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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.

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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].

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Clonazepam

Last Update: January 25, 2017.

OVERVIEW

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.

Likelihood score: D (possible but rare cause of clinically apparent liver injury).

Mechanism of Injury

The liver injury from benzodiazepines is probably due to a rarely produced intermediate metabolite. Their relative safety may relate to the low daily doses used (typically 5 to 10 mg).

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 (clobazam, clorazepate, lorazepam or diazepam), but some degree of cross sensitivity should be assumed.

Drug Class: Anticonvulsants, Benzodiazepines

CASE REPORTS

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 StartingTime After StoppingALT
(U/L)		Alk P
(U/L)		Bilirubin (mg/dL)Other
Pre40900.5
0Flurazepam started
4.5 months2252077.0
5 months01592326.6
Flurazepam stopped
4 days1742305.0
7 days1812254.5Liver biopsy
24 days791831.7
6 months4 weeks591421.0
6.5 months7 weeks471040.6
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 StartingTime After StoppingALT (U/L)Alk P (U/L)Bilirubin (mg/dL)Other
6 months01062098.28% eosinophils
1 day1222038.3
3 days1342017.2Liver biopsy
6 days1851956.6
17 days1081212.0
4 weeks601111.8
7 months7 weeks16961.0
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.

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Clonazepam – Klonopin®

DRUG CLASS

Anticonvulsants

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

DRUGCAS REGISTRY NUMBERMOLECULAR FORMULASTRUCTURE
Clonazepam 1622-61-3 C15-H10-Cl-N3-O3
Clonazepam chemical structure

REFERENCES

References updated: 25 January 2017

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    (Expert review of benzodiazepines and liver injury published in 1999; mentions rare instances of cholestatic hepatitis have been reported due to alprazolam, chlordiazepoxide, clonazepam, diazepam, flurazepam, and triazolam, and hepatocellular injury with clorazepate, but no reports of hepatic injury with lorazepam, oxazepam or temazepam).
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    (Review of drug induced liver injury mentions that there have been rare instances of acute liver injury [usually cholestatic] reported with alprazolam, bentazepam, chlordiazepoxide, clonazepam, clorazepate, clotiazepam, diazepam, flurazepam, and triazolam; a hepatitis-like pattern was reported with alprazolam and diazepam).
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    (Review of anticonvulsant induced liver injury; benzodiazepines are not discussed).
  • McNamara JO. Pharmacology of the epilepsies. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman’s the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 583-607.
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    (Textbook of pharmacology and therapeutics).
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    (Systematic review; ALT elevations occur in 4% of children on phenytoin, 6% on valproate, 1% on carbamazepine; “No child taking… benzodiazepines had raised liver enzyme levels,”).
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    (36 years of reporting to Swedish registry identified 103 cases of acute liver failure due to drugs, of which 1 was attributed to phenytoin, 1 to valproate and 1 to carbamazepine, but none to benzodiazepines).
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    (32 year old woman developed pruritis and jaundice 1-2 months after starting sertraline, aprazolam and clorazepate, resolving with stopping sertraline, but had persistent minor ALT elevations and biopsy showing mild bridging fibrosis 4 months later).
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    (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, but none were linked to benzodiazepine use).
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    (Concise review of indications and side effects of anticonvulsants including clonazepam; no mention of hepatotoxicity).
  • Björnsson ES, Bergmann OM, Björnsson HK, Kvaran RB, Olafsson S. Incidence, presentation and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology 2013; 144: 1419-25. [PubMed: 23419359]
    (In a population based study of drug induced liver injury from Iceland, 96 cases were identified over a 2 year period, but none were linked to benzodiazepines).
  • Hernández N, Bessone F, Sánchez A, di Pace M, Brahm J, Zapata R, A Chirino R, et al. Profile of idiosyncratic drug induced liver injury in Latin America. An analysis of published reports. Ann Hepatol 2014; 13: 231-9. [PubMed: 24552865]
    (Systematic review of literature of drug induced liver injury in Latin American countries published from 1996 to 2012 identified 176 cases, but none were attributed to a benzodiazepine).
  • Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology 2015; 148: 1340-52. [PMC free article: PMC4446235] [PubMed: 25754159]
    (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, 40 [4.5%] were attributed to anticonvulsants, but none to benzodiazepine anticonvulsants).

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