Amitriptyline Hydrochloride

Major Depressive Disorder

Management of major depressive disorder.c

Anxiety and Depressive Disorders

Has been used in fixed combination with chlordiazepoxide in the management of depression associated with moderate to severe anxiety.e g

Management of moderate to severe anxiety and/or agitation (in fixed combination with perphenazine) in patients with depressed mood.n

Management of severe anxiety and/or agitation (in fixed combination with perphenazine) in patients with depression.n

Management of depression and anxiety (in fixed combination with perphenazine) in association with chronic physical disease.n

Psychotic Disorders

Management of acute depressive episodes (in fixed combination with perphenazine) in patients with schizophrenia.n

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.a

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.

Migraine

Medium to high efficacy for prophylaxis of migraine headache†.

Eating Disorders

Equivocal efficacy for management of eating disorders† (e.g., bulimia†, anorexia nervosa†); avoid use in underweight individuals and in those exhibiting suicidal ideation.a

Bipolar Disorder

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

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

Postherpetic Neuralgia

Among the drugs of choice for the symptomatic treatment of postherpetic neuralgia†.a

Insomnia

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

General

• Fixed-ratio combination preparations generally should not be used as initial therapy.d e First administer each drug separately.d e If the optimum maintenance dosage corresponds to the ratio in a commercial combination preparation, a fixed-combination preparation may be used.d e If dosage adjustment is necessary, administer the drugs separately.d e Fixed-ratio combination preparations do not permit individual titration of dosages.m

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

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

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

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

Administration

Oral Administration

Administer in up to 4 divided doses or as a single daily dose at bedtime to avoid daytime sedation.c d

Dosage

Available as amitriptyline hydrochloride (alone and in fixed combination with perphenazine or chlordiazepoxide); dosage is expressed in terms of the salt.103 g n

Pediatric Patients

Major Depressive Disorder Oral

Adolescents ≥12 years of age: 10 mg 3 times daily plus 20 mg at bedtime.c

Psychotic Disorders Perphenazine/Amitriptyline Combination Therapy Oral

Adolescents: Initially, 10 mg (in fixed combination with 4 mg perphenazine) 3 or 4 times daily; adjust as required.n

Maximum daily dosages of perphenazine and amitriptyline hydrochloride not to exceed 16 and 200 mg, respectively.n

Adults

Major Depressive Disorder Outpatients Oral

Initially, 75 mg daily in divided doses or 50–100 mg once daily at bedtime.c Increase dosages in 25- or 50-mg increments until maximal therapeutic effect with minimal toxicity is achieved or up to a maximum dosage of 150 mg daily.c

Usual maintenance dosage: 50–100 mg daily, administered as a single daily dose, preferably at bedtime.c For some patients, 25–40 mg daily may be sufficient.d Continue therapy for at least 3 months to prevent relapse.c

Hospitalized Patients Oral

Initially, 100 mg daily; dosage may be increased gradually to 200–300 mg daily as needed.c

Anxiety and Depressive Disorders Chlordiazepoxide/Amitriptyline Combination Therapy Oral

Initially, amitriptyline hydrochloride 75 or 100 mg daily (in fixed combination with chlordiazepoxide 30 or 40 mg daily, respectively) in divided doses.g If needed, increase dosage to amitriptyline hydrochloride 150 mg daily (in fixed combination with chlordiazepoxide 60 mg daily) in divided doses.g

Alternatively, in patients who do not tolerate larger dosages, initial dosage of amitriptyline hydrochloride 37.5 or 50 mg daily (in fixed combination with chlordiazepoxide 15 or 20 mg daily, respectively) in divided doses.g

For some patients, amitriptyline hydrochloride 50 mg daily (in fixed combination with chlordiazepoxide 20 mg daily) in divided doses may be adequate.g

Perphenazine/Amitriptyline Combination Therapy Oral

Initially, amitriptyline hydrochloride 25 mg (in fixed combination with perphenazine 2 or 4 mg) 3 or 4 times daily.n Alternatively, amitriptyline hydrochloride 50 mg (in fixed combination with perphenazine 4 mg) twice daily.n

Carefully adjust subsequent dosage according to patient’s tolerance and therapeutic response.n During maintenance therapy, keep dosage at the lowest effective level.n Amitriptyline hydrochloride maintenance dosages usually range from 50–100 mg daily and perphenazine maintenance dosages usually range from 4–16 mg daily.n

Maximum daily dosage of perphenazine and amitriptyline hydrochloride not to exceed 16 and 200 mg, respectively.n

Psychotic Disorders Perphenazine/Amitriptyline Combination Therapy Oral

Initially, 2 tablets of amitriptyline hydrochloride 25 mg (in fixed combination with perphenazine 4 mg) 3 times daily.n If needed, a fourth dose may be given at bedtime.n

Carefully adjust subsequent dosage according to patient’s tolerance and therapeutic response.n During maintenance therapy, keep dosage at the lowest effective level.n Amitriptyline hydrochloride maintenance dosages usually range from 50–100 mg daily and perphenazine maintenance dosages usually range from 4–16 mg daily.n

Maximum daily dosage of perphenazine and amitriptyline hydrochloride not to exceed 16 and 200 mg, respectively.n

Prescribing Limits

Pediatric Patients

Psychotic Disorders Perphenazine/Amitriptyline Combination Therapy Oral

Adolescents: Maximum 16 and 200 mg daily of perphenazine and amitriptyline hydrochloride, respectively.n

Adults

Major Depressive Disorder Outpatients Oral

Maximum 150 mg daily.c

Hospitalized Patients Oral

Maximum 300 mg daily.c

Anxiety and Depressive Disorders Perphenazine/Amitriptyline Combination Therapy Oral

Maximum 16 and 200 mg daily of perphenazine and amitriptyline hydrochloride, respectively.n

Psychotic Disorders Perphenazine/Amitriptyline Combination Therapy Oral

Maximum 16 and 200 mg daily of perphenazine and amitriptyline hydrochloride, respectively.n

Special Populations

Geriatric Patients

10 mg 3 times daily plus 20 mg at bedtime.c

Anxiety and Depressive Disorders

When used in fixed combination with chlordiazepoxide, select initial dosages at the lower end of the usual ranges and gradually increase dosages if needed and tolerated.g

Psychotic Disorders

When used in fixed combination with perphenazine, an oral dosage of 10 mg of amitriptyline hydrochloride and 4 mg of perphenazine 3 or 4 times daily is recommended initially.n Subsequent dosage adjustments may be made as necessary.n

Absorption

Bioavailability

Rapidly absorbed from the GI tract;c bioavailability of 40–60%.f

Onset

Antidepressant effect may not be evident for up to 4 weeks; sedative effect usually precedes it.c

Distribution

Extent

Distributed into milk;100 101 102 concentrations in milk similar to or slightly greater than those present in maternal serum.101 102

Crosses the placenta.c

Plasma Protein Binding

Approximately 96%.f

Elimination

Metabolism

Extensively metabolized in the liver via demethylation to pharmacologically active metabolite, nortriptyline, by various CYP isoenzymes (e.g., CYP1A2, CYP2D6, CYP3A4, CYP2C).a d f

Elimination Route

Excreted principally in urine (25–50% within 24 hours) as inactive metabolites; small amounts are also excreted in feces via biliary elimination.d

Half-life

10–50 hours.d

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

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

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

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

• Importance of patients understanding that it may take more than 4 weeks before the full effects are apparent.c

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

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

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

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