Loxapine Succinate

Loxapine (loxapine succinate), a dibenzoxazepine compound, represents a subclass of tricyclic antipsychotic agents, chemically distinct from the thioxanthenes, butyrophenones, and phenothiazines. Chemically, it is 2-Chloro-11-(4-methyl-1-piperazinyl)dibenz[b,f][1,4]oxazepine. It is present as the succinate salt.

LOXAPINE (loxapine succinate) BASE

Each capsule for oral administration, contains loxapine (loxapine (loxapine (loxapine succinate) succinate) succinate) succinate 6.8, 13.6, 34.0 or 68.1 mg equivalent to 5, 10, 25 or 50 mg of loxapine (loxapine (loxapine (loxapine succinate) succinate) succinate) base respectively. It also contains the following inactive ingredients: anhydrous lactose, benzyl alcohol NF, butyl paraben NF, edetate calcium disodium USP, gelatin, magnesium stearate, methyl paraben NF, polacrilin potassium, propyl paraben NF, sodium lauryl sulfate NF, sodium propionate NF, talc, and titanium dioxide. Additionally, the 10 mg capsule contains D&C Yellow 10 and FD&C Yellow 6, the 25 mg capsule contains D&C Yellow 10 and FD&C Blue 1, the 50 mg capsule contains FD&C Blue 1.

Loxapine (loxapine (loxapine (loxapine succinate) succinate) succinate) Capsules USP are indicated for the treatment of schizophrenia. The efficacy of loxapine (loxapine (loxapine (loxapine succinate) succinate) succinate) in schizophrenia was established in clinical studies which enrolled newly hospitalized and chronically hospitalized acutely ill schizophrenic patients as subjects.

Tardive Dyskinesia

Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.

Both the risk of developing the syndrome and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses.

There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying disease process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.

Given these considerations, antipsychotics should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that, 1) is known to respond to antipsychotic drugs, and 2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.

If signs and symptoms of tardive dyskinesia appear in a patient on antipsychotics, drug discontinuation should be considered. However, some patients may require treatment despite the presence of the syndrome. (See ADVERSE REACTIONS and Information for Patients sections).

Neuroleptic Malignant Syndrome (NMS)

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias).

The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system (CNS) pathology.

The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, 2) intensive symptomatic treatment and medical monitoring, and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS.

If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported.

Loxapine (loxapine (loxapine (loxapine succinate) succinate) succinate) , like other antipsychotics, may impair mental and/or physical abilities, especially during the first few days of therapy. Therefore, ambulatory patients should be warned about activities requiring alertness (e.g., operating vehicles or machinery) and about concomitant use of alcohol and other CNS depressants.

Loxapine (loxapine (loxapine (loxapine succinate) succinate) succinate) has not been evaluated for the management of behavioral complications in patients with mental retardation, and therefore, it cannot be recommended.

Signs and symptoms of overdosage will depend on the amount ingested and individual patient tolerance. As would be expected from the pharmacologic actions of the drug, the clinical findings may range from mild depression of the CNS and cardiovascular systems to profound hypotension, respiratory depression, and unconsciousness. The possibility of occurrence of extrapyramidal symptoms and/or convulsive seizures should be kept in mind. Renal failure following loxapine (loxapine (loxapine (loxapine succinate) succinate) succinate) overdosage has also been reported.

The treatment of overdosage is essentially symptomatic and supportive. Early gastric lavage and extended dialysis might be expected to be beneficial. Centrally-acting emetics may have little effect because of the antiemetic action of loxapine (loxapine (loxapine (loxapine succinate) succinate) succinate) . In addition, emesis should be avoided because of the possibility of aspiration of vomitus. Avoid analeptics, such as pentylenetetrazol, which may cause convulsions. Severe hypotension might be expected to respond to the administration of norepinephrine or phenylephrine. EPINEPHRINE SHOULD NOT BE USED SINCE ITS USE IN A PATIENT WITH PARTIAL ADRENERGIC BLOCKADE MAY FURTHER LOWER THE BLOOD PRESSURE. Severe extrapyramidal reactions should be treated with anticholinergic antiparkinson agents or diphenhydramine hydrochloride, and anticonvulsant therapy should be initiated as indicated. Additional measures include oxygen and intravenous fluids.

Loxapine is an antipsychotic medication. It affects the actions of chemicals in your brain.

Loxapine is used to treat schizophrenia.

Loxapine may also be used for purposes not listed in this medication guide.

Contraindications

• Comatose or severe drug-induced (e.g., alcohol, barbiturates, narcotics) depressed states.a g h (See Specific Drugs under Interactions.)

• Known hypersensitivity to loxapine or other dibenzoxazepines (e.g., amoxapine).a g h

Warnings/Precautions

Warnings

Shares the toxic potentials of other antipsychotic agents (e.g., phenothiazines); observe the usual precautions associated with therapy with these agents.b i

Increased risk of death with use of either conventional (first-generation) or atypical (second-generation) antipsychotics in geriatric patients with dementia-related psychosis.122 126 ee

Antipsychotic agents, including loxapine, are not approved for the treatment of dementia-related psychosis.122 126 ee (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis in Boxed Warning.)

Tardive dyskinesia, a syndrome of potentially irreversible, involuntary, dyskinetic movements, may develop in patients receiving antipsychotic agents, including loxapine.a g h i r Consider reducing loxapine dosage or discontinuing drug and possibly switching to a second-generation (atypical) antipsychotic agent.a b g h i

Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome requiring immediate discontinuance of the drug and intensive symptomatic treatment, has been reported with antipsychotic agents, including loxapine.a b g h s bb

May impair mental and/or physical abilities, especially during the first few days of therapy; use caution with activities requiring alertness (e.g., operating vehicles or machinery).a b g h aa

Response to CNS depressants and alcohol may be potentiated.a b g h (See Specific Drugs under Interactions.)

Ensure accuracy of prescription; similarity in spelling of Loxitane (loxapine succinate) and Soriatane (acitretin) and availability of same strengths and dosage forms may result in errors.cc

Sensitivity Reactions

Possible sensitivity reactions (e.g., jaundice, hepatitis, blood dyscrasias, skin reactions [dermatitis, rashes, facial edema, pruritus]).a b e g h q

Possible cross-sensitivity with dibenzoxazepines (e.g., amoxapine).a g h (See Contraindications.)

Consider that phototoxicity and/or photosensitivity reactions may occur with loxapine.b

General Precautions

Loxapine lowers seizure threshold; seizures reported even during maintenance of routine anticonvulsant therapy.a b g h j r q v Use with extreme caution in patients with a history of seizure disorders.a b g h q (See Specific Drugs under Interactions.)

Extrapyramidal symptoms occur frequently and usually are reversible; persistent reactions usually can be controlled by concomitant therapy with an antiparkinsonian drug and subsequent dosage reduction.a b e g h i q r v aa

Incidence of extrapyramidal symptoms may be greater with IM administration (IM dosage form of loxapine hydrochloride no longer commercially available in the US) than oral administration.a b g h

Possible tachycardia and/or hypotension; use with caution in patients with cardiovascular disease.a b g h q r v

If severe hypotension occurs, administer norepinephrine or phenylephrine; epinephrine or dopamine should not be used.a b g h aa (See Specific Drugs under Interactions.)

Elevated prolactin concentrations reported; elevation persists during chronic administration.a g h aa

Clinical importance unknown; consider that approximately one-third of human breast cancers are prolactin dependent when prescribing loxapine in patients with previously detected breast cancer.a g h aa

Galactorrhea, amenorrhea, gynecomastia, and impotence reported.a g h aa

Possible anticholinergic effects (e.g., dry mouth, blurred vision, mydriasis, constipation, urinary retention).a b g h q r aa

Use with caution in patients with glaucoma or a tendency toward urinary retention.a b g h aa (See Specific Drugs under Interactions.)

Pigmentary retinopathy and lenticular pigmentation reported with prolonged therapy with other antipsychotic agents; possibility of ocular toxicity with loxapine cannot be excluded.a b g h q aa Periodic ophthalmologic examinations recommended in patients receiving prolonged loxapine therapy.a b g h

Antiemetic effects may mask signs of overdosage of other drugs (e.g., antineoplastic agents) or obscure cause of vomiting in various disorders (e.g., intestinal obstruction, Reye’s syndrome, brain tumor).a b g h aa

Specific Populations

Risk for extrapyramidal and/or withdrawal symptoms (e.g., agitation, hypertonia, hypotonia, tardive dyskinetic-like symptoms, tremor, somnolence, respiratory distress, feeding disorder) in neonates exposed to antipsychotic agents during the third trimester; monitor neonates exhibiting such symptoms.127 128 129 130 Symptoms were self-limiting in some neonates but varied in severity; some infants required intensive support and prolonged hospitalization.127 128 129 130

Safe use of loxapine during pregnancy has not been established; avoid use in pregnant women or women who might become pregnant unless potential benefits outweigh the possible risk to the woman or fetus.ee

Loxapine and its metabolites distributed into milk in dogs; not known whether distributed into human milk.a c g h Avoid loxapine in nursing women if clinically possible.a g h n

Safety and efficacy not established in pediatric patients.a g h

Geriatric patients appear to be particularly sensitive to adverse CNS (e.g., tardive dyskinesia, parkinsonian manifestations, akathisia, sedation), anticholinergic, and cardiovascular (e.g., orthostatic hypotension) effects of antipsychotic agents.a g h i aa (See Geriatric Patients under Dosage and Administration.)

Geriatric patients with dementia-related psychosis treated with either conventional or atypical antipsychotic agents are at an increased risk of death.122 123 124 125 126 ee Loxapine is not approved for the treatment of patients with dementia-related psychosis.ee (See Boxed Warning.)

Common Adverse Effects

Extrapyramidal reactions (e.g., Parkinson-like symptoms, dystonia, akathisia, tardive dyskinesia), drowsiness or sedation, anticholinergic effects (e.g., dry mouth, blurred vision), orthostatic hypotension, tachycardia.a b e g h q r s

Absorption

Bioavailability

Rapidly and almost completely absorbed from GI tract following oral administration.a b g h q r u Almost completely absorbed following IM administration (IM dosage form of loxapine hydrochloride no longer commercially available in the US).a b g h Appears to undergo first-pass metabolism.s t w x

Peak serum concentrations generally attained within 1–3 hours after oral administration;b q s t x considerable interindividual variation in peak concentrations reported.w x

Onset

Onset of sedation usually occurs within 20–30 minutes and is most pronounced within 1.5–3 hours following single-dose, oral administration.a b g h s

Antipsychotic effects usually are apparent within 2–4 weeks after initiation of oral therapy, and optimum therapeutic response usually occurs within 6 months or longer.b i q aa

Duration

Duration of sedation following single-dose, oral administration is approximately 12 hours.a b g h

Distribution

Extent

In animals, loxapine and/or its metabolites are widely distributed into body tissues, including lungs, brain, spleen, heart, liver, pancreas, and kidneys.a b g h q u Loxapine crosses blood-brain barrier.b

Although no human data are available, animal studies indicate that loxapine crosses the placenta.b c Loxapine and its metabolites distribute into milk in dogs; not known whether distributed into human milk.a b c g h j

Elimination

Metabolism

Rapidly and extensively metabolized in the liver by aromatic hydroxylation, N-demethylation, and N-oxidation to active metabolites 8-hydroxyloxapine and 7-hydroxyloxapine and inactive metabolites 8-hydroxydesmethylloxapine, 7-hydroxydesmethylloxapine, and loxapine N-oxide.a b g h j q r t u x Significant amounts of the N-oxides of the hydroxyloxapines also present.b

Elimination Route

Loxapine and its metabolites are excreted in urine and feces.a b g h q r t

Half-life

Biphasic; half-life of initial phase is approximately 5 hours and half-life of terminal phase is approximately 19 hours.b

Storage

Oral

Tight, light-resistant containers at 15–30°C.a b g h k