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DRUG RECORD

 

PHENELZINE

OVERVIEW
Phenelzine

 

Introduction

Phenelzine is a monamine oxidase inhibitor (MAO inhibitor) used in therapy of severe depression.  Phenelzine therapy is associated with rare instances of clinically apparent acute liver injury.

 

Background

Phenelzine (fen' el zeen) is a hydrazine derivative and antidepressant that acts through inhibition of monamine oxidase, an enzyme that inactivates several neurotransmitter amines such as norepinephrine and serotonin.  By inhibition of catabolism of serotonin and norepinephrine, phenelzine increases brain levels of these neurotransmitters which probably underlie its antidepressant effects.  Phenelzine was approved for use as therapy of depression in the United States in 1961, but it is now rarely used because of the availability of more potent and better tolerated antidepressants such as the tricyclic antidepressants and the selective serotonin reuptake inhibitors.  Phenelzine is available in generic forms and under the brand name of Nardil as tablets of 15 mg.  The usual adult dose of phenelzine is 15 to 30 mg three times daily.  Common side effects include drowsiness, dizziness, headache, insomnia, tremor, dry mouth, nausea, increased appetite, weight gain and sexual dysfunction.  Phenelzine interacts with many medications as well as many foods and beverages, and patients require careful monitoring and education.

 

Hepatotoxicity

Phenelzine, like most monamine oxidase inhibitors, can cause transient serum aminotransferase elevations in a proportion of patients.  These elevations are usually mild, asymptomatic and self-limited and do not require dose modification.  Phenelzine has also been associated with cases of acute, clinically apparent liver injury.  The liver injury associated with MAO inhibitors typically arises 1 to 3 months after starting therapy and presents with a hepatocellular pattern of serum enzyme elevations.  The acute hepatitis-like syndrome can be severe and even fatal.  Cholestatic liver injury due to phenelzine has also been described (Case 1).  Immunoallergic features (rash, fever, eosinophilia) are uncommon as is autoantibody formation.

 

Mechanism of Injury

The mechanism by which phenelzine causes serum aminotransferase elevation is not known.  It undergoes extensive hepatic metabolism, and a possible cause of liver injury is production of an intermediate of metabolism that is directly toxic to hepatocytes or that induces a hypersensitivity response.

 

Outcome and Management

The serum aminotransferase elevations that occur on phenelzine therapy are usually self-limited and mild and do not require dose modification or discontinuation of therapy.  The clinically apparent, acute liver injury caused by phenelzine is typically self-limited, but progressive and fatal instances of acute hepatitis have been reported.  Rechallenge usually causes a prompt recurrence of the liver injury and should be avoided.  Patients with phenelzine induced liver injury may have cross sensitivity to other monamine oxidase inhibitors, but should be able to tolerate tricyclic antidepressants or selective serotonin reuptake inhibitors.

Drug Class:  Antidepressant Agents

 

Other Drugs in the Subclass, MAO Inhibitors:  Isocarboxazid, Tranylcypromine

 

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CASE REPORT
Phenelzine

 

Case 1.  Severe and prolonged liver injury due to phenelzine.
[Modified from:  Bonkovsky HL, Blanchette PL, Schned AR. Severe liver injury due to phenelzine with unique hepatic deposition of extracellular material. Am J Med 1986; 80: 689-92. PubMed Citation]

 

A 59 year old man developed fatigue and itching followed by jaundice 2 months after starting phenelzine and shortly after a dose escalation from 45 to 60 mg daily.  He had no history of liver disease or exposure to viral hepatitis and drank alcohol only moderately.  Other medications included colchicine, probenecid, chlordiazepoxide and flurazepam.  Physical examination showed jaundice without rash or fever or signs of chronic liver disease.  Serum bilirubin was 9.8 mg/dL and serum enzymes were raised (Table).  There was no eosinophilia and tests for hepatitis B and autoantibodies were negative.  Phenelzine was stopped, but liver tests did not improve rapidly.  A liver biopsy showed areas of lobular collapse, inflammation and intrahepatic cholestasis and unusual, amorphous and unidentified extracellular deposits.  He was treated with prednisone (15 mg daily) and azathioprine (50 mg daily) with a clinical and biochemical response, but serum enzymes remained mildly abnormal for somewhat more than a year before becoming persistently normal.  Follow up liver biopsy showed resolution of the acute injury, but presence of fibrosis and partial cirrhosis.

 

Key Points

Medication: Phenelzine (60 mg daily)
Pattern: Cholestatic (R=0.6)
Severity: 3+ (jaundice and hospitalization)
Latency: 2 months
Recovery: 18 months
Other medications:Colchicine, probenecid, chlordiazepoxide, flurazepam

Laboratory Values

Time After Starting Months After Stopping AST (U/L) Alk P (U/L) Bilirubin (mg/dL) Other
Pre Pre 20 80 1.0
Phenelzine given for two months
2 months 0 148 520 9.8 Liver biopsy
3 months 1 month 55 300 1.9
4 months 2 months 100 680 1.2 Liver biopsy
5 months 3 months 95 425 1.0
6 motnhs 4 months 65 300
7 months 5 months 55 220
10 months 8 months 45 130 0.8
1 year 1 year 30 170 Liver biopsy
1.8 years 1.5 years 45 85 0.5
Normal Values <40 <85 <1.2

Dates and values estimated from Figure 1.

 

Comment

The monamine oxidase (MAO) inhibitors are no longer commonly used and most reported cases of hepatotoxicity were published before 1990.  The described case is unusual because of the prolonged injury and development of cirrhosis, despite prompt discontinuation of the medication.  Actually, clinical and histologic long term follow up is rarely available in cases of acute drug induced liver disease, and some degree of residual fibrosis and even cirrhosis may occur particularly if the acute episode is severe and prolonged.

 

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PRODUCT INFORMATION
Phenelzine

 

REPRESENTATIVE TRADE NAMES
Phenelzine Generic, Nardil®

 

DRUG CLASS
Antidepressant Agents

 

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

 

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DRUG CAS REGISTRY NUMBER MOLECULAR FORMULA STRUCTURE
Phenelzine 51-71-8 C8-H12-N2 Image of Phenelzine Chemical Structure

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REFERENCES
Phenelzine

 

References updated: 16 January 2014

  1. Zimmerman HJ. Antidepressants. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, pp. 493-8.  (Expert review of hepatotoxicity published in 1999; hepatic injury caused by monamine oxidase [MAO] inhibitors is similar to that of isoniazid with which they share structural similarity as hydrazines; the pattern of injury is typically hepatocellular and arises within 1-6 months of starting therapy; cases of fatal acute liver failure have been described, most commonly with iproniazid and less commonly with phenelzine and isocarboxazid, and least commonly with the nonhydrazide MAO inhibitor, tranylcypromine).

  2. Larrey D, Ripault MP. Hepatotoxicity of psychotropic drugs and drugs of abuse. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 443-62.  (Review of hepatotoxicity of antidepressants mentions that among MAO inhibitors iproniazid most commonly caused liver injury and phenelzine rarely).

  3. O'Donnell JM, Shelton RC. Drug therapy of depression and anxiety disorders. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman’s the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 396-415.  (Textbook of pharmacology and therapeutics).

  4. Rosenblum LE, Korn LJ, Zimmerman HJ. Hepatocellular jaundice as a complication of iproniazid therapy. Arch Intern Med 1960; 105: 115-25. PubMed Citation  (Classic paper on iproniazid hepatotoxicity; review of 90 patients; more common in women, ages 25-75 years, onset in 1-4 months [~95%], usually hepatocellular pattern similar to viral hepatitis, 22% mortality and demonstration that this is higher than in acute viral hepatitis).

  5. Holdswoth CD, Atkinson M, Goldie W. Hepatitis caused by the newer amine-oxidase-inhibiting drugs. Lancet 1961; 2: 621-23. PubMed Citation  (Four cases of severe liver injury with cross sensitivity to several MAO inhibitors including iproniazid, pheniprazine and nialamide; case 4 was a 56 year old woman who developed jaundice and itching 5 months after starting phenelzine [bilirubin 2.8 mg/dL, ALT 150 U/L, Alk P 3 times ULN], resolving rapidly upon stopping).

  6. Crisp AH, Hays P, Carter A. Three amine-oxidase inhibitor drugs in the treatment of depression. Relative value and toxic effects. Lancet 1961; 1: 17-8. PubMed Citation  (Prospective study of liver test abnormalities during courses of iproniazid [n=17], nialamide [18] and peniprazine [20] with minor increases noted; no data on frequency of levels above normal).

  7. Cook GC, Sherlock S. Jaundice and its relation to therapeutic agents. Lancet 1965; 1: 175-9. PubMed Citation  (Summary of cases of drug induced liver disease seen at Royal Free Hospital from 1959-65; 11 cases of acute liver failure due to drugs including iproniazid [n=3], phenelzine [2], phenoxypropazine [2], prochlorperazine [1] and halogenated anesthetics [3]; 20 cases of cholestatic hepatitis due to drugs, 18 due to chlorpromazine, 1 perphenazine and 1 nitrofurantoin).

  8. Daneshmend TK, Scott GL, Bradfield JW. Angiosarcoma of liver associated with phenelzine. Br Med J 1979;1: 1679. PubMed Citation  (64 year old woman who had been on phenelzine for 6 years developed angiosarcoma; phenelzine reported to cause angiosarcomas in mice).

  9. Bonkovsky HL, Blanchette PL, Schned AR. Severe liver injury due to phenelzine with unique hepatic deposition of extracellular material. Am J Med 1986; 80: 689-92. PubMed Citation  (59 year old man developed jaundice 2.5 months after starting phenelzine [bilirubin 9.8 mg/dL, AST 148 U/L, Alk P 520 U/L], prolonged course requiring corticosteroids, ultimate resolution but cirrhosis present on biopsy: Case 1).

  10. Zimmerman HJ, Ishak KG. The hepatic injury of monoamine oxidase inhibitors. J
    Clin Psychopharmacol 1987; 7: 211-3. PubMed Citation  (Editorial on the hepatotoxicity of MAO inhibitors which occurs in ~1% of patients taking iproniazid, but in a lesser proportion with other hydrazine derivatives such as phenelzine and isocarboxazid; the injury is idiosyncratic, usually hepatocellular and has a high [>10%] fatality rate).

  11. Steingart AB, Cotterchio M. Do antidepressants cause, promote, or inhibit cancers? J Clin Epidemiol 1995; 48: 1407-12. PubMed Citation  (Conflicting data from animal studies and epidemiological surveys have provided little evidence of a link between antidepressant use and breast, liver or other cancer after control for confounding variables).

  12. Gomez-Gil E, Salmeron JM, Mas A. Phenelzine-induced fulminant hepatic failure. Ann Intern Med 1996; 124: 692-3. PubMed Citation  (Reports two cases of acute liver failure due to phenelzine, but no specific results given).

  13. Lucena M, Carvajal A, Andrade R, Velasco A. Antidepressant-induced hepatotoxicity. Expert Opin Drug Saf 2003; 2: 249-62. PubMed Citation  (Review of hepatotoxicity of antidepressants; antidepressant use has increased markedly between 1992 and 2002, accounting for 5% of cases of hepatotoxicity; MAO inhibitors were first antidepressants developed; iproniazid caused a severe hepatitis and was withdrawn; phenelzine is still in use but has been associated with severe cases of hepatitis and development of cirrhosis).

  14. Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J; Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008; 135: 1924-34. PubMed Citation  (Among 300 cases of drug induced liver disease in the US collected from 2004 to 2008, none were attributed to MAO inhibitors).

  15. Reuben A, Koch DG, Lee WM; Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology 2010; 52: 2065-76. PubMed Citation  (Among 1198 patients with acute liver failure enrolled in a US prospective study between 1998 and 2007, 133 were attributed to drug induced liver injury, 3 of which were linked to antidepressants: one each for nefazodone, fluoxetine and venlafaxine, but none to phenelzine or MAO inhibitors).

  16. Sedky K, Nazir R, Joshi A, Kaur G, Lippmann S. Which psychotropic medications induce hepatotoxicity? Gen Hosp Psychiatry 2012; 34: 53-61. PubMed Citation  (Review of the hepatotoxicity of psychotropic drugs in common use, mentions that phenelzine can cause severe acute or chronic liver injury).

  17. Park SH, Ishino R. Liver injury associated with antidepressants. Curr Drug Saf 2013; 8: 207-23. PubMed Citation  (Review of drug induced liver injury due to antidepressants including MAO inhibitors).

  18. Drugs for psychiatric disorders. Treat Guidel Med Lett 2013; 11 (130): 53-64; PubMed Citation  (Review of drugs used for depression mentions that MAO inhibitors "remain valuable alternatives for patients with moderate to severe treatment resistant depression; discussion of side effects does not mention hepatotoxicity).

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OTHER REFERENCE LINKS
Phenelzine
  1. PubMed logoRecent References on Phenelzine

  2. Clinical Trials logoTrials on Phenelzine

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