INVEGA HAFYERA
Clinical safety rating: caution
Comprehensive clinical and safety monograph for INVEGA HAFYERA (INVEGA HAFYERA).
Paliperidone palmitate is an atypical antipsychotic that antagonizes D2 and 5-HT2A receptors, with additional antagonism at alpha2, alpha1, and H1 receptors.
| Metabolism | Paliperidone is metabolized via O-dealkylation, aliphatic hydroxylation, and dehydroxylation; it is a substrate of CYP2D6 and CYP3A4. |
| Excretion | Primarily renal: 59% of paliperidone excreted unchanged in urine; 32% as metabolites; 6-12% fecal. Biliary excretion is minimal. |
| Half-life | Terminal elimination half-life is 25-49 days (mean ~36 days) due to slow dissolution from intramuscular depot. Steady-state reached after 4-5 monthly injections. |
| Protein binding | 74% bound to albumin and α1-acid glycoprotein. |
| Volume of Distribution | Vd approximately 3900 L (55 L/kg for a 70 kg person), indicating extensive tissue distribution. |
| Bioavailability | IM: 100% bioavailability with a controlled release profile. Oral: Not applicable (IM only). |
| Onset of Action | IM: Initial release begins within 1-2 days, achieving therapeutic plasma levels by day 3. Maximal clinical effect observed by 2-3 weeks. |
| Duration of Action | IM: Single injection provides therapeutic coverage for 6 months. After last injection, therapeutic levels persist for 6-12 months due to long half-life. |
| Molecular Weight | 426.54 |
| Action Class | Atypical Antipsychotic |
INVEGA HAFYERA (paliperidone palmitate) is dosed once weekly via intramuscular injection in the gluteal or deltoid muscle. The recommended starting dose is 1,092 mg (deltoid or gluteal) or 1,560 mg (gluteal only) on treatment day 1 and day 8, both given in the deltoid muscle. Subsequent maintenance doses are administered once monthly. Note: INVEGA HAFYERA is only for once-weekly administration; once-monthly formulations (INVEGA SUSTENNA) are also available.
| Dosage form | SUSPENSION, EXTENDED RELEASE |
| Renal impairment | INVEGA HAFYERA is not recommended in patients with moderate to severe renal impairment (eGFR < 50 mL/min/1.73 m²). For mild impairment (eGFR 50-79 mL/min/1.73 m²), use lower doses: initiate with 819 mg (deltoid) and 1,092 mg (deltoid) on days 1 and 8, then monthly maintenance dose of 546 mg. For eGFR ≥ 80 mL/min/1.73 m², no adjustment needed. |
| Liver impairment | No dosage adjustment is necessary for mild to moderate hepatic impairment (Child-Pugh class A or B). INVEGA HAFYERA has not been studied in severe hepatic impairment (Child-Pugh class C) and should be used with caution. |
| Pediatric use | INVEGA HAFYERA is not approved for use in pediatric patients (<18 years of age). Safety and efficacy have not been established. |
| Geriatric use |
| 1st trimester | Limited data; potential risk of extrapyramidal and/or withdrawal symptoms in neonates following late third trimester exposure. In first trimester, no clear increased risk of major malformations from pooled data; however, caution is advised. |
| 2nd trimester | Similar to general population risk; no specific second trimester risks identified other than ongoing monitoring for maternal health. |
| 3rd trimester | Use in third trimester may cause extrapyramidal and/or withdrawal symptoms in neonates (e.g., agitation, feeding disorder, respiratory distress). Consider risk-benefit ratio. |
Clinical note
Comprehensive clinical and safety monograph for INVEGA HAFYERA (INVEGA HAFYERA).
| Placental transfer | Paliperidone crosses the placenta; case reports indicate cord blood concentrations approximately 30-50% of maternal plasma. Active transport via P-glycoprotein may limit but does not prevent transfer. |
| Breastfeeding |
■ FDA Black Box Warning
Increased mortality in elderly patients with dementia-related psychosis.
| Common Effects | Injection site reactions (pain, swelling, redness), Extrapyramidal symptoms (e.g., akathisia, dystonia, parkinsonism), Somnolence/sedation, Dizziness, Headache, Nausea, Constipation, Dry mouth, Weight gain, Increased appetite, Tachycardia, Orthostatic hypotension, Nasopharyngitis, Insomnia, Anxiety |
| Serious Effects | Increased mortality in elderly patients with dementia-related psychosis, Cerebrovascular adverse events (e.g., stroke, transient ischemic attack) in elderly dementia patients, 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) |
Known hypersensitivity to paliperidone or risperidoneConcurrent use with strong CYP3A4 inducers (e.g., carbamazepine, rifampin) due to reduced efficacy (INVEGA HAFYERA formulation specific)
| Precautions | Cerebrovascular adverse events in elderly with dementia, Neuroleptic malignant syndrome (NMS), Tardive dyskinesia, QT prolongation, Hyperglycemia and diabetes, Weight gain, Orthostatic hypotension, Seizures, Priapism, Leukopenia/neutropenia |
Loading safety data…
| Elderly patients (≥65 years) generally require lower doses due to reduced renal function and increased sensitivity. Initiate with 819 mg (deltoid) and 1,092 mg (deltoid) on days 1 and 8, then monthly maintenance dose of 546 mg. Monitor for orthostatic hypotension and extrapyramidal symptoms. Consider dose adjustment based on renal function. |
| Palmitoyl paliperidone (prodrug) is excreted into breast milk in low quantities; preterm neonates and those with renal impairment may have higher exposure. Monitor infant for extrapyramidal symptoms, sedation, and poor weight gain. Limited data; caution recommended. |
| Lactation Rating | L3: Limited data - probably compatible with breastfeeding, but cautious use is advised. |
| Teratogenic Risk | Paliperidone (the active metabolite of risperidone) is classified as FDA Pregnancy Category C. First trimester exposure: limited human data, but animal studies show increased fetal mortality and skeletal abnormalities at doses less than human therapeutic doses. Second and third trimester exposure: risk of extrapyramidal symptoms and withdrawal symptoms in neonates, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder. Use only if potential benefit justifies potential risk. |
| Fetal Monitoring | Monitor maternal: body weight, blood pressure (orthostatic hypotension), glucose and lipid profiles, prolactin levels, and signs of extrapyramidal symptoms. Fetal/neonatal: monitor for extrapyramidal symptoms and withdrawal symptoms (e.g., agitation, hypertonia, hypotonia, tremor, respiratory distress) after birth. Consider therapeutic drug monitoring of paliperidone levels if available. |
| Fertility Effects | Paliperidone may cause hyperprolactinemia, which can suppress gonadotropin-releasing hormone, leading to menstrual irregularities, anovulation, and reduced fertility in females. In males, hyperprolactinemia may cause decreased libido, erectile dysfunction, and impaired spermatogenesis. Effects are reversible upon dose reduction or discontinuation. |
| Food/Dietary | No known food interactions. Grapefruit juice is not expected to alter paliperidone levels. Maintain consistent dietary habits regarding potassium and sodium intake to mitigate cardiovascular effects. Avoid alcohol due to additive central nervous system depression. |
| Clinical Pearls | INVEGA HAFYERA (paliperidone palmitate) is a long-acting injectable antipsychotic administered once every 6 months. Administer only gluteal IM injections. For patients who have never used paliperidone or risperidone, tolerability should be established with oral formulations prior to starting. Due to prolonged release, side effects may persist for months; ensure patient adherence monitoring. Requires refrigeration (2–8°C) until 30 minutes before injection. Monitor for orthostatic hypotension, QTc prolongation, neuroleptic malignant syndrome, tardive dyskinesia, and weight gain. Avoid in patients with severe renal impairment (CrCl < 20 mL/min). |
| Patient Advice | This injection is given every 6 months into the muscle of your buttock; it is a long-acting treatment for schizophrenia. · If you have never taken paliperidone or risperidone before, you may first need to take a short course of oral medication to check for side effects. · Do not miss your injection appointments; you must receive your shot on schedule to keep the medicine effective. · Serious side effects include fast or irregular heartbeat, fainting, fever with muscle stiffness, confusion, or uncontrolled movements of the face or body. · This medicine may cause dizziness or drowsiness; avoid driving until you know how it affects you. · Do not drink alcohol during treatment as it may worsen side effects. · Store this medication in the refrigerator (36–46°F) until it is time for injection; do not freeze. Keep it in the original carton away from light. |