Medication Guide App

Amoxapine

Class: Tricyclics and Other Norepinephrine-reuptake Inhibitors
VA Class: CN601
Chemical Name: 2-Chloro-11-(1-piperazinyl)dibenz[b,f ][1,4]oxazepine
Molecular Formula: C17H16CIN3 O
CAS Number: 14028-44-5

Warning(s)

  • Suicidality
  • Antidepressants may increase risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (18–24 years of age) with major depressive disorder and other psychiatric disorders; balance this risk with clinical need.a d o p Amoxapine is not approved for use in pediatric patients <16 years of age.a b (See Pediatric Use under Cautions.)

  • In pooled data analyses, risk of suicidality was not increased in adults >24 years of age and apparently was reduced in adults ≥65 years of age with antidepressant therapy compared with placebo.a o p

  • Depression and certain other psychiatric disorders are themselves associated with an increased risk of suicide.a o p q

  • Appropriately monitor and closely observe all patients who are started on amoxapine therapy for clinical worsening, suicidality, or unusual changes in behavior; involve family members and/or caregivers in this process.a d o p q (See Worsening of Depression and Suicidality Risk and Pediatric Use under Cautions.)

Introduction

A dibenzoxazepine-derivative tricyclic antidepressant (TCA).101 a b c h i k l m

Uses for Amoxapine

Depressive Disorders

Symptomatic management of neurotic or reactive depressive disorders, endogenous depression, or psychotic depression.101 a b k l s

Slideshow: Depression, the Risk of Suicide, and Treatment Options

Treatment of depression accompanied by anxiety or agitation.101 a b k l s

Amoxapine Dosage and Administration

General

Depressive Disorders

  • Allow at least 2 weeks to elapse between discontinuance of therapy with an MAO inhibitor and initiation of amoxapine and vice versa.a c Also allow at least 5 weeks to elapse when switching from fluoxetine.a c

  • Monitor for possible worsening of depression, suicidality, or unusual changes in behavior, especially at the beginning of therapy or during periods of dosage adjustments.a d o p q (See Worsening of Depression and Suicidality Risk under Cautions.)

  • Duration of therapy depends on the condition being treated; during maintenance therapy, administer lowest effective dosage and periodically reassess need for continued therapy.a b c

Administration

Oral Administration

Administer orally in up to 3 divided doses or as a single daily dose (if daily dosage ≤300 mg) at bedtime to avoid daytime sedation.101 a b k l Daily dosages >300 mg daily should be administered in divided doses.101 a b k

Dosage

Individualize dosage carefully according to individual requirements and response.101 a b

Adults

Depressive Disorders
Outpatients
Oral

Initially, 50 mg 2 or 3 times daily; initial dosage of 300 mg daily may be given, but considerable sedation may occur during the first few days.101 a b k Dosage may be increased to 100 mg 2 or 3 times daily by the end of the first week.101 a b

Usual dosage: 200–300 mg daily.101 a b k Dosage may be further increased to a maximum of 400 mg daily if a satisfactory response is not achieved at a dosage of 300 mg daily for at least 2 weeks and if tolerated.101 a b k

After symptoms are controlled, gradually reduce dosage to the lowest level that will maintain relief of symptoms.101 a b

Hospitalized Patients
Oral

Initially, 50 mg 2 or 3 times daily; initial dosage of 300 mg daily may be given, but considerable sedation may occur during the first few days.101 a b k Dosage may be increased to 100 mg 2 or 3 times daily by the end of the first week.101 a b

Usual dosage: 200–300 mg daily.101 a b k Dosage may be further increased to a maximum of 600 mg daily if a satisfactory response is not achieved at a dosage of 300 mg daily for at least 2 weeks in patients without a history of seizure disorders and if tolerated.101 a b k l

After symptoms are controlled, gradually reduce dosage to the lowest level that will maintain relief of symptoms.101 a b

Prescribing Limits

Adults

Depressive Disorders
Outpatients
Oral

Maximum 400 mg daily.101 a b k

Hospitalized Patients
Oral

Maximum 600 mg daily.101 a b k l

Special Populations

Geriatric Patients

Select dosage at the lower end of recommended range since decreased hepatic and renal function are more frequent; increase dosage more gradually and monitor closely.101 a c k l (See Geriatric Use under Cautions.)

Initially, 25 mg 2 or 3 times daily.101 a b k Increase dosage to 50 mg 2 or 3 times daily by the end of the first week if tolerated.101 a Usual dosage: 100–150 mg daily; some patients may require a higher dosage (up to a maximum of 300 mg daily).101 a b

Cautions for Amoxapine

Contraindications

  • Concurrent or recent (i.e., within 2 weeks) therapy with an MAO inhibitor.101 a c (See Specific Drugs under Interactions.)

  • During the acute recovery phase following MI.101 a c

  • Known hypersensitivity to amoxapine or other dibenzoxazepine-derivative TCAs (e.g., doxepin).101 a c

Warnings/Precautions

Warnings

Shares the toxic potentials of other tricyclic antidepressants; observe the usual precautions of tricyclic antidepressant therapy.101 a b c

Worsening of Depression and Suicidality Risk

Possible worsening of depression and/or emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior in both adult and pediatric patients with major depressive disorder, whether or not they are taking antidepressants; may persist until clinically important remission occurs.a d g o p q However, suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.a o p q

Appropriately monitor and closely observe patients receiving amoxapine for any reason, particularly during initiation of therapy (i.e., the first few months) and during periods of dosage adjustments.a d o p q (See Boxed Warning and also see Pediatric Use under Cautions.)

Anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, and/or mania may be precursors to emerging suicidality.p q Consider changing or discontinuing therapy in patients whose depression is persistently worse or in those with emerging suicidality or symptoms that might be precursors to worsening depression or suicidality, particularly if severe, abrupt in onset, or not part of patient’s presenting symptoms.o p q

Prescribe in smallest quantity consistent with good patient management to reduce risk of overdosage.a c d p

Observe these precautions for patients with psychiatric (e.g., major depressive disorder, obsessive-compulsive disorder) or nonpsychiatric disorders.a c p

Bipolar Disorder

May unmask bipolar disorder.a p (See Activation of Mania or Hypomania under Cautions.) Amoxapine is not approved for use in treating bipolar depression.a

Screen for risk of bipolar disorder by obtaining detailed psychiatric history (e.g., family history of suicide, bipolar disorder, depression) prior to initiating therapy.a d p

Tardive Dyskinesia

Tardive dyskinesia, a syndrome of potentially irreversible, involuntary, dyskinetic movements, reported rarely in patients receiving amoxapine.101 a b c Consider discontinuance.101 a

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 amoxapine.101 102 a b c

Cardiovascular Effects

Possible conduction defects, arrhythmias, acute MI, stroke, and sinus tachycardia, particularly at higher dosages.101 a c f k l

Patients with preexisting cardiac disease and patients with disturbed eating behaviors (e.g., purging) that result in inadequate hydration and/or compromised cardiac status most at risk; monitor closely (e.g., perform ECG at baseline and as appropriate during therapy).101 a c f k l

Anticholinergic Effects

Use with caution in patients for whom excess anticholinergic activity could be harmful (e.g., history of urinary retention, increased IOP, angle-closure glaucoma).101 a c l

Seizures

Seizures reported; use with extreme caution in patients with a seizure disorder.101 a c l

Sensitivity Reactions

Possible sensitivity reactions including skin rash and drug fever; most likely during first few days of treatment.a c Discontinue drug if rash and/or fever occur.a

General Precautions

Activation of Mania or Hypomania

Possible activation of mania and hypomania, particularly in patients with bipolar disorder.101 a c (See Bipolar Disorder under Cautions.)

Psychosis

Possible exacerbation of psychosis in patients with schizophrenia, particularly in patients with paranoid symptoms; decrease dosage and/or administer an antipsychotic agent concomitantly.101 a c

Electroconvulsive Therapy (ECT)

Possible increased ECT risks.101 a

Specific Populations

Pregnancy

Category C.101 a e

Lactation

Distributed into milk.100 101 a e l Caution if used in nursing women; carefully assess potential benefits and risks.101 a c e

Pediatric Use

Safety and efficacy of amoxapine in pediatric patients <16 years of age have not been established.101 a b

FDA warns that a greater risk of suicidal thinking or behavior (suicidality) occurred during first few months of antidepressant treatment (4%) compared with placebo (2%) in children and adolescents with major depressive disorder, obsessive-compulsive disorder (OCD), or other psychiatric disorders based on pooled analyses of 24 short-term, placebo-controlled trials of 9 antidepressant drugs (SSRIs and others).a d p However, a more recent meta-analysis of 27 placebo-controlled trials of 9 antidepressants (SSRIs and others) in patients <19 years of age with major depressive disorder, OCD, or non-OCD anxiety disorders suggests that the benefits of antidepressant therapy in treating these conditions may outweigh the risks of suicidal behavior or suicidal ideation.g No suicides occurred in these pediatric trials.a d g p

Carefully consider these findings when assessing potential benefits and risks of amoxapine in a child or adolescent for any clinical use.a c g o p q (See Worsening of Depression and Suicidality Risk under Cautions.)

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.a

In pooled data analyses, a reduced risk of suicidality was observed in adults ≥65 years of age with antidepressant therapy compared with placebo.o p (See Boxed Warning and also see Worsening of Depression and Suicidality Risk under Cautions.)

Possible increased sensitivity to adverse effects of amoxapine (e.g., tardive dyskinesia, sedation)a c and to anticholinergic (e.g., dry mouth, constipation, vision disturbance), cardiovascular, and orthostatic hypotension effects of TCAs.

Titrate dosage carefully.a (See Geriatric Patients under Dosage and Administration.)

Common Adverse Effects

Anticholinergic effects (e.g., dry mouth, constipation, blurred vision), drowsiness, fatigue or lethargy, dizziness.101 a c k l s

Interactions for Amoxapine

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors of CYP2D6: potential pharmacokinetic interaction (increased plasma amoxapine concentrations); use with caution.a c Consider amoxapine dosage adjustment whenever a CYP2D6 inhibitor is added or discontinued.a c

Specific Drugs

Drug

Interaction

Comments

Alcohol

Potential additive CNS effects101 a c

Antiarrhythmics: class 1C (e.g., flecainide, propafenone); quinidine

Potential for decreased amoxapine metabolisma c

Dosage adjustment may be neededa c

Anticholinergic agents

Possible additive anticholinergic effects; hyperthermia, particularly during hot weather, and paralytic ileus also possible 101 a c k l

Use with caution; dosage adjustment may be neededc

Antipsychotics (e.g., phenothiazines)

Potential for decreased amoxapine metabolisma c

Dosage adjustment may be neededc

Cimetidine

Possible increased plasma amoxapine concentrations101 a c

Potential for tricyclic toxicity, particularly anticholinergic adverse effectsc

Monitor for TCA toxicity; dosage adjustment may be neededc

CNS depressants (e.g., analgesics, antihistamines, barbiturates, general anesthetics, opiates)

Potentiates the effects of CNS depressants101 a c l

Guanethidine and related compounds

Possible antagonism of the antihypertensive effects of guanethidine and related compoundsc l

Levodopa

May interfere with levodopa absorption c

Monitor levodopa dosage carefullyc

MAO inhibitors

Potentially life-threatening serotonin syndrome 101 a c l

Concomitant use contraindicated101 a c l

Allow at least 2 weeks to elapse when switching to or from these drugs101 a c

Methylphenidate

Potential for decreased metabolism and increased therapeutic efficacy and toxicity of TCAsc

SSRIs (e.g., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline)

Possible serotonin syndromec

Potential for decreased amoxapine metabolism and increased plasma concentrationsa c

Use with caution and monitor for TCA toxicity; dosage adjustment may be neededa c

Allow at least 5 weeks to elapse when switching from fluoxetinea c

Sympathomimetic agents (e.g., amphetamines, epinephrine, isoproterenol, norepinephrine, phenylephrine)

Increased vasopressor, cardiac effectsc l

Use with caution; dosage adjustment may be requiredc

Thyroid agents

Possible cardiac arrhythmiasc

Use with caution c

Amoxapine Pharmacokinetics

Absorption

Bioavailability

Rapidly and almost completely absorbed from the GI tract following oral administration.101 a b k l r s

Peak plasma concentrations usually occur within 1–2 hours after oral administration.101 a b j k l s

Onset

Antidepressant effects usually occur within 2 weeks in most patients who respond and may occur within 4–7 days.101 a b j

Distribution

Extent

Widely distributed in the body.c k l s

Amoxapine and its active metabolite, 8-hydroxyamoxapine, distribute into milk.100 101 a e l s

Plasma Protein Binding

Approximately 90%.101 a c k s

Elimination

Metabolism

Metabolized in the liver principally by CYP2D6 to 2 active metabolites, 8-hydroxyamoxapine and 7-hydroxyamoxapine.101 a b c h i j k l s Poor metabolizers of CYP2D6 metabolize the drug more slowly than normal metabolizers.a

Elimination Route

Excreted principally in urine as conjugated metabolites (60–69%) within 6 days and 7–18% excreted in feces principally as unconjugated metabolites; <5% excreted unchanged.101 a b c k l s

Half-life

Amoxapine: Approximately 8 hours.101 a b k l s

8-Hydroxyamoxapine: 30 hours.101 a b h j k l s

7-Hydroxyamoxapine: 6.5 hours.b h j k l

Stability

Storage

Oral

Tablets

Tight containers at 15–30°C.101 a b

Actions

  • Mechanism of action in the management of depressive disorders is unknown but may involve inhibition of reuptake of norepinephrine and to a lesser extent serotonin by amoxapine and its active metabolites, 8-hydroxyamoxapine and 7-hydroxyamoxapine.101 a c h k l m n s

  • Amoxapine is a derivative of the antipsychotic agent loxapine and has dopamine-receptor blocking properties; may possess some antipsychotic activity but clinical importance is unknown.b h k l m n s

Advice to Patients

  • Risk of suicidality; importance of patients, family, and caregivers being alert to and immediately reporting emergence of suicidality, worsening depression, or unusual changes in behavior, especially during the first few months of therapy or during periods of dosage adjustment.d o p q FDA recommends providing written patient information (medication guide) explaining risks of suicidality each time the drug is dispensed.o p q

  • 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.101 a

  • Importance of avoiding certain activities (e.g., operating machinery, driving a motor vehicle) until effects on the individual are known.101 a c

  • Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.101 a

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.101 a

  • Importance of informing patients of other important precautionary information.101 a (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

Amoxapine

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, scored

25 mg*

Amoxapine Tablets

Watson

50 mg*

Amoxapine Tablets

Watson

100 mg*

Amoxapine Tablets

Watson

150 mg*

Amoxapine Tablets

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.

Amoxapine 100MG Tablets (WATSON LABS): 30/$39.99 or 90/$119.96

Amoxapine 150MG Tablets (WATSON LABS): 30/$43.99 or 90/$109.98

Amoxapine 25MG Tablets (WATSON LABS): 60/$25.99 or 180/$68.99

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions October 1, 2007. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

100. Gelenberg AJ. Amoxapine, a new antidepressant, appears in human milk. J Nerv Ment Dis. 1979; 167:635-6. [PubMed 573779]

101. Lederle Laboratories. Asendin (amoxapine) prescribing information. Pearl River, NY; 1987 Nov.

102. Lesaca T. Amoxapine and neuroleptic malignant syndrome. Am J Psychiatry. 1987; 144:1514. [IDIS 235147] [PubMed 3118723]

103. Food and Drug Administration. Class suicidality labeling language for antidepressants. From the FDA website: ().

104. Food and Drug Administration. Public health advisory: suicidality in children and adolescents being treated with antidepressant medications. Rockville, MD; 2004 Oct 15. From the FDA website: ().

105. Food and Drug Administration. Medication guide: about using antidepressants in children or teenagers. Rockville, MD; 2005 Jan 16. From the FDA website: ().

a. Watson Laboratories, Inc. Amoxapine tablets prescribing information. Corona, CA; 2007 May.

b. AHFS drug information 2007. McEvoy GK, ed. Amoxapine. Bethesda, MD: American Society of Health-System Pharmacists; 2007:2362.

c. AHFS drug information 2007. McEvoy GK, ed. Tricyclic antidepressants general statement. Bethesda, MD: American Society of Health-System Pharmacists; 2007:2353-60.

d. American Psychiatric Association Practice Guidelines. Practice guideline for the treatment of patients with major depressive disorder, second edition. From the APA website ().

e. Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation. 7th ed. Baltimore, MD: Williams & Wilkins; 2005:72-3.

f. American Academy of Child and Adolescent Psychiatry. Summary of the practice parameters for the assessment and treatment of children and adolescents with depressive disorders. From the AACAP website: ().

g. Bridge JA, Iyengar S, Salary CB. Clinical response and risk for reported suicidal ideation and suicide attempts in pediatric antidepressant treatment: a meta-analysis of randomized controlled trials. JAMA. 2007; 297:1683-96. [PubMed 17440145]

h. Midha KK, Hubbard JW, McKay G et al. The role of metabolites in a bioequivalence study II: amoxapine, 7-hydroxyamoxapine, and 8-hydroxyamoxapine. Int J Clin Pharmacol Ther. 1999; 37:428-38. [PubMed 10507241]

i. Selinger K, Lebel G, Hill HM et al. A high-performance liquid chromatographic method for the analysis of amoxapine in human plasma. J Pharm Biomed Anal. 1989; 7:1001-7. [PubMed 2490101]

j. Calvo B, Garcia MJ, Pedraz JL et al. Pharmacokinetics of amoxapine and its active metabolites. Int J Clin Pharmacol Ther Toxicol. 1985; 23:180-5. [PubMed 3997304]

k. Kinney JL, Evans RL Jr. Evaluation of amoxapine. Clin Pharm. 1982; 1:417-24. [PubMed 6764165]

l. Dugas JE, Weber SS. Amoxapine (Asendin, Lederle Laboratories). Drug Intell Clin Pharm. 1982; 16:199-204. [PubMed 7037342]

m. Apiquian R, Fresan A, Ulloa RE et al. Amoxapine as an atypical antipsychotic: a comparative study vs risperidone. Neuropsychopharmacology. 2005; 30:2236-44. [PubMed 15956984]

n. Apiquian R, Ulloa E, Fresan A et al. Amoxapine shows atypical antipsychotic effects in patients with schizophrenia: results from a prospective open-label study. Schizophr Res. 2003; 59:35-9. [PubMed 12413640]

o. Food and Drug Administration. FDA news: FDA proposes new warnings about suicidal thinking, behavior in young adults who take antidepressant medications. Rockville, MD; 2007 May 2. From the FDA web site: .

p. Food and Drug Administration. Antidepressant use in children, adolescents, and adults: class revisions to product labeling. Rockville, MD; 2007 May 2. From the FDA web site: .

q. Food and Drug Administration. Revisions to medication guide: antidepressant medicines, depression and other serious mental illnesses and suicidal thoughts or actions. Rockville, MD; 2007 May 2. From the FDA web site:

r. Rudorfer MV, Potter WZ. Metabolism of tricyclic antidepressants.Cell Mol Neurobiol. 1999; 19:373-409. [PubMed 10319193]

s. Greenblatt EN, Hardy RA, Kelly RG. Amoxapine. Pharmacol Biochem Prop Drug Subst. 1979; 2:1-18.

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