Vivactil

Generic Name: Protriptyline Hydrochloride
Class: Tricyclics and Other Norepinephrine-reuptake Inhibitors
VA Class: CN601
Chemical Name: N-methyl-5H dibenzo[a,d]-cycloheptene-5-propanamine hydrochloride
Molecular Formula: C19H21N HCl
CAS Number: 1225-55-4

Warning(s)

  • Suicidality
  • 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.101 102 Protriptyline is not approved for use in pediatric patients.a (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.101 102

  • Depression and certain other psychiatric disorders are themselves associated with an increased risk of suicide.101 102 103

  • 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.101 102 103 (See Worsening of Depression and Suicidality Risk and Pediatric Use under Cautions.)

Introduction

Dibenzocycloheptene-derivative tricyclic antidepressant (TCA).a b c e k l

Uses for Vivactil

Depressive Disorders

Treatment of depression.a c

Because of its activating properties, particularly suitable for withdrawn and anergic patients.a c

Slideshow: Aging Issues: 12 of the Most Common Health Concerns Affecting Seniors

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.h i n o 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.f g h o

Vivactil Dosage and Administration

General

Depressive Disorders

  • Allow at least 2 weeks to elapse between discontinuance of therapy with an MAO inhibitor and initiation of protriptyline and vice versa.a c Also allow at least 5 weeks to elapse when switching from fluoxetine.a 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.101 102 103 a d (See Worsening of Depression and Suicidality Risk under Cautions.)

  • Avoid abrupt discontinuance of therapy in patients receiving protriptyline for prolonged periods.a b To avoid withdrawal reactions, taper dosage gradually.a b (See Withdrawal of Therapy under Cautions.)

Administration

Oral Administration

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

Dosage

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

Individualize dosage carefully according to individual requirements and response.a b c

Pediatric Patients

Depressive Disorders
Oral

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

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

Adults

Depressive Disorders
Oral

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

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

Prescribing Limits

Adults

Depressive Disorders
Oral

Maximum 60 mg daily.a b

Special Populations

Geriatric Patients

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

Cautions for Vivactil

Contraindications

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

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

  • During the acute recovery phase following MI.a

  • Known hypersensitivity to protriptyline.a

Warnings/Precautions

Warnings

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

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.101 102 103 104 d However, suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.101 102 103

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.101 102 103 d (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.102 103 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.101 102 103 (See General under Dosage and Administration.)

Prescribe in smallest quantity consistent with good patient management to reduce risk of overdosage.102 a d

Observe these precautions for patients with psychiatric (e.g., major depressive disorder, obsessive-compulsive disorder [OCD]) or nonpsychiatric disorders.102 a c

Bipolar Disorder

May unmask bipolar disorder.102 a c (See Activation of Mania or Hypomania under Cautions.) Protriptyline is not approved for use in treating bipolar depression.a

Screen for risk of bipolar disorder by obtaining detailed psychiatric history (e.g., family history of suicide, bipolar disorder, depression) prior to initiating therapy.102 a c d

Cardiovascular Effects

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

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

Interactions

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

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

Seizures

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

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).a c

Thyroid Disorders

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

Sensitivity Reactions

Photosensitivity

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

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.a c (See Bipolar Disorder under Cautions.)

Psychosis

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

Anxiety or Agitation

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

Electroconvulsive Therapy (ECT)

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

Elective Surgery

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

Blood Glucose Effects

Possible alterations in blood glucose concentrations.a

Withdrawal of Therapy

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

Specific Populations

Pregnancy

Category C.e

Lactation

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

Pediatric Use

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

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).102 a d 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.104 No suicides occurred in these pediatric trials.102 104 a d

Carefully consider these findings when assessing potential benefits and risks of protriptyline in a child or adolescent for any clinical use.101 102 103 104 a (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.a Other reported clinical experience has not revealed differences in clinical responses between geriatric and younger adult patients.a

In pooled data analyses, a reduced risk of suicidality was observed in adults ≥65 years of age with antidepressant therapy compared with placebo.101 102 (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.a c

Use with caution; titrate dosage carefully.a (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).a c k l

Interactions for Vivactil

Drugs Affecting Hepatic Microsomal Enzymes

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

Specific Drugs

Drug

Interaction

Comments

Alcohol

Potentiates the effects of alcohola c

Increased risks if overdose or suicide attempt occursa

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

Potential for decreased protriptyline metabolisma c

Dosage adjustment may be neededa c

Anticholinergic agents

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

Use with caution; dosage adjustment may be neededa c

Antipsychotics (e.g., phenothiazines)

Potential for decreased protriptyline metabolisma c

Dosage adjustment may be neededa c

Cimetidine

Possible increased plasma protriptyline concentrationsa c

Potential for TCA toxicity, particularly adverse anticholinergic effectsa c

Monitor for TCA toxicity; dosage adjustment may be neededa c

Cisapride

Increased risk of QT interval prolongation and arrhythmiasa c

Concomitant use contraindicateda c

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

Potentiates the effects of CNS depressantsa c

Guanethidine and related compounds

Possible antagonism of the antihypertensive effects of guanethidine and related compoundsa c

Levodopa

May interfere with levodopa absorptionc

Monitor levodopa dosage carefullyc

MAO inhibitors

Potentially life-threatening serotonin syndrome a c

Concomitant use contraindicateda c

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

Methylphenidate

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

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

Potential for decreased protriptyline metabolism and increased plasma concentrationsa c

Use with caution; dosage adjustment may be neededa c

Allow at least 5 weeks to elapse when switching from fluoxetinea c

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

Increased vasopressor, cardiac effectsa c

Use with caution; dosage adjustment may be requireda c

Thyroid agents

Possible cardiac arrhythmiasa c

Use with caution a c

Tramadol

Possible increased risk of seizuresa c

Vivactil Pharmacokinetics

Absorption

Bioavailability

Completely absorbed from GI tract; bioavailability averages from 75–90%.a b c k l m

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

Onset

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

Distribution

Extent

Widely distributed in the body.a c l m

Possibly distributed into milk.e

Plasma Protein Binding

Highly bound to plasma proteins.c k l m

Elimination

Metabolism

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

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

Elimination Route

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

Half-life

54–124 hours.k l m

Stability

Storage

Oral

Tablets

Tight containers at 20–25°C.a

Actions

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

  • Exhibits anticholinergic and antiadrenergic activity.a c m

  • Does not inhibit MAO.a Does not possess sedative and tranquilizing activity.a l

  • Associated with more frequent anticholinergic and cardiovascular effects than SSRIs and more frequent CNS stimulation and cardiovascular effects than other TCAs.a c

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.101 102 103 FDA recommends providing written patient information (medication guide) explaining risks of suicidality each time the drug is dispensed.101 102 103

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

  • Risk of concomitant use with alcohol.a

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.a

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

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

Preparations

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

Protriptyline Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

5 mg

Vivactil (with polyethylene glycol and propylene glycol)

Odyssey

10 mg

Vivactil (with polyethylene glycol and propylene glycol)

Odyssey

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Vivactil 10MG Tablets (TEVA/WOMENS HEALTH): 30/$127.99 or 90/$363.97

Vivactil 5MG Tablets (TEVA/WOMENS HEALTH): 30/$96.58 or 100/$288.61

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions February 1, 2008. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

100. Odyssey Pharmaceuticals, Inc. Vivactil (protriptyline hydrochloride) tablets prescribing information. East Hanover, NJ; 2003 Jan.

101. 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: .

102. 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: .

103. 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:

104. 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]

a. Odyssey Pharmaceuticals, Inc. Vivactil(protriptyline hydrochloride) tablets prescribing information. East Hanover, NJ. 2004 Oct.

b. AHFS drug information 2007. McEvoy GK, ed. Protriptyline hydrochloride. Bethesda, MD: American Society of Health-System Pharmacists; 2007:2378.

c. AHFS drug information 2007. McEvoy GK, ed. Tricyclic antidepressants general statement. Bethesda, MD: American Society of Health-System Pharmacists; 2007:2353-60.

d. American Psychiatric Association Practice Guidelines. Practice guideline for the treatment of patients with major depressive disorder, second edition. From the APA website ().

e. Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation. 7th ed. Baltimore, MD: Williams & Wilkins; 2005:1370.

f. Veasey SC, Guilleminault C, Strohl KP et al. Medical therapy for obstructive sleep apnea: a review by the Medical Therapy for Obstructive Sleep Apnea Task Force of the Standards of Practice Committee of the American Academy of Sleep Medicine. Sleep. 2006; 29:1036-44. [PubMed 16944672]

g. Black JE, Hirschkowitz M. Modafinil for treatment of residual excessive sleepiness in nasal continuous positive airway pressure-treated obstructive sleep apnea/hypopnea syndrome. Sleep. 2005; 28:464-71. [PubMed 16171291]

h. Smith I, Lasserson TJ, Wright J. Drug therapy for obstructive sleep apnoea in adults. Cochrane Database of Systematic Reviews. 2006; Issue 2:Article no. CD003002.

i. Brownell LG, West P, Sweatman P et al. Protriptyline in obstructive sleep apnea: a double-blind trial. N Engl J Med. 1982; 307:1037-42. [PubMed 6750396]

j. American Academy of Child and Adolescent Psychiatry. Summary of the practice parameters for the assessment and treatment of children and adolescents with depressive disorders. From the AACAP website: ().

k. Amsterdam J, Brunswick D, Mendels J. The clinical application of tricyclic antidepressant pharmacokinetics and plasma levels. Am J Psychiatry. 1980; 137:653-62. [PubMed 6990798]

l. Ziegler VE, Biggs JT, Wylie LT et al. Protriptyline kinetics. Clin Pharmacol Ther. 1978; 23:580-4. [PubMed 639433]

m. Rudorfer MV, Potter WZ. Metabolism of tricyclic antidepressants. Cell Mol Neurobiol. 1999; 19:373-409. [PubMed 10319193]

n. Whyte KF, Gould GA, Airlie MA et al. Role of protriptyline and acetazolamide in the sleep apnea/hypopnea syndrome. Sleep. 1988; 11:463-72. [PubMed 3067313]

o. Morgenthaler TI, Kapen S, Lee-Chiong T et al. Practice parameters for the medical therapy of obstructive sleep apnea. Sleep. 2006; 29:1031-5. [PubMed 16944671]

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