Surmontil

Generic Name: Trimipramine Maleate
Class: Tricyclics and Other Norepinephrine-reuptake Inhibitors
VA Class: CN601
Chemical Name: 5-(3-Dimethylamino-2-methylpropyl)-10,11-dihydro-5H-dibenz(b,f)azepine acid maleate
Molecular Formula: C20H26N2•C4H4O4
CAS Number: 521-78-8

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.100 101 102 Trimipramine is not approved for use in pediatric patients.100 a (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.100 101 102

  • Depression and certain other psychiatric disorders are themselves associated with an increased risk of suicide.100 101 102 103

  • Appropriately monitor and closely observe all patients who are started on trimipramine therapy for clinical worsening, suicidality, or unusual changes in behavior; involve family members and/or caregivers in this process.100 101 102 103 (See Worsening of Depression and Suicidality Risk and see Pediatric Use under Cautions.)

Introduction

Dibenzazepine-derivative tricyclic antidepressant (TCA).100 a b c i

Uses for Surmontil

Major Depressive Disorder

Management of major depressive disorder.100 a b c i

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Insomnia

Although has been used in the treatment of insomnia and other sleep disturbances in depressed patients,b i tricyclics generally are less effective for insomnia and associated with more serious adverse reactions than conventional hypnotics.b

Enuresis

Has been used in the treatment of nocturnal enuresis (bedwetting) in pediatric patients; however, clinical efficacy not established in controlled trials.c d

Surmontil Dosage and Administration

General

Major Depressive Disorder

  • Allow at least 2 weeks to elapse between discontinuance of therapy with an MAO inhibitor and initiation of trimipramine and vice versa.100 a b Also allow at least 5 weeks to elapse when switching from fluoxetine.100 a b

  • Monitor for possible worsening of depression, suicidality, or unusual changes in behavior, especially at the beginning of therapy or during periods of dosage adjustments.100 101 102 103 (See Worsening of Depression and Suicidality Risk under Cautions.)

  • Sustained therapy may be required; administer lowest effective dosage and monitor periodically for need for continued therapy.100 a b c

  • Avoid abrupt discontinuance of therapy in patients receiving trimipramine for prolonged periods.100 a b To avoid withdrawal reactions, taper dosage gradually.100 a b (See Withdrawal of Therapy under Cautions.)

Administration

Oral Administration

Administer orally in up to 4 divided doses daily or as a single daily dose (if ≤200 mg) at bedtime to avoid daytime sedation.100 a b c

Dosage

Available as trimipramine maleate; dosage is expressed in terms of trimipramine.100 a c

Individualize dosage carefully according to individual requirements and response.100 a b c

Maximum antidepressant effects may not occur for ≥2 weeks after therapy is begun.100 a b

Pediatric Patients

Major Depressive Disorder
Oral

Adolescents: Lower dosages recommended than for adults.100 a c Initially, 50 mg daily.100 a c Increase dosage gradually up to 100 mg daily based on patient response and tolerance.100 a c (See Pediatric Use under Cautions.)

After symptoms are controlled, gradually reduce dosage to the lowest level that will maintain relief of symptoms.100 a c Continue maintenance therapy for ≥3 months to prevent relapse.100 a c

Adults

Major Depressive Disorder
Outpatients
Oral

Initially, 75 mg daily given in divided doses.100 a c May increase dosage up to 150 mg daily; dosages >200 mg daily not recommended.100 a c ECG monitoring is recommended during therapy initiation and at appropriate intervals during dosage stabilization in patients with resistant depression requiring trimipramine dosages >2.5 mg/kg daily.100 a

After symptoms are controlled, gradually reduce dosage to the lowest level that will maintain relief of symptoms.100 a c Usual maintenance dosage: 50–150 mg daily.100 a c Continue maintenance therapy for ≥3 months to prevent relapse.100 a c

Hospitalized Patients
Oral

Initially, 100 mg daily given in divided doses.100 a c May gradually increase dosage up to 200 mg daily based on patient response and tolerance.100 a c Then, if there is no improvement evident within 2–3 weeks, may increase dosage up to the maximum recommended dosage of 250–300 mg daily.100 a c ECG monitoring is recommended during therapy initiation and at appropriate intervals during dosage stabilization in patients with resistant depression requiring trimipramine dosages >2.5 mg/kg daily.100 a

After symptoms are controlled, gradually reduce dosage to the lowest level that will maintain relief of symptoms.100 a c Continue maintenance therapy for ≥3 months to prevent relapse.100 a c

Prescribing Limits

Pediatric Patients

Major Depressive Disorder
Oral

Adolescents: Maximum 100 mg daily.100 a c

Adults

Major Depressive Disorder
Outpatients
Oral

Maximum 200 mg daily.100 a c

Hospitalized Patients
Oral

Maximum 300 mg daily.100 a c

Special Populations

Geriatric Patients

Lower dosages recommended for geriatric patients.100 a b Initially, 50 mg daily.100 a c Increase dosage gradually up to 100 mg daily based on patient response and tolerance.100 a c After symptoms are controlled, gradually reduce dosage to the lowest level that will maintain relief of symptoms.100 a c (See Geriatric Use under Cautions.)

Cautions for Surmontil

Contraindications

  • Concurrent or recent (i.e., within 2 weeks) therapy with an MAO inhibitor.100 a b (See Specific Drugs under Interactions.)

  • During the acute recovery phase following MI.100 a b

  • Known hypersensitivity to trimipramine.100 a b Consider possible cross-sensitivity with other dibenzazepine-derivative TCAs (e.g., clomipramine, desipramine, imipramine).100 a b

Warnings/Precautions

Warnings

Shares the toxic potentials of other TCAs; observe the usual precautions of TCA therapy.100 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.100 101 102 103 104 f However, suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.100 101 102 103

Appropriately monitor and closely observe patients receiving trimipramine for any reason, particularly during initiation of therapy (i.e., the first few months) and during periods of dosage adjustments.100 101 102 103 f (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.100 102 103 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.100 101 102 103 (See General under Dosage and Administration.)

Prescribe in smallest quantity consistent with good patient management to reduce risk of overdosage.100 102 a f

Observe these precautions for patients with psychiatric (e.g., major depressive disorder, obsessive-compulsive disorder [OCD]) or nonpsychiatric disorders.100 102 a b

Bipolar Disorder

May unmask bipolar disorder.100 102 a b (See Activation of Mania or Hypomania under Cautions.) Trimipramine is not approved for use in treating bipolar depression.100 102 a b

Screen for risk of bipolar disorder by obtaining detailed psychiatric history (e.g., family history of suicide, bipolar disorder, depression) prior to initiating therapy.100 102 a b f

Cardiovascular Effects

Possible conduction defects, arrhythmias, MI, stroke, tachycardia, and hypotension.100 a b i

Patients with preexisting or prior history of cardiac disease,100 a b geriatric patients,b and patients with disturbed eating behaviors (e.g., purging) that result in inadequate hydration and/or compromised cardiac status most at risk.b Use with caution and monitor closely (e.g., perform ECG at baseline and as appropriate during therapy).100 a b

Anticholinergic Effects

Use with caution in patients for whom excess anticholinergic activity could be harmful (e.g., history of urinary retention, increased intraocular pressure, angle-closure glaucoma, prostatic hypertrophy).100 a b

Seizures

Lowers seizure threshold; use with caution in patients with a history of seizures.100 a b

Thyroid Disorders

Possible cardiovascular toxicity (e.g., arrhythmias); use with caution in hyperthyroid patients or patients receiving thyroid agents.100 a b

Cognitive/Physical Impairment

Mental alertness or physical coordination required for performing hazardous tasks (e.g., driving, operating machinery) may be impaired.100 a b i r

Response to alcohol and other CNS depressants may be potentiated; use with caution.100 a b i (See Specific Drugs under Interactions.)

Interactions

May block hypotensive actions of guanethidine and similar compounds.100 a b (See Specific Drugs under Interactions.)

Sensitivity Reactions

Cross-hypersensitivity

Possible cross-sensitivity to other dibenzazepine-derivative TCAs (e.g., clomipramine, desipramine, imipramine).100 a b

Photosensitivity

Photosensitivity reported with TCAs; patients demonstrating photosensitivity should avoid excessive exposure to sunlight.100 a b

General Precautions

Activation of Mania or Hypomania

Possible activation of mania or hypomania, particularly in patients with bipolar disorder.100 a b (See Bipolar Disorder under Cautions.)

Psychosis

Possible exacerbation of psychosis in patients with schizophrenia; decrease dosage and/or administer an antipsychotic agent concomitantly.100 a b

Electroconvulsive Therapy (ECT)

Possible increased ECT risks; limit to patients for whom concomitant use is essential.100 a

Elective Surgery

Discontinue therapy several days prior to surgery whenever possible.100 a b

Hematologic Effects

Perform leukocyte and differential counts in any patient who develops symptoms of blood dyscrasias (e.g., fever, sore throat).100 a b If evidence of pathologic neutrophil depression is found, discontinue the drug.100 a b

Blood Glucose Effects

Possible alterations in blood glucose concentrations.100 a b

Withdrawal of Therapy

Possible withdrawal reactions (e.g., nausea, headache, malaise); avoid abrupt discontinuance of therapy and taper dosage gradually.100 a b

Specific Populations

Pregnancy

Category C.100 a

Lactation

Not known but considered likely to distribute into breast milk.b l Discontinue nursing or the drug.b l

Pediatric Use

Safety and efficacy of trimipramine in pediatric patients not established.100 a

FDA warns that a greater risk of suicidal thinking or behavior (suicidality) occurred during the 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).100 102 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.104 No suicides occurred in these pediatric trials.100 102 104

Carefully consider these findings when assessing potential benefits and risks of trimipramine in a child or adolescent for any clinical use.100 101 102 103 104 (See Worsening of Depression and Suicidality Risk under Cautions.)

Geriatric Use

Insufficient experience from clinical trials in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults; select dosage with caution.100 a b

In pooled data analyses, a reduced risk of suicidality was observed in adults ≥65 years of age with antidepressant therapy compared with placebo.100 101 102 (See Boxed Warning and also see Worsening of Depression and Suicidality Risk under Cautions.)

Possible increased sensitivity to anticholinergic (e.g., dry mouth, constipation, vision disturbance), cardiovascular, orthostatic hypotension, and sedative effects of TCAs.100 a b

Titrate dosage carefully.100 a b (See Geriatric Patients under Dosage and Administration.)

Hepatic Impairment

Use with caution.100 a

Common Adverse Effects

Drowsiness or sedation,100 a b i anticholinergic effects (e.g., dry mouth, constipation, blurred vision),100 a b i orthostatic hypotension,100 a b i weight gain.100 a b i

Interactions for Surmontil

Metabolized in the liver by various CYP isoenzymes (e.g., CYP2D6, CYP3A4, CYP2C19, CYP2C9).100 a b e j k r

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors of CYP2D6: Potential pharmacokinetic interaction (increased plasma trimipramine concentrations).100 a b k Consider trimipramine dosage adjustment whenever a CYP2D6 inhibitor is added or discontinued.100 a b

Specific Drugs

Drug

Interaction

Comments

Alcohol

Possible additive CNS effects100 a b

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

Potential for decreased trimipramine metabolism100 a b

Dosage adjustment may be needed100 a b

Anticholinergic agents

Possible additive anticholinergic effects; hyperthermia, particularly during hot weather, and paralytic ileus100 a b d

Use with caution; dosage adjustment may be needed100 a b i

Antipsychotics (e.g., phenothiazines, atypical antipsychotics)

Potential for decreased trimipramine metabolism with phenothiazines100 a b

Olanzapine: Decreased plasma olanzapine concentrations reportedo

Use with caution; dosage adjustment may be needed100 a b

Cimetidine

Potential for decreased trimipramine metabolism100 a b

Monitor for TCA toxicity; dosage adjustment may be needed100 a b

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

Potentiates the effects of CNS depressantsb

Use with cautioni

Eszopiclone and zopiclone (not commercially available in the US)

Decreased bioavailability of trimipramine and zopiclone observed during concurrent administrationq s

Consider the possibility that similar interaction could occur with eszopiclones

Guanethidine and related compounds

Possible antagonism of the antihypertensive effects of guanethidine and related compounds100 a b

Levodopa

May interfere with levodopa absorptionb

Monitor levodopa dosage carefullyb

MAO inhibitors

Potentially life-threatening serotonin syndrome100 a b

Concomitant use contraindicated100 a b

Allow at least 2 weeks to elapse when switching to or from these drugs100 a b

Methylphenidate

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

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

Potential for decreased trimipramine metabolism and increased plasma concentrations100 a b k

Possible serotonin syndromeb

Use with caution and monitor for TCA toxicity; dosage adjustment may be needed100 a b

Allow at least 5 weeks to elapse when switching from fluoxetine100 a b

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

Increased vasopressor, cardiac effectsb

Use with caution; dosage adjustment may be required100 a b

Thyroid agents

Possible increased cardiovascular toxicity100 a b

Use with caution100 a b

Venlafaxine

Possible increased risk of seizuresp

Surmontil Pharmacokinetics

Absorption

Bioavailability

Relatively well absorbed from the GI tract following oral administration with peak plasma concentrations usually attained within 2–6 hours.c e i m

Bioavailability varies but averages approximately 41–43%.g m

Onset

Maximum antidepressant effects may not be evident for ≥2 weeks.100 a b c

Distribution

Extent

Widely distributed in the body.b m

Not known but considered likely to be distributed into breast milk.b l

Plasma Protein Binding

Approximately 95%.m

Elimination

Metabolism

Extensively metabolized in the liver by various CYP isoenzymes (e.g., CYP2D6, CYP3A4, CYP2C19, CYP2C9)r to principal and pharmacologically active metabolite, desmethyltrimipramine, and other metabolites phenotype.100 a b c d e j k m r Individuals with the poor-metabolizer phenotype for CYP2D6 metabolize the drug more slowly than those with normal metabolizers.100 a b r

Elimination Route

Excreted principally in urine.b c

Half-life

14–46 hours.c i j l m

Special Populations

Single-dose pharmacokinetics reported in geriatric individuals appear similar to those reported in younger adults.100 a

Stability

Storage

Oral

Capsules

Tight containers at 20–25°C (may be exposed to 15–30°C).100 a

Actions

  • Mechanism of action in the management of depression unknown but may involve inhibition of reuptake of norepinephrine and/or serotonin.100 a b

  • Exhibits anticholinergic activity and anxiety-reducing sedative properties.100 a b i Also demonstrates antihistaminic and antiadrenergic activity.i

  • Does not substantially inhibit MAO.100 a Does not produce CNS stimulation activity.100 a

  • Associated with more frequent anticholinergic, sedative, and cardiovascular effects and weight gain than SSRIs.b i

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.101 102 103 FDA recommends providing written patient information (medication guide) explaining risks of suicidality each time the drug is dispensed.101 102 103

  • Importance of considering possible impaired ability to perform hazardous activities (e.g., operating machinery, driving a motor vehicle).100 a b r

  • Risk of concomitant use with alcohol.100 a b

  • Risk of photosensitivity reactions.100 a b

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.100 a

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses or planned surgery.100 a

  • Importance of informing patients of other important precautionary information.100 a (See Cautions.)

Preparations

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

Trimipramine Maleate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

25 mg (of trimipramine)

Surmontil

Duramed

50 mg (of trimipramine)

Surmontil

Duramed

100 mg (of trimipramine)

Surmontil

Duramed

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.

Surmontil 50MG Capsules (ODYSSEY PHARMACEUTICALS INC.): 100/$209.98 or 180/$359.97

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

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

100. Duramed Pharmaceuticals, Inc. Surmontil (trimipramine maleate) capsules prescribing information. Ponoma, NY; 2007 Jun.

101. 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.

102. 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.

103. 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.

104. 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]

a. Actavis Totowa LLC. Trimipramine maleate capsules prescribing information. Totowa, NJ. 2006 Aug.

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

c. AHFS drug information 2007. McEvoy GK, ed. Trimipramine maleate. Bethesda, MD: American Society of Health-System Pharmacists; 2007:2378-9.

d. Forsythe WI, Merrett JD, Redmond A. A controlled clinical trial of trimipramine and placebo in the treatment of enuresis. Br J Clin Pract. 1972; 26:119-21. [PubMed 4558395]

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

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

g. American Psychiatric Association (APA). APA responds to FDA’s new warning on antidepressants. Arlington, VA; 2004 Oct. 15. From the APA website.

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

i. Lapierre YD. A review of trimipramine: 30 years of clinical use. Drugs. 1989; 38(Suppl 1):17-24. [PubMed 2693051]

j. Kirchheiner J, Muller G, Meineke I et al. Effects of polymorphisms in CYP2D6, CYP2C9, and CYP2C19 on trimipramine pharmacokinetics. J Clin Psychopharmacol. 2003; 23:459-66. [PubMed 14520122]

k. Seifritz E, Holsboer-Trachsler E, Hemmeter U et al. Increased trimipramine plasma levels during fluvoxamine comedication. Eur Neuropsychopharmacol. 1994; 4:15-20. [PubMed 8204992]

l. Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation. 7th ed. Baltimore, MD: Williams & Wilkins; 2005:1637-8.

m. Abernethy DR, Greenblatt DJ, Shader RI. Trimipramine kinetics and absolute bioavailability: use of gas-liquid chromatography with nitrogen-phosphorus detection. Clin Pharmacol Ther. 1984; 35:348-53. [PubMed 6697642]

n. American Academy of Child and Adolescent Psychiatry. Summary of the practice parameters for teh assessment and treatment of children and adolescents with depressive disorders. From the AACAP website.

o. Bergemann N, Frick A, Parzer P et al. Olanzapine plasma concentration, avergae daily dose, and interaction with co-medication in schizophrenic patients.Pharmacopsychiatry. 2004; 37:63-8. [PubMed 15048613]

p. Schlienger RG, Klink MH, Eggenbeger C et al. Seizures associated with therapeutic doses of venlafaxine and trimipramine.Pharmacother. 2000; 34:1402-5.

q. Caille G, du Souich P, Spenard J et al. Pharmacokinetics and clinical parameters of zopiclone and trimipramine when administered simultaneously to volunteers.Biopharm Drug Dispos. 1984; 5:117-25. [PubMed 6743780]

r. Kirchheiner J, Sasse J, Meineke I et al. Trimipramine pharmacokinetics after intravenous and oral administration in carriers of CYP2D6 genotypes predicting poor, extensive and ultrahigh activity. Pharmacogenetics. 2002; 13:721-8.

s. Mack A, Salazar JO. Eszopiclone: a novel cyclopyrrolone with potential benefit in both transient and chronic insomnia. Formulary. 2003; 38:582-93.

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