paliperidone (Rx)

>10%

Akathisia

Somnolence

Insomnia

Parkinsonism

Tachycardia

Hyperprolactinemia

Others similar to placebo (eg, headache)

<10% (selected)

Cough

Dystonia

Extrapyramidal symptoms (EPS)

Orthostatic hypotension

QT prolongation

Sialorrhea

Priapism

Weight gain

Constipation

Indigestion

Amenorrhea

Galactorrhea

Nausea

Dyspepsia

Salivation

Xerostomia

Myalgia

Extremity pain

Nasopharyngitis

Postmarketing Reports

Angioedema, swollen tongue

Ileus

Thrombotic thrombocytopenic purpura

Urinary incontinence, urinary retention

Falls

Contraindications

Documented hypersensitivity to paliperidone or risperidone

Cautions

Avoid use in severe preexisting GI stenosis

Use caution when prescribing to patients who will be experiencing conditions which may contribute to elevation in core body temperature, eg, exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration

Rare cases of priapism reported

Rare cases of intraoperative floppy iris syndrome reported with risperidone in patients undergoing cataract surgery; paliperidone is active metabolite of risperidone; use caution; benefits or risks of interrupting paliperidone or risperidone use prior to cataract surgery not established

Hyperprolactinemia occurs and persists during long-term administration

Prolongs QT interval modestly; avoid use with drugs that also increase QT interval and in patients with risk factors for prolonged QT interval

Potential risk of neuroleptic malignant syndrome (NMS); manage with immediate discontinuation of drug and close monitoring

Risk of orthostatic hypotension; use with caution in patients with known cardiovascular or cerebrovascular disease and patients predisposed to hypotension

Increased incidence of cerebrovascular adverse reactions (e.g. stroke, transient ischemic attack, including fatalities) reported

Use cautiously in patients with a history of seizures or with conditions that lower the seizure threshold

Patients with Parkinson disease may be more sensitive to CNS and extrapyramidal effects

May mask toxicity of other drugs or conditions (eg, intestinal obstruction) due to antiemetic effects

FDA warning regarding off-label use for dementia in elderly

Leukopenia/neutropenia and agranulocytosis reported; possible risk factors for leukopenia/neutropenia include preexisting low white blood cell (WBC) count and history of drug-induced leukopenia/neutropenia

Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur

If history of clinically significant low WBC count or drug-induced leukopenia/neutropenia, monitor complete blood count (CBC) frequently during first few months of therapy; discontinue drug at first sign of clinically significant WBC decline <1000/μL in absence of other causative factors, and continue monitoring WBC until recovery

May cause CNS depression (somnolence, sedation, dizziness), which may impair abilities to perform tasks requiring mental alertness, including operating heavy machinery

Motor instability, somnolence, and orthostatic hypotension reported, which may lead to falls and, consequently, fractures or other fall-related injuries; assess risk of falls when initiating treatment and recurrently for patients receiving repeated doses, particularly the elderly, with diseases, conditions, or medications that could exacerbate these effects

Antipsychotic use has been associated with esophageal dysmotility and aspiration; use with caution in patients at risk of aspiration pneumonia; not for use in patients unable to swallow the tablet whole

Use caution in patients with history of suicidal ideation or any form of psychotic illnes; may increase risk of suicide attempt

Tardive dyskinesia

• Risk of developing tardive dyskinesia and likelihood that it will become irreversible appears to increase with duration of treatment and cumulative dose; the syndrome can develop after relatively brief treatment periods, even at low doses; it may also occur after discontinuation of treatment
• Tardive dyskinesia may remit, partially or completely, if antipsychotic treatment withdrawn; antipsychotic treatment, itself, however, may suppress (or partially suppress) signs and symptoms of the syndrome and thereby possibly mask underlying process; effect that symptomatic suppression has upon long-term course of syndrome is unknown
• Prescribed drug in a manner that is most likely to minimize occurrence of tardive dyskinesia; chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness known to respond to antipsychotic drugs, and for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate
• In patients who require chronic treatment, use lowest dose and the shortest duration of treatment producing a satisfactory clinical response; periodically reassess need for continued treatment

Metabolic changes

• Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular or cerebrovascular risk (eg, hyperglycemia, dyslipidemia, hyperprolactinemia, body weight gain)
• In some cases, hyperglycemia concomitant with use of atypical antipsychotics has been associated with ketoacidosis, hyperosmolar coma, or death

Pregnancy

There are no adequate and well controlled studies in pregnant women; use of first generation antipsychotic drugs during last trimester of pregnancy associated with extrapyramidal symptoms in neonate; symptoms are usually self-limited; not known whether paliperidone, when taken near end of pregnancy, will lead to similar neonatal signs and symptoms; in animal reproduction studies, there were no increases in fetal abnormalities when pregnant rats and rabbits were treated during the period of organogenesis with up to 8 times the maximum recommended human dose of paliperidone (on a mg/m² basis); in rat reproduction studies with risperidone, which is extensively converted to paliperidone in rats and humans, there were increases in pup deaths seen at oral doses which are less than maximum recommended human dose of risperidone on a mg/m² basis

Infertility

• Based on pharmacologic action of paliperidone (D2 receptor antagonism), treatment may result in an increase in serum prolactin levels, which may lead to a reversible reduction in fertility in females of reproductive potential

Lactation

Limited data from published literature report presence of paliperidone in human breast milk; there is no information on effects on breastfed infant, or on milk production; however, there are reports of sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements) in breastfed infants exposed to paliperidone’s parent compound, risperidone; consider developmental and health benefits of breastfeeding along with mother’s clinical need for therapy and any potential adverse effects on breastfed child from drug or from mother’s underlying condition

Infants exposed to treatment through breastmilk should be monitored for excess sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements)

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Major metabolite of risperidone; improves negative symptoms of psychoses and reduces incidence of EPS

Has high affinity for serotonin type 2 (5-HT2) receptors; binds to dopamine D2 receptors with 20 times lower affinity than that for 5-HT2 receptors; antagonizes alpha1-adrenergic, alpha2-adrenergic, and histaminergic receptors; has moderate affinity for serotonin type 1 (5-HT1C, 5-HT1D, 5-HT1A) receptors; has weak affinity for dopamine D1 receptors; has no affinity for muscarinic, beta1-adrenergic, and beta2-adrenergic receptors

Absorption

Bioavailability: 28%

Peak plasma time: PO, 24 hr; IM, 13 days

Distribution

Protein bound: 74%

Vd: 390-487 L

Metabolism

Metabolized by CYP2D6 and CYP3A4

Elimination

Half-life: PO, 23 hr; IM, 25-49 days

Excretion: Urine (80%), feces (11%)

Oral administration

May be taken with or without food

Swallow tablet whole with liquids; do not chew, crush or divide

The tablet shell, along with insoluble core components, is eliminated from the body; patients should not be concerned if they occasionally notice in their stool, something that looks like a tablet

IM administration

Each IM injection must be administered only by a healthcare professional

Prior to administration, shake the prefilled syringe vigorously for at least 15 seconds within 5 minutes prior to administration to ensure a homogeneous suspension

Once monthly IM injection

• Before initiating once monthly IM therapy, establish PO tolerability with paliperidone or risperidone
• First 2 doses are injected into deltoid; maintenance doses may be injected into either deltoid or gluteal muscle

Every 3-months IM administration

• Before initiating q3mo IM therapy, establish tolerability with once-monthly paliperidone for at least 4 months
• Initiate Invega Trinza when the next 1-month paliperidone dose is scheduled with an Invega Trinza dose based on the previous 1-month injection dose (see Adult Dosing)

Needle length and gauge

• Deltoid injection: If patient ≥90 kg, use 1.5-in. 22-gauge needle; if patient <90 kg, use 1-in. 23-gauge needle
• Gluteal injection: Use 1.5-in. 22-gauge needle regardless of patient weight

Missed Doses

Invega Sustenna

• Second dose

  • To avoid a missed dose, patients may be given the second dose 4 days before or after the one-week time point
  • <4 wk since first injection: Administer second initiation dose of 156 mg IM in deltoid muscle as soon as possible, then administer a third injection of 117 mg IM (deltoid or gluteal) 5 weeks afterwards; thereafter resume regular monthly dosing
  • 4-7 wk since first injection: Resume dose with 2 injections of 156 mg IM in deltoid muscle 1 week apart; thereafter, resume regular monthly dosing
  • >7 wk since first injection: Restart with recommended initiation (see Adult Dosing)

• Third and subsequent doses

  • To avoid a missed dose, patients may be give the injection 7 days before or after the monthly time point
  • 4-6 wk since last injection: Resume regular monthly dosing as soon as possible at previous stabilized dose; followed in monthly injections
  • >6 wk to 6 months since last injection: Resume same dose as previously stabilized, unless stabilized on 234 mg/month, then the first 2 injections should each be 156 mg given 1 wk apart; thereafter, resume previously stabilized dose 1 month later
  • >6 months since last injection: Administer 234 mg IM in deltoid on Day 1, then 156 mg IM in deltoid on Day 8; thereafter, resume administration 1 month after Day 8 at the previously stabilized dose (deltoid or gluteal)

Invega Trinza

• If necessary, patients may be given the injection up to 2 weeks before or after the 3-month time point
• Missed dose >9 months since last injection: Must reinitiate with the 1-month paliperidone as previously described (see Adult Dosing)
• Missed dose 3.5-4 months since last injection: Administer the patient’s regular dose as soon as possible, then continue with the 3-month injection following this dose
• Missed dose 4-9 months since last injection: Do not administer the next dose, instead use reinitiation schedule

• Reinitiation schedule based on last dose of Invega Trinza

  • Administer Invega Sustenna, 2 doses given 1 week apart into deltoid muscle (ie, Day 1 and Day 8), then administer Invega Trinza 1 month after Day 8 (in deltoid or gluteal muscle)
  • Last dose 273 mg: Invega Sustenna 78 mg IM on Days 1 and 8, then Invega Trinza 273 mg IM 1 month after Day 8
  • Last dose 410 mg: Invega Sustenna 117 mg IM on Days 1 and 8, then Invega Trinza 410 mg IM 1 month after Day 8
  • Last dose 546 mg: Invega Sustenna 156 mg IM on Days 1 and 8, then Invega Trinza 546 mg IM 1 month after Day 8
  • Last dose 819 mg: Invega Sustenna 156 mg IM on Days 1 and 8, then Invega Trinza 819 mg IM 1 month after Day 8

Storage

IM: Store at room temperature 20-25°C (68-77°F); excursions between 15-30°C (59-86°F) are permitted