AHFS Class:

• Dibenzoxapines 28:16.08.26

Generic Name(s):

• Loxapine Succinate

Loxapine is a tricyclic dibenzoxazepine-derivative antipsychotic agent. The drug is considered a conventional or first-generation antipsychotic agent.110

Psychotic Disorders

Loxapine is used in the symptomatic management of psychotic disorders. Drug therapy is integral to the management of acute psychotic episodes in patients with schizophrenia and generally is required for long-term stabilization to improve symptoms between episodes and to minimize the risk of recurrent acute episodes. Antipsychotic agents are the principal class of drugs used for the management of all phases of schizophrenia and generally are effective in all subtypes of the disorder and subgroups of patients. Patient response and tolerance to antipsychotic agents are variable, and patients who do not respond to or tolerate one drug may be successfully treated with an agent from a different class or with a different adverse effect profile.

Loxapine has been effective in patients with acute schizophrenic reactions and in those with chronic schizophrenia. Loxapine may control symptoms of schizophrenia such as disorientation, conceptual disorganization, perceptual distortion, hallucinations, emotional withdrawal, and hostility. Improvement in social competence, social interest, and manageability may occur. Somatic concern, anxiety, guilt feelings, depression, and tension usually show less improvement.

Although results of some studies indicate that the effectiveness of loxapine is about equal to that of chlorpromazine, trifluoperazine, and thiothixene, results in other studies have been variable and in some instances negative (possibly because of inadequate loxapine dosage and/or insufficient duration of loxapine therapy). Loxapine is sometimes effective in treating long-term, chronic schizophrenic patients who have not responded to other drugs. For further information on the symptomatic management of schizophrenia, see Uses: Psychotic Disorders, in the Phenothiazines General Statement 28:16.08.24.

Administration

Loxapine succinate is administered orally. Loxapine hydrochloride has been administered orally or by IM injection, but loxapine hydrochloride no longer is commercially available in the US.

Dosage

Although USP currently states that potency of loxapine succinate preparations should be expressed in terms of both the salt and the base (“active moiety”),100 dosage currently is expressed in terms of the base.102 (See Chemistry and Stability: Chemistry.) Dosage must be carefully adjusted according to individual requirements and response using the lowest possible effective dosage.

Psychotic Disorders

For the management of psychotic disorders, the usual initial oral adult dosage is 10 mg twice daily. Dosage may be increased fairly rapidly during the first 7-10 days of therapy according to the response and tolerance of the patient. When schizophrenic symptoms are severe, an initial oral dosage of 50 mg daily may be preferable. The usual therapeutic and maintenance oral dosage is 60-100 mg daily, administered in 2-4 divided doses. Some patients respond to a lower dosage and others require a higher dosage. Some clinicians have found that the optimal oral dosage for severely ill patients with chronic schizophrenia is 100-200 mg daily. Oral dosage should not exceed 250 mg daily. Weeks or months of treatment at optimum dosage may be necessary to produce maximum clinical improvement in patients with resistant mental and emotional disturbances.

Adverse Effects

Although loxapine differs chemically from the phenothiazines and all adverse reactions of the phenothiazines have not been reported with loxapine, the possibility that they may occur should be considered. Adverse effects of loxapine and the phenothiazines are numerous and may involve nearly all organ systems; however, they are usually reversible when dosage is reduced or the drug is discontinued. Some adverse effects may be attributed to the actions of the drug on the central and autonomic nervous systems or the cardiovascular system, whereas others are hypersensitivity reactions. Unexpected deaths have been reported during phenothiazine therapy. In some patients, cardiac arrest or asphyxia resulting from failure of the cough reflex appeared to be the cause of death. In other cases, the cause of death could not be determined nor definitely attributed to phenothiazine therapy.

The most frequent adverse effect of loxapine is transient initial drowsiness to which tolerance usually develops with continuing therapy. Drowsiness may also occur when the dosage of loxapine is increased. Extrapyramidal syndromes such as akathisia or a parkinsonism-like condition, manifested by rigidity, tremor, excessive salivation, and/or masked facies, occur frequently during loxapine therapy; the frequency of extrapyramidal effects may be greater with IM administration of the drug (IM dosage form of loxapine hydrochloride no longer commercially available in the US) than with oral administration. Other adverse neuromuscular effects include dystonias such as oculogyric crises, tongue protrusion, opisthotonos or spasms of the neck and facial muscles, or dyskinetic reactions such as choreoathetoid movements. Patients who have experienced extrapyramidal syndromes in association with other antipsychotic drugs will probably react similarly to loxapine. Neuromuscular symptoms including extrapyramidal syndromes can be controlled by administering an anticholinergic antiparkinsonian drug and/or reducing dosage or withdrawing loxapine.

Because use of antipsychotic agents, including loxapine, may be associated with tardive dyskinesia (a syndrome of potentially irreversible, involuntary, dyskinetic movements),130 loxapine should be prescribed in a manner that is most likely to minimize the occurrence of this syndrome.130 Chronic antipsychotic treatment generally should be reserved for patients who suffer from a chronic illness that is known to respond to antipsychotic agents, and for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate.130 In patients who do require chronic treatment, the lowest dosage and the shortest duration of treatment producing a satisfactory clinical response should be sought, and the need for continued treatment should be reassessed periodically.130 For additional information on tardive dyskinesia, see Tardive Dyskinesia under Cautions: Nervous System Effects, in the Phenothiazines General Statement 28:16.08.24.

Neuroleptic malignant syndrome (NMS) may occur in patients receiving loxapine or other antipsychotic therapy. NMS is potentially fatal and requires immediate discontinuance of the drug and intensive symptomatic and supportive care. For additional information on NMS, see Extrapyramidal Reactions under Cautions: Nervous System Effects, in the Phenothiazines General Statement 28:16.08.24.

Adverse effects attributed to the action of loxapine on the autonomic nervous system include dryness of the mouth, constipation, blurred vision, and nasal congestion. Adverse cardiovascular effects may include tachycardia, hypotension which is usually mild and transient, or, rarely, hypertension. A few cases of minor ECG changes similar to those seen with phenothiazine administration have been observed in patients receiving loxapine; however, these ECG changes have not been definitely attributed to loxapine.

Insomnia, dizziness, lethargy, lightheadedness, syncope, headache, ataxia, weakness, confusion, nausea, and vomiting may also occur during loxapine therapy. Other adverse effects which have occurred in a few patients include tinnitus, paresthesia, polydipsia, ptosis, dyspnea, hyperpyrexia, flushed facies, and weight gain or weight loss.

Dermatitis, facial edema, pruritus, and seborrhea have been observed during loxapine therapy. Rashes have also occurred in a few patients during hot weather. The possibility that loxapine may cause phototoxicity and/or photosensitivity reactions should be considered. Skin pigmentation and ocular changes have occurred in some patients receiving long-term therapy with some phenothiazines. Although these adverse effects have not yet been reported in patients receiving loxapine, patients receiving the drug should be carefully observed for pigmentary changes, and periodic ophthalmologic examinations (including slit-lamp examinations) should be performed in patients on prolonged loxapine therapy.

In clinical trial and/or postmarketing experience, leukopenia, neutropenia, and agranulocytosis have been temporally related to antipsychotic agents.130 Possible risk factors for leukopenia and neutropenia include preexisting low leukocyte count and a history of drug-induced leukopenia and neutropenia.130 (See Cautions: Precautions and Contraindications.)

Galactorrhea occurred in one patient receiving loxapine, and the possibility of other endocrine abnormalities should be considered. Transitory fluctuations in leukocyte counts, eosinophilia, and mildly elevated serum alkaline phosphatase concentrations without clinical symptoms have occurred rarely. Cholestatic jaundice or adverse hematologic effects (including hemolytic anemia, thrombocytopenia, and pancytopenia) have been reported in patients receiving other antipsychotic agents, and these possibilities should be considered.

Precautions and Contraindications

Loxapine shares the toxic potentials of other antipsychotic agents (e.g., phenothiazines), and the usual precautions associated with therapy with these agents should be observed. (See Cautions in the Phenothiazines General Statement 28:16.08.24.)

Geriatric patients with dementia-related psychosis treated with either conventional (first-generation) or atypical (second-generation) antipsychotic agents are at an increased risk of mortality.122,123,124,125,126 For additional information on the use of antipsychotic agents for dementia-associated psychosis and other behavioral disturbances, see Geriatric Considerations under Psychotic Disorders: Schizophrenia and Other Psychotic Disorders, in Uses and also see Cautions: Geriatric Precautions, in the Phenothiazines General Statement 28:16.08.24.

Patients should be cautioned that loxapine may impair their ability to perform hazardous activities requiring mental alertness or physical coordination such as operating machinery or driving a motor vehicle. The drug should be used with extreme caution in patients with a history of seizure disorders. Generalized tonic-clonic (grand mal) seizures, which progressed to status epilepticus in one patient, have occurred in epileptic patients receiving loxapine, even during maintenance of routine anticonvulsant therapy. The risk of extrapyramidal effects may be slightly higher following IM administration of loxapine (IM dosage form of loxapine hydrochloride no longer commercially available in the US) than generally anticipated with oral preparations. The increased risk may result from higher plasma concentrations of the drug following IM injection.

Loxapine should be used with caution in patients with cardiovascular disorders because the drug may cause tachycardia and/or hypotension. Severe hypotensive effects may be alleviated by the administration of norepinephrine or phenylephrine; epinephrine should not be used since a further lowering of blood pressure may occur. (See Drug Interactions.)

Since the possibility of ocular toxicity from loxapine cannot be excluded and since other antipsychotic agents have been associated with pigmentary retinopathy and lenticular pigmentation, patients receiving loxapine for prolonged periods should have periodic ophthalmologic examinations.

Patients with a history of clinically important low leukocyte count or drug-induced leukopenia and/or neutropenia should have their complete blood count monitored frequently during the first few months of therapy.130 Discontinuance of loxapine should be considered at the first sign of a clinically important decline in leukocyte count in the absence of other causative factors.130 Patients with clinically significant neutropenia should be carefully monitored for fever or other signs or symptoms of infection and promptly treated if such signs or symptoms occur.130 In patients with severe neutropenia (absolute neutrophil count [ANC] less than 1000/mm³), loxapine should be discontinued and the leukocyte count monitored until recovery occurs.130 (See Cautions: Adverse Effects.)

Loxapine should be used with caution, particularly in conjunction with anticholinergic antiparkinsonian agents and in patients with glaucoma or a tendency toward urinary retention because of possible anticholinergic activity. Since loxapine may have an antiemetic effect, it is possible that the drug could mask the signs of overdosage of toxic agents or interfere with the diagnosis of such conditions as intestinal obstruction or brain tumor. Loxapine is contraindicated in comatose patients, patients who have severe CNS depression from any cause, or known hypersensitivity to the drug.

Pediatric Precautions

Pending accumulation of clinical data on the use of the drug in children, loxapine is not recommended for use in children younger than 16 years of age.

Mutagenicity and Carcinogenicity

Although an increase in mammary neoplasms has been found in rodents following long-term administration of prolactin-stimulating antipsychotic agents, no clinical or epidemiologic studies conducted to date have shown an association between long-term administration of these drugs and mammary tumorigenesis in humans. Current evidence is considered too limited to be conclusive, and further study is needed to determine the clinical importance in most patients of elevated serum prolactin concentrations associated with antipsychotic agents. Since in vitro tests indicate that approximately one-third of human breast cancers are prolactin dependent, loxapine should be used with caution in patients with previously detected breast cancer.

Pregnancy and Lactation

Pregnancy

Neonates exposed to antipsychotic agents during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery.127,128,129,130 Symptoms reported in these neonates to date include agitation, hypertonia, hypotonia, tardive dyskinetic-like symptoms, tremor, somnolence, respiratory distress, and feeding disorder.127,128,129,130 Any neonate exhibiting extrapyramidal or withdrawal symptoms following in utero exposure to antipsychotic agents should be monitored.129 Symptoms were self-limiting in some neonates, but varied in severity; some infants required intensive care unit support and prolonged hospitalization.127,128,129,130 For further information on extrapyramidal and withdrawal symptoms in neonates, see Cautions: Pregnancy, Fertility, and Lactation, in the Phenothiazines General Statement 28:16.08.24.

Safe use of loxapine during pregnancy has not been established; therefore, the drug should not be used in pregnant women or women who might become pregnant unless the potential benefits outweigh the possible risk to the woman or fetus.

Lactation

The extent of distribution of loxapine and/or its metabolites into human milk is not known, but the drug and its metabolites distribute into milk in lactating dogs. The manufacturers recommend that use of loxapine in nursing women be avoided if clinically possible.

CNS Depressants

Loxapine may be additive with or may potentiate the action of other CNS depressants (including barbiturates and alcohol) or anticholinergic agents. If loxapine is used concomitantly with other depressant drugs, including alcohol, caution should be used to avoid overdosage.

Epinephrine

Loxapine inhibits the vasopressor effect of epinephrine. If patients receiving loxapine require a vasopressor agent, norepinephrine or phenylephrine should be used; epinephrine should not be used.

Acute Toxicity

Manifestations

Limited information is available on the acute toxicity of loxapine. Overdosage of loxapine presumably may be manifested by seizures, severe extrapyramidal symptoms, and other effects ranging from mild CNS depression to profound hypotension and coma.

Treatment

In the treatment of loxapine overdosage, symptomatic supportive therapy is indicated and general physiologic measures such as maintenance of adequate airway, oxygen uptake, and carbon dioxide removal should be maintained. In the absence of seizures, early gastric lavage (with an endotracheal tube with cuff inflated and in place to prevent aspiration of gastric contents) may be beneficial. Seizures may be controlled with anticonvulsants as necessary.130 Anticholinergic antiparkinsonian agents may be used to treat severe extrapyramidal reactions. Severe hypotension should respond to administration of norepinephrine or phenylephrine. Epinephrine should not be used because it may lower the blood pressure further. Although there has been no clinical experience, it has been suggested that forced diuresis or hemodialysis might be beneficial in the management of acute loxapine intoxication.

Pharmacology

Loxapine produces pharmacologic responses similar to those of the phenothiazines, butyrophenones, thioxanthenes, and molindone. Although the precise mechanism of action is not known, loxapine appears to act by reducing the firing thresholds of CNS neurons acting in polysynaptic pathways, particularly those in the reticular formation. In animals, the drug suppresses locomotor activity, conditioned avoidance behavior, and aggressive behavior. Loxapine has shown strong cataleptic activity and some antinociceptive effects in rodents. The drug does not appear to have antidepressant or anticonvulsant activity and may lower the seizure threshold. In high doses, loxapine has produced subcortical seizures and generalized seizures in epileptic animals. In addition, in patients with a history of seizure disorders, generalized tonic-clonic (grand mal) seizures have been associated with usual therapeutic doses of loxapine. (See Cautions: Precautions and Contraindications.) Although antiemetic activity in humans has not been clinically evaluated, the drug appears to have potent antiemetic effects in dogs. In patients with motor excitation, loxapine produces sedation and suppresses locomotor activity.

Pharmacokinetics

Absorption

Loxapine is rapidly and almost completely absorbed from the GI tract. The drug is also almost completely absorbed following IM administration (IM dosage form of loxapine hydrochloride no longer commercially available in the US). In healthy men, systemic bioavailability of the parent drug after oral administration of loxapine reportedly was approximately one-third that found after IM administration of an equivalent dose, which may be related to first-pass metabolism after oral administration. Peak loxapine serum concentrations usually occur within 1-2 hours and generally range from 0.006-0.013 mcg/mL following a 25-mg oral dose; peak concentrations after an equivalent IM dose reportedly are similar, while the time required to achieve peak concentrations after IM doses is approximately 5 hours. Serum concentrations of the drug (and/or its metabolites) necessary to produce antipsychotic effects are unknown. The major metabolite in serum is reported to be 8-hydroxyloxapine, an active metabolite, which reaches maximum concentrations of 0.012-0.038 mcg/mL 2-4 hours following oral administration of loxapine. Following oral administration of a single 25-mg dose of loxapine, the onset of sedative effect occurs in 20-30 minutes; peak effect occurs within 1.5-3 hours. The duration of sedative effect is approximately 12 hours.

Distribution

Animal studies with radioactive drug indicate that loxapine and/or its metabolites are widely distributed in body tissues with highest concentrations in brain, lungs, heart, liver, and pancreas. The drug appears in the CSF. Although no human data are available, animal studies indicate that loxapine crosses the placenta and distributes into milk.

Elimination

Serum concentrations of loxapine and its metabolites decline in a biphasic manner, with a half-life of 5 hours during the first phase and 19 hours during the second phase. Serum concentrations of loxapine and its metabolites reportedly reach equilibrium after the third or fourth day of therapy. The apparent half-life of the parent drug after oral or IM administration of loxapine (IM dosage form of loxapine hydrochloride no longer commercially available in the US) reportedly averages 4 (range: 1-14) or 12 (range: 8-23) hours, respectively. The prolonged half-life after IM versus oral administration may be related to prolonged absorption of the drug from muscle.

Loxapine is rapidly and extensively metabolized in the liver by aromatic hydroxylation, N -demethylation, and N -oxidation. The major metabolites of loxapine are 8-hydroxyloxapine and 7-hydroxyloxapine, which are active, and 8-hydroxydesmethylloxapine, 7-hydroxydesmethylloxapine, and loxapine N -oxide, which are inactive. Significant amounts of the N -oxides of the hydroxyloxapines are also present. These metabolites are excreted in urine and feces. Little or no unmetabolized drug has been found in urine or feces. Loxapine metabolites are excreted in urine mainly as glucuronide or sulfate conjugates; approximately 40 or 30% of an orally administered or IM dose, respectively, is excreted in urine as 5 metabolites over 48 hours. Metabolites excreted in feces are mainly in the unconjugated form. About 50% of a single oral dose of loxapine is excreted in urine and feces within 24 hours.

Chemistry and Stability

Chemistry

Loxapine is a tricyclic dibenzoxazepine-derivative antipsychotic agent. The drug is commercially available as the succinate salt. Loxapine has a pK_a of 6.6.

Loxapine succinate occurs as a white to off-white, crystalline powder and is slightly soluble in water and in alcohol. Each 1.36 mg of loxapine succinate is equivalent to 1 mg of loxapine.

USP currently states potency of loxapine succinate preparations should be expressed in terms of both the salt and the base (“active moiety”).100 Previously, potency was expressed only in terms of loxapine. Dosage currently continues to be expressed in terms of the base.102 Therefore, care should be taken to avoid confusion between labeled potencies as the salt and base and dosage of loxapine.101

Stability

Loxapine succinate capsules should be stored in tight containers at 15-30°C.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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