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Protriptyline (Monograph)

Brand name: Vivactil
Drug class: Tricyclics and Other Norepinephrine-reuptake Inhibitors
- TCAs
VA class: CN601
Chemical name: N-methyl-5H dibenzo[a,d]-cycloheptene-5-propanamine hydrochloride
Molecular formula: C19H21N HCl
CAS number: 1225-55-4


  • 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. Protriptyline is not approved for use in pediatric patients. (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.

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

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


Dibenzocycloheptene-derivative tricyclic antidepressant (TCA).

Uses for Protriptyline

Depressive Disorders

Treatment of depression.

Because of its activating properties, particularly suitable for withdrawn and anergic patients.

Obstructive Sleep Apnea/Hypopnea Syndrome (OSAHS)

Has been used for the symptomatic management of OSAHS†; however, has not been shown to reduce the frequency of apnea and may cause bothersome anticholinergic effects. Standard treatment(s) for underlying obstruction (e.g., continuous positive airway pressure) and use of adjunctive pharmacologic agents to relieve excessive daytime sleepiness (e.g., modafinil) currently are preferred in patients with this condition.

Protriptyline Dosage and Administration


Depressive Disorders


Oral Administration

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


Available as protriptyline hydrochloride; dosage expressed in terms of the salt.

Individualize dosage carefully according to individual requirements and response.

Pediatric Patients

Depressive Disorders

Adolescents: Lower dosages recommended than for adults. Initially, 5 mg 3 times daily. Increase dosage gradually if necessary. (See Pediatric Use under Cautions.)

After symptoms are controlled, gradually reduce dosage to the lowest level that will maintain relief of symptoms.


Depressive Disorders

Initially, 15–40 mg daily, depending on the severity of the condition being treated. Increase dosage gradually up to 60 mg daily if necessary; increases should be made to the morning dose if given in divided doses.

After symptoms are controlled, gradually reduce dosage to the lowest level that will maintain relief of symptoms.

Prescribing Limits


Depressive Disorders

Maximum 60 mg daily.

Special Populations

Geriatric Patients

Lower dosages recommended for geriatric patients. Initially, 5 mg 3 times daily. Increase dosage gradually if necessary. Carefully monitor for cardiac abnormalities if dosages >20 mg daily are administered.

Cautions for Protriptyline




Shares the toxic potentials of other TCAs; observe the usual precautions of TCA therapy.

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. However, suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.

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

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

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

Bipolar Disorder

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

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

Cardiovascular Effects

Tachycardia and postural hypotension may occur more frequently with protriptyline than with other TCAs. Possible arrhythmias, prolongation of the conduction time, MI, and stroke.

Patients with preexisting or prior history of cardiac disease, geriatric patients, and patients with disturbed eating behaviors (e.g., purging) that result in inadequate hydration and/or compromised cardiac status most at risk. Use with caution and monitor closely (e.g., perform ECG at baseline and as appropriate during therapy).


May block hypotensive actions of guanethidine and similar compounds. (See Specific Drugs under Interactions.)

May enhance CNS depressant effects of alcohol. Use with caution in patients with a history of excessive alcohol consumption. (See Specific Drugs under Interactions.)


Lowers seizure threshold; use with caution in patients with a history of seizures.

Anticholinergic Effects

Use with caution in patients for whom excess anticholinergic activity could be harmful (e.g., history of urinary retention, increased IOP, angle-closure glaucoma, prostatic hypertrophy).

Thyroid Disorders

Possible cardiovascular toxicity (e.g., arrhythmias); use with caution in hyperthyroid patients or patients receiving thyroid agents.

Sensitivity Reactions


Photosensitivity reported with TCAs; patients demonstrating photosensitivity should avoid excessive exposure to sunlight.

General Precautions

Activation of Mania or Hypomania

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


Possible exacerbation of psychosis in patients with schizophrenia; decrease dosage or administer an antipsychotic agent concomitantly.

Anxiety or Agitation

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

Electroconvulsive Therapy (ECT)

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

Elective Surgery

Discontinue therapy several days prior to surgery whenever possible.

Blood Glucose Effects

Possible alterations in blood glucose concentrations.

Withdrawal of Therapy

Possibly withdrawal reactions; avoid abrupt discontinuance of therapy and taper dosage gradually.

Specific Populations


Category C.


Possibly distributed into milk. Caution if used in nursing women; carefully assess potential benefits and risks.

Pediatric Use

Safety and efficacy of protriptyline in pediatric patients have not been established.

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, OCD, or other psychiatric disorders based on pooled analyses of 24 short-term, placebo-controlled trials of 9 antidepressant drugs (SSRIs and others). 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. No suicides occurred in these pediatric trials.

Carefully consider these findings when assessing potential benefits and risks of protriptyline in a child or adolescent for any clinical use. (See Worsening of Depression and Suicidality Risk under Cautions.)

Geriatric Use

Insufficient experience from clinical trials in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults. Other reported clinical experience has not revealed differences in clinical responses between geriatric and younger adult patients.

In pooled data analyses, a reduced risk of suicidality was observed in adults ≥65 years of age with antidepressant therapy compared with placebo. (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, and orthostatic hypotension effects of TCAs.

Use with caution; titrate dosage carefully. (See Geriatric Patients under Dosage and Administration.)

Common Adverse Effects

Exacerbation of anxiety/agitation, CNS stimulation, dizziness, drowsiness, weakness, fatigue, cardiovascular reactions (e.g., tachycardia, orthostatic hypotension), anticholinergic effects (e.g., dry mouth, constipation, blurred vision).

Drug Interactions

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors of CYP2D6: potential pharmacokinetic interaction (increased plasma protriptyline concentrations) with concomitant use; use with caution. Consider protriptyline dosage adjustment whenever a CYP2D6 inhibitor is added or discontinued.

Specific Drugs





Potentiates the effects of alcohol

Increased risks if overdose or suicide attempt occurs

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

Potential for decreased protriptyline metabolism

Dosage adjustment may be needed

Anticholinergic agents

Possible addictive anticholinergic effects; hyperthermia, particularly during hot weather; and paralytic ileus

Use with caution; dosage adjustment may be needed

Antipsychotics (e.g., phenothiazines)

Potential for decreased protriptyline metabolism

Dosage adjustment may be needed


Possible increased plasma protriptyline concentrations

Potential for TCA toxicity, particularly adverse anticholinergic effects

Monitor for TCA toxicity; dosage adjustment may be needed


Increased risk of QT interval prolongation and arrhythmias

Concomitant use contraindicated

CNS depressants (e.g., analgesics, antihistamines, barbiturates, general anesthetics, opiates)

Potentiates the effects of CNS depressants

Guanethidine and related compounds

Possible antagonism of the antihypertensive effects of guanethidine and related compounds


May interfere with levodopa absorption

Monitor levodopa dosage carefully

MAO inhibitors

Potentially life-threatening serotonin syndrome

Concomitant use contraindicated

Allow at least 2 weeks to elapse when switching to or from these drugs


Potential for decreased metabolism and increased therapeutic efficacy and toxicity of TCAs

SSRIs (e.g., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline)

Potential for decreased protriptyline metabolism and increased plasma concentrations

Use with caution; dosage adjustment may be needed

Allow at least 5 weeks to elapse when switching from fluoxetine

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

Increased vasopressor, cardiac effects

Use with caution; dosage adjustment may be required

Thyroid agents

Possible cardiac arrhythmias

Use with caution


Possible increased risk of seizures

Protriptyline Pharmacokinetics



Completely absorbed from GI tract; bioavailability averages from 75–90%.

Peak plasma concentrations occur within 8–12 hours after oral administration.


May have a more rapid onset of antidepressant action compared with amitriptyline or imipramine. Initial clinical effect may occur within 1 week; maximum antidepressant effects may not be evident for ≥2 weeks.



Widely distributed in the body.

Possibly distributed into milk.

Plasma Protein Binding

Highly bound to plasma proteins.



Metabolized via the same pathways as are other TCAs. 10–25% of oral dose undergoes first pass metabolism.

Poor metabolizers of CYP2D6 metabolize the drug more slowly than normal metabolizers.

Elimination Route

50% of a dose is excreted in urine as metabolites within approximately 16 days. Very small amounts excreted in feces via biliary elimination.


54–124 hours.





Tight containers at 20–25°C.


Advice to Patients


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.

Protriptyline Hydrochloride


Dosage Forms


Brand Names



Tablets, film-coated

5 mg

Vivactil (with polyethylene glycol and propylene glycol)


10 mg

Vivactil (with polyethylene glycol and propylene glycol)


AHFS DI Essentials™. © Copyright 2024, Selected Revisions February 1, 2008. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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