LOXAPINE SUCCINATE
Clinical safety rating: caution
Comprehensive clinical and safety monograph for LOXAPINE SUCCINATE (LOXAPINE SUCCINATE).
Loxapine is a dibenzoxazepine antipsychotic that exerts its effects primarily through antagonism of dopamine D2 and serotonin 5-HT2A receptors. It also has moderate affinity for histamine H1, alpha-1 adrenergic, and muscarinic acetylcholine receptors.
| Metabolism | Primarily hepatic via CYP1A2, CYP3A4, and CYP2D6. Major metabolites include 8-hydroxyloxapine and N-desmethyl derivatives, with some activity. |
| Excretion | Renal (approximately 60% as metabolites, <1% unchanged) and fecal (approximately 40% as metabolites). |
| Half-life | Terminal elimination half-life: 12–19 hours (mean 16 hours) after oral administration; steady-state reached within 3–5 days. |
| Protein binding | Approximately 96-98% bound, primarily to alpha-1-acid glycoprotein and albumin. |
| Volume of Distribution | Vd: 0.9–1.2 L/kg, indicating extensive tissue distribution. |
| Bioavailability | Oral: 33% (due to extensive first-pass metabolism); intramuscular: 100% (relative to oral). |
| Onset of Action | Oral: 20–30 minutes; intramuscular: 10–15 minutes. |
| Duration of Action | Oral: 8–12 hours; intramuscular: 12–24 hours. |
Initial: 10 mg twice daily orally; increase to 25-50 mg twice daily over 7-10 days; maximum 250 mg/day. IM: 12.5-50 mg every 4-6 hours.
| Dosage form | CAPSULE |
| Renal impairment | CrCl 50-80 mL/min: 75% of normal dose. CrCl 10-50 mL/min: 50% of normal dose. CrCl <10 mL/min: 25% of normal dose. |
| Liver impairment | Child-Pugh Class A: 50% of normal dose. Child-Pugh Class B: 25% of normal dose. Child-Pugh Class C: contraindicated. |
| Pediatric use | Adolescents (12-18 years): Initial 10 mg/day orally, titrate gradually; maximum 150 mg/day. Children <12 years: not recommended. |
| Geriatric use | Initial 5-10 mg/day orally; increase slowly by 5-10 mg increments; maximum 150 mg/day. Increased sensitivity to extrapyramidal symptoms and hypotension. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for LOXAPINE SUCCINATE (LOXAPINE SUCCINATE).
| Breastfeeding | Minimally excreted in breast milk; M/P ratio not well defined. Monitor infant for sedation, poor feeding, and extrapyramidal effects. Consider risk-benefit; alternative agents preferred. |
| Teratogenic Risk | First trimester: Limited data; animal studies show no clear teratogenicity but risk cannot be excluded. Second/third trimester: Neonatal extrapyramidal symptoms and withdrawal (e.g., agitation, hypertonia) if used near term. Overall: FDA Pregnancy Category C (pre-2015); use only if benefit outweighs risk. |
■ FDA Black Box Warning
Increased mortality in elderly patients with dementia-related psychosis. Loxapine is not approved for the treatment of dementia-related psychosis.
| Common Effects | Allergic reaction Application site reactions burning irritation itching and redness |
| Serious Effects |
["Hypersensitivity to loxapine or any component","Comatose states","Severe CNS depression (e.g., alcohol, barbiturates, opiates)","Concurrent use with other antipsychotics in dementia-related psychosis (due to black box warning)"]
| Precautions | ["Neuroleptic malignant syndrome (NMS)","Tardive dyskinesia (TD)","QT prolongation","Seizures (lower threshold)","Orthostatic hypotension","Hyperprolactinemia","Leukopenia/neutropenia/agranulocytosis","Similar to other antipsychotics: potential for venous thromboembolism"] |
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| Fetal Monitoring |
| Monitor maternal blood pressure, glucose, weight, and EPS. Fetal: Ultrasound for growth and anatomy. Neonatal: Observe for EPS, withdrawal, and sedation post-delivery. |
| Fertility Effects | May elevate prolactin levels causing galactorrhea, amenorrhea, and transient infertility. No direct evidence of permanent fertility impairment. |