A4 in the metabolism of paliperidone; however, the results of in vivo studies indicate that these isoenzymes play a limited role in the overall elimination of the drug from the body.1,39

Approximately 80% and 11% of a single 1-mg oral dose of radiolabeled, immediate-release paliperidone is recovered in urine and feces, respectively, within 1 week.1,39 About 59% of the administered dose is recovered as unchanged drug in urine and 32% is recovered as metabolites.1,39 Following single-dose oral administration as extended-release tablets, paliperidone appears to have a mean terminal elimination half-life of about 23 hours.1,39,41

Advice to Patients

Importance of advising patients and caregivers that geriatric patients with dementia-related psychosis treated with antipsychotic agents are at an increased risk of death.11,45 Patients and caregivers also should be informed that paliperidone is not approved for treating geriatric patients with dementia-related psychosis.11,45

Importance of informing patients about the risk of orthostatic hypotension, especially when initiating or reinitiating treatment or increasing the dosage.45 Importance of advising patients who experience dizziness or fainting during therapy to get up slowly when sitting or lying down.12

Because somnolence and impairment of judgment, thinking, or motor skills may be associated with paliperidone, patients should be cautioned about driving, operating machinery, or performing hazardous tasks while taking paliperidone until they gain experience with the drug's effects.1,12 Importance of avoiding alcohol during paliperidone therapy.1,12

Importance of patients being aware of the symptoms of hyperglycemia and diabetes mellitus (e.g., increased thirst, increased urination, increased appetite, weakness).45 Importance of informing patients who are diagnosed with diabetes, those with risk factors for diabetes, and those who develop hyperglycemic symptoms during treatment that they should have their blood glucose monitored at the beginning of and periodically during paliperidone therapy.45

Risk of weight gain.45 Importance of patients being aware that they should have their weight monitored regularly during therapy.45

Risk of leukopenia/neutropenia.45 Importance of advising patients with a preexisting low leukocyte count or a history of drug-induced leukopenia/neutropenia that they should have their complete blood cell (CBC) count monitored during paliperidone therapy.45

Importance of informing patients and caregivers about the risk of neuroleptic malignant syndrome (NMS), a rare but potentially life-threatening syndrome that can cause high fever, stiff muscles, sweating, fast or irregular heart beat, change in blood pressure, confusion, and kidney damage.45

Importance of clinicians informing patients in whom chronic paliperidone use is contemplated about the risk of tardive dyskinesia.45,50 Importance of informing patients to report any muscle movements that cannot be stopped to a healthcare professional.50

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription (see Drug Interactions: Drugs that Prolong QT Interval) and OTC drugs, dietary supplements, and/or herbal products, as well as any concomitant illnesses (e.g., cardiovascular disease, diabetes mellitus, seizures).1,12

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.12,45,48 Importance of clinicians informing patients about the benefits and risks of taking antipsychotics during pregnancy (see Pregnancy under Warnings/Precautions: Specific Populations, in Cautions).45,48 Importance of advising patients not to stop taking paliperidone if they become pregnant without consulting their clinician; abruptly stopping antipsychotic agents may cause complications.48

Importance of avoiding overheating or dehydration.1,12

Importance of informing patients that paliperidone extended-release tablets should be swallowed whole with the aid of liquids, and should not be chewed, divided or crushed.1,12 Patients should not be concerned if they notice a tablet-like substance in their stool.1,12

Importance of informing patients of other important precautionary information.1,12,45 (See Cautions.)

Additional Information

Overview^® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

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3. Kane J, Canas F, Kramer M et al. Treatment of schizophrenia with paliperidone extended-release tablets: a 6-week placebo-controlled trial. Schizophr Res . 2007; 90:147-61. [PubMed 17092691]

4. Kramer M, Simpson G, Maciulis V et al. Paliperidone extended-release tablets for prevention of symptom recurrence in patients with schizophrenia: a randomized, double-blind, placebo-controlled study. J Clin Psychopharmacol . 2007; 27:6-14. [PubMed 17224706]

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9. Berwaerts J, Cleton A, Van de Vliet I et al. A randomized, open-label, single-center, crossover study of the potential effects of paroxetine on the pharmacokinetics of a single dose of paliperidone extended-release tablets in healthy subjects. Poster presented at the American Psychiatric Association 160th Annual Meeting. San Diego, CA: 2007 May 19-24.

10. American Psychiatric Association. DSM-IV^®: diagnostic and statistical manual of mental disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994:273-86.

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28. Pfizer Inc. Geodon^® (ziprasidone) prescribing information. New York, NY; 2004 Aug.

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42. Eerdekens M, Kramer M, Rossenu S et al. Effect of paliperidone extended-release tablets on prolactin exposure in patients with stable schizophrenia. Poster presented at US Psychiatry & Mental Health Congress. New Orleans, LA: 2006 Nov 16-19.

43. Ortho-McNeil Janssen Scientific Affairs, LLC. Titusville, NJ: Personal communication.

44. Hough D, Kramer M, Cleton A et al. A randomized, double-blind, placebo-controlled, parallel-group study evaluating QT/QTC intervals following administration of paliperidone ER and quetiapine in patients with schizophrenia or schizoaffective disorder. Poster presented at 62nd Society of Biological Psychiatry Convention. San Diego, CA; 2007 May 17-19.

45. Janssen, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc. Invega^® (paliperidone) extended-release tablets prescribing information. Titusville, NJ; 2011 Apr.

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51. US Food and Drug Administration. Information for healthcare professionals: Conventional antipsychotics. Rockville, MD; 2008 Jun 16. From the FDA website. [Web]

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