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Loxapine

Class: Antipsychotics, Miscellaneous
VA Class: CN709
Chemical Name: 2-Chloro-11-(4-methyl-1-piperazinyl)dibenz[b,f][1,4]oxazepine
Molecular Formula: C18H18ClN3O•C4H6O4
CAS Number: 27833-64-3
Brands: Loxitane

Medically reviewed by Drugs.com on May 17, 2021. Written by ASHP.

Warning

    Increased Mortality in Geriatric Patients with Dementia-related Psychosis
  • Geriatric patients with dementia-related psychosis treated with antipsychotic agents are at an increased risk of death.

  • Analyses of 17 placebo-controlled trials in geriatric patients mainly receiving atypical antipsychotic agents revealed an approximate 1.6- to 1.7-fold increase in mortality compared with that in patients receiving placebo.

  • Most fatalities appeared to result from cardiovascular-related events (e.g., heart failure, sudden death) or infections (mostly pneumonia).

  • Observational studies suggest that conventional or first-generation antipsychotic agents also may increase mortality in such patients.

  • Antipsychotic agents, including loxapine, are not approved for the treatment of dementia-related psychosis.

Risk Evaluation and Mitigation Strategy (REMS):

FDA approved a REMS for loxapine to ensure that the benefits outweigh the risks. The REMS may apply to one or more preparations of loxapine and consists of the following: elements to assure safe use and implementation system. See https://www.accessdata.fda.gov/scripts/cder/rems/.

Introduction

Tricyclic dibenzoxazepine-derivative, conventional (prototypical, first-generation) antipsychotic agent; structurally related to amoxapine, clozapine, and olanzapine.

Uses for Loxapine

Psychotic Disorders

Symptomatic management of psychotic disorders (i.e., schizophrenia).

Has been used in the management of refractory or treatment-resistant schizophrenia.

Mental Retardation

Efficacy not established for the management of behavioral complications in patients with mental retardation.

Loxapine Dosage and Administration

General

  • Adjust dosage carefully according to individual requirements and response; use the lowest possible effective dosage.

  • Periodically evaluate patients receiving long-term therapy to determine whether maintenance dosage can be decreased or drug therapy discontinued. (See Tardive Dyskinesia under Cautions.)

  • For symptomatic relief of psychotic disorders, initial therapeutic response to antipsychotic therapy usually occurs within 2–4 weeks and optimum therapeutic response occurs within 6 months or longer.

Administration

Oral Administration

Loxapine succinate is administered orally, usually in divided doses 2–4 times daily. Loxapine hydrochloride has been given orally and parenterally, but no longer is commercially available in the US.

Dosage

Available as loxapine succinate; dosage expressed in terms of loxapine.

Adults

Psychotic Disorders
Oral

Initially, 10 mg given twice daily.

In severely schizophrenic patients, an initial dosage of up to 50 mg daily may be preferable.

May increase dosage fairly rapidly during the first 7–10 days of therapy according to patient response and tolerance.

Usual maintenance dosage: 60–100 mg daily; some patients respond to a lower dosage and others require a higher dosage. For severely ill patients with chronic schizophrenia, some clinicians recommend maintenance dosages of 100–200 mg daily.

Prescribing Limits

Adults

Psychotic Disorders
Oral

Maximum 250 mg daily.

Special Populations

Geriatric Patients

No specific dosage recommendations for geriatric patients, but generally select dosage at the lower end of recommended range; increase dosage more gradually and monitor closely. (See Geriatric Use under Cautions.)

Cautions for Loxapine

Contraindications

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

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

Warnings/Precautions

Warnings

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

Increased Mortality in Geriatric Patients with Dementia-related Psychosis

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

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

Tardive Dyskinesia

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

Neuroleptic Malignant Syndrome

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.

CNS Depression

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).

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

Possible Prescribing and Dispensing Errors

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.

Sensitivity Reactions

Hypersensitivity and Cross-sensitivity

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

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

Photosensitivity

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

General Precautions

Seizures

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

Extrapyramidal Effects

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.

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.

Cardiovascular Effects

Possible tachycardia and/or hypotension; use with caution in patients with cardiovascular disease.

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

Prolactin Secretion

Elevated prolactin concentrations reported; elevation persists during chronic administration.

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.

Galactorrhea, amenorrhea, gynecomastia, and impotence reported.

Anticholinergic Effects

Possible anticholinergic effects (e.g., dry mouth, blurred vision, mydriasis, constipation, urinary retention).

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

Ocular Effects

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

Other Precautions

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).

Specific Populations

Pregnancy

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. Symptoms were self-limiting in some neonates but varied in severity; some infants required intensive support and prolonged hospitalization.

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.

Lactation

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

Pediatric Use

Safety and efficacy not established in pediatric patients.

Geriatric Use

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. (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. Loxapine is not approved for the treatment of patients with dementia-related psychosis. (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.

Interactions for Loxapine

Drugs Affecting Hepatic Microsomal Enzymes

Pharmacokinetic interactions with inhibitors of CYP2D6, CYP3A4, or CYP1A2 are possible.

Specific Drugs

Drug

Interaction

Comments

Alcohol

Potential additive CNS depressant effects

Use with caution

Anticholinergic drugs

Possible potentiated anticholinergic effects

Use with caution

Anticonvulsants (e.g., carbamazepine, phenobarbital, phenytoin)

Anticonvulsants may decrease plasma loxapine concentrations

Loxapine may lower seizure threshold

Phenytoin: Loxapine may decrease serum phenytoin concentrations

Dosage adjustment of anticonvulsants may be necessary during concomitant use

Beta-blockers (e.g., propranolol)

Possible further lowering of BP

Use with caution and consider reduced loxapine dosage

CNS depressants (e.g., antihistamines, barbiturates, general anesthetics, opiate analgesics, sedative/hypnotics)

Possible additive effects or potentiated action of other CNS depressants

Use with caution to avoid excessive sedation or CNS depression

Epinephrine or dopamine

Possible further lowering of BP

Do not use epinephrine or dopamine for loxapine-induced hypotension (see Cardiovascular Effects under Cautions)

Lithium

An acute encephalopathic syndrome reported occasionally, especially when high serum lithium concentrations present

Observe patients receiving combined therapy for evidence of adverse neurologic effects; promptly discontinue if such signs or symptoms appear

Lorazepam

Possible respiratory depression, stupor, and/or hypotension

Loxapine Pharmacokinetics

Absorption

Bioavailability

Rapidly and almost completely absorbed from GI tract following oral administration. Almost completely absorbed following IM administration (IM dosage form of loxapine hydrochloride no longer commercially available in the US). Appears to undergo first-pass metabolism.

Peak serum concentrations generally attained within 1–3 hours after oral administration; considerable interindividual variation in peak concentrations reported.

Onset

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

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.

Duration

Duration of sedation following single-dose, oral administration is approximately 12 hours.

Distribution

Extent

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

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

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. Significant amounts of the N-oxides of the hydroxyloxapines also present.

Elimination Route

Loxapine and its metabolites are excreted in urine and feces.

Half-life

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

Stability

Storage

Oral

Capsules

Tight, light-resistant containers at 15–30°C.

Actions

  • Produces pharmacologic effects similar to those of other conventional antipsychotic agents (e.g., phenothiazines, butyrophenones, thioxanthenes, molindone).

  • Precise mechanism(s) of antipsychotic action not determined, but may be principally related to antidopaminergic and antiserotonergic effects; other neurotransmitter systems may be involved.

  • Antagonism of α1-adrenergic receptors and cholinergic receptors may contribute to adverse effects (e.g., orthostatic hypotension, dry mouth, blurred vision).

Advice to Patients

  • Importance of advising patients and caregivers that geriatric patients with dementia-related psychosis treated with antipsychotic agents are at an increased risk of death. Inform patients and caregivers that loxapine is not approved for treating geriatric patients with dementia-related psychosis.

  • Potential for drug to impair mental alertness or physical coordination; use caution when driving or operating machinery until effects on individual are known.

  • Importance of avoiding alcohol during loxapine therapy.

  • Importance of clinicians informing patients in whom chronic use is contemplated of risk of tardive dyskinesia, taking into account clinical circumstances and competency of patient to understand information provided.

  • Importance of clinicians informing patients of risk of extrapyramidal reactions and providing reassurance that these reactions usually can be controlled by administration of antiparkinsonian drugs (e.g., benztropine) and by subsequent dosage reduction.

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses (e.g., cardiovascular disease, seizure disorder).

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed. Importance of clinicians informing patients about the benefits and risks of taking antipsychotics during pregnancy (see Pregnancy under Cautions). Importance of advising patients not to stop taking loxapine if they become pregnant without consulting their clinician; abruptly stopping antipsychotic agents may cause complications.

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Loxapine Succinate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

5 mg (of loxapine)*

Loxapine Succinate Capsules

Amide, Mylan, Watson

Loxitane

Watson

10 mg (of loxapine)*

Loxapine Succinate Capsules

Amide, Mylan, Watson

Loxitane

Watson

25 mg (of loxapine)*

Loxapine Succinate Capsules

Amide, Mylan, Watson

Loxitane

Watson

50 mg (of loxapine)*

Loxapine Succinate Capsules

Amide, Mylan, Watson

Loxitane

Watson

AHFS DI Essentials™. © Copyright 2021, Selected Revisions May 27, 2019. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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