| | Altered response and pharmacokinetics | Management suggestions |
| Alcohol abstinence |
| Baclofen | - Limited hepatic metabolism.
- Preliminary safety data in cirrhosis are promising; however, efficacy is not well established.
- Can reduce alcohol craving and help to maintain abstinence.
| - Total daily dose titrated to 30 to 60 mg, given in divided doses, has been tolerated by patients with cirrhosis.
- Refer to UpToDate topic review of ascites in adults with cirrhosis initial therapy, section on alcohol abstinence.
|
| Disulfiram | - Hepatically metabolized and subject to numerous drug interactions.
- Reports of fulminant hepatotoxicity.
| - Avoid or use with extreme caution in cirrhosis.
|
| Antiseizure medications |
| Carbamazepine | - Carbamazepine is a potent inducer of hepatic enzymes and has been associated with hepatotoxicity and serious allergic reactions in genetically predisposed individuals.
- May precipitate decompensation in patents with cirrhosis.
| - In general, carbamazepine should be avoided as there are safer options for management of seizures in patients with advanced CLD or cirrhosis.
|
| Lamotrigine | - Half-life is increased up to threefold in moderate to severe hepatic impairment.
| - No adjustment required for mild impairment.
- Reduce dose by 25% for moderate to severe hepatic impairment without ascites.
- Reduce dose by 50% for moderate to severe impairment with ascites.
|
| Levetiracetam | - PK unaltered in liver disease in patients with adequate renal function (Crcl ≥60 mL/minute).
- Drug accumulation may occur in patients with renal insufficiency and advanced cirrhosis.
| - No adjustment required for compensated cirrhosis.
- Reduce dose by approximately 50% in patients with advanced CLD and renal insufficiency (Crcl <60 mL/minute).
|
| Oxcarbazepine | - PK seems to be unaltered in mild to moderate hepatic impairment with adequate renal function (Crcl ≥30 mL/minute).
| - No specific adjustment recommended for compensated cirrhosis with mild to moderate hepatic impairment.
- Use in severe hepatic impairment or decompensated disease is not recommended as data are lacking.
|
| Phenytoin | - Extensively metabolized in liver and a potent inducer of hepatic CYP enzymes.
- Highly bound to serum albumin; hypoalbuminemic patients with advanced CLD or cirrhosis generally require lower total plasma concentrations for seizure control relative to healthy individuals.
| - In general, phenytoin should be avoided in patients with cirrhosis.
- In the absence of other effective options for control of seizures, use cautiously in compensated cirrhosis.
- Avoid in patients who are actively using alcohol.
- Free phenytoin levels may be useful for monitoring serum concentrations.
- Refer to UpToDate topic review on pharmacology of antiseizure medications.
|
| Topiramate | - Topiramate clearance can be reduced in patients with advanced CLD or cirrhosis who are also receiving enzyme-inducing antiseizure medications and/or with renal insufficiency (Crcl <70 mL/minute).
- Metabolic acidosis is a frequent adverse effect of topiramate treatment. Refer to UpToDate topic review on pharmacology of antiseizure medications.
| - Topiramate dose adjustment may be needed in patients with advanced CLD or cirrhosis receiving enzyme-inducing antiseizure medications and/or renal impairment.
- Drug interactions between topiramate and enzyme-inducing antiseizure medications may be intensified in hepatic impairment.
- Serum concentration monitoring may be useful.
|
| Valproate (valproic acid) | - Extensively metabolized in liver and highly bound to serum albumin.
- Drug accumulation and toxicity has been observed in valproate treated patients with advanced CLD or cirrhosis.
- Valproate associated hyperammonemia may complicate management of HE.
| - Valproate should generally be avoided in advanced CLD or cirrhosis.
- Use is contraindicated in severe hepatic impairment.
|
| Antidepressants |
| Bupropion | - Reduced clearance and prolonged half-life in alcoholics and in patients with severe hepatic impairment.
| - Do not exceed 75 mg per day (immediate release), 100 mg per day (sustained release), or 150 mg every other day (extended release) in patients with early or moderate compensated cirrhosis.
- Avoid in severe or decompensated cirrhosis and in patients at risk for seizures.
|
| Citalopram | - Extensively metabolized in liver by CYPs 2C19 and 3A4.
- Exposure (plasma concentration versus time curve) increased twofold in setting of cirrhosis.
- Patients with cirrhosis, particularly if there is a TIPS or surgical shunt present, may be at elevated risk of developing potentially fatal ventricular arrhythmias due to QT prolongation.
| - Do not exceed 20 mg daily.
|
| Desvenlafaxine | - Metabolized in liver primarily by UGT glucuronidation.
- PK unaltered in mild hepatic impairment.
| - Initiate at 50 mg daily. Do not exceed 100 mg daily.
- Avoid in decompensated cirrhosis, cirrhosis with renal failure, and in patients at risk for seizures.
|
| Duloxetine | - 85% reduction in clearance and three- to fivefold increase in half-life and exposure (plasma concentration versus time curve) in moderate cirrhosis.
| - Alcohol abuse or CLD may be risk factors in duloxetine associated hepatotoxicity.
- Use should be avoided in hepatic impairment.
|
| Escitalopram | - Extensively metabolized in liver by CYPs 2C19 and 3A4.
- Clearance reduced by 37%, half-life increased approximately twofold in setting of cirrhosis.
| - Initiate at a low dose (5 mg daily) for first two weeks or more.
- Do not exceed 10 mg daily.
|
| Fluoxetine | - Reduced clearance.
- Half-life of active metabolite may exceed 12 days in cirrhosis.
- New steady-state concentrations may not be reached until two or more months following a dose adjustment.
| - Reduce dose or frequency in cirrhosis by 50%.
- Initiate at a low dose (eg, 5 or 10 mg daily) and titrate gradually to prevent accumulation.
- Do not exceed 20 to 40 mg daily in mild hepatic impairment.
|
| Fluvoxamine | - Extensively metabolized in liver by CYP2D6 and undergoes first-pass extraction.
- Oral bioavailability is increased and half-life prolonged to 22 to 26 hours in setting of cirrhosis.
| - Reduce dose by 50%.
- Initiate at a low dose (eg, 25 mg daily) and titrate gradually to prevent accumulation.
- Do not exceed 100 mg daily.
|
| Mirtazapine | - Half-life increased by 40% and exposure (plasma concentration versus time curve) increased approximately 55% in mild to moderate hepatic impairment.
| - Do not exceed 30 mg per day.
|
| Paroxetine | - Extensively metabolized in liver by CYP2D6 and undergoes first-pass extraction.
- Half-life prolonged and exposure (plasma concentration versus time curve) increased approximately twofold in advanced CLD or cirrhosis.
| - Initiate at 10 mg daily and titrate gradually.
- Do not exceed 40 mg daily.
|
| Sertraline | - Extensively metabolized in liver by CYP2D6 and undergoes first-pass extraction.
- Half-life prolonged by 2.5-fold and exposure (plasma concentration versus time curve) increased by up to fourfold in advanced CLD or cirrhosis.
| - Initiate at 25 mg daily and titrate gradually to prevent accumulation.
- Do not exceed 100 mg daily.
|
| Venlafaxine | - Extensively metabolized in liver by CYP2D6 and undergoes first-pass hepatic extraction.
- Wide inter-individual PK variability seen in patients with cirrhosis.
- Oral bioavailability is increased by two- to threefold in patients with mild to moderate hepatic impairment.
- Half-life of venlafaxine and its active metabolites is prolonged by up to 1.4-fold in mild to moderate hepatic impairment.
| - Initiate at a low dose (eg, 37.5 to 75 mg daily) and titrate gradually to prevent accumulation. Do not exceed 150 mg daily.
- Avoid in decompensated cirrhosis, cirrhosis with renal failure, and in patients at risk for seizures.
|
| Antipsychotics |
| Haloperidol | - Complex hepatic metabolism includes CYP3A4 and 2D6 transformations and active metabolites.
- Consistent alteration of PK in hepatic impairment has not been identified.
- Patients with cirrhosis, particularly if there is a TIPS or surgical shunt present, may be at elevated risk of developing potentially fatal ventricular arrhythmias due to QT prolongation.
| - No specific dose adjustment.
- Avoid with active alcohol consumption.
- Avoid or use caution with alcohol withdrawal syndrome due to risk of seizures.
- Preferable to benzodiazepines in patients with HE.
|
| Olanzapine | - Undergoes extensive metabolism in liver by CYPs 1A2 and 2D6.
- Half-life is expected to be increased in advanced hepatic impairment.
| - In advanced hepatic impairment initiate orally at 5 mg daily and escalate dose, if needed, more gradually.
|
| Quetiapine | - Undergoes extensive metabolism in liver by CYP3A4.
- Half-life is expected to be increased in advanced hepatic impairment.
| - Initiate orally at 25 mg daily (immediate release) and titrate in low increments (eg, 25 to 50 mg daily) according to response.
|
| Anti-infectives¶ |
| Antifungals |
| Azoles | - Azole antifungals are variably metabolized in liver, and all have been associated with hepatic function abnormalities.
- Ketoconazole, itraconazole, voriconazole, and posaconazole have potent inhibitory effects on hepatic CYP metabolism.
| - Use azoles with caution in advanced CLD or cirrhosis.
- Maintenance dose reduction and serum level monitoring are recommended for voriconazole.
- Dose of fluconazole should be adjusted in advanced CLD or cirrhosis with renal insufficiency.
- Avoid ketoconazole in patients with CLD.
- Refer to UpToDate topic review of pharmacology of azole antifungals.
|
| Echinocandins | - Caspofungin and micafungin undergo hepatic metabolism.
- Anidulafungin is not hepatically metabolized; alteration of PK due to CLD or renal insufficiency is not expected.
- Modest asymptomatic increases in hepatic transaminases occur in approximately 10% of echinocandin-treated patients without CLD.
| - Regular monitoring of hepatic transaminases is suggested during echinocandin treatment.
- Refer to UpToDate topic on pharmacology of echinocandins.
|
| Antimicrobials | - Hydrophilic antimicrobials (ie, aminoglycosides, beta-lactams, daptomycin, vancomycin) tend to exhibit increased Vd in patients with advanced CLD or cirrhosis with ascites or hypoalbuminemia. Loading dose(s) and monitoring of blood concentrations where available should be considered for treating seriously ill patients.
|
| Beta-lactams, carbapenems | - Beta-lactam-associated leukopenia may complicate impaired reticular endothelial cell function in advanced CLD or cirrhosis.
| - Monitor for beta-lactam-associated leukopenia.
|
| Fluoroquinolones | - Norfloxacin, ciprofloxacin, and levofloxacin are eliminated renally and do not undergo extensive hepatic metabolism. Levofloxacin distributes in ascitic fluid, but less extensively than cefotaxime.
- Patients with cirrhosis, particularly if there is a TIPS or surgical shunt present, may be at elevated risk of developing potentially fatal ventricular arrhythmias due to QT prolongation.
| - Norfloxacin (not available in US), levofloxacin, and ciprofloxacin dose should be adjusted for advanced CLD or cirrhosis with renal impairment. Refer to Lexicomp monographs.
- Use caution in patients with prolonged QT intervals.
|
| Macrolides | - Extensively metabolized in liver.
- Erythromycin estolate (not available in United States) may cause cholestasis in CLD.
- Certain macrolides can increase QTc interval.
| - Use clarithromycin with caution in advanced CLD or cirrhosis.
- Avoid erythromycin estolate.
|
| Metronidazole | - Metabolized in liver, reduced clearance and prolonged half-life (18 to 21 hours) in advanced CLD or cirrhosis.
| - Increase interval to every 12 hours in patients with advanced CLD or cirrhosis.
|
| Tetracyclines | - Tetracyclines are metabolized in liver and half-life may be prolonged in advanced CLD and cirrhosis.
| - Reduced dose should be considered in compensated disease.
- Use caution in advanced CLD or cirrhosis.
- In general, avoid tetracyclines in decompensated cirrhosis.
|
| Tigecycline | - Tigecycline is eliminated largely by biliary excretion and does not undergo extensive metabolism in the liver.
| - Dose of tigecycline should be adjusted in severe hepatic impairment. Refer to Lexicomp monograph.
|
| Trimethoprim-sulfamethoxazole (co-trimoxazole) | - Renally excreted.
- PK appears unaltered in mild to moderate hepatic impairment.
| - No dose adjustment recommended for CLD or cirrhosis with mild to moderate hepatic impairment.
- Reduce dose in renal insufficiency.
- Use should be avoided in severe hepatic impairment and decompensated disease according to the licensed product information.
|
| Antituberculosis drugs (isoniazid, pyrazinamide, rifampin) | - Isoniazid may accumulate in advanced CLD and cirrhosis.
- Rifampin is eliminated in bile and can potentially worsen jaundice in patients with cirrhosis due to competitive excretory inhibition.
- Increased risk of DILI.
| - Closely monitor and consider dose reduction.
- Refer to UpToDate topic on treatment of pulmonary tuberculosis in HIV-negative patients.
|
| Hepatitis B antivirals (adefovir, entecavir, lamivudine, tenofovir) | - Minor or no hepatic metabolism.
- PK unaltered in CLD.
- Safely used in decompensated cirrhosis when treatment indicated.
| - No dose adjustment necessary in CLD or cirrhosis.
- Dose reductions needed for renal impairment.
|
| HIV antiretrovirals | - Management of HIV antiretroviral therapy in patients with hepatic impairment is reviewed separately. Refer to UpToDate topic on dose modification of antiretroviral agents in adults with renal or hepatic dysfunction and separate table in UpToDate on antiretroviral dosing recommendations in patients with renal or hepatic insufficiency.
|
| Antidiabetic |
| Insulins | - Insulins are frequently used for treatment of diabetes with CLD.
| - Insulins are dosed based upon effect with close blood glucose monitoring.
|
| Metformin | - Used safely in advanced CLD and compensated cirrhosis.
- Beneficial in treatment of diabetes with various forms of CLD including NAFLD.
| - In general, a good choice for most diabetic patients with mild to moderate CLD and compensated cirrhosis.
- Dose metformin based on response.
- Metformin should be avoided in patients who consume excessive alcohol or with renal insufficiency or advanced CLD or cirrhosis due to risk of lactic acidosis, a rare but potentially fatal complication of metformin treatment.
|
| Sulfonylureas and meglitinides | - Sulfonylureas (eg, glipizide) are frequently prescribed to patients with diabetes and CLD.
- Sulfonylureas and meglitinides (eg, repaglinide, nateglinide) are hepatically metabolized, and increased concentrations in cirrhosis are expected, but specific data are lacking.
| - Sulfonylureas and meglitinides are generally safe in mild to moderate CLD and compensated cirrhosis using lowest initial dose, gradual titration based on close monitoring, and a reduced maintenance dose.
- Low-dose gliclazide (not available in United States), repaglinide, and nateglinide may be reasonable choices due to shorter duration of action and less risk of hypoglycemia observed in general diabetic population.
- Sulfonylureas should be avoided or used cautiously in older adults with cirrhosis and in patients with renal insufficiency and advanced cirrhosis.
|
| Cardiovascular |
| Antiarrhythmics | - Hepatic impairment decreases the elimination of many antiarrhythmics.
| - Dose reductions are usually required.
- Refer to Lexicomp individual drug monographs.
|
| Amiodarone | - Amiodarone is highly tissue- and protein-bound, undergoes extensive hepatic metabolism by various CYPs including 3A4 and 2C8, and is excreted fecally via bile.
- Its extremely long half-life of 25 to 100 days is expected to be further prolonged in hepatic impairment.
| - Dose reduction is expected to be necessary in hepatic impairment and cirrhosis.
- No specific recommendation is available.
|
| Antihypertensives |
| ACE inhibitors | - ACE inhibitors are generally well tolerated.
- Minor PK differences in cirrhosis include increased drug bioavailability (ie, lisinopril) or slowed conversion to active drug form (ie, enalapril), but do not translate to a markedly altered response.
- ACE inhibitors do not adequately decrease portal venous pressure to protect against variceal bleeding.
| - No dose adjustment of ACE inhibitors required in advanced CLD or compensated cirrhosis.
- Non-prodrugs (eg, lisinopril) preferred to prodrugs (eg, quinapril, enalapril).
- If combined with diuretic, use cautiously and in reduced doses.
- Discontinue ACE inhibitors in patients who develop ascites. Refer to UpToDate topic reviews of managing ascites.
|
| Beta-blockers | - PK characteristics and metabolism of individual beta-blockers vary.
- Propranolol and metoprolol have increased oral bioavailability in advanced CLD and cirrhosis due to high first-pass extraction and protein binding.
- Carvedilol is extensively metabolized by CYP, whereas nadolol and sotalol are not.
- Decreased therapeutic effect of beta-adrenergic blockade therapy may be observed in setting of advanced CLD and decompensated cirrhosis.
- Labetalol use has been associated with hepatoxicity.
| - Start at low dose and titrate based upon clinical response.
- Carvedilol dose should be reduced by up to 80%.
- Nadolol and sotalol are not hepatically metabolized. Dose adjustment needed for renal impairment.
- Nadolol and propranolol can be used for treatment of portal hypertension and the prevention of variceal hemorrhage. Refer to UpToDate topic reviews of prophylaxis against variceal hemorrhage.
- Discontinuation of beta-blockers may be necessary in patients who develop diuretic resistant ascites. Refer to UpToDate topic reviews of managing ascites.
- Labetalol is generally avoided in treatment of patients with cirrhosis.
|
| Calcium channel blockers | - Diltiazem oral bioavailability is increased, and half-life of oral and IV are prolonged by up to 50%.
- Oral bioavailability of verapamil is doubled, and half-life of oral and IV are prolonged by fourfold.
- Amlodipine is highly protein-bound and undergoes extensive hepatic metabolism via CYP3A4. Half-life is expected to be prolonged (≥56 hours) in hepatic impairment.
| - Start oral diltiazem at low dose and titrate gradually based on response.
- Reduce verapamil dose by approximately 50%.
- Initiate amlodipine at lowest dose (eg, 2.5 to 5 mg) and titrate at intervals of no less than 10 to 14 days based upon response.
|
| Diuretics |
| Furosemide, torsemide, bumetanide | - Reduced natriuretic potency depending on disease severity.
- Increased sensitivity to hypokalemia and volume depletion.
| - Furosemide is usually given orally and gradually titrated to effect.
- Combination of furosemide with spironolactone can mitigate loop-diuretic-associated hypokalemia and improve diuresis in treatment of ascites.
- Refer to UpToDate topic on initial therapy of ascites in adults with cirrhosis.
|
| Spironolactone | - Extensively metabolized in liver.
- Several active metabolites with prolonged half-life in cirrhosis permit once-daily dosing and, in some patients, alternate-day dosing.
- In combination with furosemide, counteracts hypokalemia and improves diuresis in treatment of ascites.
| - Spironolactone 100 mg per day in combination with oral furosemide 40 mg per day is suggested for initial treatment of ascites.
- Spironolactone and furosemide are titrated gradually based upon response using a ratio of 100 mg spironolactone to 40 mg furosemide.
- Refer to UpToDate topic on initial therapy of ascites in adults with cirrhosis.
|
| Triamterene | - Triamterene clearance decreased.
- Diuretic effect relatively unchanged in compensated disease.
| - Lower starting doses and less frequent dosing depending on severity of CLD.
|
| Nitrates | - Most nitrates undergo non-CYP hepatic and extrahepatic metabolism.
- Orally administered isosorbide dinitrate undergoes first-pass hepatic extraction; bioavailability may be increased in advanced CLD or cirrhosis.
- Patients with advanced CLD or cirrhosis may have a more pronounced response to nitrates, including nitrate-associated adverse effects (eg, hypotension, bradycardia).
| - No specific dose adjustment available.
- Dose should be titrated based upon clinical response.
|
| Ranolazine | - Ranolazine undergoes complex hepatic CYP3A and extrahepatic metabolism; concentrations are significantly elevated in moderate to severe hepatic impairment.
- Patients with cirrhosis, particularly if there is a TIPS or surgical shunt present, may be at elevated risk of developing potentially fatal ventricular arrhythmias due to QT prolongation.
| - Use of ranolazine in patients with cirrhosis and any degree of hepatic impairment is contraindicated according to the licensed product information.
|
| Statins | - Statins are generally well tolerated in patients with compensated cirrhosis and have established CVD benefits in treatment of patients with NAFLD, viral hepatitis, and primary biliary cholangitis.
- Most statins are subject to high first-pass extraction and/or are highly bound to plasma proteins, which can increase blood concentrations in patients with hepatic impairment.
- Pravastatin does not undergo CYP metabolism; its clearance is largely dependent upon renal function.
- Safety data are reassuring among pravastatin-treated patients with compensated non-cholestatic CLD.
- A pronounced hypolipidemic response in relation to dose may be evidence of statin accumulation.
| - Initiate statin treatment at lowest daily dose and titrate gradually based upon hypolipidemic response; for specific recommendations, refer to overview topics on pharmacology and side effects of statins.
- While no longer recommended in the general population, ALT monitoring is reasonable for statin treatment of patients with cirrhosis.
- Avoid statins with decompensated disease or significant cholestasis.
- Refer to UpToDate topic review of statin actions, side effects, and administration.
|
| Gastrointestinal |
| Proton pump inhibitors | - Proton pump inhibitors appear to be a potential risk factor for SBP, C. difficile, and other serious infections in patients with cirrhosis.
- Proton pump inhibitors appear to be a potential risk factor for hepatic encephalopathy.
| - Acid-suppressive medications should only be given to patients who have clear indications for their use.
- Refer to UpToDate topics on overview of the use of proton pump inhibitors for the treatment of acid-related disorders and on treatment and prophylaxis of spontaneous bacterial peritonitis.
|
| Herbal medicines and supplements |
| | - A variety of herbal medicines and supplements may be used by patients with cirrhosis (eg, silymarin [milk thistle]).
- Herbs and supplements may contain undisclosed ingredients and contaminants, including prescription medications that may be hepatotoxic or interact with other medications (eg, St. John's wort).
| - It is important for the clinician to ask patients with CLD or cirrhosis about herbal medicines and supplements.
- For information on silymarin (milk thistle), refer to UpToDate topic review of investigational therapies for hepatitis C virus infection.
- Additional information is found in UpToDate topic review of hepatoxicity due to herbal medications and supplements.
|
| Hypnotics and sedatives |
| Diazepam | - Extensive metabolism in liver by CYP to active metabolites.
- Clearance decreased by 50%.
- Half-life of drug and active metabolites prolonged two- to fivefold (ie, up to 500 hours).
| - No adjustment needed for initial dose.
- Risk of accumulation and over-sedation with repeated doses.
- Reduce maintenance dose and frequency by up to 50% or consider another sedative option.
- Prolonged effect might be useful for patients being treated for alcohol withdrawal or seizures.
- Avoid in patients with HE.
|
| Lorazepam | - Undergoes metabolism by glucuronidation, which is relatively preserved in mild to moderate hepatic insufficiency.
| - Generally a good choice when benzodiazepine treatment indicated.
- No specific dose adjustment; titrate gradually due to prolonged onset.
- With prolonged use or use as a continuous infusion risk of drug accumulation and oversedation.
- Avoid in patients with HE.
|
| Midazolam | - Extensively metabolized in the liver by CYP3A4 and, when administered orally, undergoes first-pass hepatic extraction.
- Half-life of drug and active metabolite are increased in hepatic impairment.
| - Oral preparation should be avoided in patients with advanced CLD or cirrhosis due to unpredictable bioavailability.
- For IV use, no specific dose adjustment; once adequately sedated using small incremental doses, a reduced maintenance dose and frequency may be needed to avoid accumulation and oversedation of patients with advanced CLD or cirrhosis.
- Avoid in patients with HE.
|
| Zolpidem | - Half-life prolonged twofold in moderate hepatic impairment and fourfold or more in advanced CLD.
| - Use lowest possible dose in patients with mild to moderate hepatic impairment.
- Immediate release preparation may be broken to provide 2.5 mg dose.
- Avoid use in advanced CLD; may precipitate or worsen HE.
|
| Opioid use disorder (opioid addiction) treatment |
| Buprenorphine-naloxone | - Buccally and sublingually administered naloxone, which is included in this combination to deter abuse (ie, crushing, snorting, injecting), is systemically absorbed in patients with moderate to severe hepatic impairment.
- Absorption of naloxone can reverse effect of buprenorphine and precipitate an opioid withdrawal syndrome.
| - Buprenorphine-naloxone combination is not recommended in patients with advanced CLD or cirrhosis due to increased bioavailability of naloxone.
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