VA Class:CN601

VA Class:AD900

AHFS Class:

• Tricyclics and Other Norepinephrine-reuptake Inhibitors 28:16.04.28

Generic Name(s):

• Nortriptyline Hydrochloride

Nortriptyline is a dibenzocycloheptene-derivative tricyclic antidepressant drug that is the active metabolite of amitriptyline.

Administration

Nortriptyline hydrochloride is administered orally. Although nortriptyline has been administered in up to 4 divided doses throughout the day, it is long-acting and the entire daily dose may be administered at one time.

Dosage

Dosage of nortriptyline hydrochloride is expressed in terms of nortriptyline. There is a wide range of dosage requirements and dosage must be carefully individualized. Initial dosages should be low and may be gradually adjusted to the level that produces maximal therapeutic effect with minimal toxicity.

Patients should be monitored for possible worsening of depression, suicidality, or unusual changes in behavior, especially at the beginning of therapy or during periods of dosage adjustment.105,106,107,109 (See Cautions: Precautions and Contraindications, in the Tricyclic Antidepressants General Statement 28:16.04.28.)

Depressive and Other Psychiatric Disorders

The manufacturers state that the usual adult dosage of nortriptyline is 75-100 mg daily and that dosages greater than 150 mg daily are not recommended; if dosage exceeds 100 mg daily, plasma nortriptyline concentrations should be monitored. Hospitalized patients under close supervision may generally be given higher dosages than outpatients. Geriatric and adolescent patients should usually be given lower than average dosages. The manufacturers state that these patients may obtain satisfactory improvement with 30-50 mg of nortriptyline daily. Maximal antidepressant effects may not occur for 2 or more weeks after therapy is begun.

After symptoms are controlled, dosage should be gradually reduced to the lowest level which will maintain relief of symptoms. To avoid the possibility of precipitating withdrawal symptoms, nortriptyline should not be terminated abruptly in patients who have received high dosage for prolonged periods.

Smoking Cessation

For use in the cessation of smoking†, nortriptyline therapy has been initiated in clinical studies at a dosage of 25 mg daily, and then gradually increased to a target dosage of 75-100 mg daily.104 So that steady state can be reached at the targeted dosage, nortriptyline therapy should be initiated 10-28 days before the date set for cessation of smoking.104 Nortriptyline was continued for approximately 12 weeks in clinical studies for smoking cessation.104

Nortriptyline shares the pharmacologic actions, uses, and toxic potentials of the tricyclic antidepressants, and the usual precautions of tricyclic antidepressant administration should be observed. Patients should be fully advised about the risks, especially suicidal thinking and behavior (suicidality), associated with tricyclic antidepressant therapy.106,107,109 For a complete discussion, see Cautions: Precautions and Contraindications and Cautions: Pediatric Precautions, in the Tricyclic Antidepressants General Statement 28:16.04.28.

Some commercially available formulations of nortriptyline hydrochloride contain sodium bisulfite, a sulfite that may cause allergic-type reactions, including anaphylaxis and life-threatening or less severe asthmatic episodes, in certain susceptible individuals. The overall prevalence of sulfite sensitivity in the general population is unknown but probably low; such sensitivity appears to occur more frequently in asthmatic than in nonasthmatic individuals.

Pediatric Precautions

Safety and efficacy of nortriptyline in children have not been established. Therefore, at least one manufacturer of nortriptyline recommends that the drug not be used in children.

The US Food and Drug Administration (FDA) has determined that antidepressants increase the risk of suicidal thinking and behavior (suicidality) in children and adolescents with major depressive disorder and other psychiatric disorders.106,109 However, the FDA also states that depression and certain other psychiatric disorders are themselves associated with an increased risk of suicide.106,109 Anyone considering the use of nortriptyline in a child or adolescent for any clinical use must therefore balance the potential risk of therapy with the clinical need.106,107,108,109 (See Cautions: Precautions and Contraindications and Cautions: Pediatric Precautions, in the Tricyclic Antidepressants General Statement 28:16.04.28.)

Pharmacokinetics

Absorption

No information is available on the rate or degree of absorption of nortriptyline hydrochloride from the GI tract. Peak plasma concentrations occur within 7-8.5 hours after oral administration. Optimal response to the drug appears to be associated with plasma concentrations of 50-150 ng/mL.103

Distribution

Nortriptyline is distributed 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

The plasma half-life of nortriptyline ranges from 16 to more than 90 hours. Nortriptyline is metabolized via the same pathways as are other tricyclic antidepressants. Approximately one-third of a dose of nortriptyline is excreted in urine as metabolites within 24 hours, and small amounts are excreted in feces via biliary elimination.

Chemistry and Stability

Chemistry

Nortriptyline is a dibenzocycloheptene-derivative tricyclic antidepressant drug that is the active metabolite of amitriptyline. Nortriptyline hydrochloride occurs as a white to off-white powder with a slight characteristic odor and is soluble in water and in alcohol. The drug has a pK_a of 9.73.

Stability

The commercially available oral solution of nortriptyline hydrochloride should be stored in tight, light-resistant containers at a temperature less than 30°C. Nortriptyline hydrochloride capsules should be stored in tight containers at a temperature less than 30°C.

Additional Information

For further information on chemistry, pharmacology, pharmacokinetics, uses, cautions, drug interactions, acute toxicity, and dosage and administration of nortriptyline, see the Tricyclic Antidepressants General Statement 28:16.04.28.

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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. [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. [PubMed 3881999]

104. Fiore MC, Jaén CR, Baker TB, et al. Treating tobacco use and dependence: 2008 update. Clinical Practice Guideline. Rockville, MD: US Department of Health and Human Services, Public Health Service. 2008 May.

105. 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. [Web]

106. 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. [Web]

107. 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. [Web]

108. 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]

109. Mallinckrodt Inc. Pamelor^® (nortriptyline) prescribing information. Hazelwood, MO; 2007 Sep.