Loxapine Succinate

Pronunciation

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

Warning(s)

Special Alerts:

[Posted 02/22/2011] ISSUE: FDA notified healthcare professionals that the Pregnancy section of drug labels for the entire class of antipsychotic drugs has been updated. The new drug labels now contain more and consistent information about the potential risk for abnormal muscle movements (extrapyramidal signs or EPS) and withdrawal symptoms in newborns whose mothers were treated with these drugs during the third trimester of pregnancy.

The symptoms of EPS and withdrawal in newborns may include agitation, abnormally increased or decreased muscle tone, tremor, sleepiness, severe difficulty breathing, and difficulty in feeding. In some newborns, the symptoms subside within hours or days and do not require specific treatment; other newborns may require longer hospital stays.

BACKGROUND: Antipsychotic drugs are used to treat symptoms of psychiatric disorders such as schizophrenia and bipolar disorder.

RECOMMENDATION: Healthcare professionals should be aware of the effects of antipsychotic medications on newborns when the medications are used during pregnancy. Patients should not stop taking these medications if they become pregnant without talking to their healthcare professional, as abruptly stopping antipsychotic medications can cause significant complications for treatment. For more information visit the FDA website at: and .

[Posted 06/16/2008] FDA notified healthcare professionals that both conventional and atypical antipsychotics are associated with an increased risk of mortality in elderly patients treated for dementia-related psychosis. In April 2005, FDA notified healthcare professionals that patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death. Since issuing that notification, FDA has reviewed additional information that indicates the risk is also associated with conventional antipsychotics. Antipsychotics are not indicated for the treatment of dementia-related psychosis. The prescribing information for all antipsychotic drugs will now include the same information about this risk in a BOXED WARNING and the WARNINGS section. For more information visit the FDA website at: , and .

Introduction

Tricyclic dibenzoxazepine-derivative, conventional (prototypical, first-generation) antipsychotic agent; structurally related to amoxapine, clozapine, and olanzapine.a b e g h i j q r s u v w x

Uses for Loxapine Succinate

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Psychotic Disorders

Symptomatic management of psychotic disorders (i.e., schizophrenia).a b e g h i j q r

Slideshow: The Side Effects of Stress - 8 of the Most Common

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

Mental Retardation

Efficacy not established for the management of behavioral complications in patients with mental retardation.a b g h

Loxapine Succinate Dosage and Administration

General

  • Adjust dosage carefully according to individual requirements and response; use the lowest possible effective dosage.a b g h j q r v

  • Periodically evaluate patients receiving long-term therapy to determine whether maintenance dosage can be decreased or drug therapy discontinued.a g h aa (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.b i q aa v

Administration

Oral Administration

Loxapine succinate is administered orally, usually in divided doses 2–4 times daily.a b g h j v Loxapine hydrochloride has been given orally and parenterally, but no longer is commercially available in the US.b e j k

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Available as loxapine succinate; dosage expressed in terms of loxapine.a b g h k

Adults

Psychotic Disorders
Oral

Initially, 10 mg given twice daily.a b g h j q r v

In severely schizophrenic patients, an initial dosage of up to 50 mg daily may be preferable.a b g h j q r v

May increase dosage fairly rapidly during the first 7–10 days of therapy according to patient response and tolerance.a b g h j q r v

Usual maintenance dosage: 60–100 mg daily; some patients respond to a lower dosage and others require a higher dosage.a b g h i j q r t v For severely ill patients with chronic schizophrenia, some clinicians recommend maintenance dosages of 100–200 mg daily.b

Prescribing Limits

Adults

Psychotic Disorders
Oral

Maximum 250 mg daily.a b g h v

Special Populations

Geriatric Patients

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

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.i j r aa dd (See Geriatric Use under Cautions.)

Cautions for Loxapine Succinate

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

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

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

Tardive Dyskinesia

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

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

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).a b g h aa

Response to CNS depressants and alcohol may be potentiated.a b g h (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.cc

Sensitivity Reactions

Hypersensitivity and Cross-sensitivity

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.)

Photosensitivity

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

General Precautions

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Seizures

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 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.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

Cardiovascular Effects

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.)

Prolactin Secretion

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

Anticholinergic Effects

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.)

Ocular Effects

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

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).a b g h aa

Specific Populations

Pregnancy

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Category C.c

Lactation

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

Pediatric Use

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

Geriatric Use

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

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.)

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

Interactions for Loxapine Succinate

Drugs Affecting Hepatic Microsomal Enzymes

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

Specific Drugs

Drug

Interaction

Comments

Alcohol

Potential additive CNS depressant effectsa b g h j q r v

Use with cautiona b g h

Anticholinergic drugs

Possible potentiated anticholinergic effectsa b g h

Use with cautiona b g h

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

Anticonvulsants may decrease plasma loxapine concentrationss

Loxapine may lower seizure thresholda b g h j q r

Phenytoin: Loxapine may decrease serum phenytoin concentrationsq r

Dosage adjustment of anticonvulsants may be necessary during concomitant usej s

Beta-blockers (e.g., propranolol)

Possible further lowering of BPr v

Use with caution and consider reduced loxapine dosager v

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

Possible additive effects or potentiated action of other CNS depressantsa b g h j q r

Use with caution to avoid excessive sedation or CNS depressiona b g h r

Epinephrine or dopamine

Possible further lowering of BPa b g h aa

Do not use epinephrine or dopamine for loxapine-induced hypotensiona b g h aa (see Cardiovascular Effects under Cautions)

Lithium

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

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

Lorazepam

Possible respiratory depression, stupor, and/or hypotensiona g h p s

Loxapine Succinate Pharmacokinetics

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

Stability

Storage

Oral

Capsules

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

Actions

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

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

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

Advice to Patients

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

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

  • Importance of avoiding alcohol during loxapine therapy.a g h r

  • 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.a g h

  • 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.a g h aa

  • 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).a g h

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.a g h

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

Preparations

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

* 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

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Loxapine Succinate 5MG Capsules (WATSON LABS): 30/$28.99 or 90/$60.97

Loxapine Succinate 50MG Capsules (WATSON LABS): 30/$39.99 or 90/$99.97

Loxitane 5MG Capsules (WATSON LABS): 60/$99.35 or 180/$279.67

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions March 15, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

100. The United States pharmacopeia, 22nd rev, and the national formulary, 17th ed. Rockville, MD: The United States Pharmacopeial Convention, Inc; 1989 (Suppl 3):2356-7.

101. The USP Drug Nomenclature Committee. Nomenclature policies and recommendations: I. Review and current proposals and decisions. Pharmacopeial Forum. 1991; 17:1509-11.

102. Loxitane (loxapine succinate) prescribing information. In: Barnhart ET, publisher. Physicians’ desk reference. 44th ed. Oradell, NJ: Medical Economics Company Inc; 1991:1181-2.

a. Watson Laboratories, Inc. Loxapine capsules prescribing information. Corona, CA; 2005 Sept.

b. AHFS drug information 2007. McEvoy GK, ed. Loxapine succinate. Bethesda, MD: American Society of Health-System Pharmacists; 2007:2459-61.

c. Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation. 7th ed. Baltimore, MD: Williams & Wilkins; 2005:949.

d. American Academy of Pediatrics. Use of psychoactive medication during pregnancy and possible effects on the fetus and newborn. Pediatrics. 2000; 105:880-87. [PubMed 10742343]

e. Chakrabati A, Bagnall A, Chue P et al. Loxapine for schizophrenia. Cochrane Database Systematic Reviews. 2007; Issue 4:Article No.: CD001943. DOI: 10.1002/14651858.CD001943.pub2.

f. The United States Pharmacopeial Convention, Inc. USAN and the USP Dictionary drug names. Rockville, MD: United States Pharmacopeial Convention, Inc; 2007:509-10.

g. Watson Laboratories, Inc. Loxitane (loxapine succinate) capsules prescribing information. Corona, CA; 2007 Oct.

h. Mylan Pharmaceuticals Inc. Loxapine capsules prescribing information. Morgantown, WV; 2004 Apr.

i. American Psychiatric Association. Practice guideline for the treatment of patients with schizophrenia, second edition. From the APA website:

j. AMA Division of Drugs. AMA drug evaluations. ed. City: American Medical Association; 1994:1-29.

k. Lederle Laboratories. Loxitane (loxapine) capsules, oral concentrate, and injection prescribing information. Pearl River, NY; 1983 Sep.

l. Cohen LS, Heller VL, Rosenbaum JF. Treatment guidelines for psychotropic drug use in pregnancy. Psychosomatics. 1989; 30:25-33. [PubMed 2643809]

m. Calabrese JR, Gulledge AD. Psychotropics during pregnancy and lactation: a review. Psychosomatics. 1985; 26:413-26. [PubMed 2859631]

n. Goldberg H, Nissim R. Psychotropic drugs in pregnancy and lactation. Int J Psychiatry Med. 1994; 24:129-49. [PubMed 7960421]

o. Altshuler LL, Cohen L, Szuba MP et al. Pharmacologic management of psychiatric illness during pregnancy: dilemmas and guidelines. Am J Psychiatry. 1996; 153:592-606. [PubMed 8615404]

p. Battaglia J, Thornton L. Loxapine-lorazepam-induced hypotension and stupor. J Clin Psychopharmacol. 1989; 9:227-8. Letter. [PubMed 2738184]

q. Heel RC, Brogden RN, Speight TM et al. Loxapine: a review of its pharmacological properties and therapeutic efficacy as an antipsychotic agent. Drugs. 1978; 15:198-217. [PubMed 25167]

r. DePaulo JR, Ayd FJ. Loxapine: fifteen years’ clinical experience. Psychosomatics. 1982; 23:261-71. [PubMed 7041162]

s. Ereshefsky L. Pharmacologic and pharmacokinetic considerations in choosing an antipsychotic. J Clin Psychiatry. 1999; 60(Suppl 10):20-30. [PubMed 10340684]

t. Milton GV, Jann MW. Emergency treatment of psychotic symptoms: pharmacokinetic considerations for antipsychotic drugs. Clin Pharmacokinet. 1995; 28:494-504. [PubMed 7656507]

u. Gershon S, Hekimian LJ, Burdock EI et al. Antipsychotic properties of loxapine succinate. Cur Ther Res Clin Exp. 1970; 12:280-5.

v. Ayd FJ. Loxapine update: 1966-1976. Dis Nerv Syst. 1977; 38:883-7. [PubMed 410614]

w. Midha KK, Hubbard JW, McKay G et al. The role of metabolites in a bioequivalence study 1: loxapine, 7-hydroxyloxapine and 8-hydroxyloxapine. Int J Clin Pharmacol Ther Toxicol. 1993; 31:177-83. [PubMed 8500919]

x. Cooper SF, Dugal R, Bertrand MJ. Determination of loxapine in human plasma and urine and identification of three urinary metabolites. Xenobiotica. 1979; 9:405-14. [PubMed 494666]

y. Prakash R, Reed RM, Bass AD. Loxapine yields amoxapine. J Clin Psychopharmacol. 1984; 4:363-4. [PubMed 6512010]

z. Chong LS, Abbott PM. Neuroleptic malignant syndrome secondary to loxapine. Br J Psychiatry. 1991; 159:572-3. [PubMed 1751872]

aa. AHFS drug information 2007. McEvoy GK, ed. Phenothiazines general statement. Bethesda, MD: American Society of Health-System Pharmacists; 2007: 2439-50.

bb. Ewert AL, Klock J, Wells B et al. Neuroleptic malignant syndrome associated with loxapine. J Clin Psychiatry. 1983; 44:37-8. Letter. [PubMed 6822486]

cc. Food and Drug Administration. Important prescribing notice. Rockville, MD; 1998. From the FDA web site: .

dd. Howard R, Rabins PV, Seeman MY and the International Late-Onset Schizophrenia group. Late-onset schizophrenia and very-late-onset schizophrenia like psychosis: an international consensus. Am J Psychiatry. 2000; 157:172-8. [PubMed 10671383]

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