VA Class:CN601

AHFS Class:

• Tricyclics and Other Norepinephrine-reuptake Inhibitors 28:16.04.28

Generic Name(s):

• Amitriptyline Hydrochloride

• Chlordiazepoxide and Amitriptyline Hydrochloride

• Perphenazine and Amitriptyline Hydrochloride

Amitriptyline hydrochloride is a dibenzocycloheptene-derivative tricyclic antidepressant.

Administration

Amitriptyline hydrochloride is given orally. Although amitriptyline has been administered in up to 4 divided doses throughout the day, it is long-acting and the entire oral daily dose may be administered at one time. Administration of the entire daily dose at bedtime may reduce daytime sedation.

In patients who were unwilling or unable to take amitriptyline orally, the drug also has been given IM. However, a parenteral dosage form is no longer commercially available in the US. Oral therapy should replace IM administration as soon as possible.

Dosage

There is a wide range of oral amitriptyline hydrochloride dosage requirements, and dosage must be carefully individualized.

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 (See Cautions: Precautions and Contraindications, in the Tricyclic Antidepressants General Statement 28:16.04.28.)

Initial dosages should be low and generally range from 75-100 mg daily, depending on the severity of the condition being treated. Dosage may be gradually adjusted (preferably the late-afternoon and/or bedtime doses) to the level that produces maximal therapeutic effect with minimal toxicity and may range from 150-300 mg daily. 103,104 Alternatively, the manufacturers recommend an initial amitriptyline hydrochloride dosage of 50-100 mg daily at bedtime.103 Dosage then can be increased by 25 or 50 mg as necessary to a suggested maximum of 150 mg daily.103 Hospitalized patients under close supervision may generally be given higher dosages than outpatients. Hospitalized patients generally may receive an initial amitriptyline dosage of 100 mg daily; dosage may be increased gradually to 200 mg daily as needed.103 Some patients may require dosages as high as 300 mg daily.103 Geriatric and adolescent patients should usually be given lower than average dosages. Manufacturers state that these patients may obtain satisfactory improvement with 10 mg of amitriptyline hydrochloride 3 times daily plus 20 mg at bedtime. Maximum antidepressant effects may not occur for 30 days after therapy is begun.103

After symptoms are controlled, dosage should be gradually reduced to the lowest level that will maintain relief of symptoms. If maintenance therapy is necessary, the manufacturers recommend 50-100 mg of amitriptyline hydrochloride daily; however, 25-40 mg daily may be sufficient for some patients. During maintenance therapy, the total daily dosage may be administered as a single daily dose, preferably at bedtime.103 The manufacturers recommend that maintenance therapy be continued for at least 3 months to prevent relapse.103 To avoid the possibility of precipitating withdrawal symptoms, amitriptyline should not be terminated abruptly in patients who have received a high dosage for prolonged periods.

When amitriptyline is used in conjunction with a phenothiazine, commercially available fixed-ratio combination preparations should not be used initially. Dosage should first be adjusted by administering each drug separately. If it is determined that the optimum maintenance dosage corresponds to the ratio in a commercial combination, such a preparation may be used. However, whenever dosage adjustment is necessary, the drugs should be administered separately.

Amitriptyline 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 For a complete discussion, see Cautions: Precautions and Contraindications and Cautions: Pediatric Precautions, in the Tricyclic Antidepressants General Statement 28:16.04.28.

Pediatric Precautions

Safety and efficacy of amitriptyline in children younger than 12 years of age have not been established. Therefore, the manufacturers state that the drug should not be used in this age group.103

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 However, the FDA also states that depression and certain other psychiatric disorders are themselves associated with an increased risk of suicide.106 Anyone considering the use of amitriptyline in a child or adolescent for any clinical use must therefore balance the potential risk of therapy with the clinical need.105,106 (See Cautions: Precautions and Contraindications and Cautions: Pediatric Precautions, in the Tricyclic Antidepressants General Statement 28:16.04.28.)

Pharmacokinetics

Absorption

Amitriptyline hydrochloride is rapidly absorbed from the GI tract and from parenteral sites. Peak plasma concentrations occur within 2-12 hours after oral or IM (a parenteral dosage form no longer is commercially available in the US) administration.

Distribution

Amitriptyline and its active metabolite, nortriptyline, are distributed into milk.100,101,102 Amitriptyline and nortriptyline concentrations in milk appear to be similar to or slightly greater than those present in maternal serum.101,102 It is estimated that a nursing infant would ingest less than 1% of the daily maternal dose of amitriptyline, and the drug was not detected in the serum of several nursing infants whose mothers were receiving 75-100 mg daily.101,102

Elimination

The plasma half-life of amitriptyline ranges from 10-50 hours. Amitriptyline is metabolized via the same pathways as are other tricyclic antidepressants; nortriptyline, its N -monodemethylated metabolite, is pharmacologically active. Approximately 25-50% of a dose of amitriptyline is excreted in urine as inactive metabolites within 24 hours; small amounts are excreted in feces via biliary elimination.

Chemistry and Stability

Chemistry

Amitriptyline hydrochloride is a dibenzocycloheptene-derivative tricyclic antidepressant. Amitriptyline hydrochloride occurs as a white or practically white, odorless or practically odorless, crystalline powder or small crystals with a bitter, burning taste and is freely soluble in water and in alcohol. The drug has a pK_a of 9.4.

Stability

Amitriptyline hydrochloride tablets should be stored in well-closed containers at a temperature preferably between 15-30°C; exposure to temperatures exceeding 30°C should be avoided.103 Perphenazine and amitriptyline hydrochloride tablets should be stored at 2-25°C; in addition, unit-dose packages of these tablets should be protected from excessive moisture. Following the date of manufacture, amitriptyline hydrochloride preparations have expiration dates of 3-5 years depending on the manufacturer and dosage form.

Additional Information

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

Only references cited for selected revisions after 1984 are available electronically.

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. [PubMed 7386673]

103. Zeneca Pharmaceuticals. Elavil^® (amitriptyline hydrochloride tablets and injection) prescribing information. Wilmington, DE, 2000 Dec.

104. American Psychiatric Association. Practice guideline for the treatment of patients with major depressive disorder (revision). Am J Psychiatry . 2000; 157(suppl):1-45.

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]