Paliperidone

Pronunciation

Pronunciation: PAL-ee-PER-i-done
Class: Antipsychotic agent, Benzisoxazole derivative

Trade Names

Invega
- Tablets, ER, oral 1.5 mg
- Tablets, ER, oral 3 mg
- Tablets, ER, oral 6 mg
- Tablets, ER, oral 9 mg

Invega Sustenna
- Injection, suspension, ER 39 mg per 0.25 mL
- Injection, suspension, ER 78 mg per 0.5 mL
- Injection, suspension, ER 117 mg per 0.75 mL
- Injection, suspension, ER 156 mg/mL
- Injection, suspension, ER 234 mg per 1.5 mL

Pharmacology

Possibly due to dopamine and serotonin receptor blockade in the CNS. Also an antagonist at alpha-1 and alpha-2 adrenergic receptors and H 1 histaminic receptors. Paliperidone is the active metabolite of risperidone.

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Pharmacokinetics

Absorption

Dose-related pharmacokinetics. Oral bioavailability is approximately 28%. C max occurs approximately 24 h after oral dosing. Steady-state concentrations are reached within 4 to 5 days of oral dosing. Mean steady-state peak-to-trough ratio ranges from 1.2 to 3.1 (oral). Following a single IM dose, T max was 13 days and mean steady-state peak-to-trough ratio was 1.8 (gluteal administration) and 2.2 (deltoid administration). After IM administration, the release of the drug starts as early as day 1 and lasts for as long as 126 days.

Distribution

Vd is 487 L (oral) and 391 L (IM). Plasma protein binding is 74%.

Metabolism

Four metabolite pathways: dealkylation, hydroxylation, dehydrogenation, and benzisoxazole scission. Limited degree of metabolism by CYP2D6 and CYP3A4.

Elimination

Elimination half-life is approximately 23 h (oral). Elimination of the injection is approximately 80% in urine and 11% in feces; 32% of the oral dose is recovered as metabolites. The mean apparent half-life following a single IM dose (39 to 243 mg) ranged from 25 to 49 days.

Special Populations

Renal Function Impairment

Reduce oral dose in patients with moderate or severe impairment and reduce IM injection dose in patients with mild impairment. The IM injection is not recommended in patients with moderate or severe renal impairment.

Hepatic Function Impairment

No adjustments needed in patients with mild or moderate impairment. Effect of severe impairment has not been determined.

Elderly

Dosage adjustment is not recommended based on age alone; however, dosage adjustments may be needed based on renal function.

Gender

Slower IM absorption observed in women; dosage adjustment based on gender is not recommended.

Race

Dosage adjustment based on race is not recommended.

Indications and Usage

Acute and maintenance treatment of schizophrenia; treatment of schizoaffective disorder as monotherapy or as an adjunct to mood stabilizers and/or antidepressants (oral only).

Contraindications

Hypersensitivity to risperidone, paliperidone, or any component of the product.

Dosage and Administration

Schizoaffective Disorder
Adults

PO 6 mg once daily (range, 3 to 12 mg/day). Dosage increases should only occur at intervals of no more than 4 days in increments of 3 mg/day (max, 12 mg/day).

Schizophrenia
Adults PO

6 mg once daily (range, 3 to 12 mg/day). Dosage increases should be made at increments of 3 mg/day at intervals of at least 5 days (max, 12 mg/day).

IM

234 mg on treatment day 1 and 156 mg 1 wk later, both administered in the deltoid muscle. Monthly maintenance dose is 117 mg administered in deltoid or gluteal muscle; recommended dose range is 39 to 234 mg based on individual tolerability and efficacy. Adjust maintenance dose monthly.

Adolescents (12 to 17 y of age)

PO 3 mg once daily. Dosage increases should be made at increments of 3 mg/day at intervals of at least 5 days (max, 6 mg/day for patients weighing less than 51 kg; 12 mg/day for patients weighing 51 kg or more).

Missed Doses Adults

IM To avoid a missed dose, give the second dose 2 days before or after the 1-wk time point. Similarly, the third and subsequent injections after the initiation regimen are recommended to be given monthly. To avoid a missed monthly dose, patients may be given the injection up to 7 days before or after the monthly time point. If more than 6 wk have elapsed since the last dose, resume the same dose the patient was stabilized on (unless the patient was stabilized on 234 mg, then the first 2 injections should each be 156 mg) in the following manner: a deltoid injection as soon as possible, followed by another deltoid injection (same dose) 1 wk later, and resumption of either deltoid or gluteal dosing at monthly intervals. If more than 6 mo have elapsed since the last injection, dosing should be restarted.

Switching from Oral to IM

3 mg/day orally converts to 39 to 78 mg/mo IM; 6 mg/day orally converts to 117 mg/mo IM; 12 mg/day orally converts to 234 mg/mo IM.

Switching from Long-Acting Injectable Antipsychotics

IM Initiate paliperidone in place of the next scheduled injection. Continue at monthly intervals. The 1-wk initiation regimen is not required.

Renal Function Impairment PO

For mild impairment (CrCl 50 to less than 80 mL/min), recommended initial dosage is 3 mg/day, not to exceed 6 mg once daily. For moderate to severe impairment (CrCl 10 to less than 50 mL/min), recommended initial dosage is 1.5 mg/day, not to exceed 3 mg once daily.

IM

For mild impairment, initiate with 156 mg on treatment day 1 and 117 mg 1 wk later, both administered in deltoid muscle. Continue with 78 mg monthly in the deltoid or gluteal muscle. The IM injection is not recommended in patients with moderate to severe renal impairment.

General Advice

  • Oral
  • May be taken with or without food.
  • Tablets must be swallowed whole and not divided, chewed, or crushed.
  • Initial dose titration is not required.
  • Injection
  • For IM use only; inject slowly, deep into muscle.
  • Injection is for single use only.
  • Do not administer intravascularly or subcutaneously.

Storage/Stability

Store at 59° to 86°F. Protect from moisture.

Drug Interactions

Alcohol, CNS-acting drugs

Use CNS-acting drugs with caution. Avoid alcohol.

Antihypertensive agents

Effects may be enhanced by paliperidone. Alpha-blocking activity of paliperidone may induce orthostatic hypotension and syncope. Monitor BP and orthostatic vital signs.

Carbamazepine

Paliperidone plasma concentrations and AUC may be reduced, decreasing the efficacy. Evaluate the paliperidone dose when carbamazepine is started or stopped. Adjust the paliperidone dose as needed.

Charcoal

Paliperidone absorption may be decreased, reducing the efficacy.

Divalproex sodium, valproate sodium, valproic acid

Paliperidone C max and AUC may be elevated, increasing the pharmacologic effects and risk of adverse reactions. Evaluate the clinical response of the patient when valproic acid is started or stopped. Adjust the paliperidone dose as needed.

Drugs that cause orthostatic hypotension

Possible additive effect with paliperidone.

Drugs that prolong the QTc interval (eg, antibiotics [gatifloxacin, moxifloxacin], antipsychotic agents [eg, chlorpromazine, thioridazine], arsenic trioxide, chloroquine, cisapride, class IA antiarrhythmic agents [eg, procainamide, quinidine], class III antiarrhythmic agents [eg, amiodarone, dofetilide, sotalol], dronedarone, halofantrine, haloperidol, macrolide antibiotics [eg, erythromycin], maprotiline, methadone, romidepsin, tetrabenazine, toremifene, tyrosine kinase receptor antagonists [eg, lapatinib], vandetanib)

Risk of life-threatening arrhythmias, including torsades de pointes, may be increased. Avoid coadministration of paliperidone with these agents.

Food

Administration of paliperidone with a standard high-fat/high-caloric meal may increase paliperidone mean C max and AUC values compared with administration under fasting conditions. However, paliperidone may be taken without regard to food.

Levodopa and other dopamine agonists

Effects may be antagonized by paliperidone.

Paroxetine

Paliperidone exposure may be increased. Evaluate the clinical response of the patient when paroxetine is started or stopped. Adjust the paliperidone dose as needed.

Sympathomimetics (eg, dopamine, epinephrine)

For treatment of paliperidone-induced hypotension, do not use dopamine or other sympathomimetics with beta-agonist activity because beta stimulation may worsen the hypotension caused by paliperidone-induced alpha blockade.

Adverse Reactions

Cardiovascular

Oral

Tachycardia (14%); orthostatic hypotension (4%); bundle branch block (3%); first-degree AV block, sinus arrhythmia (2%); bradycardia, hypertension, hypotension, palpitations, syncope (less than 2%).

Injection

Hypertension (2%); bradycardia; bundle branch block; cerebrovascular accident; first-degree AV block; palpitations; postural orthostatic tachycardia syndrome; QT prolonged; syncope; tachycardia.

CNS

Oral

Somnolence (26%); extrapyramidal disorder (20%); akathisia, hyperkinesia (17%); parkinsonism (15%); dystonia, headache (14%); tremor (12%); anxiety, dyskinesia (9%); dizziness (6%); asthenia, dysarthria, fatigue (4%); lethargy, sleep disorder (3%); agitation, insomnia, nightmare, opisthotonus (less than 2%); tardive dyskinesia (postmarketing).

Injection

Headache, insomnia (15%); parkinsonism (12%); agitation (10%); anxiety (8%); somnolence/sedation (7%); akathisia, dizziness, dyskinesia (6%); extrapyramidal disorder (5%); hyperkinesia (4%); tremor (3%); asthenia, dystonia, fatigue, nightmare, suicidal ideation (2%); bradykinesia; convulsions; dizziness postural; drooling; dysarthria; dystonia; hypertonia; lethargy; NMS; oromandibular dystonia; psychomotor hyperactivity; restlessness; tardive dyskinesia; vertigo.

Dermatologic

Oral

Pruritus, rash (less than 2%).

Injection

Injection-site reactions (10%); skin laceration (2%); drug eruption; pruritus; rash; urticaria.

EENT

Oral

Vision blurred (3%); eye movement disorder.

Injection

Eye movement disorder, eye rolling, oculogyric crisis, vision blurred.

GI

Oral

Vomiting (11%); nausea (8%); dyspepsia, salivary hypersecretion (6%); constipation (5%); abdominal discomfort/upper abdominal pain, dry mouth, increased appetite, swollen tongue, tongue paralysis (3%); decreased appetite, stomach discomfort (2%); flatulence (less than 2%).

Injection

Constipation, vomiting (5%); abdominal discomfort/abdominal pain upper, nausea (4%); diarrhea, dry mouth, toothache (3%); increased or decreased appetite; salivary hypersecretion; swollen tongue (postmarketing).

Genitourinary

Oral

Amenorrhea (6%); galactorrhea (4%); gynecomastic (3%); breast discomfort, menstruation irregular, retrograde ejaculation, UTI (less than 2%); priapism, urinary incontinence, urinary retention (postmarketing).

Injection

UTI (2%); amenorrhea; breast discharge; erectile dysfunction; galactorrhea; gynecomastia; menstrual disorder; menstruation delayed; menstruation irregular; sexual dysfunction; priapism, urinary incontinence, urinary retention (postmarketing).

Lab Tests

Oral

ALT increased, AST increased (less than 2%).

Injection

ALT increased (2%); abnormal ECG, increased blood glucose, increased cholesterol, increased triglycerides.

Metabolic-Nutritional

Oral

Weight gain (7%); edema (less than 2%).

Injection

Weight gain (4%); hyperglycemia, hyperinsulinemia.

Musculoskeletal

Oral

Myalgia (4%); back pain (3%) pain in extremity (less than 2%).

Injection

Back pain, pain in extremity (3%); musculoskeletal stiffness, myalgia (2%); joint stiffness, muscle rigidity, muscle spasms, muscle tightness, muscle twitching, nuchal rigidity.

Respiratory

Oral

Nasopharyngitis (5%); cough, rhinitis (3%); pharyngolaryngeal pain, upper respiratory tract infection (2%); nasal congestion (less than 2%).

Injection

Nasopharyngitis, upper respiratory tract infection (4%); cough (3%).

Miscellaneous

Oral

Anaphylactic reaction (less than 2%); angioedema (postmarketing).

Injection

Hyperprolactinemia; angioedema (postmarketing).

Precautions

Warnings

Increased mortality

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death compared with those taking placebo. Although the causes of death were varied, most of the deaths appeared to be either CV (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature. Paliperidone is not approved for the treatment of dementia-related psychosis.


Monitor

Consider monitoring renal function in elderly patients. Monitor CBC during the first few months of therapy in patients with a history of clinically significant low WBC or drug-induced leukopenia/neutropenia. Monitor diabetic patients regularly for worsening of glucose control and for symptoms of hyperglycemia, including polydipsia, polyuria, polyphagia, and weakness. Ensure that patients with risk factors for diabetes mellitus (eg, obesity, family history of diabetes) who are starting atypical antipsychotic therapy undergo fasting blood glucose testing at the beginning of treatment and periodically thereafter. Monitor orthostatic vital signs in patients who are vulnerable to hypotension. Periodically reassess patients to determine the need for continued treatment. Suicide attempt is inherent in psychotic illnesses; closely monitor high-risk patients during drug therapy. If a patient requires paliperidone treatment after recovery from NMS, carefully monitor the patient because recurrences of NMS have been reported.


Pregnancy

Category C . Neonates exposed to antipsychotics during the third trimester of pregnancy are at risk of extrapyramidal and/or withdrawal symptoms.

Lactation

Excreted in breast milk. Breast-feeding women should not breast-feed when receiving paliperidone injection.

Children

Oral

Safety and efficacy in the treatment of schizophrenia not established in patients younger than 12 y. Safety and efficacy not established in the treatment of schizoaffective disorder.

Injection

Safety and efficacy not established.

Elderly

Adjust dose according to renal function.

Hypersensitivity

Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been observed.

Renal Function

Individualize the oral dose according the patient's renal function status. Dosage adjustment is recommended for the injection doseform when used in patients with mild renal impairment; paliperidone injection is not recommended for patients with moderate or severe renal impairment.

Special Risk Patients

Patients with Parkinson disease or dementia with Lewy bodies may have increased sensitivity to paliperidone, which may manifest as confusion, extrapyramidal symptoms, NMS, obtundation, or postural instability with frequent falls.

Antiemetic effect

Because paliperidone may have an antiemetic effect, signs and symptoms of overdosage with certain drugs or conditions (eg, brain tumor, intestinal obstruction) may be masked.

Body temperature regulation

Antipsychotics disrupt the ability to reduce core body temperature. Use with caution in patients who will experience conditions that may contribute to an elevation in core body temperature (eg, concomitant anticholinergic therapy, dehydration, exposure to extreme heat, strenuous exercise).

Cerebrovascular events

Cerebrovascular events (eg, stroke, transient ischemic attack), including fatalities, have been seen in elderly patients with dementia-related psychoses. Use with caution.

Cognitive and motor performance

Judgment, thinking, or motor skills may be impaired.

CV

Because QTc prolongation may occur, avoid use in patients receiving other drugs that prolong the QTc interval and in patients with congenital long QT syndrome or history of cardiac arrhythmias. Use with caution in patients with known CV disease (eg, heart failure, history of MI).

Dysphagia

Antipsychotics have been associated with esophageal dysmotility and aspiration. Use with caution in patients at risk of aspiration pneumonia.

GI

Because tablet does not change shape in the GI tract, do not administer paliperidone to patients with preexisting severe GI narrowing (eg, cystic fibrosis).

Hematologic effects

Leukopenia, neutropenia, and agranulocytosis have been reported.

Hyperglycemia and diabetes mellitus

Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported.

Hyperprolactinemia

Prolactin levels may be elevated.

NMS

Has occurred and is potentially fatal. Signs and symptoms include altered mental status, diaphoresis, hyperpyrexia, irregular BP, irregular pulse, muscle rigidity, and tachycardia.

Orthostatic hypotension

Orthostatic hypotension associated with bradycardia, dizziness, syncope, and tachycardia may occur. Use with caution in patients with cerebrovascular disease, CV disease (eg, heart failure), or conditions that predispose the patient to hypotension (eg, dehydration, hypovolemia).

Priapism

May occur; severe priapism may require surgical intervention.

Seizures

May occur; use with caution in patients with a history of seizures or other conditions that potentially lower the seizure threshold.

Suicide

Possible suicide attempts are inherent in psychotic illnesses. Supervise high-risk patients. Prescribe lowest quantity consistent with good patient management in order to reduce risk of overdose.

Tardive dyskinesia

Syndrome of potentially irreversible, involuntary dyskinetic movements may develop. Prevalence is higher in elderly patients, especially women. Use lowest effective dose for shortest period of time needed.

Weight gain

May occur.

Overdosage

Symptoms

Drowsiness, extrapyramidal symptoms, hypotension, QT prolongation, sedation, tachycardia, torsades de pointes, unsteady gait, ventricular fibrillation.

Patient Information

  • Advise patient that drug may cause drowsiness or impaired judgment or thinking skills, and to use caution while driving, riding a bike, or performing other tasks requiring mental alertness until tolerance is determined.
  • Advise patient to get up slowly from a lying or sitting position and to avoid sudden position changes to prevent postural hypotension.
  • Advise patient to avoid alcohol while taking paliperidone.
  • Advise patient to avoid strenuous activity during periods of high temperature or humidity and to avoid overheating and dehydration.
  • Advise patient to swallow tablet whole, and not to divide, chew, or crush.
  • Advise patients that the tablet shell may be eliminated through the stool.
  • Advise patients not to breast-feed during therapy.
  • Advise patients to notify their health care provider if they become pregnant or intend to become pregnant during treatment.

Copyright © 2009 Wolters Kluwer Health.

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