FAZACLO ODT
Clinical safety rating: caution
Comprehensive clinical and safety monograph for FAZACLO ODT (FAZACLO ODT).
Clozapine is an atypical antipsychotic that antagonizes serotonin 5-HT2A and dopamine D2 receptors, with higher affinity for 5-HT2A. It also blocks muscarinic M1, histaminergic H1, and adrenergic α1 and α2 receptors.
| Metabolism | Primarily hepatic via CYP1A2, with minor contributions from CYP2D6, CYP3A4, and CYP2C19. Major metabolites: norclozapine (desmethylclozapine) and clozapine N-oxide. |
| Excretion | Renal: 50% as metabolites (30% conjugated, 20% desmethylclozapine), 30% as unchanged; Fecal: 30% (biliary/fecal elimination of metabolites). |
| Half-life | Terminal elimination half-life: 14 hours (range 6-26 hours) at steady state; increases with dose/duration. Context: Twice-daily dosing achieves steady state in 5-7 days. |
| Protein binding | 97% bound (primarily alpha1-acid glycoprotein and albumin). |
| Volume of Distribution | 3-4 L/kg (apparent Vd), indicating extensive tissue distribution (e.g., brain, liver). |
| Bioavailability | Oral (ODT): 60-70% due to first-pass metabolism (clozapine); bioavailability similar to conventional tablets. |
| Onset of Action | Oral (ODT): Sedation within 1-2 hours; antipsychotic effect: 2-4 weeks for initial response. |
| Duration of Action | Sedation: 6-12 hours after single dose; antipsychotic effect: sustained with continuous dosing (monitoring required). |
| Molecular Weight | 326.82 |
Clozapine (FAZACLO ODT) is an atypical antipsychotic. For schizophrenia, the typical starting dose is 12.5 mg orally once daily or twice daily, titrated by 25-50 mg/day to a target dose of 300-450 mg/day divided, up to a maximum of 900 mg/day. For treatment-resistant schizophrenia, the target dose is 300-450 mg/day, with doses above 500 mg/day requiring slower titration. The oral disintegrating tablet is taken sublingually or swallowed whole.
| Dosage form | TABLET, ORALLY DISINTEGRATING |
| Renal impairment | Severe renal impairment (CrCl < 30 mL/min): Use with caution; dose reduction may be necessary due to increased risk of accumulation. No specific GFR-based dose guidelines exist; initiate at 12.5 mg once daily, titrate slowly with close monitoring. In end-stage renal disease (ESRD), avoid use or use with extreme caution. |
| Liver impairment | Clozapine is extensively metabolized in the liver. In hepatic impairment: For Child-Pugh Class A (mild): No adjustment necessary. For Child-Pugh Class B (moderate): Consider a 50% dose reduction and slow titration. For Child-Pugh Class C (severe): Contraindicated or use with extreme caution; limited data exist. Monitor liver function tests regularly. |
| Pediatric use | Not FDA-approved for pediatric patients under 18 years. However, off-label use for treatment-resistant schizophrenia in adolescents (≥13 years) is sometimes considered: Starting dose 12.5 mg once or twice daily, titrate by 25-50 mg/day to target 300-450 mg/day, maximum 900 mg/day. Weight-based dosing is not established; dosing is based on adult protocol with slower titration. |
| 1st trimester | Clozapine crosses the placenta; limited human data, but use only if benefit outweighs risk; risk of congenital malformations unclear. |
| 2nd trimester | Use only if clearly needed; monitor for maternal weight gain, glucose intolerance, and agranulocytosis; fetal growth may be affected. |
| 3rd trimester | Use with caution; risk of neonatal withdrawal (irritability, respiratory distress, feeding problems) and extrapyramidal symptoms; monitor neonate. |
Clinical note
Comprehensive clinical and safety monograph for FAZACLO ODT (FAZACLO ODT).
| Placental transfer | Clozapine crosses the placenta with maternal-to-fetal ratio of approximately 0.5 in animal studies; human data limited but significant transfer expected. |
| Breastfeeding | Clozapine is excreted into breast milk in low to moderate amounts; relative infant dose estimated around 1-2% of maternal weight-adjusted dose. Monitor infant for drowsiness, poor feeding, and agranulocytosis (rare); generally avoid or use with caution. American Academy of Pediatrics: 'use may be of concern'. |
■ FDA Black Box Warning
Severe neutropenia; myocarditis, cardiomyopathy, and mitral valve incompetence; seizure; orthostatic hypotension, bradycardia, syncope; increased mortality in elderly patients with dementia-related psychosis.
| Serious Effects |
History of clozapine-induced agranulocytosis or severe granulocytopeniaActive myeloproliferative disorderParalytic ileusSevere CNS depression or comaConcurrent use of agents known to suppress bone marrow function
| Precautions | Severe neutropenia (absolute neutrophil count <500/μL requires discontinuation), myocarditis (especially during first 2 months), seizures (dose-related), orthostatic hypotension with syncope, QT prolongation, eosinophilia, thromboembolism, anticholinergic toxicity, hepatotoxicity, hyperglycemia, dyslipidemia, weight gain, tardive dyskinesia, withdrawal symptoms. |
| Food/Dietary | Avoid alcohol and beverages containing alcohol. Grapefruit juice may increase clozapine levels; avoid concurrent use. High-fat or high-calorie meals may slightly increase absorption but no specific food restriction. Caffeine may increase clozapine plasma concentrations; monitor for toxicity if caffeine intake changes. Clozapine-induced constipation may require increased dietary fiber and fluid intake. |
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| Geriatric use | In elderly patients (≥65 years), initiate at 12.5 mg once daily due to increased sensitivity and risk of adverse effects (e.g., sedation, hypotension, agranulocytosis). Titrate slowly by 25 mg/day increments, target lower maintenance doses (usually 150-300 mg/day). Monitor for orthostatic hypotension, anticholinergic effects, cognitive decline, and falls. Avoid in dementia-related psychosis due to increased mortality risk. |
| Lactation Rating | L4 (Possibly Hazardous) |
| Teratogenic Risk | Pregnancy Category B. No evidence of teratogenicity in animal studies; however, adequate human studies are lacking. Use only if benefit outweighs risk. First trimester: limited human data; animal studies show no fetal harm. Second/third trimester: no known teratogenic effects; monitor for maternal hypotension and neonatal extrapyramidal symptoms. |
| Fetal Monitoring | Monitor maternal blood counts (ANC) weekly during pregnancy due to risk of agranulocytosis. Assess maternal blood pressure and heart rate regularly due to orthostatic hypotension. Fetal monitoring: consider ultrasound for growth and development, and neonate observation for extrapyramidal signs, withdrawal, or sedation after delivery. |
| Fertility Effects | Clozapine may increase serum prolactin, leading to galactorrhea, amenorrhea, and potential reversible infertility. In males, may cause erectile dysfunction or decreased libido. Effects are dose-dependent and resolve upon discontinuation. |
| Clinical Pearls | FAZACLO ODT (clozapine orally disintegrating tablets) is used for treatment-resistant schizophrenia and to reduce suicidal behavior in schizophrenia or schizoaffective disorder. Monitoring for neutropenia is mandatory due to risk of agranulocytosis; absolute neutrophil count (ANC) must be monitored weekly for first 6 months, then biweekly, then monthly after 1 year of stable counts. Severe constipation occurs in up to 60% of patients; prophylactic bowel regimen is recommended. Orthostatic hypotension, tachycardia, and myocarditis are risks; titrate slowly. Smoking induces clozapine metabolism; dose adjustments needed if smoking status changes. Do not break or cut ODT; place on tongue and allow to dissolve without water. Avoid alcohol and central nervous system depressants. |
| Patient Advice | Take this tablet by placing it on your tongue; it will dissolve quickly without water. · Do not crush, chew, or split the tablet. · You must have regular blood tests (weekly initially) to monitor your white blood cell count. · Contact your doctor immediately if you experience signs of infection: fever, sore throat, mouth sores, or flu-like symptoms. · Avoid alcohol and other sedatives while taking this medication. · You may experience drowsiness, dizziness, or low blood pressure when standing up; rise slowly. · Maintain adequate fluid intake and fiber to prevent constipation. · Do not change your smoking habits without consulting your doctor; smoking affects how this medication works. · Report any chest pain, palpitations, shortness of breath, or severe abdominal pain to your doctor. · Do not stop taking this medication abruptly; withdrawal symptoms may occur. |