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Paliperidone

Class: Atypical Antipsychotics
VA Class: CN709
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
CAS Number: 144598-75-4
Brands: Invega

Medically reviewed by Drugs.com on Mar 22, 2021. Written by ASHP.

Warning

    Increased Mortality in Geriatric Patients
  • Substantially higher mortality rate (4.5%) in geriatric patients with dementia-related psychosis† receiving atypical antipsychotic agents (e.g., risperidone, aripiprazole, olanzapine, quetiapine) compared with those receiving placebo (2.6%).

  • Most fatalities resulted from cardiac-related events (e.g., heart failure, sudden death) or infections (mostly pneumonia).

  • Atypical antipsychotics are not approved for the treatment of dementia-related psychosis. (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis under Cautions.)

Introduction

Atypical or second-generation antipsychotic agent.

Uses for Paliperidone

Schizophrenia

Acute and maintenance treatment of schizophrenia.

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).

Paliperidone Dosage and Administration

Administration

Oral Administration

Administer orally once daily in the morning without regard to meals.

Paliperidone extended-release tablets should be swallowed whole, with fluids; do not chew, divide, or crush.

Dosage

Adults

Schizophrenia
Oral

6 mg once daily; dosage titration is not required.

If required, may increase dosage in increments of 3 mg daily at intervals of >5 days to a maximum dosage of 12 mg once daily; increase dosage only after clinical reassessment.

Maximal efficacy generally observed at dosage of 6 mg daily; dosages >6 mg trended toward greater clinical effects; however, weigh potential increased clinical efficacy against the potential for increased adverse effects.

Optimum duration of therapy is not known, but maintenance therapy with antipsychotics is well established. In responsive patients, continue as long as clinically necessary and tolerated, but at lowest possible effective dosage; periodically reassess need for continued therapy.

In patients with remitted first or multiple episodes, the APA recommends either indefinite maintenance therapy or gradual discontinuance of the antipsychotic with close follow-up and a plan to reinstitute treatment upon symptom recurrence. Consider antipsychotic therapy discontinuance only after ≥1 year of symptom remission or optimal response while taking antipsychotic. Indefinite maintenance treatment is recommended if multiple previous psychotic episodes or 2 episodes within 5 years.

Prescribing Limits

Adults

Schizophrenia
Oral

Maximum 12 mg once daily.

Special Populations

Hepatic Impairment

No dosage adjustment required in patients with mild to moderate hepatic impairment (Child-Pugh class A and B); not studied in patients with severe hepatic impairment. (See Distribution: Special Populations under Pharmacokinetics.)

Renal Impairment

Mild renal impairment (Clcr 50–79 mL/minute): Maximum 6 mg once daily.

Moderate to severe renal impairment (Clcr 10–49 mL/minute): Maximum 3 mg once daily. (See Elimination: Special Populations under Pharmacokinetics.)

Geriatric Patients

No dosage adjustments except those related to renal impairment. (See Renal Impairment under Dosage and Administration.)

Gender, Race, or Smoking Status

No dosage adjustment required.

Cautions for Paliperidone

Contraindications

  • Known hypersensitivity to paliperidone, risperidone, or any ingredient in the formulation.

Warnings/Precautions

Warnings

Increased Mortality in Geriatric Patients with Dementia-related Psychosis

Possible increased risk of death with use of atypical antipsychotics in geriatric patients with dementia-related psychosis.

Atypical antipsychotics, including paliperidone, are not approved for the treatment of dementia-related psychosis. (See Increased Mortality in Geriatric Patients in Boxed Warning and see Geriatric Use under Cautions.)

Prolongation of QT Interval

Paliperidone causes a modest increase in the corrected QT (QTc) interval.

Avoid use in patients with congenital prolonged QT interval, bradycardia, uncorrected electrolyte disorders (e.g., hypokalemia, hypomagnesemia), or a history of cardiac arrhythmias. Also avoid use in those receiving other drugs known to prolong the QTc interval. (See Drugs that Prolong QT Interval and also Specific Drugs under Interactions.)

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome requiring immediate discontinuance of the drug and intensive symptomatic treatment, reported in patients receiving antipsychotic agents, including paliperidone.

Tardive Dyskinesia

Tardive dyskinesia, a syndrome of potentially irreversible, involuntary dyskinetic movements, reported. The APA recommends assessing patients receiving second-generation antipsychotic agents for abnormal involuntary movements every 12 months; for patients at increased risk for tardive dyskinesia, assess every 6 months. Consider discontinuance of paliperidone if signs and symptoms of tardive dyskinesia appear.

Hyperglycemia and Diabetes Mellitus

Severe hyperglycemia, sometimes associated with ketoacidosis, hyperosmolar coma, or death, reported in patients receiving atypical antipsychotic agents.

Closely monitor patients with preexisting diabetes mellitus for worsening of glucose control and perform fasting glucose tests at baseline and periodically for patients with risk factors for diabetes (e.g., obesity, family history of diabetes). If manifestations of hyperglycemia occur, perform fasting blood glucose testing.

GI Effects

Extended-release paliperidone tablets are a nondeformable material that does not appreciably change shape in the GI tract. Rare cases reported of obstructive symptoms in patients with known strictures in association with nondeformable, controlled-release formulations. Avoid administration to patients with severe, preexisting GI narrowing (either pathologic or iatrogenic).

Esophageal dysmotility and aspiration possible; use caution in patients at risk for aspiration pneumonia (e.g., those with advanced Alzheimer’s dementia).

General Precautions

Orthostatic Hypotension

Orthostatic hypotension and syncope reported. Use with caution in geriatric patients and in patients with known cardiovascular (e.g., heart failure, history of MI or ischemia, conduction abnormalities) or cerebrovascular disease or other conditions (e.g., dehydration, hypovolemia, concomitant antihypertensive therapy) that would predispose them to hypotension. Consider monitoring orthostatic vital signs in patients vulnerable to hypotension. (See Geriatric Use under Cautions.)

Nervous System Effects

Seizures may occur; use with caution in patients with a history of seizures or other conditions that may lower the seizure threshold (e.g., dementia of the Alzheimer’s type, geriatric patients). (See Geriatric Use under Cautions.)

Disruption of ability to regulate core body temperature possible. Use caution in patients exposed to conditions that may contribute to an elevation in core body temperature (e.g., dehydration, extreme heat, strenuous exercise, concomitant use of anticholinergic agents.)

Somnolence reported; potential impairment of judgment, thinking, or motor skills.

Antiemetic effect demonstrated in animals; also may occur in humans and mask manifestations of overdosage with certain drugs or of underlying conditions (e.g., intestinal obstruction, Reye’s syndrome, brain tumor).

Hematologic Effects

Thrombotic thrombocytopenic purpura reported in association with risperidone therapy; however, currently no reports of this effect with paliperidone.

Suicide

Attendant risk with psychotic illnesses; closely supervise high-risk patients. Prescribe in the smallest quantity consistent with good patient management to reduce the risk of overdosage.

Hyperprolactinemia

Elevated prolactin concentrations possible; may persist during chronic administration.

Concomitant Illnesses

Experience in patients with certain concomitant diseases is limited.

Possible increased risk of NMS and increased sensitivity to antipsychotic agents in patients with parkinsonian syndrome or dementia with Lewy bodies; manifestations of sensitivity may include confusion, obtundation, postural instability with more frequent falling, or extrapyramidal adverse effects. (See Geriatric Use under Cautions.)

Specific Populations

Pregnancy

Category C.

Risk for extrapyramidal and/or withdrawal symptoms (e.g., agitation, hypertonia, hypotonia, tardive dyskinetic-like symptoms, tremor, somnolence, respiratory distress, feeding disorder) in neonates exposed to antipsychotic agents during the third trimester; monitor neonates exhibiting such symptoms. Symptoms were self-limiting in some neonates but varied in severity; some infants required intensive support and prolonged hospitalization.

Lactation

Distributed into milk. Caution if used in nursing women.

Pediatric Use

Safety and efficacy not established in children <18 years of age.

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults; however, manufacturer states greater sensitivity of some older individuals cannot be ruled out. Use with caution due to greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in elderly patients. (See Concomitant Illnesses and also Nervous System Effects under Cautions and see Renal Impairment under Dosage and Administration.)

Consider monitoring orthostatic vital signs and renal function in geriatric patients. (See Orthostatic Hypotension under Cautions.)

Possible increased risk of death in geriatric patients with dementia-related psychosis. Substantial (1.6- to 1.7-fold) increase in mortality rate reported in geriatric patients with dementia who received atypical antipsychotic agents (i.e., risperidone, aripiprazole, olanzapine, quetiapine) for treatment of behavioral disorders; most fatalities resulted from cardiac-related events (e.g., heart failure, sudden death) or infections (e.g., pneumonia). In addition, adverse cerebrovascular effects, sometimes fatal, reported in geriatric patients with dementia-related psychosis receiving atypical antipsychotic agents (i.e., risperidone, aripiprazole, olanzapine). Paliperidone is not approved for the treatment of dementia-related psychosis. (See Increased Mortality in Geriatric Patients in Boxed Warning and see Increased Mortality in Geriatric Patients with Dementia-related Psychosis under Warnings in Cautions.)

Common Adverse Effects

Tremor, headache, orthostatic hypotension, tachycardia, somnolence, akathisia, insomnia, anxiety, extrapyramidal reaction, dizziness, dystonia, QTc interval prolongation, nausea, dyspepsia, weight gain.

Interactions for Paliperidone

In vivo results indicate that CYP2D6 and CYP3A4 play a limited role in overall elimination of paliperidone.

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors or inducers of CYP isoenzymes 2D6, 3A4, 1A2, 2A6, 2C9, and 2C19: Pharmacokinetic interaction unlikely.

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP isoenzymes 1A2, 2A6, 2C8/9/10, 2D6, 2E1, 3A4, or 3A5: Pharmacokinetic interaction unlikely.

Drugs Inhibiting P-glycoprotein Transport System

Does not inhibit P-glycoprotein; clinically relevant interactions unlikely.

Drugs that Prolong QT Interval

Potential pharmacologic interaction (additive effect on QT-interval prolongation); avoid concomitant use with drugs known to prolong the QT interval. (See Prolongation of QT Interval under Cautions.)

Protein-bound Drugs

Pharmacokinetic interactions unlikely.

Specific Drugs

Drug

Interaction

Comments

Alcohol

Possible additive CNS effects

Avoid concomitant use

Amiodarone

Possible additive QT prolongation effects

Avoid concomitant use

Antiarrhythmics (e.g., procainamide, quinidine, sotalol)

Possible additive QT prolongation effects

Avoid concomitant use

Chlorpromazine

Possible additive QT prolongation effects

Avoid concomitant use

CNS agents

Additive CNS effects

Use with caution

Dopamine agonists (e.g., levodopa)

Potential antagonistic effects

Fluoroquinolones (e.g., moxifloxacin, gatifloxacin)

Possible additive QT prolongation effects

Avoid concomitant use

Hypotensive agents

Additive hypotensive effects

Use with caution; monitor for orthostatic hypotension in susceptible patients

Paroxetine

Possible increased paliperidone AUC in CYP2D6 extensive metabolizers

Clinical importance unknown

Risperidone

Paliperidone is principal active metabolite of risperidone; possible additive paliperidone exposure

Thioridazine

Possible additive QT prolongation effects

Avoid concomitant use

Paliperidone Pharmacokinetics

Absorption

Bioavailability

Absolute oral bioavailability is 28%; single-dose peak plasma concentrations attained approximately 24 hours after dosing.

Food

Food increases rate and extent of absorption, and possible increase in exposure.

Special Populations

Decreased bioavailability in patients with decreased GI transit time (e.g., diarrhea); increased bioavailability in patients with increased GI transit time (e.g., GI neuropathy, diabetic gastroparesis). Changes in bioavailability more likely when transit time changes occur in the upper GI tract. (See GI Effects under Cautions.)

Distribution

Extent

Not known whether paliperidone crosses the placenta. Risperidone (the parent drug of paliperidone) crosses the placenta in rats. Paliperidone is distributed into human milk.

Plasma Protein Binding

74%.

Special Populations

In mild to moderate hepatic impairment (Child-Pugh class B); decreased total paliperidone exposure due to decreased protein binding. (See Hepatic Impairment under Dosage and Administration.)

Elimination

Metabolism

In vitro studies suggested a role for CYP2D6 and CYP3A4; however, in vivo results suggest a limited role.

Elimination Route

Paliperidone and its metabolites excreted in urine (80%), mainly as unchanged drug, and in the feces (11%).

Half-life

Terminal half-life is approximately 23 hours.

Special Populations

In patients with renal impairment, mean plasma terminal half-life is 24, 40, and 51 hours in individuals with mild, moderate, and severe renal impairment, respectively. (See Renal Impairment under Dosage and Administration.)

No difference in exposure or clearance of paliperidone between extensive metabolizers and poor metabolizers of CYP2D6.

Stability

Storage

Oral

Extended-release Tablets

25°C (may be exposed to 15–30°C); protect from moisture.

Actions

  • Benzisoxazole derivative; major active metabolite of risperidone.

  • Exact mechanism of antipsychotic action has not been fully elucidated; may involve antagonism of central dopamine type 2 (D2) receptors and serotonin type 2 (5-hydroxytryptamine [5-HT2A]) receptors.

  • Antagonism at other receptors (e.g., α1- and α2-adrenergic receptors, histamine H1 receptors) may contribute to other therapeutic and adverse effects.

  • Paliperidone possesses no affinity for cholinergic, muscarinic, or β1- and β2-adrenergic receptors.

Advice to Patients

  • Risk of orthostatic hypotension. Importance of using nonpharmacologic methods (e.g., sitting on edge of bed for several minutes upon waking, slowly rising from sitting to standing position) to minimize effects.

  • Risk of somnolence. Importance of avoiding driving, operating machinery, or performing hazardous tasks until the patient gains experience with the drug’s effects.

  • Importance of avoiding alcohol during paliperidone therapy.

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, dietary supplements, and/or herbal products, as well as any concomitant illnesses (e.g., cardiovascular disease, diabetes mellitus, seizures).

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

  • Importance of avoiding overheating or dehydration.

  • Importance of swallowing paliperidone tablets whole with the aid of liquids; do not chew, divide, or crush tablets. Patients should not be concerned if they notice a tablet-like substance in their stool.

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Paliperidone

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, extended-release

3 mg

Invega (with povidone and propylene glycol)

Janssen

6 mg

Invega (with povidone and propylene glycol)

Janssen

9 mg

Invega (with povidone and propylene glycol)

Janssen

AHFS DI Essentials™. © Copyright 2022, Selected Revisions March 30, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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