Paliperidone Er (paliperidone)
Last reviewed · Source: First Databank (FDB) drug data
Overview
Paliperidone and paliperidone palmitate are atypical antipsychotic agents.
Paliperidone is a benzisoxazole-derivative antipsychotic agent that differs chemically from other currently available first-generation (typical) antipsychotic agents (e.g., butyrophenones, phenothiazines) and has been referred to as an atypical or second-generation antipsychotic agent. Paliperidone is the major active metabolite of risperidone, another atypical antipsychotic agent. Paliperidone palmitate is a prodrug of paliperidone and is hydrolyzed to its active ingredient, paliperidone, following administration.
The exact mechanism of paliperidone's antipsychotic action, like that of other antipsychotic agents, has not been fully elucidated, but may involve antagonism of central dopamine type 2 (D2) and serotonin type 2 (5-hydroxytryptamine (5-HT2A)) receptors. Antagonism at alpha1- and alpha2-adrenergic and histamine (H1) receptors may contribute to other therapeutic and adverse effects observed with the drug. Paliperidone possesses no affinity for cholinergic muscarinic and beta1- and beta2-adrenergic receptors.
After oral administration of a single-dose, administered as extended-release tablets, paliperidone levels in plasma peak around 24 hours. Its pharmacokinetics are dose-proportional across the approved range, with a terminal half-life of about 23 hours. Steady-state levels are typically achieved within 4-5 days, with a peak-to-trough ratio of 1.7 (range, 1.2-3.1) for a 9 mg dose.
Paliperidone's oral bioavailability is 28%. A high-fat meal increases Cmax and AUC by 60% and 54%, respectively, compared to fasting. The drug is 74% protein-bound.
Approximately 80% and 11% of a single 1-mg oral dose of radiolabeled, immediate-release paliperidone is recovered in urine and feces, respectively, within 1 week. About 59% of the administered dose is recovered as unchanged drug in urine and 32% is recovered as metabolites.
For one-month paliperidone palmitate extended-release IM suspension formulations (Invega Sustenna(R)) after a single injection, plasma levels rise gradually, peaking around day 13, with drug release beginning on day 1 and continuing up to 126 days. Injecting into the deltoid muscle yields about 28% higher peak concentrations than the gluteal site. Initial loading doses (234 mg on day 1 and 156 mg on day 8, both deltoid) rapidly achieve therapeutic levels.
The drug shows sustained exposure, with AUC values proportional to dose (39-234 mg), though peak concentrations increase less than proportionally above 78 mg. Steady-state peak-to-trough ratios are 1.8 for gluteal and 2.2 for deltoid administration at 156 mg. The plasma protein binding of racemic paliperidone is 74%.
The median apparent half-life of paliperidone after a single Invega Sustenna(R) dose (39-234 mg) ranges from 25-49 days. Overall, initial plasma concentrations achieved with Invega Sustenna(R) fall within the exposure range of 6-12 mg oral extended-release paliperidone.
For one-month paliperidone palmitate extended-release IM suspension formulations (Erzofri(R)), after a single injection, paliperidone levels peak between 16 and 28 days, with drug release beginning on day 1 and lasting up to 176 days. For Erzofri(R), steady-state plasma levels are achieved within 7 days of the initial injection. In patients receiving multiple injections (351 mg on day 1, followed by 156 mg every 28 days for five more doses), average plasma concentrations were around 30.3 ng/mL during initiation, stabilizing at 42.6 ng/mL (Cmax), 28.3 ng/mL (Ctrough), and 909 ng*hr/mL (AUC) at steady state.
Deltoid injections produced higher peak concentrations than gluteal injections (43% higher for 156 mg and 21% higher for 351 mg). Despite these differences, overall drug exposure (AUC) between injection sites was similar across the 39-234 mg dose range. The plasma protein binding of racemic paliperidone is 74%.
The median apparent half-life following Erzofri(R) single-dose administration at 156 mg is approximately 27 days.
For every-3-month paliperidone palmitate extended-release IM suspension (Invega Trinza(R)), after a single IM dose, peak plasma concentrations are reached between days 30 and 33. Invega Trinza(R) begins releasing paliperidone as early as day 1 and continues for up to 18 months. Deltoid injections produce 11-12% higher peak levels compared to gluteal injections.
The formulation maintains therapeutic drug levels over a 3-month period, with dose-proportional total and peak exposure across the 273-819 mg range. At steady state, the peak-to-trough ratio averages 1.6 for gluteal and 1.7 for deltoid administration. The plasma protein binding of racemic paliperidone is 74%.
The median half-life ranges from 84-95 days (deltoid) to 118-139 days (gluteal). Residual drug levels at 18 months post-dose are estimated at 3% (deltoid) and 7% (gluteal) of steady-state levels. Doses of Invega Trinza(R) that are 3.5 times higher than monthly paliperidone doses yield paliperidone exposures that are comparable to once-monthly formulations and extended-release oral tablets.
The pharmacokinetics for every-6-month paliperidone palmitate extended-release IM suspension (Invega Hafyera(R)) that are described are based on gluteal administration only. Invega Hafyera(R) begins releasing the drug on day 1 and sustains exposure for over 18 months. Administered in doses of 1,092 mg or 1,560 mg via gluteal injection, peak plasma levels are reached between days 29 and 32.
These doses provide total drug exposure within the range of equivalent once monthly or every-3-month doses of paliperidone palmitate, or daily extended-release oral paliperidone. However, trough levels are 20-25% lower, while peak concentrations are 1.4-1.5 times higher compared to every-3-month formulations. The median half-life is 148 days for 1,092 mg and 159 days for 1,560 mg.
At 18 months post-dose, about 18% of steady-state paliperidone remains in circulation. The plasma protein binding of racemic paliperidone is 74%. Exposure is consistent across the 2 dose levels, with a steady-state peak-to-trough ratio of around 3.0-3.1, indicating sustained plasma concentrations over the 6-month dosing interval.
Paliperidone extended release tablets (Invega(R)) are used for the treatment of schizophrenia in adults and adolescents 12-17 years of age and treatment of schizoaffective disorder as monotherapy or as an adjunct to mood stabilizers and/or antidepressants in adults.
Generic name: paliperidone
Pronunciation: (PAL-ee-PER-i-done)
Reference product & biosimilars
No reference, biosimilar or interchangeable associated with this drug.
Today’s intelligence on Paliperidone Er
Indications
The following indications are listed for Paliperidone Er:
- Schizoaffective Disorder
- Schizophrenia
Also known as: Dementia Praecox, Parergasia.
Dosing
For patients naive to oral paliperidone or oral or injectable risperidone, tolerability with oral paliperidone or oral risperidone should be established prior to initiating treatment with paliperidone palmitate extended-release IM suspension formulations (Invega Sustenna(R); Erzofri(R)).
Paliperidone palmitate extended-release IM suspension (Invega Trinza(R)) should be initiated only after a patient has been stabilized on the once-monthly paliperidone palmitate extended-release injectable suspension for a minimum of 4 months.
Paliperidone palmitate extended-release IM suspension (Invega Hafyera(R)) should be initiated in patients who have been appropriately stabilized with either: a once-monthly paliperidone palmitate extended-release injection (for a minimum of 4 months), or an every-3-month paliperidone palmitate extended-release injection (for at least one 3-month dosing cycle).
Paliperidone is administered orally. Paliperidone palmitate is administered only by IM injection.
No dosing information is available for this tab.
No dosing information is available for this tab.
Drug interactions
Since paliperidone palmitate is hydrolyzed to paliperidone, results from studies with oral paliperidone should be taken into consideration when assessing drug-drug interaction potential.
There are no contraindication interactions for this drug.
There are no severe interactions for this drug.
There are no moderate interactions for this drug.
Contraindications
*Known hypersensitivity to paliperidone, risperidone, or any ingredient in the paliperidone or paliperidone palmitate formulations.
There are no contraindication contraindications for this drug.
There are no severe contraindications for this drug.
There are no moderate contraindications for this drug.
Adverse reactions
Adverse effects reported in 5% or more of adults receiving oral paliperidone for schizophrenia and at a frequency at least twice that reported with placebo include extrapyramidal symptoms, tachycardia, and akathisia.
Adverse effects reported in 5% or more of adolescents receiving oral paliperidone for schizophrenia and at a frequency at least twice that reported with placebo include somnolence, extrapyramidal symptoms (e.g., akathisia, tremor, dystonia, cogwheel rigidity), anxiety, increased weight, and tachycardia.
Adverse effects reported in 5% or more of adults receiving oral paliperidone for schizoaffective disorder and at a frequency at least twice that reported with placebo include extrapyramidal symptoms, somnolence, dyspepsia, constipation, increased weight, and nasopharyngitis.
Adverse effects reported in 5% or more of adults receiving a monthly IM formulation of paliperidone palmitate (Invega Sustenna(R); Erzofri(R)) at a frequency at least twice that reported with placebo include injection site reactions, somnolence/sedation, dizziness, akathisia, and extrapyramidal disorder.
Adverse effects reported in 5% or more of adults receiving IM paliperidone palmitate dosed every 3 months (Invega Trinza(R)) at a frequency at least twice that reported with placebo include injection site reaction, increased weight, headache, upper respiratory tract infection, akathisia, and parkinsonism.
The most common adverse effects reported in adults receiving IM paliperidone palmitate dosed every 6 months (Invega Hafyera(R)) include upper respiratory tract infection, injection site reaction, increased weight, headache, and parkinsonism.
There are no severe adverse reactions for this drug.
There are no less severe adverse reactions for this drug.
Precautions
No enhanced messaging available.
Safety and efficacy of oral paliperidone in the treatment of schizophrenia in adolescents 12-17 years of age have been established in a double-blind, placebo-controlled study of 6 weeks' duration.
Safety and efficacy of oral paliperidone in the treatment of schizophrenia have not been established in pediatric patients younger than 12 years of age.
Safety and efficacy of oral paliperidone in the treatment of schizoaffective disorder have not been established in pediatric patients younger than 18 years of age.
The safety and efficacy of IM formulations of paliperidone palmitate have not been established in pediatric patients <18 years of age.
The manufacturer states that the long-term effects of paliperidone on growth and sexual maturation have not been fully evaluated in children and adolescents.
A pregnancy exposure registry is available to track outcomes in women who are exposed to atypical antipsychotics, such as paliperidone, during pregnancy. Healthcare providers are encouraged to enroll patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 866-961-2388 or online at https://womensmentalhealth.org/research/pregnancyregistry/.
Overall, data from published epidemiological studies involving pregnant women exposed to paliperidone have not shown a clear link between the drug and an increased risk of major birth defects, miscarriage, or negative outcomes for the mother or fetus. However, both untreated schizophrenia and the use of antipsychotics like paliperidone during pregnancy carry potential risks for the mother.
Neonates exposed to antipsychotic agents during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. Symptoms reported to date have included agitation, hypertonia, hypotonia, tardive dyskinetic-like symptoms, tremor, somnolence, respiratory distress, and feeding disorder. Neonates exhibiting such symptoms should be monitored. The complications have varied in severity; some neonates recovered within hours to days without specific treatment while others have required intensive care unit support and prolonged hospitalization.
Limited published data indicate that paliperidone can pass into human breast milk, though its effects on nursing infants and milk production are unknown. However, exposure to risperidone (paliperidone's parent compound) has been linked to sedation, poor weight gain, jitteriness, and movement disorders in breast-fed infants. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for paliperidone and any potential adverse effects on the breast-fed child from paliperidone or the mother's underlying condition. Infants exposed to paliperidone through breastmilk should be monitored for sedation, failure to thrive, jitteriness, and abnormal movements.
The manufacturers of paliperidone and paliperidone palmitate make no specific dosage recommendations for geriatric patients.
Because geriatric patients may have reduced renal function, dosage adjustment for oral paliperidone may be required based on renal function status. Geriatric patients with normal renal function generally may receive the same dosage recommended for younger adults with normal renal function. In geriatric patients with moderate or severe renal impairment, (creatinine clearance 10-49 mL/min), the maximum recommended paliperidone dosage is 3 mg once daily.
Lower doses for paliperidone palmitate IM formulations (Invega Sustenna(R); Erzofri(R); Invega Trinza(R)) are recommended in patients with impaired renal function; since older adults are more likely to have reduced kidney function, dosing should be adjusted accordingly based on renal status. Invega Hafyera(R) is not recommended to be used in elderly patients with mild, moderate or severe renal impairment.
In clinical studies of oral paliperidone, approximately 7% of nearly 1800 patients were 65 years of age or older. In addition, the short-term efficacy and safety of paliperidone have been demonstrated in a placebo-controlled trial of 6 weeks' duration in 114 geriatric patients with schizophrenia. While no substantial differences in efficacy or safety relative to younger adults were observed in these studies or in other clinical experience with the drug, increased sensitivity cannot be ruled out.
Clinical trials for paliperidone palmitate IM formulations (Invega Sustenna(R); Erzofri(R); Invega Trinza(R); Invega Hafyera(R)) included too few participants aged 65 and older to assess whether their response differs from that of younger individuals.
Because geriatric patients may have reduced renal function, oral paliperidone dosage adjustment may be required based on renal function status; consider monitoring renal function. Lower doses for paliperidone palmitate IM formulations (Invega Sustenna(R); Erzofri(R); Invega Trinza(R)) in patients with impaired renal function are recommended; since older adults are more likely to have reduced kidney function, dosing should be adjusted accordingly based on renal status. Invega Hafyera(R) use is not recommended to be used in elderly patients with mild, moderate, or severe renal impairment.
ICD codes
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Last reviewed · Source: First Databank (FDB) drug data
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