INVEGA

Clinical safety rating: caution

Comprehensive clinical and safety monograph for INVEGA (INVEGA).

How it works

Paliperidone is the major active metabolite of risperidone. It is a benzisoxazole derivative antipsychotic with high affinity for serotonin 5-HT2A and dopamine D2 receptors. It also acts as an antagonist at α1 and α2 adrenergic receptors and H1 histaminergic receptors. It has no affinity for muscarinic receptors.

What the body does with it

Metabolism	Paliperidone is primarily metabolized via N-dealkylation and monohydroxylation, with minor contributions from CYP2D6 and CYP3A4. It is a substrate for P-glycoprotein (P-gp). Approximately 59% of the dose is excreted unchanged in urine, indicating that renal excretion is a major route of elimination.
Excretion	Primarily renal: 59-80% of dose excreted unchanged in urine (as parent drug and metabolites). Fecal: ~20-30%. Biliary elimination is minimal.
Half-life	Terminal elimination half-life is approximately 23-29 hours for oral administration (paliperidone extended-release). Once-daily dosing achieves steady-state within 4-5 days.
Protein binding	Paliperidone is 74% bound to plasma proteins, primarily to albumin and alpha-1-acid glycoprotein.
Volume of Distribution	Volume of distribution is 0.7 L/kg (range 0.5-1.0 L/kg), indicating moderate tissue distribution.
Bioavailability	Oral (extended-release): Absolute bioavailability is 28% due to first-pass metabolism. The extended-release formulation provides a smooth plasma concentration profile.
Onset of Action	Oral: Therapeutic effects may be observed within 1-2 weeks of initiation, but full response may take several weeks. No immediate-release IV/IM formulation.
Duration of Action	Oral (extended-release): Duration of action is approximately 24 hours with once-daily dosing. Continuous coverage is maintained with regular administration.

Classification & Brands

Dosing & administration

Oral: 6 mg once daily; may increase to 9 mg/day if needed. IM (extended-release): 234 mg on day 1, 156 mg on day 8, then 117 mg monthly; adjust within range 39-234 mg per month.

Dosage form	TABLET, EXTENDED RELEASE
Renal impairment	CrCl >=50 mL/min: no adjustment. CrCl 10-49 mL/min: oral max 3 mg daily; IM initial 156 mg on day 1, 78 mg on day 8, then 39-78 mg monthly. CrCl <10 mL/min: not recommended.
Liver impairment	Mild to moderate hepatic impairment (Child-Pugh A or B): no adjustment. Severe hepatic impairment (Child-Pugh C): not studied.
Pediatric use	Adolescents (12-17 years, weight >=51 kg): oral 3 mg once daily; can increase to 6 mg/day after 5 days, then max 12 mg/day. For IM, safety in adolescents not established.
Geriatric use	Initiate oral at 3 mg once daily; may increase to 6 mg/day after 5 days. For IM, start with 156 mg on day 1, 78 mg on day 8, then 39-78 mg monthly. Use lowest effective dose due to increased sensitivity.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for INVEGA (INVEGA).

Breastfeeding	Paliperidone is excreted in human breast milk. The milk-to-plasma ratio is unknown. In a study of 7 women, paliperidone was detected in milk (range 4.0-8.9 ng/mL), with relative infant dose estimated at <5% of maternal weight-adjusted dose. Caution: monitor infant for sedation, poor feeding, and extrapyramidal signs.
Teratogenic Risk	Paliperidone (INVEGA) is not teratogenic in animal studies at doses up to 2 times the human therapeutic dose. No adequate well-controlled studies in pregnant women. Third trimester exposure to antipsychotics may cause extrapyramidal symptoms or withdrawal in neonates. Use only if benefit outweighs risk; register patient in Atypical Antipsychotics Pregnancy Registry (1-866-961-2388).

Warnings & precautions

■ FDA Black Box Warning

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. INVEGA is not approved for the treatment of patients with dementia-related psychosis.

Side Effect Profile

Serious Effects

Absolute Contraindications

["Known hypersensitivity to paliperidone or risperidone","Patients taking strong CYP3A4 inducers or inhibitors (relative contraindication, may require dose adjustment)"]

Clinical Precautions

Precautions

["Increased mortality in elderly patients with dementia-related psychosis","Cerebrovascular adverse events (including stroke) in elderly patients with dementia","Neuroleptic malignant syndrome (NMS)","Tardive dyskinesia","Metabolic changes (hyperglycemia, diabetes, dyslipidemia, weight gain)","Hyperprolactinemia","Orthostatic hypotension and syncope","Leukopenia, neutropenia, and agranulocytosis","QT prolongation","Seizures","Potential for cognitive and motor impairment","Dysphagia","Priapism","Body temperature regulation disruption","Antiemetic effect","Suicide risk","Use in pregnancy: Neonatal extrapyramidal symptoms and withdrawal"]

Clinical Tips & Counseling

Drug interactions

Loading safety data…

INVEGA

Clinical safety rating: caution

Comprehensive clinical and safety monograph for INVEGA (INVEGA).

How it works

What the body does with it

Metabolism	Paliperidone is primarily metabolized via N-dealkylation and monohydroxylation, with minor contributions from CYP2D6 and CYP3A4. It is a substrate for P-glycoprotein (P-gp). Approximately 59% of the dose is excreted unchanged in urine, indicating that renal excretion is a major route of elimination.
Excretion	Primarily renal: 59-80% of dose excreted unchanged in urine (as parent drug and metabolites). Fecal: ~20-30%. Biliary elimination is minimal.
Half-life	Terminal elimination half-life is approximately 23-29 hours for oral administration (paliperidone extended-release). Once-daily dosing achieves steady-state within 4-5 days.
Protein binding	Paliperidone is 74% bound to plasma proteins, primarily to albumin and alpha-1-acid glycoprotein.
Volume of Distribution	Volume of distribution is 0.7 L/kg (range 0.5-1.0 L/kg), indicating moderate tissue distribution.
Bioavailability	Oral (extended-release): Absolute bioavailability is 28% due to first-pass metabolism. The extended-release formulation provides a smooth plasma concentration profile.
Onset of Action	Oral: Therapeutic effects may be observed within 1-2 weeks of initiation, but full response may take several weeks. No immediate-release IV/IM formulation.
Duration of Action	Oral (extended-release): Duration of action is approximately 24 hours with once-daily dosing. Continuous coverage is maintained with regular administration.

Classification & Brands

Dosing & administration

Oral: 6 mg once daily; may increase to 9 mg/day if needed. IM (extended-release): 234 mg on day 1, 156 mg on day 8, then 117 mg monthly; adjust within range 39-234 mg per month.

Dosage form	TABLET, EXTENDED RELEASE
Renal impairment	CrCl >=50 mL/min: no adjustment. CrCl 10-49 mL/min: oral max 3 mg daily; IM initial 156 mg on day 1, 78 mg on day 8, then 39-78 mg monthly. CrCl <10 mL/min: not recommended.
Liver impairment	Mild to moderate hepatic impairment (Child-Pugh A or B): no adjustment. Severe hepatic impairment (Child-Pugh C): not studied.
Pediatric use	Adolescents (12-17 years, weight >=51 kg): oral 3 mg once daily; can increase to 6 mg/day after 5 days, then max 12 mg/day. For IM, safety in adolescents not established.
Geriatric use	Initiate oral at 3 mg once daily; may increase to 6 mg/day after 5 days. For IM, start with 156 mg on day 1, 78 mg on day 8, then 39-78 mg monthly. Use lowest effective dose due to increased sensitivity.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for INVEGA (INVEGA).

Breastfeeding	Paliperidone is excreted in human breast milk. The milk-to-plasma ratio is unknown. In a study of 7 women, paliperidone was detected in milk (range 4.0-8.9 ng/mL), with relative infant dose estimated at <5% of maternal weight-adjusted dose. Caution: monitor infant for sedation, poor feeding, and extrapyramidal signs.
Teratogenic Risk	Paliperidone (INVEGA) is not teratogenic in animal studies at doses up to 2 times the human therapeutic dose. No adequate well-controlled studies in pregnant women. Third trimester exposure to antipsychotics may cause extrapyramidal symptoms or withdrawal in neonates. Use only if benefit outweighs risk; register patient in Atypical Antipsychotics Pregnancy Registry (1-866-961-2388).

Warnings & precautions

■ FDA Black Box Warning

Side Effect Profile

Serious Effects

Absolute Contraindications

["Known hypersensitivity to paliperidone or risperidone","Patients taking strong CYP3A4 inducers or inhibitors (relative contraindication, may require dose adjustment)"]