Drugs Requiring Liver Dose Adjustment

DOSE MODIFICATION IN LIVER IMPAIRMENT

Drugs Requiring Liver Dose Adjustment

Alprazolam Reduce dose by 50 % to 60% or avoid in cirrhosis. Benzodiazepines can be cautiously used in decompensated cirrhosis. 

Aminophylline

Adjusted according to serum level measurement during the first 12 to 24 hours. Use with caution. 

Amiodarone If hepatic enzymes exceed 3 times normal or double in patient with an elevated baseline, consider decreasing the dose or discontinuing amiodarone. 

Amitryptylline Increase sedative effect; avoid or use with caution in liver disease. 

Amlodipine Starting dose 2.5mg. AspirinAvoid use in severe liver disease; may increase risk of GI bleeding. 

Atorvastatin Contraindicated in active liver disease or in unexplained persistent increase in serum transaminase. 

Azithromycin Not necessary. Specific dosing guidelines for hepatic impairment have not been established. Macrolide antibiotics excreted and detoxified by liver. Should be used with cautions due to potential of hepatotoxicity especially in cirrhotic patients. 

Bupivacaine Use with caution. Consider dose adjustment in severe impairment. 

Calcium Polystyrene Sulfonate Powder No adjustment as drug not absorbed systematically. 

Carbamazepine Avoided if aggravated liver dysfunction or active liver disease. 

Caspofungin Mild (Child-pugh score 5-6): no adjustment necessary (70mg on day 1, subsequent dosing 50mg/day). Moderate (Child-pugh score 7-9): 70mg (invasive infections) or 35mg/day (esophageal candidiasis) on day 1, followed by 35mg once daily. Severe (Child-pugh score >9): no clinical experience. 

Cefoperazone Sulbactam (Sulperazone) Dose adjustment may be necessary in patients with liver dysfunction.  Cefoperazone extensively excreted in the bile. The serum half-life of cefoperazone increased 2- to 4-fold in patient with hepatic disease and/or biliary obstruction. Total daily dose above 9g should not be given. 

Cefotaxime Moderate dosage reduction is recommended in severe liver disease. 

Ceftriaxone To consider dose reduction in patient with hepatic and severe renal impairment. (Dose ≤ 2g/day). 

Celecoxib Moderate (Child-pugh class B): reduce dose by 50%. Severe: use is not recommended. Abnormal liver function tests (persistent or worsening): discontinue use. 

Clarithromycin Elderly: age related reduction in renal function; monitor and adjust dose if necessary. 

Clindamycin Dose reduction is recommended in severe hepatic diseases. No specific dosing recommendations available. Clindamycin excreted and detoxified by liver, should be used with cautions in cirrhotic patients.

 Clonazepam Contraindicated in significant liver disease. Caution in hepatic disease patients.

Clopidogrel. Caution (risk of bleeding); avoid in severe hepatic impairment. Reduced dose in moderate case. 

Dantrolene Chronic therapy contraindicated in active liver disease; has potential for hepatotoxicity. 

Dexmedetomidine Dose reduction may need to be considered (↓ clearence).

 Diazepam Benzodiazepines can be cautiously used in decompensated cirrhosis.

 Digoxin No specific dosage adjustment is necessary. 

Diltiazem No specific dosing recommendations available; extensively metabolized by the liver; half-life is increased in patients with cirrhosis. 

Enalapril No adjustment. Hydrolysis may be delayed and/or impaired in severe hepatic impairment, but the pharmacodynamic effects of the drug do not appear to be significantly altered. 

Enoxaparine Use with caution in hepatic impairment. 

Ertapenem Adjustments cannot be recommended (lack of experience and research in this patient population). 

Erythromycin Macrolide antibiotics excreted and detoxified by liver, should be used with cautions in cirrhotic patients. No specific dosing recommendations available.

 Esomeprazole Mild to moderate (Child-Pugh class A or B) - no adjustment.                                                          Severe (Child-Pugh Class C) - dose should not exceed 20mg. 

Felodipine Begin at dose of 2.5mg/day. Do not use dose above 10mg/day as incidence and severity of adverse event outweighs additional hypotensive effects. 

Fluconazole No specific dosing recommendations available. Should be used with caution in patients with hepatic dysfunction or previous hepatotoxicity from other azole derivatives. Patient who develops abnormal liver function tests during fluconazole therapy should be monitored closely and discontinued if symptoms consistent with liver disease develop. 

Frusemide Cirrhotic patient may have diminished natriuretic effect with increased sensitivity to hypokalemia and volume depletion, and may require higher dose. Monitor side effect particularly with high dose. No specific dosing recommendations available. 

Fucidic acid Avoid in hyperbilirubinemia patient. 

Granisetron Kinetic studies in patients with hepatic impairment showed that total clearance was approximately halved, however standard doses were much tolerated, and dose adjustments are not necessary. 

Hydrocortisone Should be used with caution in patients with hepatic dysfunction including cirrhosis.  Long term use has been associated with fluid retention. 

Imipenem-Cilastatin (Tienam®) Hepatic dysfunction may further impair cilastin clearance; consider decreasing the dosing frequency. 

Insulin - Insulin requirements may be reduced. Closed monitoring of blood glucose and adjustment of therapy is required in hepatic impairment.

 Isoniazid No adjustment required. However, use with caution; may accumulate and additional liver damage may occur in patients with pre-existing liver disease. For ALT or AST > 3 x ULN, discontinue or temporarily withhold treatment. Refer Clinical Practice Guidelines: Management of Tuberculosis, 3rd edition for management of tuberculosis in liver impairment. 

Itraconazole Use with caution in patient with hepatic impairment. 

Ketorolac Use with caution, may cause elevation of liver enzyme. Hepatic dose may prolong elimination half life. Discontinue if clinical signs and symptoms of liver disease develop.

Labetalol Chronic liver disease may reduce metabolism of labetalol. Dosage reduction is required to avoid decrease in heart rate and supine blood pressure.

 Lamotrigine Mild (Child-Pugh class A): no adjustment required. Moderate to severe (Child-Pugh class B or C) without ascites: initial escalation & MD should ↓ by 25%. Moderate to severe (Child-Pugh class B or C) with ascites: initial escalation & MD should ↓ by 50%. 

Lansoprazole In severe liver disease, consider dose reduction.

 Levetiracetam Mild to moderate (Child-Pugh class A or B):  no need adjustment. Severe (Child-Pugh class C): ↓ dose by 50%.

 Levobupivacaine Caution in liver disease. 

Lignocaine Consider dose reduction in acute hepatitis and cirrhosis. 

Linezolid Mild to moderate (Child-Pugh class A or B): no dosage adjustment. Severe (Child-Pugh class C): not been adequately evaluated. 

Losartan Reduce initial dose to 25mg/day. 

Lovastatin Use with caution in patient with past history of liver disease; active liver disease is contraindicated. 

Metformin Liver disease is a risk factor for lactic acidosis, should be avoided in patients with hepatic insufficiency. 

Metoprolol Dosage adjustment may be required; reduce dose slightly.

 Metronidazole Reduce dose by 50% in patients with severe cirrhosis and/or associated renal insufficiency. 

Midazolam Reduced midazolam clearance in patients with cirrhosis. Benzodiazepines can be cautiously used in decompensated cirrhosis. 

Morphine Mild: no dose adjustment. 

Severe: avoid. Excessive sedation may occur in cirrhosis. Duration of action prolonged, dosage should be adjusted.Dosing interval suggested to be increased  1.5 to 2 times normal dose. 

Nalbuphine Administer with caution; reduced doses. 

Nifedipine Reduce dose by 50% to 60% in patients with cirrhosis.

 Ofloxacin Severe impairment: maximum dose 400mg/day.

Omeprazole Bioavailability is increased with chronic liver disease. Consider dosage adjustment, especially for maintenance of erosive esophagitis. Specific guidelines are not available. 

Oxycodone Reduce dosage in patients with severe liver disease. 

Pantoprazole No adjustment needed. Dose above 40mg/day have not been studied. Use with caution in severe hepatic impairment. 

Paracetamol. Use with caution. Avoid chronic use and large dose in hepatic impairment. Safely administered in therapeutic dose in stable hepatic disease. Patients with cirrhosis: recommended dose < 2-3 g/day. 

Parecoxib Mild: No adjustment. 

Moderate (Child-Pugh score 7-9): Should be initiated with half the usual recommended dose and the maximum dose should be reduced to 40mg. 

Pethidine Reduce initial dose in severe hepatic impairment; use with caution. 

Phenobarbital Use with caution; initial dose should be reduced.

Phenytoin Clearance may be substantially reduced in cirrhosis. Plasma level monitoring with dose adjustment advisable. Free phenytoin levels should be monitored closely. 

Piracetam. Cirrhosis: clearance ↓; dose adjustment necessary. 

Prazosin Initially 0.5mg od; increased with caution. 

Propranolol Marked slowing of heart rate may occur during cirrhosis with conventional dose; low initial dose required. 

Pyrazinamide Monitor hepatic function; idiosyncratic hepatoxicity more common. Specific dosage recommendation not provided. Refer Clinical Practice Guidelines: Management of Tuberculosis, 3rd edition for management of tuberculosis in liver impairment. 

Ranitidine May have minor changes in ranitidine half-life, distribution, clearance, and bioavailability in hepatic impairment; dosing adjustments not necessary. 

Rifampicin Monitor hepatic function ; idiosyncratic hepatoxicity more common Specific dosage recommendation not provided. Refer Clinical Practice Guidelines: Management of Tuberculosis, 3rd edition for management of tuberculosis in liver impairment. 

Rocuronium Reductions may be necessary in patients with liver disease; duration of neuromuscular blockade may be prolonged. 

Ropivacaine Consider dose reduction or avoid. SevofluraneUse with caution in patient with underlying hepatic condition. 

Simvastatin Contraindicated in active liver disease. 

Sodium bicarbonate In patient with fluid retention, avoid those contain large amount of sodium. 

Suxamethonium Prolonged apnea may occur in severe liver disease due to reduced hepatic synthesis of pseudocholinesterase. May ↓dose. 

Telmisartan 20 - 40mg od in mild / moderate impairment, avoid in severe.

 Theophylline Monitor serum level and ↓ dose. 

Tigecycline Mild to moderate (Child-Pugh classes A and B): No dosage adjustment. Severe (Child-Pugh class C): 100mg single dose; maintenance: 25mg q12h. 

Topiramate Use with caution in hepatic impairment; may decrease clearance but no specific dosing. 

Tramadol Cirrhosis: 50mg bd. 

Valpraote  (valproic acid) Reduce dose. Clearance is decreased with liver impairment. Hepatic disease is also associated with decreased albumin concentrations and 2 to 2.6-fold increase in the unbound fraction. Free concentrations of valproate may be elevated while total concentrations appear normal.

 Use is contraindicated in severe impairment. 

Valsartan Mild to moderate ≤ 80mg/day; avoid if severe. 

Vecuronium Not recommended; if must be used, lowest effective dose is recommended. 

Verapamil Reduce dose by 20% to 50% of normal dose; patient should be monitored for abnormal prolongation of the PR interval. 

Voriconazole Mild to moderate (Child-Pugh classes A and B): follow standard LD, reduce MD by 50%. Severe (Child-Pugh classes C): used only if benefit outweighs risk. 

Warfarin Avoid in severe liver disease especially if PT already prolonged. Respond to oral anticoagulant may be enhanced in obstructive jaundice (due to ↓ vit K absorption), hepatitis and cirrhosis (due to ↓ production of vit K dependent clotting factor).

Reference

1. Micromedex (R) Healthcare Series. Vol 141. 

2. Lexi-comp 17th Edition. 

3. Deepak, N.A. (2011). Prescribing Medications in Patients with Decompensated Liver Cirrhosis International Journal of Hepatology, article ID: 519526. 4. Albers, I., Hartmann, H., Bircher, J., & Creutzfeld, I.N. (1989). Superiority of the Child-Pugh Classification to quantitive liver function tests for assessing prognosis of liver cirrhosis. Scand J Gastroebterol, 24, 269-276.