loxapine LOXITANE
Class: First Generation Antipsychotic/DibenzoxazepineFDA Indications: Schizophrenia, Agitation Associated With Schizophrenia Or Bipolar I Disorder In Adults (ADASUVE Inhalation Powder)
Off-Label Use: Irritability In Autism Spectrum Disorders, Reversal Of Antipsychotic-Induced Metabolic Disturbances
Prescribing
Forms: 5, 10, 25, 50mg tablet; 10mg single-use, disposable inhaler (Adasuve); 25mg/ml po soln; 50mg/ml injectableDose Range: 20-250 mg/day
Starting: 10 mg bid. Dosage should then be increased fairly rapidly over the first seven to ten days until there is effective control of symptoms of schizophrenia. The usual therapeutic and maintenance range is 60 mg to 100 mg daily.
Stopping: Taper 6-8 weeks, rapid d/c can lead to rebound psychosis
Monitoring:
Precautions
Contraindications: Contraindicated in severe central nervous system depression (alcohol, barbiturates, narcotics, etc.) or comatose statesSerious Side Effects: , , Neutropenia and/or Agranulocytosis (rare), Hyperprolactinemia
This drug is under active review for possible risk of QT prolongation and torsades de pointes. It has not been placed in one of the four QTdrugs categories at this time.
Side Effects: EPS, akathisia, drowsiness, xerostomia, constipation
Pharmacodynamics
1° MOA: 5HT2A–D2 antagonistTarget: D2 (very high), D4 (very high), 5HT2A (high), α1 (moderate), H1 (moderate), M1 (low)
Pharmacokinetics
t½: 4 (1-14)° TMAX: 1°Substrate of: 1A2, 2D6, 3A4, FMO
Inhibits: ∅ ; Induces: ∅
Active Metabolites: amoxapine, 7-OH-loxapine
DDIs
- - 1A2, 2D6 & 3A4 inhibitors can ↑ levels; 1A2, 2D6 & 3A4 inducers can ↓ levels
- - caution when co-prescribed with other medications that can lower blood pressure
- - caution when co-prescribed with other CNS depressants
- - caution when co-prescribed with other medications that can lower seizure threshold
Misc
- - exhibits atypicality at low doses
- - minimial weight gain
- - its chemical structure is similar to clozapine
- - receptor binding profile, especially its high 5HT2/D2 ratio, is more characteristic of atypical antipsychotics (similar binding profile as clozapine and olanzapine)
- - binds with higher affinity to D4 than the other dopaminergic receptors (again similar to clozapine)
- - IM formulation has longer t½ (12°) and Tmax (5°) than PO and inhaled form
- - one of its 2° metabolites is the tetracyclic antidepressant, amoxapine
- - not associated with QTc prolongation
Special Populations
Category C—Although the human pregnancy experience with loxapine is very limited, structural anomalies have not been associated with other agents in this subclass. Because of the very limited human pregnancy experience with atypical antipsychotics, ACOG does not recommend the routine use of these agents in pregnancy, but a risk-benefit assessment may indicate that such use is appropriate. A 1996 review on the management of psychiatric illness concluded that patients with histories of chronic psychosis represent a high-risk group (for both the mother and the fetus) and should be maintained on pharmacologic therapy before and during pregnancy.
No reports describing the use during human lactation have been located. The relatively low molecular weight of loxapine (about 328) suggests that the drug are excreted into breast milk. The effect of this exposure on a nursing infant is unknown. In 2001, the American Academy of Pediatrics classified antipsychotics as drugs whose effect on the nursing infant is unknown but may be of concern. Because of the very limited human experience with antipsychotics, the ACOG does not recommend the routine use of these agents during lactation, but a risk-benefit assessment may indicate that such use is appropriate.
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Elderly and debilitated patients should be started on lower dosage.
2019 BEE℞S Recommendation: Avoid, except in schizophrenia or bipolar disorder. Increased risk of CVA and greater rate of cognitive decline and mortality in persons with dementia. Avoid antipsychotics for behavioral problems of dementia or delirium unless nonpharmacological options have failed or are not possible and the older adult is threatening substantial harm to self or others.
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
Although specific dosage guidelines are not available for oral loxapine, adjustments may be needed depending upon clinical response and the degree of hepatic impairment due to extensive metabolism of loxapine in the liver.