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
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
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
ActionsActions
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
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 04/2011. 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/$25.99 or 90/$55.97
Loxapine Succinate 50MG Capsules (WATSON LABS): 30/$39.99 or 90/$99.97
Loxitane 5MG Capsules (WATSON LABS): 60/$91.99 or 180/$258.95
Disclaimer
This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.
The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.
AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions March 15, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.
References
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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.
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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]
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