What is the risk of Clarithromycin (generic name) induced hepatic injury?

From the Guidelines

Clarithromycin can cause liver injury, though this is an uncommon side effect occurring in patients, and the most recent evidence suggests that azithromycin is preferred over clarithromycin due to better tolerability and fewer drug interactions 1.

Key Points to Consider

• The liver injury typically manifests as a mild, asymptomatic elevation in liver enzymes (transaminases) that resolves upon discontinuation of the medication.
• More severe hepatotoxicity is rare but can present as cholestatic hepatitis with jaundice, usually appearing within 1-3 weeks of starting treatment.
• Patients with pre-existing liver disease or those taking other hepatotoxic medications may be at higher risk.
• If a patient on clarithromycin develops symptoms such as fatigue, nausea, abdominal pain, dark urine, or yellowing of the skin/eyes, the medication should be immediately discontinued and liver function tests obtained.
• The mechanism of clarithromycin-induced liver injury is believed to be an idiosyncratic immune-mediated reaction rather than direct toxicity.
• Most cases resolve completely within 4-8 weeks after stopping the medication.
• No specific treatment beyond discontinuation is typically required, though supportive care may be necessary in severe cases.
• Healthcare providers should monitor liver function in patients with risk factors and consider alternative antibiotics when appropriate, with azithromycin being a preferred option due to its better tolerability and fewer drug interactions 1.

Monitoring and Management

• Regular monitoring of liver function is essential in patients with risk factors.
• Alternative antibiotics, such as azithromycin, should be considered in patients with pre-existing liver disease or those taking other hepatotoxic medications.
• Patients should be educated on the signs and symptoms of liver injury and instructed to seek medical attention immediately if they experience any adverse effects.
• In cases of severe hepatotoxicity, supportive care and close monitoring of liver function are necessary to prevent long-term liver damage.

Evidence-Based Recommendations

• The most recent evidence suggests that azithromycin is preferred over clarithromycin due to better tolerability and fewer drug interactions 1.
• Clarithromycin should not be used in doses above 500 mg twice daily, as higher doses have been associated with excess mortality in certain populations 1.
• Healthcare providers should be aware of the potential for drug interactions between clarithromycin and other medications, particularly those that inhibit cytochrome P450 isoenzyme 3A4 1.

From the FDA Drug Label

Hepatic dysfunction, including increased liver enzymes, and hepatocellular and/or cholestatic hepatitis, with or without jaundice, has been reported with clarithromycin. This hepatic dysfunction may be severe and is usually reversible In some instances, hepatic failure with fatal outcome has been reported and generally has been associated with serious underlying diseases and/or concomitant medications. Symptoms of hepatitis can include anorexia, jaundice, dark urine, pruritus, or tender abdomen. Discontinue clarithromycin immediately if signs and symptoms of hepatitis occur.

Clarithromycin-induced liver injury is a potential risk, with reported cases of hepatocellular and/or cholestatic hepatitis, which may be severe and reversible. In rare instances, hepatic failure with fatal outcome has occurred, often associated with serious underlying diseases and/or concomitant medications. If signs and symptoms of hepatitis occur, discontinue clarithromycin immediately 2.

From the Research

Clarithromycin Induced Liver Injury

• Clarithromycin, a macrolide antibiotic, has been reported to cause liver injury in several cases, with six reported cases of acute liver failure (ALF) 3.
• A case report of a 60-year-old nonalcoholic man who developed clarithromycin-associated ALF after completing a 7-day course of clarithromycin 500 mg twice daily for suspected upper respiratory infection 3.
• The patient's liver function tests showed a significant rise in AST and ALT, with development of severe hepatic encephalopathy and severe coagulopathy, leading to massive upper gastrointestinal bleeding and eventual death 3.
• Another case report of a 34-year-old male who developed drug-induced liver injury (DILI) after 14-day triple therapy with clarithromycin for eradicating Helicobacter pylori infection 4.
• A 58-year-old white woman developed fulminant liver failure while being treated with clarithromycin for pneumonia, with liver biopsy revealing centroacinar necrosis and beginning fibrous reorganization, compatible with recent centroacinar damage 5.
• A case of progressive cholestatic liver disease associated with clarithromycin treatment was reported in a 59-year-old woman with diabetes mellitus and chronic renal insufficiency, who received clarithromycin 500 mg twice daily for 3 days for acute maxillary sinusitis 6.
• Although azithromycin, another macrolide antibiotic, has been reported to cause liver injury, the mechanism of clarithromycin-induced liver injury is not fully understood, but it is thought to be related to its hepatic metabolism 7, 3, 5.

Characteristics of Clarithromycin Induced Liver Injury

• The liver injury associated with clarithromycin can range from mild elevations in liver enzymes to severe liver failure, including ALF and fulminant liver failure 3, 5.
• The onset of liver injury can occur within days to weeks after starting clarithromycin therapy, with a temporal relationship between initiation of the drug and the onset of clinical signs and symptoms 3, 4.
• The liver injury can be characterized by significant elevations in AST and ALT, with development of severe hepatic encephalopathy and severe coagulopathy, leading to massive upper gastrointestinal bleeding and eventual death 3.
• Liver biopsy can show centroacinar necrosis and beginning fibrous reorganization, compatible with recent centroacinar damage, or pure bilirubinostasis without parenchymal inflammation 5, 6.

Risk Factors and Prevention

• The risk factors for clarithromycin-induced liver injury are not fully understood, but it is thought to be related to its hepatic metabolism and potential interactions with other drugs 5.
• Patients with pre-existing liver disease, such as cirrhosis or hepatitis, may be at increased risk of developing liver injury with clarithromycin therapy 3.
• Clinicians should exercise caution and be alert to the potential hepatotoxic effects of clarithromycin, especially when initiating therapy in patients with risk factors for liver disease 4.