Loxapine is a conventional antipsychotic used in the therapy of schizophrenia. Loxapine therapy is commonly associated with minor serum aminotransferase elevations and in very rare instances has been linked to clinically apparent acute liver injury.
Loxapine (lox' a peen) is a dibenzoxazepine tricyclic derivative which appears to act by blocking dopamine type 2 (D2) receptors. Loxapine has other central and peripheral effects including anticholinergic and α-adrenergic blockade. Loxapine is indicated for the therapy of psychotic disorders and was approved for this use in the United States in 1976. In recent years, loxapine has been replaced in large part by the atypical antipsychotics, which have fewer extrapyramidal side effects. Loxapine is available as tablets of 5, 10, 25 and 50 mg and in generic forms and under the brand name Loxitane. Recommended doses of oral loxapine are 10 mg twice daily initially, increasing to a maximum of 100 mg in divided doses daily. An aerosol formulation of loxapine has recently been developed that is recommended for use in acute agitation in patients with bipolar disorder or schizophrenia. Common side effects include drowsiness, dizziness, headache, blurred vision, dry mouth, and tremor. Loxapine, unlike many antipsychotic agents, is not associated with significant weight gain.
Liver test abnormalities have been reported to occur in a small proportion of patients on long term therapy with loxapine, but elevations are uncommonly above 3 times the upper limit of normal. The aminotransferase abnormalities are usually mild, asymptomatic and transient, reversing even with continuation of medication. Instances of clinically apparent acute liver injury have been reported due to loxapine and to the structurally related tricylic amoxapine (not available in the United States), but cases are rare. The onset of jaundice is within 4 to 8 weeks, and the pattern of serum enzyme elevations is typically hepatocellular. Immunoallergic features and autoantibody formation are not typical.
Mechanism of Injury
The mechanism by which loxapine causes serum aminotransferase elevations is not known, but is likely due to production of a toxic intermediate by its metabolism. Loxapine is extensively metabolized by the liver via sulfoxidation and oxidation, partially via P450 system.
Outcome and Management
The serum aminotransferase elevations that occur on loxapine therapy are usually self-limited and do not require dose modification or discontinuation of therapy. No instances of acute liver failure or vanishing bile duct syndrome due to loxapine have been reported. Patients with loxapine induced liver injury probably do not have cross sensitivity to atypical antipsychotics.
REPRESENTATIVE TRADE NAMES
Loxapine – Generic, Loxitane®
Product labeling at DailyMed, National Library of Medicine, NIH
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References updated: 24 February 2014
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Allison DB, Mentore JL, Heo M, Chandler LP, Cappelleri JC, Infante MC, Weiden PJ. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry 1999; 156: 1686-96. PubMed Citation (Systematic review of 81 articles on weight change with antipsychotics, using change after 10 weeks to compare agents: clozapine +5.7, olanzapine +4.2, chlorpromazine +4.2, quetiapine +2.5, risperidone +1.7, loxapine +0.6, haloperidol +0.5, ziprasidone +0.3, molindone -0.1, and pimozide -2.7 kilograms).
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Torrent C, Amann B, Sanchez-Moreno J, Colom F, Feinares M, Comes M, Rosa AR, et al. Weight gain in bipolar disorder: pharmacological treatment as a contributing factor. Acta Psychiatr Scand 2008; 118: 4-18. PubMed Citation (Review of frequency of weight gain in patients treated for bipolar disorders, most weight gain occurred with clozapine and olanzapine, but some weight gain also with quetiapine, risperidone, lithium, valproate and gabapentin; little or none with molindone, loxapine, carbamazepine and lamotrigine).
Allen MH, Feifel D, Lesem MD, Zimbroff DL, Ross R, Munzar P, Spyker DA,
et al. Efficacy and safety of loxapine for inhalation in the treatment of
agitation in patients with schizophrenia: a randomized, double-blind,
placebo-controlled trial. J Clin Psychiatry 2011; 72: 1313-21. PubMed Citation (Controlled trial of inhaled loxapine in 129 patients with acute agitation and schizophrenia; side effects included dysgeusia, dizziness, and local irritation; no mention of hepatotoxicity).
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DA, et al. Rapid acute treatment of agitation in patients with
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with inhaled loxapine. Bipolar Disord 2012; 14: 31-40. PubMed Citation (Controlled trial of inhaled loxapine 314 patients with acute agitation and bipolar disorder; no serious adverse events or mention of liver injury).
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treatment of agitation. Clin Schizophr Relat Psychoses 2013; 7: 25-32. PubMed Citation (Review of the safety and efficacy of inhaled loxapine).
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