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Paliperidone

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

Trade Names:
Invega
- Tablets, ER 1.5 mg
- Tablets, ER 3 mg
- Tablets, ER 6 mg
- Tablets, ER 9 mg

Trade Names:
Invega Sustenna
- Injection, suspension, ER 39 mg
- Injection, suspension, ER 78 mg
- Injection, suspension, ER 117 mg
- Injection, suspension, ER 156 mg
- Injection, suspension, ER 234 mg

Pharmacology

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Antipsychotic effects, possibly due to dopamine and serotonin receptor blockade in the CNS.

Pharmacokinetics

Absorption

Dose-related pharmacokinetics. Bioavailability is approximately 28%. C _max occurs approximately 24 h after dosing. Steady-state concentrations are reached within 4 to 5 days. Mean steady-state peak: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:trough ratio was 1.8 (gluteal administration) and 2.2 (deltoid administration).

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 recovered as metabolites. The mean apparent half-life following an IM single 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 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; acute 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 in the morning. Some patients may benefit from dosages of 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 in the morning. Some patients may benefit from dosages of 3 to 12 mg/day. Dosage increases above 6 mg/day should be made only after reassessment and 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 week 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.

Missed doses Adults

IM To avoid a missed dose, give the second dose 2 days before or after the 1-week time point. Similarly, the third and subsequent injections after the initiation regimen are recommended to be given monthly. To avoid a missed monthly dose, patients may be given the injection up to 7 days before or after the monthly time point.

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.

Renal Function Impairment

PO For mild impairment (CrCl 50 to 80 mL/min), recommended initial dosage is 3 mg/day orally, not to exceed 6 mg orally once daily. For moderate to severe impairment (CrCl 10 to less than 50 mL/min), recommended initial dosage is 1.5 mg/day orally, not to exceed 3 mg orally 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. Follow with monthly injections of 78 mg 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.

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, cisapride, class IA antiarrhythmic agents [eg, procainamide, quinidine], class III antiarrhythmic agents [eg, amiodarone, dofetilide, sotalol], macrolide antibiotics [eg, erythromycin], methadone, perflutren, tetrabenazine, tyrosine kinase receptor antagonists [eg, lapatinib])

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

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.

Laboratory Test Interactions

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.

Pregnancy

Category C .

Lactation

Excreted in breast milk.

Children

Safety and efficacy not established.

Elderly

Take care in dose selection.

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, or obtundation.

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 adverse reactions (eg, stroke, transient ischemic attack), including fatalities, may occur. Use with caution.

CV

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

Dysphagia

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 effect

Leukopenia, neutropenia, and agranulocytosis have been reported.

Hyperglycemia

Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, may occur.

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.

Suicide

Supervise depressed patients at risk during initial therapy. 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, unsteady gait.

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.