With ADR risk to liver patients, clinicians need support beyond the label

Very few drugs have adequate information in the product labeling to appropriately dose drugs in patients with liver dysfunction. Clinicians often must rely on extrapolating pharmacokinetics data from patients without liver dysfunction or from an aggregate of post-marketing publications to determine proper dosing in these patients. Evaluation of the literature must be combined with expertise in the pathophysiology of the liver and the impact of changes in liver dysfunction on drug dosing. To come up with a safe and effective dosing strategy for patients with liver dysfunction can take a substantial amount of time, and clinicians may have limited experience with the nuances of the pharmacokinetic/pharmacodynamic changes that occur in patients with liver dysfunction.

Studies show that drug referential solutions have been little help to clinicians regarding hepatic dosing. Clinicians require better support by experts in the field of hepatology and drug disposition to address dosing for patients with hepatic dysfunction.

Insufficient dosing instructions and the impact on liver dysfunction patients

Safe use of medications in patients with cirrhosis or liver dysfunction centers on applying dose adjustments based on knowledge of the drug’s pharmacokinetics and dynamics. But product label recommendations are frequently absent, unclear, vague, or inconsistent when it comes to hepatic adjustments. In fact, the U.S. Food and Drug Administration demonstrated that between 2004 and 2011, of 157 drugs approved, the label failed to provide specific dosing instructions in liver insufficiency for approximately 30% of drugs.

The result is a high likelihood of a preventable drug error. One cross-sectional study that evaluated hospitalized patients with cirrhosis found:

• 30% experienced an ADR
• 78% of those were deemed preventable

Without hepatic dosing, a ‘best guess’ approach

Often in the absence of information, clinicians assume that there is no dosage adjustment necessary, which can be far from reality and may result in these drug misadventures.

In those cases, bedside clinicians are forced to:

1. Use the drug incorrectly, with no dosage adjustment.
2. Choose another, potentially less effective drug, that has dosing recommendations.
3. Call in a specialty consultant, if available, which may delay care.
4. Do a literature search and try to find an appropriate dose, no matter how long that takes.
5. Make their best guess and hope for the best.

Creating evidence-based recommendations and ‘guardrails’ to help treat liver patients

It was clear that resources were needed beyond the package insert that could help clinicians make hepatic dosing adjustment decisions in less time than an extensive literature review.

UpToDate® Lexidrug referential drug information has been enhancing its hepatic dosing content to fill this need by going beyond product label recommendations to provide the “why” behind the warnings of use in liver dysfunction. Content designed for the point of care explains how the drug is handled by the liver and if that process will be impacted in the setting in liver dysfunction.

That includes recommendations for special situations commonly encountered by clinicians, such as what to do with the drug when the patient with cirrhosis is hospitalized.

Other examples include:

• Some antibiotics used to treat infections in patients with cirrhosis accumulate and may look like worsening of liver dysfunction versus drug toxicity, so clinicians need to know when to implicate the drug versus the disease.
• Discontinuing drugs too quickly in patients with liver disease may cause worsening complications of liver dysfunction (e.g., encephalopathy). If an appropriate taper were used, then this could be avoided, along with the impact on the patient and the healthcare system.
• Sometimes a clinician may need to prescribe a larger dose of a drug when a patient has cirrhosis because they have a higher volume of distribution secondary to fluid retention in the setting of hypoalbuminemia. In order to get the drug to the target (e.g., bacteria), a higher or more frequent dose may be required.
• Some pain medications must be metabolized in the liver to become active (e.g., tramadol, codeine, oxycodone), and this does not occur in the setting of cirrhosis. Selecting these pain medications will lead to inadequate pain control and can contribute to poor patient outcomes and lead to prolonged hospital stays or readmissions.

Lexidrug provides the additional guardrails to make dosing better even when limited information is available, using experts who are versed in pharmacokinetics and pharmacodynamics specifically in liver insufficiency to help synthesize the literature for the bedside clinician. What makes it unique is that it provides consistent, actionable recommendations for various levels of liver impairment at initiation and during continuation of therapy. It also provides specific recommendations for the acute worsening and improvement in liver dysfunction along with providing key pearls about the drug and how it acts in liver dysfunction all in one spot.

The content also crosses over to Medi-Span® and UpToDate® for congruency.

Factors affecting hepatic dosing recommendations

Take, for example, a widely used medication such as metformin. We think of hepatic impairment dosing as dosing based on how the drug is metabolized by the liver and how that changes based on liver function. But in the case of metformin it’s really about the kidneys and the accumulation of lactic acid, which cannot be metabolized when the liver isn’t working, resulting in life-threatening lactic acidosis.

In liver, we don’t have a surrogate measure of function, like creatinine for kidneys, and a single measure (e.g., international normalized ratio or INR, liver transaminases) does not tell you the full story. The clinician must know:

• If the drug is bound to proteins.
• How it is distributed in the body.
• How and where it is metabolized.
• If the drug needs to be metabolized to become active.
• If the metabolites are toxic, and if they accumulate in various settings of organ dysfunction.
• If the drug is directly toxic to the liver and when to be concerned.
• How all of the above change at various levels of liver dysfunction.

Dosing may change between severities of liver dysfunction and/or based on individual factors of the patient (e.g., presence of a transjugular intrahepatic portosystemic shunt). The dose may also need to be adjusted if the patient’s liver gets better.

Lexidrug recommendations are based on Child-Turcotte-Pugh classification, since this is the most consistent index used to identify the level of liver disease severity in the literature. But they include other pertinent considerations if needed, such as:

• Coagulation factors / INR
• Protein or albumin level
• Bilirubin
• Encephalopathy grade
• Liver transaminases

If clinicians wanted to create their own evidenced-based recommendation for their patient, they certainly could, if they had the appropriate expertise and several hours to days of free time!

For example, if a clinician was trying to look up “metformin dosing in liver dysfunction” in PubMed, they would get thousands of results. If they narrowed their search a bit further to “metformin + cirrhosis” they would review 700 results. Lexidrug saves the clinician those hours or days to put the story together and get that safe and effective recommendation to the bedside in minutes. The fact is most clinicians could not synthesize the proper answer even if they had the data.

Best practices: four tips on safe dosing for liver dysfunction

1. Remember: Liver transaminases do not indicate liver function!
2. Metabolism of drugs in the liver differs based on route of administration, so the intravenous dose for a patient with severe liver dysfunction may be different than the oral dose.
3. Most of the dosing and experience with drugs in patients with liver dysfunction occurs post-marketing and does not make it to the package insert!
4. Experts, both physicians and pharmacists, with an understanding of pharmacokinetics parameters (e.g., protein binding, volume of distribution), pathophysiology, and clinical practice experience are needed to provide recommendations when information is not available to ensure safe and effective use of medications in the setting of liver dysfunction.

Learn more about UpToDate Lexidrug dosing resources for specific patient populations.