Maprotiline Hydrochloride

Class: Tricyclics and Other Norepinephrine-reuptake Inhibitors
VA Class: CN609
Chemical Name: N-methyl-9,10-ethanoanthracene-9(10H)-propylamine hydrochloride
Molecular Formula: C20H23N HCl
CAS Number: 10347-81-6

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.103 104 107 Maprotiline is not approved for use in pediatric patients.107 (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.103 104

  • Depression and certain other psychiatric disorders are themselves associated with an increased risk of suicide.103 104 105

  • Appropriately monitor and closely observe all patients who are started on maprotiline therapy for clinical worsening, suicidality, or unusual changes in behavior; involve family members and/or caregivers in this process.103 104 105 (See Worsening of Depression and Suicidality Risk and Pediatric Use under Cautions.)

Introduction

Dibenzo-bicyclo-octadiene-derivative tetracyclic antidepressant; pharmacologically similar to tricyclic antidepressants (TCAs).107 b e k l

Uses for Maprotiline Hydrochloride

Depressive and Anxiety Disorders

Management of depressive disorders, including dysthymic disorder (depressive neurosis) and major depressive disorder.107 b e l

Management of anxiety associated with depression.107 b

Slideshow: Top 9 Symptoms Of Depression To Watch For

Bipolar Disorder

Has been used for the management of acute depressive episodes in bipolar disorder.107 b

However, the American Psychiatric Association (APA) currently does not recommend antidepressant monotherapy for the management of acute depressive episodes in patients with bipolar disorder† to avoid precipitation of hypomania or manic episodes.a 104 107 When antidepressants are used in combination with first-line therapies (e.g., lithium, lamotrigine) in patients with bipolar disorder, antidepressants other than TCAs (e.g., bupropion, SSRIs, venlafaxine) generally are preferred.a 104 107 c (See Bipolar Disorder and see also Activation of Mania or Hypomania under Cautions.)

Maprotiline Hydrochloride Dosage and Administration

General

Depressive and Anxiety Disorders

  • Allow at least 2 weeks to elapse between discontinuance of therapy with an MAO inhibitor and initiation of maprotiline and vice versa.107 c e l

  • Monitor for possible worsening of depression, suicidality, or unusual changes in behavior, especially at the beginning of therapy or during periods of dosage adjustments.103 104 105 107 d (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.107 b c

Administration

Oral Administration

Administer orally in up to 3 divided doses or as a single daily dose (e.g., at bedtime to reduce daytime sedation).107 b e l Has been given parenterally†, but a parenteral dosage form is not commercially available in the US.e l

Dosage

Available as maprotiline hydrochloride; dosage is expressed in terms of the salt.107

Individualize dosage carefully according to individual requirements and response; initiate at low dosage and gradually increase.107 b l

Adults

Depressive and Anxiety Disorders
Outpatients
Oral

Patients with illness of mild to moderate severity: Initially, 75 mg daily; maintain initial dosage for 2 weeks.107 b e l May gradually increase dosage in 25-mg increments as necessary based on tolerability and response.107 b e l

After symptoms are controlled, gradually reduce dosage to the lowest level that will maintain relief of symptoms.107 b l Usual maintenance dosage: 75–150 mg daily.107 b e l To reduce risk of seizures, maintenance dosage should be <200 mg daily.100 b (See Seizures under Cautions.)

Hospitalized Patients
Oral

More seriously ill patients: Initially, 100–150 mg daily.107 b e l May gradually increase dosage as necessary based on tolerability and response.107 b Most patients respond to 150 mg daily but dosages of ≤225 mg daily may be required in some patients.107 b

After symptoms are controlled, gradually reduce dosage to the lowest level that will maintain relief of symptoms.107 b l Usual maintenance dosage: 75–150 mg daily.107 b e l To reduce risk of seizures, maintenance dosage should be <200 mg daily.100 b (See Seizures under Cautions.)

Prescribing Limits

Adults

Depressive and Anxiety Disorders
Outpatients
Oral

Maximum 150 mg daily.107 b

Hospitalized Patients
Oral

Maximum 225 mg daily initially.107 b l Maintenance dosage should be <200 mg daily.100 b

Special Populations

Geriatric Patients

Lower dosages recommended for patients >60 years of age; maintenance dosages of 50–75 mg daily generally are satisfactory.107 b e l

Cautions for Maprotiline Hydrochloride

Contraindications

  • Concurrent or recent (i.e., within 2 weeks) therapy with an MAO inhibitor.107 c e l (See Specific Drugs under Interactions.)

  • Known or suspected seizure disorders.107 (See Seizures under Cautions.)

  • During the acute recovery phase following MI.107

  • Known hypersensitivity to maprotiline.107

Warnings/Precautions

Warnings

Shares the toxic potentials of TCAs; observe the usual precautions of TCA therapy.107 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.103 104 105 106 107 d However, suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.103 104 105

Appropriately monitor and closely observe patients receiving maprotiline for any reason, particularly during initiation of therapy (i.e., the first few months) and during periods of dosage adjustments.103 104 105 107 d (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.104 105 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.103 104 105 107 (See General under Dosage and Administration.)

Prescribe in smallest quantity consistent with good patient management to reduce risk of overdosage.104 107 c d

Observe these precautions for patients with psychiatric (e.g., major depressive disorder, obsessive-compulsive disorder [OCD]) or nonpsychiatric disorders.104 107 c

Bipolar Disorder

May unmask bipolar disorder.104 107 a c e (See Activation of Mania or Hypomania under Cautions.) Maprotiline is not approved for use in treating bipolar depression.104 107 (See Bipolar Disorder under Uses.)

Screen for risk of bipolar disorder by obtaining detailed psychiatric history (e.g., family history of suicide, bipolar disorder, depression) prior to initiating therapy.104 107 c d

Seizures

Seizures reported; most cases occurred in patients with no previous history of seizures, but risk factors (e.g., concurrent use of drugs known to lower seizure threshold, rapid escalation of maprotiline dosage, administration of higher than recommended maprotiline dosages) were present in some cases.100 107 b e f l Concomitant use of phenothiazines or rapid tapering of benzodiazepine dosage also may increase seizure risk.100 107 (See Specific Drugs under Interactions.)

Minimize risk of seizures by initiating maprotiline at a low dosage, maintaining initial dosage for 2 weeks prior to gradually increasing dosage in small increments, and using the lowest effective maintenance dosage.100 107 b l (See Dosage and Administration.)

Cardiovascular Effects

Possible conduction defects, arrhythmias, MI, stroke, hypotension, and tachycardia, particularly at higher dosages.107 b c e

Use with extreme caution and monitor closely (e.g., perform ECG at baseline and as appropriate during therapy) in patients with history of MI, patients with a history of or preexisting cardiovascular disease, and patients with disturbed eating behaviors (e.g., purging) that result in inadequate hydration and/or compromised cardiac status.107 c h (See Contraindications under Cautions.)

Possible Prescribing and Dispensing Errors

Ensure accuracy of prescription; similarity in spelling of Ludiomil (maprotiline hydrochloride; no longer commercially available under this trade name in the US) and Lamictal (lamotrigine) may result in errors.101 102 b

Sensitivity Reactions

Possible sensitivity reactions, including skin rash, petechiae, pruritus, photosensitization, edema, and drug fever.107 e l

General Precautions

Activation of Mania or Hypomania

Activation of mania and hypomania reported in some patients receiving TCAs, particularly in patients with bipolar disorder; such reactions also reported in patients receiving maprotiline.104 107 a c e l (See Bipolar Disorder under Uses and also under Cautions.)

Cognitive/Physical Impairment

Mental alertness or physical coordination required for performing hazardous tasks (e.g., driving, operating machinery) may be impaired.107 c e l

Response to alcohol and other CNS depressants may be potentiated; use with caution.107 c l (See Specific Drugs under Interactions.)

Anticholinergic Effects

Use with caution in patients for whom excess anticholinergic activity could be harmful (e.g., IOP, history of urinary retention or angle-closure glaucoma, prostatic hypertrophy).107 c e l

Hematological Effects

Perform leukocyte and differential counts in any patient who develops symptoms of blood dyscrasias (e.g., fever, sore throat).107 c If evidence of pathologic neutrophil depression is found, discontinue the drug.107 c

Electroconvulsive Therapy (ECT)

Avoid concomitant administration because of insufficient experience.107

Thyroid Disorders

Possible increased cardiovascular toxicity of maprotiline.107 c Use with caution in hyperthyroid patients or patients receiving thyroid agents.107 c

Elective Surgery

Discontinue therapy for as long as clinically feasible prior to surgery.107

Specific Populations

Pregnancy

Category B.107 j

Lactation

Distributes into breast milk.107 b e j l Use with caution.107 e l

Pediatric Use

Safety and efficacy of maprotiline in pediatric patients <18 years of age have not been established.107 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, OCD, or other psychiatric disorders based on pooled analyses of 24 short-term, placebo-controlled trials of 9 antidepressant drugs (SSRIs and others).104 107 d 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.106 No suicides occurred in these pediatric trials.104 106 107 d

Carefully consider these findings when assessing potential benefits and risks of maprotiline in a child or adolescent for any clinical use.103 104 105 106 107 (See Worsening of Depression and Suicidality Risk under Cautions.)

Geriatric Use

Maprotiline is generally effective and well tolerated in geriatric patients.e l

In pooled data analyses, a reduced risk of suicidality was observed in adults ≥65 years of age with antidepressant therapy compared with placebo.103 104 (See Boxed Warning and also see Worsening of Depression and Suicidality Risk under Cautions.)

Titrate dosage carefully.107 b c e h l (See Geriatric Patients under Dosage and Administration.)

Common Adverse Effects

Anticholinergic effects (e.g., dry mouth, constipation),107 e l drowsiness,107 e l dizziness,107 e l nervousness,107 tremor,107 e l skin rash.107 e l

Interactions for Maprotiline Hydrochloride

Drugs Affecting Hepatic Microsomal Enzymes

Potential pharmacokinetic interaction (increased or decreased plasma maprotiline concentrations) with concomitant use of CYP2D6 inhibitors or inducers; use with caution.107 c Consider maprotiline dosage adjustment whenever a CYP2D6 inhibitor or inducer is added or discontinued.107 c

Specific Drugs

Drug

Interaction

Comments

Alcohol

Possible additive CNS effects107 c

Use with caution107

Anticholinergic agents

May potentiate atropine-like effects; possible hyperthermia, particularly during hot weather, and paralytic ileus 107 c l

Use with caution and under close supervision; dosage adjustment may be needed107 c

Antipsychotic agents (e.g., phenothiazines)

Possible increased risk of seizures during concomitant phenothiazine therapy 100 107

Benzodiazepines

Possible increased risk of seizures when benzodiazepine dosage rapidly decreased100 107

Cimetidine

Possible increased plasma maprotiline concentrations107 c

Monitor for maprotiline toxicity; dosage adjustment may be needed107 c

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

Potentiates the effects of CNS depressants107 c

Barbiturates: Possible decreased plasma maprotiline concentrations107

Use with caution107

Barbiturates: Dosage adjustment may be needed107

Guanethidine and related compounds

Possible antagonism of the antihypertensive effects of guanethidine and related compounds107 c e l

Use with caution107

MAO inhibitors

Potentially life-threatening serotonin syndrome c

Concomitant use contraindicated107 c e l

Allow at least 2 weeks to elapse when switching to or from these drugs107 c e l

Phenytoin

Possible decreased plasma maprotiline concentrations107

Dosage adjustment may be needed107

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

Potential for decreased maprotiline metabolism and increased plasma concentrations107 c

Use with caution; dosage adjustment may be needed107 c

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

Possible increased vasopressor, cardiac effects107 c l

Use with caution and under close supervision; dosage adjustment may be needed107 c

Thyroid agents

Possible increased cardiovascular toxicity107 c

Use with caution 107 c

Maprotiline Hydrochloride Pharmacokinetics

Absorption

Bioavailability

Slowly and completely absorbed from GI tract.107 b e g h l

Peak plasma concentrations usually occur within 7–24 hours after single-dose, oral administration; steady-state concentrations usually are attained within 7 days.107 b e g h l

Onset

Antidepressant effects may occur within 3–7 days but 2–3 weeks usually is necessary.107 b l

Distribution

Extent

Distributed into liver, lung, kidney, brain, adrenal gland, heart, and muscle.b l

Distributed into milk; concentrations in milk similar to those present in maternal serum.107 b e j l

Plasma Protein Binding

Approximately 88%.b e l

Elimination

Metabolism

Slowly metabolized in the liver principally to active metabolites desmethylmaprotiline, which may undergo further transformation, and maprotiline-N-oxide.b e k

Elimination Route

Approximately 60% excreted in urine within 21 days principally as conjugated metabolites; approximately 30% excreted in feces.b e k l

Half-life

Average: 51 hours (range: 27–58 hours).107 b e g l

Special Populations

Single-dose pharmacokinetics in geriatric patients appear similar to those reported in younger adults.h

Stability

Storage

Oral

Tablets

Tight, light-resistant containers at 20–25°C.107

Actions

  • Pharmacology is similar to that of the TCAs.107 b e l

  • Mechanism of action in the management of depressive and anxiety disorders is unknown but may involve inhibition of norepinephrine reuptake.107 b e l Unlike most TCAs, maprotiline does not appear to influence serotonin reuptake.107 b e l

  • Exhibits anticholinergic activity and sedative properties.107 b e l

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.103 104 105 107 d FDA recommends providing written patient information (medication guide) explaining risks of suicidality each time the drug is dispensed.103 104 105 107

  • Importance of informing patients about possibility of seizures during maprotiline therapy and that the risk of seizures may be increased in patients with a history of seizure disorders or in those concomitantly receiving certain medications known to lower seizure threshold (e.g., phenothiazines, rapid tapering of benzodiazepine dosage).100 107 b (See Seizures under Cautions and also see Specific Drugs under Interactions.)

  • Importance of considering possible impaired ability to perform hazardous activities (e.g., operating machinery, driving a motor vehicle).107 c e l

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.107

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses (e.g., seizure disorders) or planned surgery.107

  • Importance of informing patients of other important precautionary information.107 (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

Maprotiline Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

25 mg*

Maprotiline Hydrochloride Tablets (with polyethylene glycol)

Mylan

50 mg*

Maprotiline Hydrochloride Tablets (with polyethylene glycol)

Mylan

75 mg*

Maprotiline Hydrochloride Tablets (with polyethylene glycol)

Mylan

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.

Maprotiline HCl 25MG Tablets (MYLAN): 60/$48.39 or 180/$120.96

Maprotiline HCl 50MG Tablets (MYLAN): 60/$68.19 or 180/$189.18

Maprotiline HCl 75MG Tablets (MYLAN): 60/$90.19 or 180/$249.66

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions January 1, 2008. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

100. Dessain EC, Schatzberg AF, Woods BT et al. Maprotiline treatment in depression: a perspective on seizures. Arch Gen Psychiatry. 1986; 43:86-90. [IDIS 208809] [PubMed 3942475]

101. Pattishall EN. Dear healthcare provider letter regarding dispensing errors involving Lamictal (lamotrigine). Research Triangle Park, NC: GlaxoSmithKline; undated.

102. Pattishall EN. Dear pharmacist letter: Dispensing errors alert. Research Triangle Park, NC: GlaxoSmithKline; 2001 Aug.

103. 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.

104. 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.

105. 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.

106. 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]

107. Mylan Pharmaceuticals Inc. Maprotiline hydrochloride tablets prescribing information. Morgantown, WV. 2006 Feb.

108. American Academy of Pediatrics (AAP). Children, antidepressants and a black box warning. Washington, D.C; 2004 Oct. 15. From the AAP website.

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

a. American Psychiatric Association. Practice guideline for the treatment of patients with bipolar disorder (revised). Am J Psychiatry. 2002; 159(Suppl):1-49.

b. AHFS drug information 2007. McEvoy GK, ed. Maprotiline hydrochloride. Bethesda, MD: American Society of Health-System Pharmacists; 2007:2375-7.

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. Pinder RM, Brogden RN, Speight TM et al. Maprotiline: a review of its pharmacological properties and therapeutic efficacy in mental depressive states. Drugs. 1977; 13:321-52. [PubMed 326531]

f. Jabbari B, Bryan GE, Marsh EE et al. Incidence of seizures with tricyclic and tetracyclic antidepressants. Arch Neurol. 1985; 42:480-1. [PubMed 3994566]

g. Maguire KP, Norman TR, Burrows GD et al. An evaluation of maprotiline intravenous kinetics and comparison of two oral doses. Eur J Clin Pharmacol. 1980; 18:249-54. [PubMed 7439244]

h. Hrdina PD, Rovei V, Henry JF et al. Comparison of single-dose pharmacokinetics of imipramine and maprotiline in the elderly.Psychopharmacology. 1980; 70:29-34. [PubMed 6775331]

i. 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.

j. Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation. 7th ed. Baltimore, MD: Williams & Wilkins; 2005:962-3.

k. Rotzinger S, Bourin M, Akimoto Y et al. Metabolism of some “second”- and “fourth”-generation antidepressants: iprindole, viloxazine, bupropion, mianserin, maprotiline, trazodone, nefazodone, and venlafaxine. Cell Mol Neurobiol. 1999; 19:427-42. [PubMed 10379419]

l. Wells BG, Gelenberg AJ. Chemistry, pharmacology, pharmacokinetics, adverse effects, and efficacy of the antidepressant maprotiline hydrochloride. Pharmacotherapy. 1981; 1:121-39. [PubMed 6765485]

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