Appendix 7a: Hepatic Impairment

Dosing considerations in hepatic impairment

Hepatobiliary system plays an important role in the interactions between drugs and the body. Liver diseases can affect pharmacokinetics and pharmacodynamics of various drugs. However there has to be moderate to severe hepatic impairment to significantly alter the response to drugs as liver has a large reserve capacity. Hepatic impairment may alter response to drugs not only because of its role in metabolism of drugs but it also affects their absorption and distribution. Looking at the importance of liver in dealing with the drug, knowledge of a patient’s hepatic function is required for the safe prescribing of many drugs. Unlike renal disease, where estimation of renal function based on creatinine clearance can fairly help in knowing the drug elimination and, hence, dose adjustment, there is no endogenous marker for hepatic clearance that can be used as a guide for drug dosing.

Hepatic impairment can lead to altered response to drugs due to all or some of the following reasons:

• Metabolism of many drugs depend on adequate liver function. Generally, metabolism result in the loss of pharmacological activity and, therefore, reduced metabolism in case of impaired liver function can lead to the accumulation of drug in the body to the toxic level at the normal dose. However, in some cases drugs are metabolised to the active form and in these drugs normal dose may not be able to achieve desired response.

• For drugs with low bioavailability (high hepatic extraction), bioavailability increases and hepatic clearance decreases in cirrhotic patients. If such drug is to be administered orally to cirrhotic patients, their initial dose has to be reduced according to their hepatic extraction. For drugs with low bioavailability (low hepatic extraction), hepatic clearance may be affected due to impaired metabolism. For such drugs, only the maintenance dose has to be adjusted according to estimated decrease in their hepatic metabolism.

• Portal hypertensive gastropathy and ulcers of upper gastrointestinal tract, frequently seen in cirrhotic patients, may alter the absorption of orally administered drugs. Absorption of drugs may be increased because of high intestinal permeability in patients with portal hypertension. Impaired gastrointestinal motility seen in cirrhotic patients can lead to delayed drug absorption.

• Volume of distribution of hydrophilic drugs is increased due to presence of oedema and/or ascitis. Hence, loading dose of these drugs may have to be increased if a rapid action is required. On the other hand, increase in volume of distribution is associated with an increase in the elimination half life of such drugs.

• Impaired elimination of drugs, which are excreted in the bile, can lead to their accumulation in the body. Impaired albumin production can lead to decreased protein binding and increased toxicity of highly plasma protein bound drugs.

• High percentage of drugs may reach systemic circulation without passing through liver due to development of portosystemic shunts in cirrhotic patients.

• Cirrhotic patients can often have impaired renal function and in these cases dosage of the drugs have to be carefully adjusted.

The use of certain drugs in patients with cirrhosis may increase the risk of hepatic decompensation. In patients with impaired liver function, dose related hepatotoxic reaction may occur at lower doses. Drugs that cause fluid retention (e.g., prednisolone, ibuprofen, dexamethasone, etc.) may exacerbate oedema and ascitis in chronic liver disease. Sensitivity of brain to depressant action of some drugs (e.g., morphine and barbiturates) is markedly increased in cirrhotic patients and can precipitate hepatic encephalopathy at normal doses.

As evident from above, there are complex interactions between the drugs and liver function. Absence of any endogenous marker for hepatic clearance makes it highly difficult to accurately adjust the dose of various drugs in hepatic impairment. Therefore, if no immediate pharmacological effect is needed, drug therapy should be started cautiously in these patients and titrated individually until desired effect is achieved or toxicity appears. Drugs with a narrow therapeutic range and low hepatic extraction (e.g., theophylline) are the most dangerous drugs. If such drugs are administered orally, both loading dose and maintenance doses have to be reduced by ≥ 50% of the normal dose, depending on the severity of hepatic impairment.

The following table contains information to help prescribing common drugs in hepatic impairment. The table provided is not exhaustive and abscence from this table does not imply safety of drug, it is, therefore, important to refer to the individual drug entries.

Drug

Status

Comments

Abacavir

Avoid in severe hepatic impairment

Avoid in moderate hepatic impairment unless essential

Acetylsalicylic acid

Avoid in severe hepatic impairment

Increased risk of Gastrointestinal bleeding

Allopurinol

Reduce the dose

Aluminium hydroxide

Avoid in severe hepatic impairment

Can precipitate hepatic encephalopathy by causing constipation; Antacids containing high amount of sodium to be avoided in patients with fluid retention

Amidotrizoate

Use with caution

Amitryptyline

Avoid in severe hepatic impairment

Increased sedation

Amlodipine

Reduce dose

Half life of amlodipine is prolonged

Amodiaquine

Avoid in hepatic impairment

Amoxycillin + Clavulanic acid

Use with caution

Monitor liver function, cholestatic jaundice reported either during or shortly after therapy (more common in males and patients over 65 years), duration of treatment should not exceed 2 weeks

Azathioprine

Reduce dose

Azithromycin

Avoid

May cause jaundice

Bupivacaine

Avoid or reduce dose in severe hepatic impairment

Carbamazepine

Avoid in severe moderate to severe hepatic impairment

Cautiously given in mild hepatic impairment

Ceftriaxone

Reduce dose and monitor plasma concentration if there is associated renal impairment

Chlorambucil

Reduce dose and use cautiously in hepatic impairment

Chloramphenicol

Avoid if possible; reduce dose and monitor plasma concentration

Increased risk of bone marrow depression

Chlorpheniramine

Avoid

May cause inappropriate sedation

Chlorpromazine

Use with caution

May precipitate coma

Clindamycin

Reduce dose

 

Clomifene

Avoid in severe hepatic impairment

 

Clomipramine

Avoid in severe hepatic impairment

Increased sedation

Cloxacillin

Use with caution

Cholestatic jaundice may occur up to several weeks after treatment has stopped; risk increases with increasing age and if given for more than 2 weeks

Codeine

Avoid or reduce dose

May precipitate coma; Causes constipation

Contraceptive, oral

Avoid in case of active liver disease

Avoid if history of cholestasis and pruritus during pregnancy

Cyclophosphamide

Reduce dose

Monitor plasma level

Cyclosporine

Reduce dose and use with caution

Hepatotoxic

Cytarabine

Reduce dose

 

Dacarbazine

Avoid in severe hepatic impairment

Dose reduction in mild to moderate hepatic impairment

Daunorubicin

Reduce dose

Use with caution as toxicity increases in hepatic impairment

Diazepam

Avoid in severe hepatic impairment

Can precipitate coma

Didanosine

Monitor for toxicity

 

Doxorubicin

Reduce dose according to bilirubin concentration

 

Doxycycline

Avoid or use with caution

 

Efavirenz

Avoid in severe hepatic impairment

Dose reduction and/or use with caution in mild to moderate hepatic impairment

Enalapril

Use with caution

Closely monitor liver function in patients with hepatic impairment

Ergometrine

Avoid in severe hepatic impairment

 

Erythromycin

Avoid in severe hepatic impairment

May cause idiosyncratic hepatotoxicity

Ethinylestradiol

Avoid

See also Contraceptives, Oral

Etoposide

Avoid in severe hepatic impairment

Increased risk of toxicity in case of hepatic impairment

Fluconazole

Use with caution

Hepatotoxicity

5-Fluorouracil

Use with caution; dose reduction may be required

 

Fluoxetine

Reduce dose or administer on alternate days

 

Fluphenazine

Avoid in severe hepatic impairment

Hepatotoxic, can precipitate coma

Furosemide

Avoid or use with caution in severe hepatic impairment

Hypokalaemia may precipitate coma (use potassium sparing diuretic to prevent this); Increased risk of hypomagnesaemia in alcoholic cirrhosis

Glibenclamide

Avoid or reduce the dose

Increased risk of hypoglycaemia; can produce jaundice

Griseofulvin

Avoid in severe hepatic impairment

 

Haloperidol

Use with caution

Can precipitate coma

Heparin

Reduce dose in severe liver disease

 

Hydralazine

Reduce dose

 

Hydrochlorothiazide

Avoid in severe hepatic impairment

Hypokalaemia may precipitate coma (use potassium sparing diuretic to prevent this); increased risk of hypomagnesaemia in alcoholic cirrhosis

Ibuprofen

Avoid in severe hepatic impairment

Increased risk of gastrointestinal bleeding and can also cause fluid retention

Indinavir

Reduce dose to 600 mg 8th hly in mild to moderate hepatic impairment; not studied in severe hepatic impairment

 

Isoniazid

Use with caution

Regularly monitor liver function and particularly frequently in first 2 months

Levonorgestrel

Use with caution in active liver disease and recurrent cholestatic jaundice

 

Lidocaine

Avoid or reduce the dose in severe hepatic impairment

 

Magnesium hydroxide/sulphate

Avoid in hepatic coma if risk of renal failure

 

Medroxyprogesterone

Avoid in active liver disease

Avoid if history of pruritus and cholestasis during pregnancy

Mefloquine

Avoid for prophylaxis in severe liver disease

 

6-Mercaptopurine

May need dose reduction

 

Metformin

Avoid

Withdraw if tissue hypoxia likely

Methadone

Avoid or reduce the dose

May precipitate coma

Methotrexate

Avoid in severe hepatic impairment

Hepatotoxic; monitor liver functions

Methyldopa

Avoid in active liver disease

 

Metoclopramide

Reduce dose

 

Metronidazole

Reduce total daily dose to one third and give once daily in case of severe hepatic impairment

 

Morphine

Avoid or reduce the dose

May precipitate coma

Nevirapine

Avoid in severe hepatic impairment

Use with caution in moderate hepatic impairment

Nitrofurantoin

Use with caution

Cholestatic jaundice and chronic active hepatitis reported

Norethisterone

Avoid in active liver disease.

Avoid if history of pruritus and cholestasis during pregnancy

Ofloxacin

Reduce dose in severe hepatic impairment

Hepatic dysfunction reported

Paracetamol

Avoid large doses- dose related toxicity

 

Phenobarbital

Avoid in severe hepatic impairment

May precipitate coma

Phenytoin

Reduce dose to avoid toxicity

 

Prednisolone

Use with caution

Adverse effects more common

Procainamide

Avoid or reduce the dose

 

Procarbazine

Avoid in severe hepatic impairment

 

Promethazine

Avoid in severe hepatic impairment

May precipitate coma; Hepatotoxic

Propylthiouracil

Reduce dose

 

Pyrazinamide

Avoid in severe hepatic impairment

Monitor hepatic function- idiosyncratic hepatotoxicity more common

Pyrimethamine

Use with caution

 

Ranitidine

Reduce dose

Increased risk of confusion

Ribavirin

Avoid in severe hepatic impairment

 

Rifampicin

Avoid or do not exceed 8 mg/kg daily

Monitor liver function

Saquinavir

Avoid in severe hepatic impairment; Caution in moderate hepatic impairment

 

Simvastatin

Avoid in active liver disease or unexplained persistent elevation in serum transaminases

 

Sodium nitroprusside

Avoid in severe hepatic impairment

 

Sulfadiazine

Avoid in severe hepatic impairment

 

Sulfamethoxazole + trimethoprim

Avoid in severe hepatic impairment

 

Suxamethonium

 

Prolonged apnoea may occur in severe liver disease due to reduced hepatic synthesis of plasma cholinesterase

Testosterone

Preferably avoid

Possibility of dose related toxicity and fluid retention

Thiopental

Reduce dose in severe liver disease

 

Valproic acid

Avoid, if possible

Hepatotoxicity and hepatic failure may occasionally occur (usually in first 6 months)

Verapamil

Reduce oral dose

 

Vinblastine

Reduction of dose may require

 

Vincristine

Reduction of dose may require

 

Warfarin

Avoid in severe liver disease

Reduced production of clotting factors in hepatic impairment; may increase risk of bleeding

Zudovudine

Reduction of dose as accumulation may occur