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DRUG RECORD

 

CLONAZEPAM

OVERVIEW
Clonazepam

 

Introduction
Clonazepam is a benzodiazepine used predominantly as an anticonvulsant as adjunctive therapy in management of epilepsy.  Therapy with clonazepam is not associated with serum aminotransferase elevations, and clinically apparent liver injury from clonazepam, if it occurs at all, must be exceedingly rare.

Background
Clonazepam (kloe naz' e pam) is a benzodiazepine with particularly potent activity against spread of seizure activity in several animal models.  The antiseizure activity of the benzodiazepines is mediated by their ability to enhance gamma-aminobutyric acid (GABA) mediated inhibition of synaptic transmission through binding to the GABA A receptor.  Clonazepam was approved in the United States for treatment of epilepsy in 1997 and currently more than 20 million prescriptions are filled yearly.  Clonazepam is currently indicated for management of absence seizures and myoclonic seizures in children as well as generalized seizure disorders in both adults and children.  Clonazepam is effective in status epilepticus, but diazepam and lorazepam are preferable because of their longer half lives.  Clonazepam is also used for restless leg syndrome, dysarthria, tic disorders, panic disorder and acute mania.  Clonazepam is available in generic forms and under the brand name Klonopin in tablets of 0.5, 1.0 and 2 mg as well as in orally disintegrating tablets for pediatric use.  The recommended initial dose for adults is 1.5 mg daily in three divided doses, increasing as needed to a maximum dose of 20 mg daily.  The most common side effects of clonazepam are dose related and include drowsiness, lethargy, ataxia, dysarthria and dizziness.  Tolerance develops to these side effects, but tolerance may also develop to the antiseizure effects.

Hepatotoxicity
Clonazepam as with other benzodiazepines is rarely associated with serum ALT elevations, and clinically apparent liver injury from clonazepam is extremely rare.  However, at least one convincing case report of acute liver injury from clonazepam with recurrence on reexposure has been reported.  Rare instances of drug induced liver injury has been reported with other benzodiazepines, such as chlordiazepoxide, diazepam, flurazepam, triazolam, clorazepate and alprazolam.  In benzodiazepine related cases of acute liver injury, the latency has ranged from a few weeks to 6 months; the typical pattern of liver enzyme elevations has been cholestatic or mixed, but hepatocellular patterns have also been reported.  The injury is usually mild to moderate in severity and self-limited.  Fever and rash have not been described nor has autoantibody formation.

Mechanism of Injury
The liver injury from benzodiazepines is probably due to a rarely produced intermediate metabolite.

Outcome and Management
The case reports of hepatic injury due to clonazepam were followed by complete recovery without evidence of residual or chronic injury.  No cases of acute liver failure or chronic liver injury due to clonazepam have been described.  There is no information about cross reactivity with other benzodiazepines (clorazepate, lorazepam or diazepam), but some degree of cross sensitivity should be assumed.

 

References regarding clonazepam hepatotoxicity and safety are given in the Overview section of the benzodiazepines.

 

Drug Class:  Anticonvulsants, Benzodiazepines.

 

 

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CASE REPORT
Clonazepam

 

Case 1.  Cholestatic hepatitis due to flurazepam.
[Modified from:  Fang MH, Ginsberg AL, Dobbins WO 3rd. Cholestatic jaundice associated with
flurazepam hydrochloride. Ann Intern Med 1978; 89: 363-4. PubMed Citation]

 

A 70 year old man developed anorexia, weakness and fatigue 2 months after starting flurazepam for insomnia.  Two and a half months later he developed dark urine and jaundice. He had no previous history of liver disease, risk factors for acquiring hepatitis and drank no alcohol.  He had coronary artery disease, angina pectoris and type 2 diabetes for which he took chlorthalidone, isosorbide dintitrate, digoxin and tolbutamide chronically.  On admission he was jaundiced, but had no fever or rash.  Liver tests, which had been normal before starting flurazepam, were elevated (Table).  Ultrasound of the abdomen was unremarkable, HBsAg was negative, and a percutaneous cholangiogram was normal.  A liver biopsy showed intrahepatic cholestasis.  Flurazepam was stopped and liver tests improved, although pruritus did not resolve for four months.  The other medications were apparently continued.

 

Key Points

Medication:Flurazepam (30 mg orally as needed)
Pattern: Mixed→Cholestatic (R=2.4→1.8)
Severity: 3+ (jaundice and hospitalization)
Latency: 2 months until nausea, 4.5 months to jaundice
Recovery: Complete recovery 2 months after stopping
Other medications:Isosorbide dinitrate, chlorthalidone, digoxin, tolbutamide

Laboratory Values

Time After Starting Time After Stopping

ALT

(U/L)

Alk P

(U/L)

Bilirubin (mg/dL) Other
Pre 40 90 0.5
0 Flurazepam started
4.5 months 225 207 7.0
5 months 0 159 232 6.6
Flurazepam stopped
4 days 174 230 5.0
7 days 181 225 4.5 Liver biopsy
24 days 79 183 1.7
6 months 4 weeks 59 142 1.0
6.5 months 7 weeks 47 104 0.6
Normal Values <49 <90 <1.2

Comment

Cholestatic hepatitis arising after 4 months of intermittent use of flurazepam.  Other possible causes were tolbutamide, but the liver injury resolved despite it being continued.  Mild self-limited cholestatic hepatitis is the typical pattern of benzodiazepam induced acute liver injury, but it is very rare and has not been associated with acute liver failure or chronic liver injury.

 

Case 2.  Cholestatic hepatitis due to flurazepam.
[Modified from:  Reynolds R, Lloyd DA, Slinger RP. Cholestatic jaundice induced by flurazepam hydrochloride. Can Med Assoc J 1981; 124: 893-4. PubMed Citation]

 

A 44 year old Dutch woman visiting relatives in Canada developed anorexia, nausea and abdominal discomfort.  She had been taking flurazepam for insomnia intermittently for 6 months, but more frequently while visiting.  After developing jaundice and pruritis, she was admitted for evaluation.  She had no previous history of liver disease, risk factors for acquiring hepatitis and drank little alcohol.  She took no other medications.  She was jaundiced but had no fever, rash or signs of chronic liver disease.  Liver tests were elevated (Table).  Ultrasound of the abdomen was unremarkable and HBsAg was negative.  A liver biopsy showed intrahepatic cholestasis.  Flurazepam was stopped and liver tests improved rapidly.

 

Key Points

Medication:Flurazepam (30 mg orally as needed)
Pattern: Mixed→(R=2.5)
Severity: 3+ (jaundice and hospitalization)
Latency: 6 months to onset of symptoms
Recovery:Complete recovery one month after stopping
Other medications:None

Laboratory Values

Time After Starting Time After Stopping ALT  (U/L) Alk P (U/L) Bilirubin (mg/dL) Other
6 months 0 106 209 8.2 8% eosinophils
1 day 122 203 8.3
3 days 134 201 7.2 Liver biopsy
6 days 185 195 6.6
17 days 108 121 2.0
4 weeks 60 111 1.8
7 months 7 weeks 16 96 1.0
Normal Values <24 <120 <1.2

Comment

The benzodiazepines are widely used agents for therapy of anxiety, insomnia, tremor and some forms of seizures.  They are extremely well tolerated and only rarely associated with significant liver injury.  This case is typical of the rare instances of hepatotoxicity reported with benzodiazepines, marked by a self-limited cholestatic hepatitis arising after several months of use.  Signs of hypersensitivity or autoimmunity are uncommon, although this patient had mild eosinophilia.  Liver enzymes were only modestly elevated and the calculated R value suggested that the pattern of injury was “mixed.”  However, the prominence of jaundice and pruritis along with the liver biopsy findings indicate that the injury was predominantly cholestatic.

 

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PRODUCT INFORMATION
Clonazepam

 

REPRESENTATIVE TRADE NAMES
Clonazepam – Klonopin®

 

DRUG CLASS
Anticonvulsants

 

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

 

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DRUG CAS REGISTRY NUMBER MOLECULAR FORMULA STRUCTURE
Clonazepam 1622-61-3 C15-H10-Cl-N3-O3 Clonazepam chemical structure

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OTHER REFERENCE LINKS
Clonazepam

 

  1. PubMed logoRecent References on Clonazepam

  2. Clinical Trials logoTrials on Clonazepam

  3. TOXLINE logoTOXLINE Citations on Clonazepam

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