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Nortriptyline Hydrochloride

Pronunciation

Class: Tricyclics and Other Norepinephrine-reuptake Inhibitors
VA Class: CN601
CAS Number: 894-71-3
Brands: Pamelor

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.h i Nortriptyline is not approved for use in pediatric patients.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.h i

  • Depression and certain other psychiatric disorders are themselves associated with an increased risk of suicide.h i j

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

Introduction

Tricyclic antidepressant (TCA);a active metabolite of amitriptyline.d

Uses for Nortriptyline Hydrochloride

Major Depressive Disorder

Management of major depressive disorder.a

Results of several studies of TCAs in preadolescent and adolescent patients with major depression indicate lack of overall efficacy in this age group.

Attention Deficit Hyperactivity Disorder

Second-line agent in attention deficit hyperactivity disorder (ADHD) patients unable to tolerate or unresponsive to stimulants; should be used only under close supervision.b

Associated with a narrower margin of safety than some other therapeutic agents; use only if clearly indicated and with careful monitoring, including baseline and subsequent determinations of ECG and other parameters.

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Eating Disorders

Has been used for management of eating disorder (e.g., bulimia, anorexia nervosa) with equivocal results; avoid use in underweight individuals and in those exhibiting suicidal ideation.b

Smoking Cessation

Second-line agent for the management of nicotine (tobacco) dependence in patients who received first-line drugs (e.g., bupropion [as extended-release tablets], nicotine polacrilex gum, transdermal nicotine) but were not able to quit smoking or in whom these drugs are contraindicated.

Bipolar Disorder

Has been used for the short-term management of acute depressive episodes in bipolar disorder.b e

TCAs associated with a greater risk of precipitating hypomania or manic episodes than other classes of antidepressants;e should always be used in combination with a mood stabilizer (e.g., lithium).e

Schizophrenia

Has been used for the management of acute depressive episodes (in combination with an antipsychotic) in patients with schizophrenia.b

Anxiety Disorders

Has been used for the management of anxiety (in combination with anxiolytics, sedatives, or antipsychotics) in patients with depression.b

Postherpetic Neuralgia

Among the drugs of choice for the symptomatic treatment of postherpetic neuralgia.b

Insomnia

Less effective for insomnia and associated with more serious adverse reactions than conventional hypnotics.b

Nortriptyline Hydrochloride Dosage and Administration

General

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

  • 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 h i j (See Worsening of Depression and Suicidality Risk under Cautions.)

  • Sustained therapy may be required; monitor periodically for need for continued therapy.a

  • Avoid abrupt discontinuance in patients receiving high dosages for prolonged periods.a b To avoid withdrawal reactions, taper dosage gradually.a b

Administration

Oral Administration

Administer orally in up to 4 divided doses or as a single daily dose.a

Dosage

Available as nortriptyline hydrochloride; dosage is expressed in terms of nortriptyline.a

Adults

Major Depressive Disorder
Oral

Initially, 25 mg daily.g Gradually adjust to level that produces maximal therapeutic effects (up to 200 mg daily).d

Usual dosage: Manufacturer recommends 75–100 mg daily, but some experts state usual dosage range is 50–200 mg daily.a g After symptoms are controlled, dosage should be gradually reduced to the lowest level that will maintain relief of symptoms.d

Hospitalized patients under close supervision may generally be given higher dosages than outpatients.d

Smoking Cessation
Oral

25 mg daily, and then gradually increase to a target dosage of 75–100 mg daily.104

Initiate nortriptyline therapy 10–28 days before date set for cessation of smoking.104

Nortriptyline was continued for approximately 12 weeks in clinical studies.104

Prescribing Limits

Adults

Major Depressive Disorder
Oral

Manufacturer does not recommend dosages >150 mg daily, but higher dosages (e.g., 200 mg daily) have been used.a g

Special Populations

Geriatric Patients

30–50 mg daily.a

Cautions for Nortriptyline Hydrochloride

Contraindications

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

  • During the acute recovery phase following MI.a

  • Known hypersensitivity to nortriptyline, other dibenzazepine-derivative TCAs, or any ingredient in the formulation.a

Warnings/Precautions

Warnings

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, whether or not they are taking antidepressants; may persist until clinically important remission occurs.h i j k However, suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.h i j

Appropriately monitor and closely observe patients receiving nortriptyline for any reason, particularly during initiation of therapy (i.e., the first few months) and during periods of dosage adjustments.h i j (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.i j 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.h i j

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

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

Bipolar Disorder

May unmask bipolar disorder.i (See Activation of Mania or Hypomania under Cautions.) Nortriptyline 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.i

Cardiovascular Effects

Possible arrhythmias, sinus tachycardia, prolongation of the conduction time, MI, and stroke.a

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;b monitor closely.a

Interactions

May block hypotensive actions of guanethidine and similar agents.a

May enhance effects of alcohol.a Use with caution in patients with a history of excessive alcohol consumption.a (See Interactions.)

Possible pharmacokinetic (increased systemic exposure to nortriptyline) interaction with quinidine.a

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).a b

Seizures

Risk of seizures; use with caution in patients with a history of seizures.a

Hyperthyroidism

Possible development of cardiac arrhythmias; use with caution and under close supervision in hyperthyroid patients or patients receiving thyroid agents.a

Cognitive/Physical Impairment

Performance of activities requiring mental alertness and physical coordination may be impaired.a

Sensitivity Reactions

Cross-hypersensitivity

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

Photosensitivity

Avoid excessive exposure to sunlight.a

General Precautions

Activation of Mania or Hypomania

Possible activation of mania and hypomania, particularly in patients with bipolar disorder;a decrease dosage and/or administer an antipsychotic agent (e.g., perphenazine) concomitantly.e (See Bipolar Disorder under Cautions.)

Increased anxiety, agitation, and hostility also may occur, particularly when administered to overactive or agitated patients.a

Psychosis

Risk of manifestations of psychosis in patients with schizophrenia.a

Electroconvulsive Therapy (ECT)

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

Elective Surgery

Discontinue therapy several days prior to surgery whenever possible.a

Blood Glucose Effects

Possible alterations in blood glucose concentrations.a

Specific Populations

Pregnancy

Category D.f Possible cardiovascular or limb reduction anomalies.f

Lactation

Distributes into milk;100 101 102 use not recommended.a f

Pediatric Use

Not effective in management of depression in children or adolescents in clinical studies; manufacturer states not recommended for use in children <18 years of age.a

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).i 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.k No suicides occurred in these pediatric trials.i k

Carefully consider these findings when assessing potential benefits and risks of nortriptyline in a child or adolescent for any clinical use.h i j k (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; select dosage with caution.a

In pooled data analyses, a reduced risk of suicidality was observed in adults ≥65 years of age with antidepressant therapy compared with placebo.h i (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, hepatic (e.g., elevated liver enzymes, jaundice),a orthostatic hypotension, and sedative effects of TCAs. Monitor carefully, particularly for cardiovascular toxicity (e.g., arrhythmias, fluctuations in BP).a

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

Hepatic Impairment

Use with caution.a

Common Adverse Effects

Anticholinergic effects (e.g., dry mouth,b constipation,b vision disturbance),b orthostatic hypotension,b sedation,b weakness,b lethargy,b fatigue.b

Interactions for Nortriptyline Hydrochloride

Metabolized in the liver by various CYP isoenzymes (e.g., CYP1A2, CYP2C, CYP2D6, CYP3A4).b

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors of CYP2D6: Potential pharmacokinetic interaction (increased nortriptyline concentrations).a Adjust nortriptyline dosage whenever a CYP2D6 inhibitor is added or discontinued.a

Specific Drugs

Drug

Interaction

Comments

Alcohol

Potentiates the effects of alcohola

Increased risks if overdose or suicide attempt occursa

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

Potential for decreased nortriptyline metabolisma

Possible increased plasma nortriptyline concentrations and prolonged half-life when quinidine administered concomitantlya

Monitor for TCA toxicitya

Anticholinergic agents

Hyperthermia, particularly during hot weather, and paralytic ileusb

Use with caution; dosage adjustment may be neededa

Anticoagulants (e.g., warfarin)

Possible increased PTb

Antipsychotics (e.g., phenothiazines)

Potential for decreased nortriptyline metabolismb

Use with cautionb

Chlorpropamide

Substantial hypoglycemia possiblea

Cimetidine

Potential for decreased nortriptyline metabolisma

Hypotensive agents (e.g., guanethidine)

Antagonizes the antihypertensive effects of guanethidinea

Levodopa

May interfere with levodopa absorptionb

Monitor levodopa dosage carefullyb

MAO inhibitors

Potentially life-threatening serotonin syndromea

Concomitant use contraindicateda

Allow at least 14 days to elapse when switching to or from these drugsa

Reserpine

Possible stimulating effect in depressed patientsa

SSRIs (e.g., fluoxetine, paroxetine, sertraline)

Possible serotonin syndromea

Potential for decreased nortriptyline metabolism and increased plasma concentrationsa

Use with caution; monitor for TCA toxicitya

Allow at least 5 weeks to elapse when switching from fluoxetinea

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

Increased vasopressor, cardiac effectsb

Use with caution; dosage adjustment may be requiredb

Thyroid agents

Possible cardiac arrhythmiasa

Use with caution and under close supervisiona

Nortriptyline Hydrochloride Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentrations occur within 7–8.5 hours after oral administration.d

Onset

Antidepressant effects may not be evident for ≥2 weeks.b

Plasma Concentrations

Optimal antidepressant effect may be associated with plasma concentrations of 50–150 ng/mL.103

Distribution

Extent

Distributes into milk;100 101 102 nortriptyline concentrations in milk appear to be similar to or slightly greater than those present in maternal serum.101 102

Elimination

Metabolism

Extensively metabolized in the liver via demethylation by various CYP isoenzymes (e.g., CYP1A2, CYP2D6, CYP3A4, CYP2C).b

Elimination Route

Excreted principally in urine (33% within 24 hours) as inactive metabolites; small amounts are also excreted in feces via biliary elimination.d

Half-life

Plasma half-life ranges from 16 to >90 hours.d

Stability

Storage

Oral

Capsules and Oral Solution

Tight, light-resistant containers at 25°C (may be exposed to 15–30°C).a

Actions

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

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

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.h i j FDA recommends providing written patient information (medication guide) explaining risks of suicidality each time the drug is dispensed.h i j

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

  • Importance of patients understanding that it may take more than 2 weeks before the full effects are apparent.a d

  • Importance of avoiding alcohol-containing beverages or products.a

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

  • Importance of informing patients of other important precautionary information.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

Nortriptyline Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

10 mg (of nortriptyline)*

Nortriptyline Hydrochloride Capsules

Mylan, Teva, Watson

Pamelor (with benzyl alcohol and parabens)

Mallinckrodt

25 mg (of nortriptyline)*

Nortriptyline Hydrochloride Capsules

Mylan, Teva, Watson

Pamelor (with benzyl alcohol and parabens)

Mallinckrodt

50 mg (of nortriptyline)*

Nortriptyline Hydrochloride Capsules

Mylan, Teva, Watson

Pamelor (with benzyl alcohol parabens and sodium bisulfite)

Mallinckrodt

75 mg (of nortriptyline)*

Nortriptyline Hydrochloride Capsules

Mylan, Teva

Pamelor (with benzyl alcohol and parabens)

Mallinckrodt

Solution

10 mg (of nortriptyline) per 5 mL*

Nortriptyline Hydrochloride Oral Solution

Pharmaceutical Associates, Ranbaxy

Pamelor (with alcohol 4%)

Mallinckrodt

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.

Nortriptyline HCl 10MG Capsules (WATSON LABS): 90/$22.99 or 180/$33.97

Nortriptyline HCl 10MG/5ML Solution (PHARMACEUTICAL ASSOCIATES): 473/$53.99 or 1419/$150.99

Nortriptyline HCl 25MG Capsules (TEVA PHARMACEUTICALS USA): 30/$12.99 or 60/$15.98

Nortriptyline HCl 50MG Capsules (WATSON LABS): 30/$19.99 or 60/$28.97

Nortriptyline HCl 75MG Capsules (WATSON LABS): 30/$19.99 or 60/$28.97

Pamelor 10MG Capsules (MALLINCKRODT): 30/$695.99 or 90/$2,029.97

Pamelor 25MG Capsules (MALLINCKRODT): 30/$695.99 or 90/$2,029.97

Pamelor 75MG Capsules (MALLINCKRODT): 30/$541.01 or 90/$1,451.01

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions September 1, 2007. 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. Roche Products Inc. Endep prescribing information. In: Huff BB, ed. Physicians’ desk reference. 39th ed. Oradell, NJ: Medical Economics Company Inc; 1985:1711-2.

101. Brixen-Rasmussen L, Halgrener J, Jorgensen A. Amitriptyline and nortriptyline excretion in human breast milk. Psychopharmacology. 1982; 76:94-5. [PubMed 6805016]

102. Bader TF, Newman K. Amitriptyline in human breast milk and the nursing infant’s serum. Am J Psychiatry. 1980; 137:855-6. [IDIS 117830] [PubMed 7386673]

103. American Psychiatric Association Task Force on the Use of Laboratory Tests in Psychiatry. Tricyclic antidepressants—blood level measurements and clinical outcome: an APA Task Force Report. Am J Psychiatry. 1985; 142:155-62. [IDIS 195887] [PubMed 3881999]

104. Fiore MC, Bailey WC, Cohen SJ et al. Treating tobacco use and dependence: clinical practice guideline. Rockville, MD: US Department of Health and Human Service. 2000 Jun.

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

106. 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 web site: ().

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

a. Mallinckrodt Inc., Pamelor (nortriptyline hydrochloride) capsules and oral solution prescribing information. St. Louis, MO; 2001 Oct 11.

b. AHFS drug information 2004. McEvoy GK, ed. Tricyclic antidepressants general statement. Bethesda, MD: American Society of Health-System Pharmacists; 2004:2234-41.

d. AHFS drug information 2004. McEvoy GK, ed. Nortriptyline hydrochloride. Bethesda, MD: American Society of Health-System Pharmacists; 2004:2256-7.

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

f. Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and lactation. 5th ed. Baltimore, MD: Williams & Wilkins; 2002:693-4.

g. American Psychiatric Association. Practice guideline for the treatment of patients with major depressive disorder (revision). Am J Psychiatry. 2000; 150(Suppl 4):1-45.

h. 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:

i. 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:

j. 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:

k. 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]

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