Drug class: Tricyclics and Other Norepinephrine-reuptake Inhibitors
VA class: CN601
CAS number: 549-18-8

Amitriptyline Hydrochloride is also contained as an ingredient in the following combinations:
Chlordiazepoxide and Amitriptyline Hydrochloride
Perphenazine and Amitriptyline Hydrochloride

Medically reviewed by Drugs.com on Sep 18, 2023. Written by ASHP.

Introduction

Tricyclic antidepressant (TCA).^c

Uses for Amitriptyline

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^{† [off-label]} (ADHD) patients unable to tolerate or unresponsive to stimulants;^y should be used only under close supervision.^a

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

Migraine

Medium to high efficacy for prophylaxis of migraine headache^{† [off-label]}.^z

Eating Disorders

Equivocal efficacy for management of eating disorders^{† [off-label]} (e.g., bulimia^{† [off-label]}, anorexia nervosa^{† [off-label]}); 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

Related/similar drugs

gabapentin, acetaminophen, ibuprofen, sertraline, trazodone, tramadol, diclofenac

Amitriptyline Dosage and Administration

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

Cautions for Amitriptyline

Contraindications

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

• Concurrent therapy with cisapride.^c (See Specific Drugs under Interactions.)

• During the acute recovery phase following MI.^c

• Known hypersensitivity to amitriptyline or any component in the formulations.^{c g n}

Warnings/Precautions

Warnings

Shares the toxic potentials of other tricyclic antidepressants; observe the usual precautions of tricyclic antidepressant therapy.^{a d g n}

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.^{i j k l} However, suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.^{i j k}

Appropriately monitor and closely observe patients receiving amitriptyline for any reason, particularly during initiation of therapy (i.e., the first few months) and during periods of dosage adjustments.^{i j k} (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.^{j k} 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.^{i j k} (See General under Dosage and Administration.)

Prescribe in smallest quantity consistent with good patient management to reduce risk of overdosage.^j

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

Bipolar Disorder

May unmask bipolar disorder.^j (See Activation of Mania or Hypomania under Cautions.) Amitriptyline is not approved for use in treating bipolar depression.^d

Screen for risk of bipolar disorder by obtaining detailed psychiatric history (e.g., family history of suicide, bipolar disorder, depression) prior to initiating therapy.^j

Interactions

May block hypotensive actions of guanethidine and similar agents.^{c n}

May enhance effects of alcohol, barbiturates, and other CNS depressants.^{c n} Use with caution in patients with a history of excessive alcohol consumption.^c

Delirium reported when used concomitantly with disulfiram.^c

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).^c Usual dosages may precipitate an attack of angle-closure glaucoma.^c

Seizures

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

Cardiovascular Effects

Possible arrhythmias, sinus tachycardia, and prolongation of the conduction time, MI, and stroke, particularly at higher dosages.^c

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;^a monitor closely.^c

Hyperthyroidism

Use with caution and under close supervision in hyperthyroid patients or patients receiving thyroid agents.^c

General Precautions

Activation of Mania or Hypomania

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

Psychosis

Risk of manifestations of psychosis in patients with schizophrenia, particularly in patients with paranoid symptoms.^c

CNS Effects

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

Electroconvulsive Therapy (ECT)

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

Elective Surgery

Discontinue therapy several days prior to surgery whenever possible.^c

Blood Glucose Effects

Possible alterations in blood glucose concentrations.^c

Use of Fixed Combinations

When used in fixed combination with perphenazine or chlordiazepoxide, consider the cautions, precautions, and contraindications associated with the concomitant agent.^{g n}

Specific Populations

Pregnancy

Category C.^c

Lactation

Distributes into milk;^{o p c} discontinue nursing or the drug.^c

Pediatric Use

Amitriptyline hydrochloride not shown to be effective in management of depression in children^† or adolescents in clinical studies;^{w x} not recommended by the manufacturers for use in children <12 years of age.^{103 c}

Safety and efficacy of the chlordiazepoxide-amitriptyline hydrochloride and perphenazine-amitriptyline hydrochloride fixed combinations not established in pediatric patients.^{e g n}

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).¹⁰⁵ 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.^l No suicides occurred in these pediatric trials.^{105 l j}

Carefully consider these findings when assessing potential benefits and risks of amitriptyline in a child or adolescent for any clinical use.^{i j k l} (See Worsening of Depression and Suicidality Risk under Cautions.)

Geriatric Use

No substantial differences in efficacy relative to younger adults.^c

In pooled data analyses, a reduced risk of suicidality was observed in adults ≥65 years of age with antidepressant therapy compared with placebo.^{i j} (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^{s t u v} and increased risk for falls.^c

No overall differences in safety and efficacy of amitriptyline hydrochloride in fixed combination with chlordiazepoxide in geriatric patients relative to younger adults; however, increased sensitivity cannot be ruled out.^g

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

Hepatic Impairment

Use with caution.^c

Common Adverse Effects

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

Drug Interactions

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

Drugs Affecting Hepatic Microsomal Enzymes

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

Specific Drugs

Amitriptyline Pharmacokinetics

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

Stability

Storage

Oral

Tablets

Tight, light-resistant containers at 15–30°C.^c

Fixed-combination (with Chlordiazepoxide) Tablets

Store in a dry place at 25°C (may be exposed to 15–30°C).^g

Fixed-combination (with Perphenazine) Tablets

Tight, light-resistant containers at 20–25°C.ⁿ

Actions

• 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

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.^{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.)

Preparations

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

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Preparations containing amitriptyline hydrochloride in fixed combination with chlordiazepoxide are subject to control under the Federal Controlled Substances Act of 1970 as schedule IV (C-IV) drugs.^{e g}

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Frequently asked questions

• What are some common side effects of antidepressants?

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