Monday, August 20, 2012

Norpramin


Generic Name: Desipramine Hydrochloride
Class: Tricyclics and Other Norepinephrine-reuptake Inhibitors
VA Class: CN601
CAS Number: 58-28-6


  • 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.108 109 Desipramine is not approved for use in pediatric patients.104 (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.108 109




  • Depression and certain other psychiatric disorders are themselves associated with an increased risk of suicide.108 109 110




  • Appropriately monitor and closely observe all patients who are started on desipramine therapy for clinical worsening, suicidality, or unusual changes in behavior; involve family members and/or caregivers in this process. 108 109 110 (See Worsening of Depression and Suicidality Risk under Cautions.)




Introduction

Tricyclic antidepressant (TCA);104 active metabolite of imipramine.a c e


Uses for Norpramin


Major Depressive Disorder


Management of major depressive disorder.104


Results of several studies of TCAs in preadolescent and adolescent patients with major depression indicate lack of overall efficacy in this age group.


Panic Disorder


Has been used for the management of panic disorder with or without agoraphobia.a


Eating Disorders


Has been used for the management of eating disorders (e.g., bulimia, anorexia nervosa) with equivocal results; 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 b should always be used in combination with a mood stabilizer (e.g., lithium).b


Schizophrenia


Has been used for the management of acute depressive episodes (in combination with an antipsychotic) in patients with schizophrenia.a


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


Attention Deficit Hyperactivity Disorder (ADHD)


Not recommended for use in children with ADHD.101 102 103 (See Pediatric Use under Cautions.)


Norpramin Dosage and Administration


General



  • Allow at least 2 weeks to elapse between discontinuance of therapy with an MAO inhibitor and initiation of desipramine and vice versa.104 Also allow at least 5 weeks to elapse when switching from fluoxetine.104




  • Monitor for possible worsening of depression, suicidality, or unusual changes in behavior, especially at the beginning of therapy or during periods of dosage adjustments.108 109 110 (See Worsening of Depression and Suicidality Risk under Cautions.)




  • Sustained therapy may be required; administer lowest effective dosage and monitor periodically for need for continued therapy.104




  • Avoid abrupt discontinuance in patients receiving high dosages for prolonged periods.104 a To avoid withdrawal reactions, taper dosage gradually.104 a



Administration


Oral Administration


Initially, administer in up to 3 divided doses or as a single daily dose at bedtime (to avoid daytime sedation) or in the morning (to avoid insomnia and/or stimulation from the drug); for maintenance therapy, may be given as a single daily dose for patient compliance and convenience.112 c


Administer desipramine hydrochloride dosages of 300 mg daily in a hospital setting, where regular visits by the physician, skilled nursing care, and frequent ECGs are available.104


Dosage


Available as desipramine hydrochloride; dosage is expressed in terms of the salt.c


Pediatric Patients


Major Depressive Disorder

Oral

Adolescents ≥12 years of age: Initially, 25–50 mg daily.c Increase dosage gradually until maximal therapeutic effect with minimal toxicity is achieved or up to a maximum dosage of 100 mg daily.104 (See Pediatric Use under Cautions.)


Usual dosage: 25–100 mg daily.104 Dosage may be further increased to 150 mg daily, if necessary, in more seriously ill patients.104


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


Adults


Major Depressive Disorder

Oral

Initially, 75–150 mg daily, depending on the severity of the condition being treated.c Increase dosage gradually until maximal therapeutic effect with minimal toxicity is achieved.c


Usual dosage: 100–200 mg daily.104 Dosage may be further increased to 300 mg daily, if necessary, in more seriously ill patients.104


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


Prescribing Limits


Pediatric Patients


Major Depressive Disorder

Oral

Adolescents ≥12 years of age: Maximum 150 mg daily.104


Adults


Major Depressive Disorder

Oral

Maximum 300 mg daily.104


Special Populations


Geriatric Patients


Initially, 25–50 mg daily.c Increase dosage gradually until maximal therapeutic effect with minimal toxicity is achieved or up to a usual maximum dosage of 100 mg daily.104


Usual dosage: 25–100 mg daily.104 Dosage may be further increased to 150 mg daily, if necessary, in more seriously ill patients.104


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


Cautions for Norpramin


Contraindications



  • Concurrent or recent (i.e., within 2 weeks) therapy with an MAO inhibitor.104 (See Specific Drugs under Interactions.)




  • During the acute recovery phase following MI.104




  • Known hypersensitivity to desipramine.104 (See Cross-Hypersensitivity under Cautions.)



Warnings/Precautions


Warnings


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.108 109 110 111 However, suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.108 109 110


Appropriately monitor and closely observe patients receiving desipramine for any reason, particularly during initiation of therapy (i.e., the first few months) and during periods of dosage adjustments.108 109 110 (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.109 110 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.108 109 110 (See General under Dosage and Administration.)


Prescribe in smallest quantity consistent with good patient management to reduce risk of overdosage.104 109


Observe these precautions for patients with psychiatric (e.g., major depressive disorder, obsessive-compulsive disorder [OCD]) or nonpsychiatric disorders.109


Bipolar Disorder

May unmask bipolar disorder.109 (See Activation of Mania or Hypomania under Cautions.) Desipramine is not approved for use in treating bipolar depression.104


Screen for risk of bipolar disorder by obtaining detailed psychiatric history (e.g., family history of suicide, bipolar disorder, depression) prior to initiating therapy.109


Cardiovascular Effects

Possible conduction defects, arrhythmias, tachycardia, strokes, and acute MI; use with extreme caution in patients with preexisting cardiovascular disease.112 Monitor such patients closely (e.g., perform ECG at baseline and as appropriate during therapy).a Also use with extreme caution in patients with a family history of sudden death, cardiac dysrhythmias, or cardiac conduction disturbances.112 113 114


Use with caution in patients with disturbed eating behaviors (e.g., purging) that result in inadequate hydration and/or compromised cardiac status.a


Toxicity in Overdosage

Overdosage of desipramine has resulted in a higher death rate compared with overdosages of other tricyclic antidepressants.112 113 114 115


Interactions

May block hypotensive actions of guanethidine and similar agents.104


May enhance effects of alcohol, sedative/hypnotics, and other CNS depressants.104 Use with caution in patients with a history of excessive alcohol consumption.104


Anticholinergic Effects

Use with extreme caution in patients for whom excess anticholinergic activity could be harmful (e.g., history of urinary retention, increased intraocular pressure, angle-closure glaucoma).104


Seizures

Risk of seizures; use with extreme caution in patients with a history of seizure disorder.112 In some patients, seizures precede cardiac dysrhythmias and death.112 113 114


Hyperthyroidism

Possible cardiovascular toxicity (e.g., arrhythmias); use with extreme caution in patients with thyroid disease or patients receiving thyroid agents.112


Cognitive/Physical Impairment

Performance of activities requiring mental alertness and physical coordination may be impaired.104


Sensitivity Reactions


Cross-Hypersensitivity

Possible cross sensitivity to other dibenzazepine-derivative TCAs (e.g., clomipramine, imipramine, trimipramine).104


Photosensitivity

Avoid excessive exposure to sunlight.104


General Precautions


Activation of Mania or Hypomania

Possible activation of hypomania in patients with bipolar disorder.104


Psychosis

Possible exacerbation of psychosis in patients with schizophrenia.104


Hematologic Effects

Perform leukocyte and differential counts in any patient who develops symptoms of blood dyscrasias (e.g., fever, sore throat).104 If evidence of pathologic neutrophil depression is found, discontinue the drug.104


Electroconvulsive Therapy (ECT)

Possible increased ECT risks.104


Elective Surgery

Discontinue therapy several days prior to surgery whenever possible.104 Hypertensive episodes have occurred during surgery in patients receiving desipramine.104


Blood Glucose Effects

Possible alterations in blood glucose concentrations.104


Storage

Keep out of reach of children.104 If possible, dispense in containers with child-resistant safety closures.104


Specific Populations


Pregnancy

Category C.e


Lactation

Distributes into milk;100 e discontinue nursing or the drug.104 e


Pediatric Use

Not effective in management of depression in children or adolescents in clinical studies.


Collapse and/or sudden death reported in children, some of whom received the drug for the treatment of ADHD;101 102 103 104 not recommended for use in children.101 102 103 104 105


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).109 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.111 No suicides occurred in these pediatric trials.109 111


Carefully consider these findings when assessing potential benefits and risks of desipramine in a child or adolescent for any clinical use.108 109 110 111 (See Worsening of Depression and Suicidality Risk under Cautions.)


Geriatric Use

In pooled data analyses, a reduced risk of suicidality was observed in adults ≥65 years of age with antidepressant therapy compared with placebo.108 109 (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 and increased risk for falls and/or other desipramine-induced toxicity.104 Monitor renal function.104


Titrate dosage carefully.104 (See Geriatric Patients under Dosage and Administration.)


Renal Impairment

Use with caution.104


Common Adverse Effects


Anticholinergic effects (e.g., dry mouth,104 a constipation,104 a vision disturbance),104 a orthostatic hypotension, sedation, weakness, lethargy, fatigue.a


Interactions for Norpramin


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 plasma desipramine concentrations).a Adjust desipramine dosage whenever a CYP2D6 inhibitor is added or discontinued.a


Specific Drugs
















































Drug



Interaction



Comments



Alcohol



Potentiates CNS depressant effects of alcohol104



Increased risks if overdose or suicide attempt occurs104



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



Potential for decreased desipramine metabolism104



Monitor for TCA toxicity104



Anticholinergic agents



Hyperthermia, particularly during hot weather, and paralytic ileusa



Use with caution; dosage adjustment may be needed104



Antipsychotics (e.g., phenothiazines)



Potential for decreased desipramine metabolism104



Use with caution104



Benzodiazepines (e.g., chlordiazepoxide, diazepam)



Additive sedative effects104



Use with caution104



Cimetidine



Potential for decreased desipramine metabolism104



CNS depressants



Potentiates the effects of CNS depressants104



Use with caution104



Guanethidine



Antagonizes the antihypertensive effects of guanethidine104



Levodopa



May interfere with levodopa absorptiona



Monitor levodopa dosage carefullya



MAO inhibitors



Potentially life-threatening serotonin syndrome104



Concomitant use contraindicated104


Allow at least 14 days to elapse when switching to or from these drugs104



Methylphenidate



Potential for decreased desipramine metabolism104



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



Possible serotonin syndrome104


Potential for decreased desipramine metabolism104



Use with caution; monitor for TCA toxicity104


Allow at least 5 weeks to elapse when switching from fluoxetine104



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



Increased vasopressor, cardiac effectsa



Use with caution; dosage adjustment may be requireda



Thyroid agents



Possible cardiovascular toxicity, including arrhythmias112



Use with extreme caution and under close supervision112


Norpramin Pharmacokinetics


Absorption


Bioavailability


Well absorbed from the GI tract following oral administration, with peak plasma concentration usually attained within 4–6 hours.c


Onset


Antidepressant effects may occasionally be seen in 2–5 days, but full therapeutic effect may not be evident for up to 3 weeks.104


Distribution


Extent


Distributed into milk; concentrations in milk may be greater than or equal to those in maternal serum.100 e


Elimination


Metabolism


Extensively metabolized in the liver via oxidation to pharmacologically active metabolite, 2-hydroxydesipramine,104 106 107 by various CYP isoenzymes (e.g., CYP1A2, CYP2D6, CYP3A4, and CYP2C).114 a


Elimination Route


Excreted principally in urine (70%).104


Half-life


Plasma half-life of desipramine ranges from 7 to >60 hours.c


Special Populations


In geriatric patients, the ratio of the principal metabolite, 2-hydroxydesipramine, to desipramine appears to be increased, most likely because of decreased renal elimination that occurs with aging.104


Stability


Storage


Oral


Tablets

Tight containers at room temperature, preferably <30°C.104 Protect from excessive heat.104


ActionsActions



  • Mechanism of action in the management of depression unknown but may involve inhibition of reuptake of norepinephrine and/or serotonin.104




  • Associated with more frequent anticholinergic, sedative, and 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.108 109 110 112 FDA recommends providing written patient information (medication guide) explaining risks of suicidality each time the drug is dispensed.108 109 110




  • Importance of considering possible impaired ability to perform hazardous activities (e.g., operating machinery, driving a motor vehicle).104




  • Importance of patients understanding that it may take up to 3 weeks before the full effects are apparent.104




  • Importance of avoiding alcohol-containing beverages or products.104




  • Importance of patients or caregivers supervising storage of the drug in the home and of keeping it out of reach of children.104




  • Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.104




  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses or planned surgery.112




  • Importance of informing patients of other important precautionary information.104 (See Cautions.)



Preparations


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


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




































































Desipramine Hydrochloride

Routes



Dosage Forms



Strengths



Brand Names



Manufacturer



Oral



Tablets



10 mg*



Desipramine Hydrochloride Tablets



25 mg*



Desipramine Hydrochloride Tablets



50 mg*



Desipramine Hydrochloride Tablets



75 mg*



Desipramine Hydrochloride Tablets



100 mg*



Desipramine Hydrochloride Tablets



150 mg*



Desipramine Hydrochloride Tablets



Tablets, film-coated



10 mg



Norpramin



Sanofi-Aventis



25 mg



Norpramin



Sanofi-Aventis



50 mg



Norpramin



Sanofi-Aventis



75 mg



Norpramin



Sanofi-Aventis



100 mg



Norpramin



Sanofi-Aventis



150 mg



Norpramin



Sanofi-Aventis


Comparative Pricing


This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.


Desipramine HCl 10MG Tablets (SANDOZ): 60/$55.99 or 120/$104.98


Desipramine HCl 100MG Tablets (SANDOZ): 30/$99.99 or 90/$265.97


Desipramine HCl 150MG Tablets (SANDOZ): 30/$139.99 or 90/$375.97


Desipramine HCl 25MG Tablets (SANDOZ): 60/$65.99 or 120/$124.98


Desipramine HCl 50MG Tablets (SANDOZ): 60/$114.97 or 180/$314.96


Desipramine HCl 75MG Tablets (SANDOZ): 60/$157.67 or 180/$431.98


Norpramin 10MG Tablets (SANOFI-AVENTIS U.S.): 60/$65.99 or 180/$189.98


Norpramin 100MG Tablets (SANOFI-AVENTIS U.S.): 30/$125 or 90/$349.97


Norpramin 150MG Tablets (SANOFI-AVENTIS U.S.): 30/$180 or 90/$529.97


Norpramin 25MG Tablets (SANOFI-AVENTIS U.S.): 60/$79.99 or 180/$219.96


Norpramin 50MG Tablets (SANOFI-AVENTIS U.S.): 60/$149.99 or 180/$429.96


Norpramin 75MG Tablets (SANOFI-AVENTIS U.S.): 60/$189.98 or 180/$555.98



Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.


The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions February 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.


† Use is not currently included in the labeling approved by the US Food and Drug Administration.




References


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



100. Sovner R, Orsulak PJ. Excretion of imipramine and desipramine in human breast milk. Am J Psychiatry. 1979; 136:451-2. [PubMed 426114]



101. Popper CW. Antidepressants in the treatment of attention-deficit/hypersensitivity disorder. J Clin Psychiatry. 1997; 58(Supp 14):14-29. [IDIS 398614] [PubMed 9418743]



102. Dulcan M. Practice parameters for the assessment and treatment of children, adolescents, and adults with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 1997; 36(Supp 10):85S-121S. [IDIS 395904] [PubMed 9334567]



103. Carrey NJ, Wiggins DM, Milin RP. Pharmacological treatment of psychiatric disorders in children and adolescents. Focus on guidelines for the primary care practitioner. Drugs. 1996; 51:750-9. [PubMed 8861545]



104. Aventis Pharmaceuticals, Inc. Norpramin (desipramine hydrochloride) tablets prescribing information (dated 2000 Jul). In: Physicians’ desk reference, 56th ed. Montvale, NJ: Medical Economics Company, Inc; 2002:755-6.



105. American Academy of Pediatrics Committee on Quality Improvement and Subcommittee on Attention-Deficit/Hyperactivity Disorder. Clinical treatment guideline: treatment of the school-aged child with attention-deficit/hyperactivity disorder. Pediatrics. 2001; 108:1033-44. [IDIS 470916] [PubMed 11581465]



106. Baldessarini RJ. Drugs and the treatment of psychiatric disorders: depression and anxiety disorders. In: Hardman JG, Limbird LE, Molinoff PB et al, eds. Goodman and Gilman's the pharmacological basis of therapeutics. 10th ed. New York: McGraw-Hill; 2001:463.



107. Cyclic antidepressants. In: Ellenhorn MJ, Schonwald S, Ordog G et al, eds. Ellenhorn's medical toxicology: diagnosis and treatment of human poisoning. 2nd ed. Baltimore: Williams & Wilkins; 1997:625.



108. 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.



109. 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.



110. 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.



111. 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]



112. Sanofi-Aventis U.S. LLC. Norparmin (desipramine hydrochloride) tablets prescribing information. Bridgewater, NJ; 2009 Oct.



113. Mirski D. Dear healthcare professional letter regarding an update to Norpramin (desipramine hydrochloride tablets USP) prescribing information. Bridgewater, NJ; 2009 Dec.



114. Food and Drug Administration. Norpramin (desipramine hydrochloride) tablets. Detailed view: Safety labeling changes approved by FDA Center for Drug Evaluation and Research (CDER) -- October 2009. Rockville, MD; 2009 Oct. From the FDA web site.



115. Sandoz Inc. Desipramine hydrochloride tablets, USP prescribing information. Princeton, NJ; 2010 Jan.



a. AHFS drug information 2004. McEvoy GK, ed. Tricyclic antidepressants general statement. Bethesda, MD: American Society of Health-System Pharmacists; 200:2234-41.



b. American Psychiatric Association. Practice guideline for the treatment of patients with bipolar disorder (revised). Am J Psychiatry. 2002; 159(suppl):1-49.



c. AHFS drug information 2004. McEvoy GK, ed. Desipramine hydrochloride. Bethesda, MD: American Society of Health-System Pharmacists; 2004:2252-4.



e. Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation. 6th ed. Baltimore, MD: Williams & Wilkins; 2002:377-8.



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