INVEGA
Clinical safety rating: caution
Comprehensive clinical and safety monograph for INVEGA (INVEGA).
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.
| 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. |
| Molecular Weight | 426.48 |
| Action Class | Atypical Antipsychotic |
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. |
| 1st trimester | Limited data; potential risk of malformations based on animal studies. Use only if benefit outweighs risk. |
| 2nd trimester | May be used if necessary; monitor for extrapyramidal symptoms in neonate. |
| 3rd trimester | Avoid in late pregnancy due to risk of neonatal extrapyramidal symptoms and withdrawal. |
Clinical note
Comprehensive clinical and safety monograph for INVEGA (INVEGA).
| Placental transfer | Paliperidone crosses the placenta in animal studies; human data limited but likely similar. Active transport via P-glycoprotein may limit exposure. |
| Breastfeeding | Paliperidone is excreted in breast milk in low amounts; however, monitor infant for sedation, extrapyramidal symptoms, and poor feeding. Consider risk-benefit. |
| Lactation Rating |
■ 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.
| Common Effects | Extrapyramidal symptoms (e.g., dystonia, akathisia, parkinsonism), Somnolence/sedation, Headache, Insomnia, Anxiety, Nausea, Constipation, Dyspepsia, Tachycardia, Orthostatic hypotension, Nasopharyngitis, Weight gain, Hyperprolactinemia |
| Serious Effects | Increased mortality in elderly patients with dementia-related psychosis, Cerebrovascular adverse events (e.g., stroke, transient ischemic attack) in elderly patients with dementia, Neuroleptic malignant syndrome (NMS), Tardive dyskinesia, QT interval prolongation, Seizures, Priapism, Thrombotic thrombocytopenic purpura (TTP), Dysphagia, Hyperprolactinemia, Metabolic changes: hyperglycemia, diabetes mellitus, dyslipidemia, weight gain |
Hypersensitivity to paliperidone or risperidone
| 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 |
Loading safety data…
| L3 (Moderately Safe) |
| 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). |
| Fetal Monitoring | Monitor maternal weight, blood pressure, blood glucose, lipids, and prolactin levels. Assess for extrapyramidal symptoms. Fetal monitoring: ultrasound for growth and development if exposed in first trimester. Neonatal monitoring: observe for extrapyramidal symptoms, withdrawal, or sedation for 48 hours. |
| Fertility Effects | Paliperidone elevates prolactin levels, which may suppress hypothalamic-pituitary-gonadal axis, leading to decreased libido, erectile dysfunction, amenorrhea, anovulation, and impaired fertility. Effects are reversible upon discontinuation. No specific data on male fertility. |
| Food/Dietary | Avoid concomitant consumption of grapefruit or grapefruit juice, as grapefruit inhibits CYP3A4 and may increase paliperidone concentrations. Alcohol should be avoided due to additive CNS depression. High-fat meals may increase absorption of the oral tablet; take consistently with or without food, but avoid high-fat meals during the first few days of treatment to reduce variability. |
| Clinical Pearls | INVEGA (paliperidone) is the major active metabolite of risperidone, offering a similar efficacy profile with potentially less need for dose adjustment in hepatic impairment. It is FDA-approved for schizophrenia and schizoaffective disorder. The extended-release oral formulation (OROS) provides once-daily dosing with a gradual release over 24 hours. Dose titration is generally not required but may be necessary based on renal function; reduce dose in moderate renal impairment (CrCl 30-49 mL/min) and avoid in severe impairment (CrCl <30 mL/min). Monitor for extrapyramidal symptoms, weight gain, metabolic changes (glucose, lipids), and prolactin elevation. QT prolongation risk is lower than with some antipsychotics but still present; caution with other QT-prolonging drugs. Taper when discontinuing to avoid withdrawal symptoms or rebound psychosis. |
| Patient Advice | Take this medication once daily at the same time each day; do not crush, chew, or dissolve the tablet, as it uses a special delivery system. · You may see a tablet shell in your stool; this is normal and does not mean the medication wasn't absorbed. · Avoid alcohol and grapefruit/grapefruit juice while taking INVEGA as they can affect how it works. · Seek medical help if you experience symptoms of neuroleptic malignant syndrome (fever, muscle rigidity, confusion) or tardive dyskinesia (involuntary movements). · Do not stop taking INVEGA abruptly; consult your doctor for a gradual dose reduction to avoid withdrawal symptoms. · Report signs of high blood sugar (increased thirst, hunger, urination), unusual weight gain, or changes in menstrual periods or breast enlargement/discharge. · INVEGA may cause dizziness, drowsiness, or blurred vision; avoid driving or operating machinery until you know how it affects you. · If you are pregnant or planning to become pregnant, discuss the risks and benefits with your doctor; a pregnancy registry is available. |