Loxapine

Absorption of loxapine after oral or i.m. administration is rapid and almost complete. The bioavailability of the oral route is one-third that of the i.m. route, possibly due to first-pass metabolism. The oral tablet has an onset of action of 30 minutes with a peak effect occurring at 1 to 3 hours and a duration of action of 12 hours. The i.m. route has a similar onset of action; however, the peak concentration takes longer to reach due to prolonged absorption from the muscles.

Loxapine is distributed mainly to the brain, lungs, heart, liver, pancreas and CSF. It is extensively metabolized by the liver with little or no parent drug excreted unchanged in the urine or feces. There are active metabolites which, along with loxapine, are eliminated in a biphasic manner. The first phase (alpha-phase) has a half-life of 5 hours and the second phase (beta-phase) has a half-life of 19 hours.

Anticholinergic agents: Concomitant use with anticholinergic agents may increase side effects such as dry mouth, blurred vision and urinary retention. Use of high dose anticholinergics can lead to toxic psychosis.

Anti-Parkinson's agents: Antipsychotics, through dopamine blockade, can reduce the dopaminergic effects of anti-Parkinson's drugs.

Carbamazepine: Loxapine may decrease plasma levels of carbamazepine and its metabolites.

CNS depressants: The effects of CNS depressants (e.g., alcohol, barbiturates, opiates) may be increased with concomitant loxapine use.

Drugs that prolong the QTc interval: Loxapine should be used with caution in combination with other drugs that prolong the QTc interval (e.g., amantadine, amiodarone, ampicillin, chlorpromazine, citalopram, clarithromycin, co-trimoxazole, disopyramide, domperidone, erythromycin, indapamide, lithium, moxifloxacin, procainamide, quetiapine, quinidine, thioridazine{*The use of thioridazine with any drug that prolongs the QTc interval is contraindicated.}, tricyclic antidepressants) because of the risk of additive prolongation of the QTc interval and possible life-threatening arrhythmias such as torsades de pointes.

Patients should be warned that loxapine may impair their ability to perform hazardous tasks such as driving or operating heavy machinery.

Antipsychotics have been detected in breast milk in concentrations of 0.2 to 11%. There have been no reports of loxapine use in nursing mothers. Use with caution in lactation because of the possible sedative and anticholinergic side effects in the infant.

Pending further studies, the manufacturer does not recommend the use of loxapine in children less than 16 years of age. Children are more prone to the adverse effects of antipsychotics including extrapyramidal effects, tardive dyskinesia (up to 51% of patients), sedation, weight gain and hyperprolactinemia. Second-generation antipsychotics may be preferred since they are generally better tolerated. If treatment of an antipsychotic is to be initiated, start at the lowest possible dose, titrate slowly, assess the need for the antipsychotic regularly and limit the duration of therapy.

Antipsychotics have not been clearly shown to be teratogenic; however, exposure in the first trimester should be avoided if possible. If therapy is required, a nonphenothiazine, high potency antipsychotic should be started at the lowest possible dose. If possible, discontinue the antipsychotic 1 week prior to delivery. There have been no reports of loxapine use in human pregnancy. Use only when the benefits outweigh the risks.

Agranulocytosis, thrombocytopenia and leukopenia have rarely occurred.

urinary retention, adynamic ileus.

galactorrhea, amenorrhea, gynecomastia and menstrual irregularity have rarely occurred.

weight gain, weight loss, sexual dysfunction, neuroleptic malignant syndrome, seizures.

pruritus, photosensitivity, rashes, hyperpigmentation.

pigmentary retinopathy and lenticular pigmentation.

tachycardia and ECG abnormalities (e.g., QTc prolongation).

jaundice.

Symptoms include CNS depression, hypotension, respiratory depression, extrapyramidal effects, convulsions, agitation, restlessness, fever, hypothermia, hyperthermia, coma, ECG changes and cardiac arrhythmias.

Patients who have ingested loxapine in overdose occasionally require respiratory and hemodynamic support. This may include intubation, ventilation, boluses of isotonic i.v. fluids, and inotropic support. Patients who seize should be treated with benzodiazepines. Ventricular arrhythmias are uncommon, and should be treated with boluses of sodium bicarbonate as well as conventional arrhythmics such as lidocaine. In the rare patient with torsades de pointes, i.v. magnesium sulfate and/or a pacemaker should be used. Once the patient's airway is adequately protected, 1 dose of activated charcoal can be administered to minimize absorption of orally ingested loxapine. Extrapyramidal reactions may be treated with i.v. benztropine or diphenhydramine.

Initial dose of loxapine in the elderly is 5 to 10 mg once or twice daily.