Paliperidone

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Suspension, Intramuscular, as palmitate:

Invega Sustenna: 39 mg/0.25 mL (0.25 mL); 78 mg/0.5 mL (0.5 mL); 117 mg/0.75 mL (0.75 mL); 156 mg/mL (1 mL); 234 mg/1.5 mL (1.5 mL) [contains polyethylene glycol]

Invega Trinza: 410 mg/1.315 mL (1.315 mL); 273 mg/0.875 mL (0.875 mL); 546 mg/1.75 mL (1.75 mL); 819 mg/2.625 mL (2.625 mL) [contains polyethylene glycol]

Tablet Extended Release 24 Hour, Oral:

Invega: 1.5 mg, 3 mg, 6 mg, 9 mg

Generic: 1.5 mg, 3 mg, 6 mg, 9 mg

Pharmacology

Mechanism of Action

Paliperidone is considered a benzisoxazole atypical antipsychotic as it is the primary active metabolite of risperidone. As with other atypical antipsychotics, its therapeutic efficacy is believed to result from mixed central serotonergic and dopaminergic antagonism. The addition of serotonin antagonism to dopamine antagonism (classic neuroleptic mechanism) is thought to improve negative symptoms of psychoses and reduce the incidence of extrapyramidal side effects (Huttunen 1995). Similar to risperidone, paliperidone demonstrates high affinity to α₁, α₂, D₂, H₁, and 5-HT_2A receptors and low affinity for muscarinic receptors. In contrast to risperidone, paliperidone displays nearly 10-fold lower affinity for α₂ and 5-HT_2A receptors, and nearly three- to fivefold less affinity for 5-HT_1A and 5-HT_1D, respectively.

Pharmacokinetics/Pharmacodynamics

Absorption

IM: Slow release (Monthly: Begins on day 1 and continues up to 126 days; 3-month: Begins on day 1 and continues up to 18 months)

Distribution

V_d: Oral: 487 L; Monthly IM: 391 L; 3-month IM: 1960 L

Metabolism

Hepatic via CYP2D6 and 3A4 (limited role in elimination); minor metabolism (<10% each) via dealkylation, hydroxylation, dehydrogenation, and benzisoxazole scission

Excretion

Urine (80%; 59% as unchanged drug); feces (11%)

Time to Peak

Oral: ~24 hours; Monthly IM: 13 days; 3-month IM: 30 to 33 days

Half-Life Elimination

Oral: 23 hours; 24 to 51 hours with renal impairment (CrCl <80 mL/minute)

Monthly IM (following a single-dose administration): Range: 25 to 49 days

3-month IM: Deltoid injection range: 84 to 95 days; gluteal injection range: 118 to 139 days

Protein Binding

74%

Use in Specific Populations

Special Populations: Renal Function Impairment

Elimination of paliperidone decreased with decreasing estimated creatinine clearance.

Special Populations: Gender

Slower monthly IM absorption observed in women.

Use: Labeled Indications

Schizophrenia: Treatment of schizophrenia

Schizoaffective disorder (oral and monthly IM paliperidone): Treatment of schizoaffective disorder as monotherapy and as an adjunct to mood stabilizers or antidepressants

Use: Off Label

Bipolar disorder, acute manic or mixed episodes and maintenancebyes

Data from randomized, double-blind, placebo-controlled studies support the use of paliperidone monotherapy in the treatment of acute manic or mixed episodes of bipolar disorder Berwaerts 2012, Vieta 2010. Data from a randomized, double-blind, placebo-controlled maintenance study supports the use of paliperidone monotherapy in the prevention of future mood episodes in patients with bipolar disorder after a manic or mixed episode Berwaerts 2012, Vieta 2010.

Based on the 2018 Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) guidelines for the management of patients with bipolar disorder, paliperidone monotherapy is recommended for acute manic episodes and for maintenance treatment of bipolar disorder. Based on the 2017 World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the biological treatment of acute and long-term treatment of mixed states in bipolar disorder, paliperidone is recommended as monotherapy for the acute treatment of manic mixed episodes in bipolar disorder.

Delusional infestation (also called delusional parasitosis)c

Data from a limited number of case reports suggest that paliperidone may be beneficial for the treatment of delusional infestation (also called delusional parasitosis)

Psychosis/agitation associated with dementiayes

Based on the American Psychiatric Association practice guideline on the use of antipsychotics to treat agitation or psychosis in patients with dementia, antipsychotics, such as paliperidone, may be considered for the treatment of agitation and psychosis in certain patients with dementia; however, evidence for efficacy is modest and use should be limited to patients whose symptoms are dangerous, severe, or cause significant patient distress due to safety risks associated with antipsychotic use.

Contraindications

Hypersensitivity to paliperidone, risperidone, or any component of the formulation

Dosage and Administration

Dosing: Adult

Bipolar disorder:

Acute manic or mixed episodes (off-label use): 3 to 6 mg once daily; may increase dose based on response and tolerability in increments of 3 mg at intervals of ≥1 day to a usual dose of 3 to 12 mg/day (Berwaerts 2012a; Vieta 2010).

Maintenance treatment to prevent manic or mixed episodes (alternative agent) (off-label use): Continue dose and combination regimen that was used to achieve control of the acute episode (CANMAT [Yatham 2018]).

Delusional infestation (also called delusional parasitosis) (off-label use): Oral: Initial: 3 mg daily; adjust dose based on response and tolerability up to 9 mg/day. Responses to therapy commonly observed after 2 weeks with maximal effect after 4 weeks (Albayrak 2011; Altınöz 2014; Freudenmann 2009). Additional data may be necessary to further define the role of paliperidone in this condition.

Schizoaffective disorder:

Oral: Usual: 6 mg once daily (administered in the morning in clinical trials); titration not required, though some may benefit from lower or higher doses (range: 3 to 12 mg daily). If exceeding 6 mg daily, increases of 3 mg daily are recommended at intervals of more than 4 days, up to a maximum of 12 mg daily.

Injection: Monthly IM: Note: Prior to initiation of monthly IM paliperidone, for patients naive to oral paliperidone or oral or injectable risperidone tolerability should be established with a test dose of oral paliperidone or oral risperidone. Previous oral antipsychotic regimen can be gradually discontinued at the time of initiation of monthly IM paliperidone. Dosing based on paliperidone palmitate (US labeling) or paliperidone base (Canadian labeling).

Initiation of therapy:

Initial: 234 mg (as palmitate) or 150 mg (as base) on treatment day 1 followed by 156 mg (as palmitate) or 100 mg (as base) 1 week later with both doses administered in the deltoid muscle. The second dose may be administered 4 days before or after the weekly time point.

Maintenance: Following the 1-week initiation regimen, adjust the dose based on response and tolerability and begin a maintenance dose of 39 to 234 mg (as palmitate) or 25 to 150 mg (as base) every month administered in either the deltoid or gluteal muscle (the 39 mg dose [as palmitate] was not studied in schizoaffective disorder trials). The monthly maintenance dose may be administered 7 days before or after the monthly time point.

Conversion from oral paliperidone to monthly IM paliperidone:

Initiate monthly IM paliperidone as described using the 1-week initiation regimen. Patients previously stabilized on oral doses can expect similar steady state exposure during maintenance treatment with monthly IM paliperidone using the following conversion:

Oral extended-release dose of 12 mg daily, then IM maintenance dose of 234 mg (as palmitate) or 150 mg (as base) monthly

Oral extended-release dose of 9 mg daily, then IM maintenance dose of 156 mg (as palmitate) or 100 mg (as base) monthly

Oral extended-release dose of 6 mg daily, then IM maintenance dose of 117 mg (as palmitate) or 75 mg (as base) monthly

Oral extended-release dose of 3 mg daily, then IM maintenance dose of 39 to 78 mg (as palmitate) or 25 to 50 mg (as base) monthly

Conversion from other oral antipsychotics to monthly IM paliperidone: There is no systematically collected data to address switching patients from other oral antipsychotics to monthly IM paliperidone.

Switching from other long-acting injectable antipsychotics (at steady-state) to monthly IM paliperidone: Initiate monthly IM paliperidone in the place of the next scheduled injection and continue at monthly intervals. The two initiation doses are not required in these patients.

When switching from injectable risperidone (Risperdal Consta) to monthly IM paliperidone the following recommendations have been made (Invega Sustenna Canadian product labeling):

Risperdal Consta dose of 25 mg every 2 weeks, then IM paliperidone maintenance dose of 78 mg (as palmitate) or 50 mg (as base) monthly

Risperdal Consta dose of 37.5 mg every 2 weeks, then IM paliperidone maintenance dose of 117 mg (as palmitate) or 75 mg (as base) monthly

Risperdal Consta dose of 50 mg every 2 weeks, then IM paliperidone maintenance dose of 156 mg (as palmitate) or 100 mg (base) monthly

Dosage adjustments: Adjustments may be made monthly (full effect from adjustments may not be seen for several months)

Missed second initiation dose:

If <4 weeks have elapsed since the first injection: Administer the missed dose 156 mg (as palmitate) or 100 mg (as base) in the deltoid as soon as possible, followed by a third dose of 117 mg (as palmitate) or 75 mg (as base) in either the deltoid or gluteal muscle 5 weeks after the first injection (regardless of when the second injection was administered), then begin normal monthly maintenance dosing.

If ≥4 weeks and ≤7 weeks have elapsed since the first injection: Administer a dose of 156 mg (as palmitate) or 100 mg (as base) in the deltoid as soon as possible, followed by another 156 mg dose (as palmitate) or 100 mg dose (as base) in the deltoid 1 week later, then begin normal monthly maintenance dosing.

If >7 weeks has elapsed since the first injection: Therapy must be reinitiated following dosing recommendations for initiation of therapy.

Missed maintenance dose:

If ≥4 weeks and ≤6 weeks have elapsed since the last monthly injection: Administer the missed dose as soon as possible and continue therapy at monthly intervals.

If >6 weeks and ≤6 months have elapsed since the last monthly injection:

If the maintenance dose was <234 mg (as palmitate) or 150 mg (as base): Administer the same dose the patient was previously stabilized on in the deltoid as soon as possible, followed by a second equivalent dose in the deltoid 1 week later, then resume maintenance dose at monthly intervals.

If the maintenance dose was 234 mg (as palmitate) or 150 mg (as base): Administer a 156 mg dose (as palmitate) or 100 mg dose (as base) in the deltoid as soon as possible, followed by a second dose of 156 mg (as palmitate) or 100 mg dose (as base) in the deltoid 1 week later, then resume maintenance dose at monthly intervals.

If >6 months have elapsed since last monthly maintenance injection: Therapy must be reinitiated following dosing recommendations for initiation of therapy.

Schizophrenia:

Oral: Usual: 6 mg once daily (administered in the morning in clinical trials); titration not required, though some may benefit from lower or higher doses (range: 3 to 12 mg daily). If exceeding 6 mg daily, increases of 3 mg daily are recommended no more frequently than every 5 days, up to a maximum of 12 mg daily.

Injection:

IM:

Monthly paliperidone (Invega Sustenna): Note: Prior to initiation of monthly IM paliperidone, for patients naïve to oral paliperidone or oral or injectable risperidone tolerability should be established with a test dose of oral paliperidone or oral risperidone. Previous oral antipsychotic regimen can be gradually discontinued at the time of initiation of monthly IM paliperidone. Dosing based on paliperidone palmitate (US labeling) or paliperidone base (Canadian labeling).

Initiation of therapy:

Initial: 234 mg (as palmitate) or 150 mg (as base) on treatment day 1 followed by 156 mg (as palmitate) or 100 mg (as base) 1 week later with both doses administered in the deltoid muscle. The second dose may be administered 4 days before or after the weekly time point.

Maintenance: Following the 1-week initiation regimen, begin a maintenance dose of 117 mg (as palmitate) or 75 mg (as base) every month administered in either the deltoid or gluteal muscle. Some patients may benefit from higher or lower monthly maintenance doses (monthly maintenance dosage range: 39 to 234 mg [as palmitate] or 25 to 150 mg [as base]). The monthly maintenance dose may be administered 7 days before or after the monthly time point.

Conversion from oral paliperidone to IM paliperidone:

Initiate IM therapy as described using the 1-week initiation regimen. Patients previously stabilized on oral doses can expect similar steady state exposure during maintenance treatment with IM therapy using the following conversion:

Oral extended-release dose of 12 mg daily, then IM maintenance dose of 234 mg (as palmitate) or 150 mg (as base) monthly

Oral extended-release dose of 9 mg daily, then IM maintenance dose of 156 mg (as palmitate) or 100 mg (as base) monthly

Oral extended-release dose of 6 mg daily, then IM maintenance dose of 117 mg (as palmitate) or 75 mg (as base) monthly

Oral extended-release dose of 3 mg daily, then IM maintenance dose of 39 to 78 mg (as palmitate) or 25 to 50 mg (as base) monthly

Conversion from other oral antipsychotics to IM paliperidone: There is no systematically collected data to address switching patients from other oral antipsychotics to IM paliperidone.

Switching from other long-acting injectable antipsychotics (at steady-state) to IM paliperidone: Initiate IM paliperidone in the place of the next scheduled injection and continue at monthly intervals. The two initiation doses are not required in these patients.

When switching from injectable risperidone (Risperdal Consta) to monthly IM paliperidone the following recommendations have been made (Invega Sustenna Canadian product labeling):

Risperdal Consta dose of 25 mg every 2 weeks, then IM paliperidone maintenance dose of 50 mg (as base) monthly

Risperdal Consta dose of 37.5 mg every 2 weeks, then IM paliperidone maintenance dose of 75 mg (as base) monthly

Risperdal Consta dose of 50 mg every 2 weeks, then IM paliperidone maintenance dose of 100 mg (as base) monthly

Dosage adjustments: Adjustments may be made monthly (full effect from adjustments may not be seen for several months)

Missed second initiation dose:

If <4 weeks have elapsed since the first injection: Administer the missed dose (156 mg [as palmitate] or 100 mg [as base]) in the deltoid as soon as possible, followed by a third dose of 117 mg (as palmitate) or 75 mg (as base) in either the deltoid or gluteal muscle 5 weeks after the first injection (regardless of when the second injection was administered), then begin normal monthly maintenance dosing.

If ≥4 weeks and ≤7 weeks have elapsed since the first injection: Administer a dose of 156 mg (as palmitate) or 100 mg (as base) in the deltoid as soon as possible, followed by another 156 mg dose (as palmitate) or 100 mg dose (as base) in the deltoid 1 week later, then begin normal monthly maintenance dosing.

If >7 weeks have elapsed since the first injection: Therapy must be reinitiated following dosing recommendations for initiation of therapy.

Missed maintenance dose:

If ≥4 weeks and ≤6 weeks have elapsed since the last monthly injection: Administer the missed dose as soon as possible and continue therapy at monthly intervals.

If >6 weeks and ≤6 months have elapsed since the last monthly injection:

If the maintenance dose was <234 mg (as palmitate) or <150 mg (as base): Administer the same dose the patient was previously stabilized on in the deltoid as soon as possible, followed by a second equivalent dose in the deltoid 1 week later, then resume maintenance dose at monthly intervals.

If the maintenance dose was 234 mg (as palmitate) or 150 mg (as base): Administer a 156 mg dose (as palmitate) or 100 mg dose (as base) in the deltoid as soon as possible, followed by a second dose of 156 mg (as palmitate) or 100 mg (as base) in the deltoid 1 week later, then resume maintenance dose at monthly intervals.

If >6 months have elapsed since last monthly maintenance injection: Therapy must be reinitiated following dosing recommendations for initiation of therapy.

Three-month paliperidone (Invega Trinza): Note: Three-month IM paliperidone is to be used only after monthly IM paliperidone (Invega Sustenna) has been established as adequate treatment for at least 4 months. The last 2 doses of monthly IM paliperidone should be the same dosage strength before starting 3-month IM paliperidone.

Conversion from monthly injection to 3-month injection: Initiate 3-month IM paliperidone when the next monthly IM paliperidone dose is scheduled. Base the 3-month dose on the previous monthly dose, using the equivalent 3.5 times higher dose. Three-month IM paliperidone may be administered up to 7 days before or after the next monthly dose date. Following the initial injection, administer every 3 months. Patients may be given the injection up to 2 weeks before or after the 3-month time point. Conversion from monthly IM paliperidone (Invega Sustenna) 39 mg (as palmitate) or 25 mg (as base) to 3-month IM paliperidone (Invega Trinza) has not been studied.

Monthly IM paliperidone (Invega Sustenna) 78 mg (as palmitate) or 50 mg (as base) = 3-month IM paliperidone (Invega Trinza) 273 mg (as palmitate) or 175 mg (as base)

Monthly IM paliperidone (Invega Sustenna) 117 mg (as palmitate) or 75 mg (as base) = 3-month IM paliperidone (Invega Trinza) 410 mg (as palmitate) or 263 mg (as base)

Monthly IM paliperidone (Invega Sustenna) 156 mg (as palmitate) or 100 mg (as base) = 3-month IM paliperidone (Invega Trinza) 546 mg (as palmitate) or 350 mg (as base)

Monthly IM paliperidone (Invega Sustenna) 234 mg (as palmitate) or 150 mg (as base) = 3-month IM paliperidone (Invega Trinza) 819 mg (as palmitate) or 525 mg (as base)

Conversion from 3-month IM paliperidone to monthly IM paliperidone: Initiate monthly IM paliperidone when the next 3-month IM paliperidone dose is scheduled. Base the monthly dose on the previous 3-month dose, using the equivalent 3.5 times lower dose. Following the initial injection, administer once monthly.

3-month IM paliperidone (Invega Trinza) 273 mg (as palmitate) or 175 mg (as base) = Monthly IM paliperidone (Invega Sustenna) 78 mg (as palmitate) or 50 mg (as base)

3-month IM paliperidone (Invega Trinza) 410 mg (as palmitate) or 263 mg (as base) = Monthly IM paliperidone (Invega Sustenna) 117 mg (as palmitate) or 75 mg (as base)

3-month IM paliperidone (Invega Trinza) 546 mg (as palmitate) or 350 mg (as base) = Monthly IM paliperidone (Invega Sustenna) 156 mg (as palmitate) or 100 mg (as base)

3-month IM paliperidone (Invega Trinza) 819 mg (as palmitate) or 525 mg (as base) = Monthly IM paliperidone (Invega Sustenna) 234 mg (as palmitate) or 150 mg (as base)

Conversion from 3-month IM paliperidone to paliperidone extended-release tablets: Initiate paliperidone extended release tablets 3 months after the last dose of 3-month IM paliperidone. Base the once daily extended-release tablet dose on the last 3-month injection dose and weeks since last administered. Use the following conversion.

If the last 3-month IM paliperidone dose was:

273 mg (as palmitate) or 175 mg (as base): 3 months to >24 weeks since the last dose = 3 mg paliperidone extended-release tablets

410 mg (as palmitate) or 263 mg (as base):

3 months to 24 weeks since the last dose = 3 mg paliperidone extended-release tablets

>24 weeks since the last dose = 6 mg paliperidone extended-release tablets

546 mg (as palmitate) or 350 mg (as base):

3 months to 18 weeks since the last dose = 3 mg paliperidone extended-release tablets

>18 weeks to 24 weeks since the last dose = 6 mg paliperidone extended-release tablets

>24 weeks since the last dose = 9 mg paliperidone extended-release tablets

819 mg (as palmitate) or 525 mg (as base):

3 months to 18 weeks since the last dose = 6 mg paliperidone extended-release tablets

>18 weeks to 24 weeks since the last dose = 9 mg paliperidone extended-release tablets

>24 weeks since the last dose = 12 mg paliperidone extended-release tablets

Dosage adjustments: Dosage adjustments can be made every 3 months in increments within the range of 273 to 819 mg (as palmitate) or 175 to 525 mg (as base) based on response and tolerability. Due to the long-acting nature, the patient's response to an adjusted dose may not be apparent for several months.

Missed dose 3 ¹/₂ months to 4 months since last injection: Administer the previous 3-month dose as soon as possible and continue with normal dosing.

Missed dose 4 months to 9 months since last injection: Do not administer the next 3-month dose. If the last 3-month dose was:

273 mg (as palmitate) or 175 mg (as base): Administer 78 mg (as palmitate) or 50 mg (as base) of monthly IM paliperidone (Invega Sustenna) into the deltoid muscle. Repeat same dose of monthly IM paliperidone (Invega Sustenna) one week later. One month following the second injection, administer 273 mg (as palmitate) or 175 mg (as base) of 3-month IM paliperidone (Invega Trinza) into the deltoid or gluteal muscle and resume normal dosing at 3-month intervals.

410 mg (as palmitate) or 263 mg (as base): Administer 117 mg (as palmitate) or 75 mg (as base) of monthly IM paliperidone (Invega Sustenna) into the deltoid muscle. Repeat same dose of monthly IM paliperidone (Invega Sustenna) one week later. One month following the second injection, administer 410 mg (as palmitate) or 263 mg (as base) of 3-month IM paliperidone (Invega Trinza) into the deltoid or gluteal muscle and resume normal dosing at 3-month intervals.

546 mg (as palmitate) or 350 mg (as base): Administer 156 mg (as palmitate) or 100 mg (as base) of monthly IM paliperidone (Invega Sustenna) into the deltoid muscle. Repeat same dose of monthly IM paliperidone (Invega Sustenna) one week later. One month following the second injection, administer 546 mg (as palmitate) or 350 mg (as base) of 3-month IM paliperidone (Invega Trinza) into the deltoid or gluteal muscle and resume normal dosing at 3-month intervals.

819 mg (as palmitate) or 525 mg (as base): Administer 156 mg (as palmitate) or 100 mg (as base) of monthly IM paliperidone (Invega Sustenna) into the deltoid muscle. Repeat same dose of monthly IM paliperidone (Invega Sustenna) one week later. One month following the second injection, administer 819 mg (as palmitate) or 525 mg (as base) of 3-month IM paliperidone (Invega Trinza) into the deltoid or gluteal muscle and resume normal dosing at 3-month intervals.

Missed dose longer than 9 months since last injection: Re-initiate treatment with monthly IM paliperidone (Invega Sustenna). Three-month IM paliperidone can be resumed after the patient has been adequately treated with monthly IM paliperidone for at least 4 months.

Discontinuation of therapy: American Psychiatric Association (APA), Canadian Psychiatric Association (CPA), and World Federation of Societies of Biological Psychiatry (WFSBP) guidelines recommend gradually tapering antipsychotics to avoid withdrawal symptoms and minimize the risk of relapse (APA [Lehman 2004]; Cerovecki 2013; CPA [Addington 2005]; WFSBP [Hasan 2012]); risk for withdrawal symptoms may be highest with highly anticholinergic or dopaminergic antipsychotics (Cerovecki 2013). When stopping antipsychotic therapy in patients with schizophrenia, the CPA guidelines recommend a gradual taper over 6 to 24 months, and the APA guidelines recommend reducing the dose by 10% each month (APA [Lehman 2004]; CPA [Addington 2005]). Continuing anti-parkinsonism agents for a brief period after discontinuation may prevent withdrawal symptoms (Cerovecki 2013). When switching antipsychotics, 3 strategies have been suggested: Cross-titration (gradually discontinuing the first antipsychotic while gradually increasing the new antipsychotic), overlap and taper (maintaining the dose of the first antipsychotic while gradually increasing the new antipsychotic, then tapering the first antipsychotic), and abrupt change (abruptly discontinuing the first antipsychotic and either increasing the new antipsychotic gradually or starting it at a treatment dose). Evidence supporting ideal switch strategies and taper rates is limited, and results are conflicting (Cerovecki 2013; Remington 2005).

Dosing: Geriatric

Refer to adult dosing; use with caution. Additional monitoring of renal function and orthostatic blood pressure may be warranted.

Psychosis/agitation associated with dementia (off-label use): Oral: Initial: One-third to one-half the usual dose to treat psychosis in younger adults or the smallest available dosage. In patients without a clinically significant response after 4 weeks, taper and withdraw therapy. In patients with an adequate response, attempt to taper and withdraw therapy within 4 months, unless symptoms recurred with a previous taper attempt. Assess symptoms at least monthly during taper and for at least 4 months after withdrawal of therapy (APA [Reus 2016]).

Dosing: Pediatric

Irritability associated with autistic disorder: Limited data available: Children ≥12 years and Adolescents: Oral: Extended-release tablet: Initial: 3 mg once daily; titrate on a weekly basis in 3 mg/day increments until clinical response or intolerance; maximum daily dose: 12 mg/day. Dosing based on an open-label trial of 25 patients (mean age: 15.3 years; age range: 12 to 21 years); therapeutic response was reported in 84% of patients at a mean final dose: 7.1 mg/day (Stigler 2012).

Schizoaffective disorder:

Oral: Extended-release tablet: Adolescents ≥18 years: Usual: 6 mg once daily (administered in the morning in clinical trials); titration not required, though some may benefit from lower or higher doses (range: 3 to 12 mg daily). If exceeding 6 mg daily, increases of 3 mg daily are recommended at intervals of more than 4 days, up to a maximum daily dose: 12 mg/day.

Parenteral: Adolescents ≥18 years: Monthly paliperidone injection (Invega Sustenna): IM: Note: Prior to initiation of monthly IM paliperidone, patients naive to oral paliperidone or oral or injectable risperidone should have tolerability established with a test dose of oral paliperidone or oral risperidone. Previous oral antipsychotic regimen can be gradually discontinued at the time of initiation of monthly IM paliperidone.

Initiation of therapy (2-dose series):

Initial: 234 mg on treatment day 1 followed by 156 mg 1 week later with both doses administered in the deltoid muscle. The second dose may be administered 4 days before or after the weekly time point.

Missed second initiation dose: If the target administration date of 1 week ± 4 days for the second dose is missed, catch-up dosing depends on the time elapsed since the first dose.

Table converted to the following text:

If <4 weeks have elapsed since the first injection: Administer the missed dose of 156 mg in the deltoid as soon as possible, followed by a third dose of 117 mg (in either the deltoid or gluteal muscle) 5 weeks after the first injection (regardless of when the second injection was administered), then begin normal monthly maintenance dosing.

If ≥4 weeks to ≤7 weeks have elapsed since the first injection: Administer a dose of 156 mg (in the deltoid) as soon as possible, followed by another 156 mg dose in the deltoid 1 week later, then begin normal monthly maintenance dosing.

If >7 weeks has elapsed since the first injection: Reinitiate following dosing recommendations for initiation of therapy.

Maintenance: First maintenance injection should be administered 5 weeks after the first injection of the initial series. Adjust the dose based on response and tolerability and begin a maintenance dose of 78 to 234 mg (every month administered in either the deltoid or gluteal muscle). The monthly maintenance dose may be administered 7 days before or after the monthly time point.

Missed maintenance dose: Dose and interval dependent upon time since last dose, see table:

Table converted to the following text:

If ≥4 weeks to ≤6 weeks have elapsed since the last monthly injection: Administer the missed dose as soon as possible and continue therapy at monthly intervals.

If >6 weeks to ≤6 months have elapsed since the last monthly injection:

If the maintenance dose was <234 mg: Administer the same dose the patient was previously stabilized on in the deltoid as soon as possible, followed by a second equivalent dose in the deltoid 1 week later, then resume maintenance dose at monthly intervals.

If the maintenance dose was 234 mg: Administer a 156 mg dose in the deltoid as soon as possible, followed by a second dose of 156 mg in the deltoid 1 week later, then resume maintenance dose at monthly intervals.

If >6 months have elapsed since last monthly maintenance injection: Reinitiate following dosing recommendations for initiation of therapy.

Conversion from oral extended-release paliperidone to monthly IM paliperidone:

Initiate monthly IM paliperidone as described using the 1-week initiation regimen. Patients previously stabilized on oral doses can expect similar steady state exposure during maintenance treatment with monthly IM paliperidone using the following conversion:

Table converted to the following text:

Oral extended-release dose of 3 mg daily, then IM maintenance dose of 39 to 78 mg monthly

Oral extended-release dose of 6 mg daily, then IM maintenance dose of 117 mg monthly

Oral extended-release dose of 9 mg daily, then IM maintenance dose of 156 mg monthly

Oral extended-release dose of 12 mg daily, then IM maintenance dose of 234 mg

Conversion from other oral antipsychotics to monthly IM paliperidone: There is no systematically collected data to address switching patients from other oral antipsychotics to monthly IM paliperidone.

Switching from other long-acting injectable antipsychotics (at steady-state) to monthly IM paliperidone: Initiate monthly IM paliperidone in the place of the next scheduled injection and continue at monthly intervals; may be administered in the deltoid or gluteal muscle. The two initiation doses are not required in these patients.

Dosage adjustments: Adjustments may be made monthly (full effect from adjustments may not be seen for several months)

Schizophrenia:

Oral: Extended-release tablet:

Children ≥12 and Adolescents <18 years: 3 mg once daily; titration not necessary; if after clinical assessment a dosage increase is required, may increase dose in 3 mg/day increments at least every 5 days; maximum daily dose is weight dependent: <51 kg: 6 mg/day; ≥51 kg: 12 mg/day; Note: During adolescent clinical trials, higher doses were not associated with greater efficacy, but increased risk of adverse effects.

Adolescents: ≥18 years: Usual dose: 6 mg once daily (administered in the morning in clinical trials); titration not required, though some may benefit from lower or higher doses (range: 3 to 12 mg daily). If exceeding 6 mg daily, increases of 3 mg daily are recommended no more frequently than every 5 days, up to a maximum of 12 mg daily.

Parenteral: Adolescents ≥18 years:

Monthly paliperidone injection (Invega Sustenna): IM: Note: Prior to initiation of monthly IM therapy, tolerability should be established with oral paliperidone or oral risperidone; may require test dose of oral paliperidone or risperidone. Previous oral antipsychotics can be discontinued at the time of initiation of IM therapy.

Initiation of therapy (2-dose series):

Initial: 234 mg on treatment day 1 followed by 156 mg 1 week later with both doses administered in the deltoid muscle. The second dose may be administered 4 days before or after the weekly time point.

Missed second initiation dose: If the target administration date of 1 week ± 4 days for the second dose is missed, catch-up dosing depends on the time elapsed since the first dose.

Table converted to the following text:

If <4 weeks have elapsed since the first injection: Administer the missed dose of 156 mg (in the deltoid) as soon as possible, followed by a third dose of 117 mg (in either the deltoid or gluteal muscle) 5 weeks after the first injection (regardless of when the second injection was administered), then begin normal monthly maintenance dosing.

If ≥4 weeks to ≤7 weeks have elapsed since the first injection: Administer a dose of 156 mg (in the deltoid) as soon as possible, followed by another 156 mg dose (in the deltoid) 1 week later, then begin normal monthly maintenance dosing.

If >7 weeks has elapsed since the first injection: Reinitiate following dosing recommendations for initiation of therapy.

Maintenance: First maintenance injection should be administered 5 weeks after the first injection of the initial series. Begin with a maintenance dose 117 mg every month administered in either the deltoid or gluteal muscle. Some patients may benefit from higher or lower monthly maintenance doses (monthly maintenance dosage range: 39 to 234 mg). The monthly maintenance dose may be administered 7 days before or after the monthly time point.

Missed maintenance dose: Dose and interval dependent upon time since last dose, see table:

Table converted to the following text:

If ≥4 weeks to ≤6 weeks have elapsed since the last monthly injection: Administer the missed dose as soon as possible and continue therapy at monthly intervals.

If >6 weeks to ≤6 months have elapsed since the last monthly injection:

If the maintenance dose was <234 mg: Administer the same dose the patient was previously stabilized on in the deltoid as soon as possible, followed by a second equivalent dose in the deltoid 1 week later, then resume maintenance dose at monthly intervals.

If the maintenance dose was 234 mg: Administer a 156 mg dose in the deltoid as soon as possible, followed by a second dose of 156 mg in the deltoid 1 week later, then resume maintenance dose at monthly intervals.

If >6 months have elapsed since last monthly maintenance injection: Reinitiate following dosing recommendations for initiation of therapy

Conversion from oral paliperidone to IM paliperidone monthly injection: Initiate IM therapy as described using the 1-week initiation regimen. Patients previously stabilized on oral doses can expect similar steady state exposure during maintenance treatment with IM therapy using the following conversion:

Table converted to the following text:

Oral extended-release dose of 3 mg daily, then IM maintenance dose of 39 to 78 mg monthly

Oral extended-release dose of 6 mg daily, then IM maintenance dose of 117 mg monthly

Oral extended-release dose of 9 mg daily, then IM maintenance dose of 156 mg monthly

Oral extended-release dose of 12 mg daily, then IM maintenance dose of 234 mg monthly

Switching from other long acting injectable antipsychotics to IM paliperidone: Initiate IM paliperidone in the place of the next scheduled injection and continue at monthly intervals. The 1-week initiation regimen is not required in these patients.

Dosage adjustments: Adjustments may be made monthly (full effect from adjustments may not be seen for several months)

Three-month paliperidone (Invega Trinza): IM: Note: 3-month IM paliperidone is to be used only after monthly IM paliperidone (Invega Sustenna) has been established as adequate treatment for at least 4 months. The last 2 doses of monthly IM paliperidone should be the same dosage strength before starting 3-month IM paliperidone.

Conversion from monthly injection and 3-month injection:

Monthly to 3-month injections: Initiate 3-month IM paliperidone when the next monthly IM paliperidone dose is scheduled. Base the 3-month dose on the previous monthly dose, using the equivalent 3.5 times higher dose (see following table). Three-month IM paliperidone may be administered up to 7 days before or after the next monthly dose date. Following the initial injection, administer every 3 months. Patients may be given the injection up to 2 weeks before or after the 3-month time point.

Three-month to monthly injections: Initiate monthly IM paliperidone when the next 3-month IM paliperidone dose is scheduled. Base the monthly dose on the previous 3-month dose, using the equivalent 3.5 times lower dose (see following table). After initial injection, administer once monthly.

Table converted to the following text:

Monthly IM paliperidone (Invega Sustenna) 78 mg = 3-month IM paliperidone (Invega Trinza) 273 mg

Monthly IM paliperidone (Invega Sustenna) 117 mg = 3-month IM paliperidone (Invega Trinza) 410 mg

Monthly IM paliperidone (Invega Sustenna) 156 mg = 3-month IM paliperidone (Invega Trinza) 546 mg

Monthly IM paliperidone (Invega Sustenna) 234 mg = 3-month IM paliperidone (Invega Trinza) 819 mg

Note: Conversion from monthly IM paliperidone (Invega Sustenna) 39 mg to 3-month IM paliperidone (Invega Trinza) has not been studied.

Conversion from 3-month IM paliperidone to oral paliperidone extended-release tablets: Initiate paliperidone extended-release tablets at least 3 months after the last dose of 3-month IM paliperidone. Base the once daily extended-release tablet dose on the last 3-month injection dose and weeks since last administered. Use the following conversion.

Table converted to the following text:

If the last 3-month IM paliperidone dose was:

273 mg: 3 months to >24 weeks since the last dose = 3 mg paliperidone extended-release tablets

410 mg:

3 months to 24 weeks since the last dose = 3 mg paliperidone extended-release tablets

>24 weeks since the last dose = 6 mg paliperidone extended-release tablets

546 mg:

3 months to 18 weeks since the last dose = 3 mg paliperidone extended-release tablets

>18 weeks to 24 weeks since the last dose = 6 mg paliperidone extended-release tablets

>24 weeks since the last dose = 9 mg paliperidone extended-release tablets

819 mg:

3 months to 18 weeks since the last dose = 6 mg paliperidone extended-release tablets

>18 weeks to 24 weeks since the last dose = 9 mg paliperidone extended-release tablets

>24 weeks since the last dose = 12 mg paliperidone extended-release tablets

Dosage adjustments: Dosage adjustments can be made every 3 months in increments within the range of 273 to 819 mg based on response and tolerability. Due to the long-acting nature, the patient's response to an adjusted dose may not be apparent for several months.

Missed doses: Dose and interval dependent upon time since last dose; use of the monthly dosage form (Invega Sustenna) may be necessary in some cases; see table:

Table converted to the following text:

3¹/₂ months to 4 months since last injection: Administer the previous 3-month dose as soon as possible and continue with normal dosing.

4 months to 9 months since last injection: Do not administer the next 3-month dose. If the last 3-month dose was:

273 mg: Administer 78 mg of monthly IM paliperidone (Invega Sustenna) into the deltoid muscle. Repeat same dose of monthly IM paliperidone (Invega Sustenna) 1 week later. One month following the second injection, administer 273 mg of 3-month IM paliperidone (Invega Trinza) into the deltoid or gluteal muscle and resume normal dosing at 3-month intervals.

410 mg: Administer 117 mg of monthly IM paliperidone (Invega Sustenna) into the deltoid muscle. Repeat same dose of monthly IM paliperidone (Invega Sustenna) 1 week later. One month following the second injection, administer 410 mg of 3-month IM paliperidone (Invega Trinza) into the deltoid or gluteal muscle and resume normal dosing at 3-month intervals.

546 mg: Administer 156 mg of monthly IM paliperidone (Invega Sustenna) into the deltoid muscle. Repeat same dose of monthly IM paliperidone (Invega Sustenna) 1 week later. One month following the second injection, administer 546 mg of 3-month IM paliperidone (Invega Trinza) into the deltoid or gluteal muscle and resume normal dosing at 3-month intervals.

819 mg: Administer 156 mg of monthly IM paliperidone (Invega Sustenna) into the deltoid muscle. Repeat same dose of monthly IM paliperidone (Invega Sustenna) 1 week later. One month following the second injection, administer 819 mg of 3-month IM paliperidone (Invega Trinza) into the deltoid or gluteal muscle and resume normal dosing at 3-month intervals.

Longer than 9 months since last injection: Re-initiate treatment with monthly IM paliperidone (Invega Sustenna). Three-month IM paliperidone can be resumed after the patient has been adequately treated with monthly IM paliperidone for at least 4 months.

Administration

Oral: Administer without regard to meals. Extended release tablets should be swallowed whole with liquids; do not crush, chew, or divide.

IM injection: Administer by IM route only as a single injection (do not divide); do not administer by any other route. Avoid inadvertent injection into vasculature.

Monthly paliperidone (Invega Sustenna): Do not mix with any other product or diluent. Prior to injection, shake syringe for at least 10 seconds to ensure a homogenous suspension. Administer using only the needles that are provided in the kit. The 2 initial injections should be administered in the deltoid muscle using a 1¹/₂ inch, 22-gauge needle for patients ≥90 kg, and a 1 inch, 23-gauge needle for patients <90 kg. The 2 initial deltoid intramuscular injections help attain therapeutic concentrations rapidly. Alternate deltoid injections (right and left deltoid muscle). The second dose may be administered 4 days before or after the weekly time point. Monthly maintenance doses can be administered in either the deltoid or gluteal muscle. Administer injections in the gluteal muscle using a 1¹/₂ inch, 22-gauge needle (regardless of patient weight) in the upper-outer quadrant of the gluteal area. Alternate gluteal injections (right and left gluteal muscle). The monthly maintenance dose may be administered 7 days before or after the monthly time point.

Three-month paliperidone (Invega Trinza): Prior to injection, shake syringe for with tip pointing up at least 15 seconds to ensure a homogenous suspension. Inject within 5 minutes of shaking vigorously. Inject slowly, deep into the deltoid or gluteal muscle. Must be administered using only the thin wall needles that are provided in the pack. Do not use needles from monthly IM paliperidone or other commercially-available needles to reduce the risk of blockage. Administer into the center of the deltoid muscle using a 1¹/₂ inch, 22-gauge thin wall needle for patients ≥90 kg, and a 1 inch, 22-gauge thin wall needle for patients <90 kg. Alternate deltoid injections (right and left deltoid muscle). Administer injections in the gluteal muscle using a 1¹/₂ inch, 22-gauge thin wall needle (regardless of patient weight) in the upper-outer quadrant of the gluteal area. Alternate gluteal injections (right and left gluteal muscle). In the event of an incompletely administered dose, do not re-inject the dose remaining in the syringe and do not administer another dose. Closely monitor and treat the patient with oral supplementation as clinically appropriate until the next scheduled 3-month injection.

Storage

Oral, Monthly IM: Store at ≤25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect tablets from moisture.

3-month IM: Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Do not mix with any other product or diluent.

Drug Interactions

Acetylcholinesterase Inhibitors (Central): May enhance the neurotoxic (central) effect of Antipsychotic Agents. Severe extrapyramidal symptoms have occurred in some patients. Monitor therapy

Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Monitor therapy

Alizapride: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Amifampridine: Agents With Seizure Threshold Lowering Potential may enhance the neuroexcitatory and/or seizure-potentiating effect of Amifampridine. Monitor therapy

Amisulpride: Antipsychotic Agents may enhance the adverse/toxic effect of Amisulpride. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Avoid combination

Amphetamines: Antipsychotic Agents may diminish the stimulatory effect of Amphetamines. Monitor therapy

Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Anti-Parkinson Agents (Dopamine Agonist): Antipsychotic Agents (Second Generation [Atypical]) may diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Management: Consider using an alternative antipsychotic agent when possible in patients with Parkinson disease. If an atypical antipsychotic is necessary, consider using clozapine or quetiapine, which may convey the lowest interaction risk. Consider therapy modification

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Avoid combination

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Consider therapy modification

Blood Pressure Lowering Agents: May enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Monitor therapy

Brexanolone: CNS Depressants may enhance the CNS depressant effect of Brexanolone. Monitor therapy

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Bromopride: May enhance the adverse/toxic effect of Antipsychotic Agents. Avoid combination

Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Avoid combination

Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants. Consider therapy modification

BuPROPion: May enhance the neuroexcitatory and/or seizure-potentiating effect of Agents With Seizure Threshold Lowering Potential. Monitor therapy

Cannabidiol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Cannabis: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

CarBAMazepine: May decrease the serum concentration of Paliperidone. Monitor therapy

Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Consider therapy modification

Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Monitor therapy

Deutetrabenazine: May enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, the risk for akathisia, parkinsonism, or neuroleptic malignant syndrome may be increased. Monitor therapy

Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Monitor therapy

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Consider therapy modification

Erdafitinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

Esketamine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Consider therapy modification

Guanethidine: Antipsychotic Agents may diminish the therapeutic effect of Guanethidine. Monitor therapy

Haloperidol: QT-prolonging Agents (Indeterminate Risk - Avoid) may enhance the QTc-prolonging effect of Haloperidol. Monitor therapy

HYDROcodone: CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Avoid concomitant use of hydrocodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Inducers of CYP3A4 (Strong) and P-glycoprotein: May decrease the serum concentration of Paliperidone. Management: Avoid using the 3-month extended-release injectable suspension (Invega Trinza) with inducers of both CYP3A4 and P-glycoprotein during the 3-month dosing interval if possible. If combination is necessary, consider using extended-release tablets. Consider therapy modification

Iohexol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iohexol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iohexol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic anticonvulsants. Consider therapy modification

Iomeprol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iomeprol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iomeprol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic anticonvulsants. Consider therapy modification

Iopamidol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iopamidol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iopamidol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic anticonvulsants. Consider therapy modification

Itraconazole: May enhance the QTc-prolonging effect of Paliperidone. Itraconazole may decrease the metabolism of Paliperidone. Consider therapy modification

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

Lasmiditan: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Avoid combination

Lemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Consider therapy modification

Lithium: May enhance the neurotoxic effect of Antipsychotic Agents. Lithium may decrease the serum concentration of Antipsychotic Agents. Specifically noted with chlorpromazine. Monitor therapy

Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Monitor therapy

Lumacaftor and Ivacaftor: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. Lumacaftor and Ivacaftor may increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Mequitazine: Antipsychotic Agents may enhance the arrhythmogenic effect of Mequitazine. Management: Consider alternatives to one of these agents when possible. While this combination is not specifically contraindicated, mequitazine labeling describes this combination as discouraged. Consider therapy modification

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Consider therapy modification

Methylphenidate: Antipsychotic Agents may enhance the adverse/toxic effect of Methylphenidate. Methylphenidate may enhance the adverse/toxic effect of Antipsychotic Agents. Monitor therapy

Metoclopramide: May enhance the adverse/toxic effect of Antipsychotic Agents. Avoid combination

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Monitor therapy

MetyroSINE: May enhance the adverse/toxic effect of Antipsychotic Agents. Monitor therapy

Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Opioid Agonists: CNS Depressants may enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Avoid combination

Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Avoid combination

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Avoid combination

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Consider therapy modification

P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

Piribedil: Antipsychotic Agents may diminish the therapeutic effect of Piribedil. Piribedil may diminish the therapeutic effect of Antipsychotic Agents. Management: Use of piribedil with antiemetic neuroleptics is contraindicated, and use with antipsychotic neuroleptics, except for clozapine, is not recommended. Avoid combination

QT-prolonging Agents (Highest Risk): QT-prolonging Agents (Indeterminate Risk - Avoid) may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

Quinagolide: Antipsychotic Agents may diminish the therapeutic effect of Quinagolide. Monitor therapy

Ranolazine: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

RisperiDONE: May enhance the adverse/toxic effect of Paliperidone. Management: Additive paliperidone exposure is expected with this combination. Consider using an alternative combination when possible. Consider therapy modification

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Monitor therapy

Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Monitor therapy

Serotonergic Agents (High Risk): May enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, serotonergic agents may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotic Agents may enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Monitor therapy

Sodium Oxybate: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to combined use. When combined use is needed, consider minimizing doses of one or more drugs. Use of sodium oxybate with alcohol or sedative hypnotics is contraindicated. Consider therapy modification

St John's Wort: May decrease the serum concentration of Paliperidone. Management: Avoid using the 3-month extended-release injectable suspension (Invega Trinza) with inducers of both CYP3A4 and P-glycoprotein during the 3-month dosing interval if possible. If combination is necessary, consider using extended-release tablets. Consider therapy modification

Sulpiride: Antipsychotic Agents may enhance the adverse/toxic effect of Sulpiride. Avoid combination

Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Consider therapy modification

Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Avoid concomitant use of tapentadol and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Tetrabenazine: May enhance the adverse/toxic effect of Antipsychotic Agents. Monitor therapy

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Tetrahydrocannabinol and Cannabidiol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Avoid combination

Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Valproate Products: May increase the serum concentration of Paliperidone. Monitor therapy

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Consider therapy modification

Adverse Reactions

Unless otherwise noted, frequency of adverse effects is reported for the oral/IM formulation in adults.

>10%:

Cardiovascular: Tachycardia (adolescents and adults: 3% to 14%)

Central nervous system: Drowsiness (oral, adolescents: 13% to 26%; adults: 5% to 12%), extrapyramidal reaction (oral, adolescents and adults: 5% to 23%; IM: 2% to 5%), akathisia (adolescents and adults: 4% to 17%), headache (adolescents and adults: 4% to 15%), parkinsonian-like syndrome (adolescents and adults: 2% to 15%), dystonia (adolescents and adults: 1% to 14%)

Endocrine & metabolic: Increased serum prolactin (males: ≤56%; females: ≤44%), decreased HDL cholesterol (oral; adolescents and adults: 23% to 29%; IM: 14% to 16%), increased LDL cholesterol (adolescents and adults: 4% to 14%), weight gain (oral: adults: 3% to 9%, adolescents: 2% to 19%; IM: 6% to 13%), increased serum triglycerides (adolescents and adults: 6% to 13%), increased serum cholesterol (adolescents and adults: 4% to 11%), hyperglycemia (adolescents and adults: 3% to 11%)

Gastrointestinal: Vomiting (adolescents and adults: 5% to 11%)

Neuromuscular & skeletal: Hyperkinesia (oral, adolescents and adults: 6% to 17%; IM: 4% to 5%), tremor (oral, adolescents and adults: 4% to 12%; IM: 1%)

1% to 10%:

Cardiovascular: Orthostatic hypotension (oral: 2% to 4%; IM: <1%), bundle branch block (3%), first degree atrioventricular block (2%), hypertension (adolescents and adults: ≤2%), sinus arrhythmia (oral: ≤2%), bradycardia (adolescents and adults: <2%), edema (adolescents and adults: <2%), palpitations (adolescents and adults: <2%)

Central nervous system: Agitation (IM: 8% to 10%; oral: adolescents and adults: <2%), anxiety (adolescents and adults: 8% to 9%), sedation (IM: 5% to 7%), dizziness (adolescents and adults: 2% to 6%), dysarthria (1% to 4%), lethargy (adolescents: 3%), fatigue (adolescents and adults: 2% to 3%), sleep disorder (oral: 2% to 3%), nightmares (adolescents and adults: ≤2%), insomnia (adolescents and adults: <2%), opisthotonus (oral, adolescents and adults: <2%)

Dermatologic: Pruritus (adolescents and adults: <2%), skin rash (adolescents and adults: <2%)

Endocrine & metabolic: Amenorrhea (adolescents and adults: 2% to 6%), galactorrhea (IM, women: 1% to 4%), gynecomastia (adolescents and adults: 3%), decreased libido (IM: 1%)

Gastrointestinal: Nausea (4% to 8%), dyspepsia (5% to 6%), sialorrhea (adolescents and adults: 1% to 6%), constipation (4% to 5%), abdominal distress (≤4%), upper abdominal pain (≤4%), diarrhea (IM: 3%), swollen tongue (adolescents: 3%), increased appetite (2% to 3%), toothache (IM: 2% to 3%), xerostomia (adolescents and adults: 2% to 3%), stomach discomfort (oral: 2%), decreased appetite (1% to 2%), flatulence (adolescents and adults: <2%)

Genitourinary: Urinary tract infection (adolescents and adults: ≤3%), breast tenderness (adolescents and adults: <2%), irregular menses (adolescents and adults: <2%), retrograde ejaculation (adolescents and adults:<2%), erectile dysfunction (IM: ≤1%)

Hepatic: Increased serum ALT (adolescents and adults: <2%), increased serum AST (adolescents and adults: <2%)

Hypersensitivity: Anaphylaxis (adolescents and adults: <2%)

Local: Injection site reaction (IM: 3% to 10%), erythema at injection site (IM: ≤2%), swelling at injection site (IM: ≤2%)

Neuromuscular & skeletal: Dyskinesia (adolescents and adults: 2% to 9%), myalgia (1% to 4%), weakness (adolescents and adults: ≤4%), back pain (3%), tongue paralysis (oral, adolescents: 3%), limb pain (adolescents and adults: ≤3%), muscle rigidity (IM: 2%), arthralgia (adolescents and adults: <2%)

Ophthalmic: Blurred vision (adolescents and adults: 3%), abnormal eye movements (adolescents and adults: <2%; includes eye rolling)

Respiratory: Upper respiratory tract infection (2% to 10%), nasopharyngitis (adolescents and adults: 2% to 5%), cough (2% to 3%), rhinitis (oral: 1% to 3%), epistaxis (oral, adolescents: 2%), pharyngolaryngeal pain (oral: 1% to 2%), nasal congestion (adolescents and adults: <2%)

Frequency not defined:

Cardiovascular: Cerebrovascular accident (IM), ECG abnormality (IM), hypotension (oral), ischemia (oral), left bundle branch block (oral), peripheral edema (oral), postural orthostatic tachycardia (IM), transient ischemic attacks (oral)

Central nervous system: Abnormal gait (oral; parkinsonian gait), cogwheel rigidity (IM), drooling, hypertonia (IM), orthostatic dizziness (IM), psychomotor agitation (IM), restlessness (IM), seizure, tonic-clonic seizures (oral), trismus (oral), vertigo (IM)

Dermatologic: Fixed drug eruption (IM), papular rash (oral), urticaria (IM)

Endocrine & metabolic: Menstrual disease (IM)

Gastrointestinal: Abdominal pain (oral), hyperinsulinism (IM), oromandibular dystonia (IM)

Genitourinary: Breast engorgement (oral), breast hypertrophy (IM), breast swelling (IM), ejaculatory disorder (IM), mastalgia, nipple discharge (IM), sexual disorder (IM)

Hypersensitivity: Hypersensitivity (IM)

Neuromuscular & skeletal: Bradykinesia (IM), joint stiffness (IM), muscle spasm (IM), muscle twitching (IM), musculoskeletal pain (oral), neck stiffness (IM), torticollis (oral)

Ophthalmic: Oculogyric crisis (IM)

Respiratory: Aspiration pneumonia

<1%, postmarketing, and/or case reports: Agranulocytosis, angioedema, antiemetic effect, diabetes mellitus, intestinal obstruction (includes small intestine), leukopenia, motor dysfunction, neuroleptic malignant syndrome, neutropenia, priapism, prolonged Q-T interval on ECG, sensory disturbance (sensory instability), somnambulism, syncope, tardive dyskinesia, thrombotic thrombocytopenic purpura, urinary incontinence, urinary retention

Warnings/Precautions

Concerns related to adverse effects:

• Altered cardiac conduction: May alter cardiac conduction and prolong the QTc interval; life-threatening arrhythmias have occurred with therapeutic doses of antipsychotics (Ray 2009). Risk may be increased by conditions or concomitant medications that cause bradycardia, hypokalemia, and/or hypomagnesemia. Avoid use in combination with QTc-prolonging drugs. Avoid use in patients with congenital long QT syndrome and in patients with history of cardiac arrhythmia.
• Antiemetic effects: May mask toxicity of other drugs or conditions (eg, intestinal obstruction, Reye syndrome, brain tumor) due to antiemetic effects.
• Blood dyscrasias: Leukopenia, neutropenia, and agranulocytosis (sometimes fatal) have been reported in clinical trials and postmarketing reports with antipsychotic use; presence of risk factors (eg, preexisting low WBC or ANC, history of drug-induced leuko-/neutropenia) should prompt periodic blood count assessment. Monitor patients with clinically significant neutropenia for a fever or other signs of infection, and discontinue therapy if absolute neutrophil count <1,000/mm³.
• Cerebrovascular effects: An increased incidence of cerebrovascular adverse effects (eg, transient ischemic attack, stroke), including fatalities, has been reported in placebo-controlled trials of risperidone (paliperidone is the primary active metabolite of risperidone) for the unapproved use in elderly patients with dementia-related psychosis.
• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery, driving).
• Dyslipidemia: Increased cholesterol and triglycerides and decreased HDL have been noted. Use with caution in patients with a preexisting abnormal lipid profile.
• Esophageal dysmotility/Aspiration: Antipsychotic use has been associated with esophageal dysmotility and aspiration; risk increases with age. Use with caution in patients at risk for aspiration pneumonia (eg, Alzheimer disease), particularly in patients >75 years of age (Herzig 2017; Maddalena 2004).
• Extrapyramidal symptoms: May cause extrapyramidal symptoms (EPS), including pseudoparkinsonism, acute dystonic reactions, akathisia, and tardive dyskinesia (risk of these reactions is generally much lower relative to typical/conventional antipsychotics; frequencies reported are similar to placebo). Risk of dystonia (and probably other EPS) may be greater with increased doses, use of conventional antipsychotics, males, and younger patients. Factors associated with greater vulnerability to tardive dyskinesia include older in age, female gender combined with postmenopausal status, Parkinson disease, pseudoparkinsonism symptoms, affective disorders (particularly major depressive disorder), concurrent medical diseases such as diabetes, previous brain damage, alcoholism, poor treatment response, and use of high doses of antipsychotics (APA [Lehman 2004]; Soares-Weiser 2007). Consider therapy discontinuation with signs/symptoms of tardive dyskinesia.
• Falls: May increase the risk for falls due to somnolence, orthostatic hypotension, and motor or sensory instability. Complete fall risk assessments at baseline and periodically during treatment in patients with diseases or on medications that may also increase fall risk.
• Hyperglycemia: Atypical antipsychotics have been associated with development of hyperglycemia; in some cases, may be extreme and associated with ketoacidosis, hyperosmolar coma, or death. All patients should be monitored for symptoms of hyperglycemia (eg, polydipsia, polyuria, polyphagia, weakness). Use with caution in patients with diabetes (or risk factors) or other disorders of glucose regulation; monitor for worsening of glucose control. Patients with risk factors for diabetes (eg, obesity or family history) should have a baseline fasting blood sugar and periodically during treatment.
• Hyperprolactinemia: Use is associated with increased prolactin levels; clinical significance of hyperprolactinemia in patients with breast cancer or other prolactin-dependent tumors is unknown.
• Hypersensitivity: Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been reported.
• Intraoperative floppy iris syndrome: Few case reports describe intraoperative floppy iris syndrome (IFIS) in patients receiving risperidone and undergoing cataract surgery (Ford 2011). IFIS has not been reported with paliperidone, but caution is advised because it is the active metabolite of risperidone. Prior to cataract surgery, evaluate for prior or current paliperidone or risperidone use. The benefits or risks of interrupting paliperidone or risperidone prior to surgery have not been established; clinicians are advised to proceed with surgery cautiously.
• Neuroleptic malignant syndrome: Use may be associated with neuroleptic malignant syndrome; monitor for mental status changes, fever, muscle rigidity, and/or autonomic instability (risk may be increased in patients with Parkinson disease or Lewy body dementia).
• Orthostatic hypotension: May cause orthostatic hypotension and syncope; use with caution in patients with known cardiovascular disease (heart failure, history of myocardial infarction or ischemia, conduction abnormalities), cerebrovascular disease, or conditions that predispose the patient to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medications).
• Priapism: Rare cases of priapism have been reported.
• Suicidal ideation: The possibility of a suicide attempt is inherent in psychotic illness or bipolar disorder; use with caution in high-risk patients during initiation of therapy. Prescriptions should be written for the smallest quantity consistent with good patient care.
• Temperature regulation: Impaired core body temperature regulation may occur; use caution with strenuous exercise, heat exposure, dehydration, and concomitant medication possessing anticholinergic effects.
• Weight gain: Significant weight gain has been observed with antipsychotic therapy; incidence varies with product. Monitor waist circumference and body mass index.

Disease-related concerns:

• Dementia: [US Boxed Warning]: Elderly patients with dementia-related psychosis treated with antipsychotics are at an increased risk of death compared to placebo. Most deaths appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature. Use with caution in patients with Lewy body dementia or Parkinson disease dementia due to greater risk of adverse effects, increased sensitivity to extrapyramidal effects, and association with irreversible cognitive decompensation or death. (APA [Reus 2016]). Paliperidone is not approved for the treatment of dementia-related psychosis.
• Renal impairment: Use with caution in patients with mild renal disease; dosage reduction is recommended. Not recommended in patients with moderate (IM route only) to severe impairment.
• Seizures: Use with caution in patients at risk of seizures, including those with a history of seizures, head trauma, brain damage, alcoholism, or concurrent therapy with medications that may lower seizure threshold. Elderly patients may be at increased risk of seizures due to an increased prevalence of predisposing factors.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Dosage form specific issues:

• Extended-release tablet: Use is not recommended in patients with preexisting severe GI-narrowing disorders (nondeformable controlled-release formulation). Patients with upper GI tract alterations in transit time may have increased or decreased bioavailability of paliperidone. Formulation consists of drug within a nonabsorbable shell; following drug release/absorption, the shell is expelled in the stool.

Other warnings/precautions:

• Discontinuation of therapy: When discontinuing antipsychotic therapy, the American Psychiatric Association (APA), Canadian Psychiatric Association (CPA), and World Federation of Societies of Biological Psychiatry (WFSBP) guidelines recommend gradually tapering antipsychotics to avoid physical withdrawal symptoms, including anorexia, anxiety, diaphoresis, diarrhea, dizziness, dyskinesia, headache, myalgia, nausea, paresthesia, restlessness, tremulousness, and vomiting (APA [Lehman 2004]; CPA [Addington 2005]; Lambert 2007; WFSBP [Hasan 2012]). The risk of withdrawal symptoms is highest following abrupt discontinuation of highly anticholinergic or dopaminergic antipsychotics (Cerovecki 2013). Additional factors such as duration of antipsychotic exposure, the indication for use, medication half-life, and risk for relapse should be considered. In schizophrenia, there is no reliable indicator to differentiate the minority who will not from the majority who will relapse with drug discontinuation. However, studies in which the medication of well-stabilized patients were discontinued indicate that 75% of patients relapse within 6 to 24 months. Indefinite maintenance antipsychotic medication is generally recommended, and especially for patients who have had multiple prior episodes or 2 episodes within 5 years (APA [Lehman 2004]).

Monitoring Parameters

Mental status; vital signs (as clinically indicated); blood pressure (baseline; repeat 3 months after antipsychotic initiation, then yearly); weight, height, BMI, waist circumference (baseline; repeat at 4, 8, and 12 weeks after initiating or changing therapy, then quarterly; consider switching to a different antipsychotic for a weight gain ≥5% of initial weight); CBC (as clinically indicated; monitor frequently during the first few months of therapy in patients with preexisting low WBC or history of drug-induced leukopenia/neutropenia); electrolytes, renal and liver function (annually and as clinically indicated); personal and family history of obesity, diabetes, dyslipidemia, hypertension, or cardiovascular disease (baseline; repeat annually); fasting plasma glucose level/HbA_1c (baseline; repeat 3 months after starting antipsychotic, then yearly); fasting lipid panel (baseline; repeat 3 months after initiation of antipsychotic; if LDL level is normal repeat at 2- to 5-year intervals or more frequently if clinical indicated); changes in menstruation, libido, development of galactorrhea, erectile and ejaculatory function (at each visit for the first 12 weeks after the antipsychotic is initiated or until the dose is stable, then yearly); abnormal involuntary movements or parkinsonian signs (baseline; repeat weekly until dose stabilized for at least 2 weeks after introduction and for 2 weeks after any significant dose increase); tardive dyskinesia (every 12 months; high-risk patients every 6 months); ocular examination (yearly in patients >40 years; every 2 years in younger patients) (ADA 2004; Lehman 2004; Marder 2004).

Pregnancy

Pregnancy Considerations

Information specific to paliperidone in pregnancy is limited (Onken 2018; Özdemir 2015; Zamora Rodriguez 2017).

Antipsychotic use during the third trimester of pregnancy has a risk for extrapyramidal symptoms (EPS) and/or withdrawal symptoms in newborns following delivery. Symptoms in the newborn may include agitation, feeding disorder, hypertonia, hypotonia, respiratory distress, somnolence, and tremor. These effects may be self-limiting and allow recovery within hours or days with no specific treatment, or they may be severe requiring prolonged hospitalization.

The ACOG recommends that therapy during pregnancy be individualized; treatment with psychiatric medications during pregnancy should incorporate the clinical expertise of the mental health clinician, obstetrician, primary healthcare provider, and pediatrician. Safety data related to atypical antipsychotics during pregnancy is limited and routine use is not recommended. However, if a woman is inadvertently exposed to an atypical antipsychotic while pregnant, continuing therapy may be preferable to switching to a typical antipsychotic that the fetus has not yet been exposed to; consider risk:benefit (ACOG 2008).

Paliperidone may cause hyperprolactinemia, which may cause a reversible decrease in fertility in females.

Paliperidone is the active metabolite of risperidone; refer to Risperidone monograph for additional information.

Health care providers are encouraged to enroll women 18 to 45 years of age exposed to paliperidone during pregnancy in the Atypical Antipsychotics Pregnancy Registry (1-866-961-2388 or http://www.womensmentalhealth.org/pregnancyregistry).

Patient Education

What is this drug used for?

• It is used to treat schizophrenia.
• It is used to treat schizoaffective disorder.
• It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Headache
• Weight gain
• Constipation
• Fatigue
• Anxiety
• Nausea
• Vomiting
• Stuffy nose
• Sore throat
• Restlessness
• Loss of strength and energy
• Tablet shell in stool
• Injection site irritation

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Infection
• High blood sugar like confusion, feeling sleepy, more thirst, hunger, passing urine more often, flushing, fast breathing, or breath that smells like fruit
• Fast heartbeat
• Severe dizziness
• Passing out
• Abnormal heartbeat
• Behavioral changes
• Mood changes
• Tremors
• Trouble moving
• Rigidity
• Slow heartbeat
• Trouble swallowing
• Seizures
• Drooling
• Bruising
• Bleeding
• Involuntary eye movements
• Lack of sweating
• Enlarged breasts
• Sexual dysfunction
• Loss of sex drive
• Nipple discharge
• Breast pain
• No menstrual periods
• Erection that lasts more than 4 hours
• Neuroleptic malignant syndrome like fever, muscle cramps or stiffness, dizziness, very bad headache, confusion, change in thinking, fast heartbeat, abnormal heartbeat, or sweating a lot.
• Tardive dyskinesia like unable to control body movements; tongue, face, mouth, or jaw sticking out; mouth puckering; and puffing cheeks.
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.