Rashmikant Patel, PharmD
Seta Socheata San, PharmD
Los Angeles County
Rancho Los Amigos National Rehabilitation Center
Medications can prevent, mitigate, and, in some cases, even cure a wide range of medical conditions. But each drug presents a unique set of challenges in achieving an acceptable benefit-to-risk ratio. One of the most vexing of those challenges is to adequately account for the degree to which renal and hepatic dysfunction may adversely affect drug metabolism. This is a particularly acute problem in elderly patients, who often have impaired renal and hepatic function and who may take many medications for multiple diseases. In such patients, elimination of a drug can be severely compromised, leading to potentially toxic adverse reactions, compromised patient outcomes and excessive health care costs. It, therefore, is critical to account for these variables in drug metabolism if we are to ensure successful outcomes.
But elderly patients should not be our only concern. Pregnancy is another condition that can affect drug metabolism significantly and should be factored into the drug prescribing and management equation.
The question is how do we systematically ensure that all of these factors are indeed considered by prescribers? We have developed a simple drug labeling tool that we feel can accomplish this important goal. Specifically, we are proposing that all drug labels carry the following information as an aid to prescribers:
- R = Renal
- M = Metabolism/hepatic function
- P = Pregnancy
The “RMP” label, as we call it, should be printed on all medication bottles, in much the same way that National Drug Codes (NDC) are listed. This will help ensure that patients with impaired renal or hepatic function are given appropriate doses, and it will provide a final check on whether a patient is pregnant and, thus, in need of dosing adjustments or if there is a contraindication to such use.
Here are some additional considerations for why each of these individual labeling categories is needed:
R–Renal: The number of patients with chronic kidney disease (CKD) is increasing steadily, in part due to the aging population. This trend is likely to continue, in part related to advances in dialysis technique and medication development, both of which have resulted in increased survival and quality of life possible for patients with CKD. In 2002, the National Kidney Foundation issued guidelines for staging CKD.1 According to the guidelines, there are five stages:
- Stage 1: Normal or slightly increased glomerular filtration rate (GFR) or some form of kidney damage (90 mL/min/1.73 m2 or higher)
- Stage 2: Slightly decreased GFR (60 to 89 mL/min)
- Stage 3: Moderately decreased GFR (30 to 59 mL/min)
- Stage 4: Severely decreased GFR (15 to 29 mL/min)
- Stage 5: Kidney failure (less than 15 mL/min; or dialysis)
For purposes of the RMP code, R will be defined as:
- R0: No renal adjustment is necessary for a given drug because it is not renally cleared
- R1: Creatinine clearance (CrCl) is 60-75 mL/min; may or may not need dose adjustment
- R2: CrCl is 30-59 mL/min; need dose adjustment
- R3: CrCl is 20-29 mL/min; need dose adjustment
- R4: CrCl is less than 20 mL/min; need dose adjustment
M–Metabolism: Most drugs are eliminated from the body, at least in part, by being chemically altered (i.e., metabolized) to less lipid-soluble products that are excreted via the kidneys or liver. Cytochrome (CYP) P450 enzymes affect the metabolism of approximately 75% of all drugs, with the CYP3A subfamily accounting for half of this activity.2 Many drugs have been identified as inducers and/or inhibitors of CYP enzymes. Clinically significant interactions often can occur when CYP-affected drugs are used in combination—especially when one of the medications has a narrow therapeutic index, thus causing decreased or increased metabolism of the involved substrate.2 Thus, the metabolism of a drug is a very important factor to consider before a medication is prescribed; hence we have included it in our drug labeling tool.
For purposes of the RMP code, M will be defined as:
- M0: Drug is not metabolized by the liver
- M1: Data are not available
- M2: Data are not available; may need dose adjustment
- M3: The benefits of use may be acceptable despite risk (i.e., in life-threatening situations or for serious diseases for which safer drugs cannot be used or are ineffective)
- M4: Drug is contraindicated in liver diseases
In addition to these numbered labeling designations, the M label also will have an arrow-up or arrow-down symbol to denote whether the drug is a metabolic inducer or inhibitor. This will allow clinicians to adjust medications or dosages, if necessary, in patients who are taking other medications that are affected by inducers or inhibitors. This action will help to avoid drug–drug interactions, reduce side effects and reduce the risk for subtherapeutic dosages.
P–Pregnancy: Given the fact that medications are able to cross the placenta to some extent, there is a risk that drugs administered to parturients can harm the fetus. Indeed, the fetus always must be kept in mind as a potential unintended recipient of a given drug. This is an important clinical issue because the fetus does not have fully formed organs and other body systems during many stages of pregnancy, and those systems can be adversely affected by certain drug regimens.
For purposes of the RMP code, P will be defined using the following categories, based on FDA categories that have been published and adapted in various drug information resources3:
- PA: Controlled studies in women do not demonstrate a risk to the fetus in the first trimester; there is no evidence of risk in later trimesters; and possibility of fetal harm appears remote.
- PB: Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women, or animal reproduction studies have shown an adverse effect (other than decreased fertility) that was not confirmed in controlled studies in women in the first trimester (and no evidence of risk in later trimesters).
- PC: Animal reproduction studies have documented adverse effects on the fetus, but there are no adequate and well-controlled studies in women. A drug should be given only if the potential benefit justifies the potential risk to the fetus.
- PD: There is positive evidence of human fetal risk based on adverse reaction data from studies in humans, but the potential benefits of use in pregnant women may be acceptable despite the risk (e.g., in a life-threatening situation or use is for a serious disease for which a safer drug cannot be used or is ineffective).
- PX: Studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience, and the risks of using the drug in pregnant women clearly outweigh potential benefits.
A Worthy Endeavor
Placing the RMP code on each medication bottle (similar to how the National Drug Code is listed) would provide clinicians easy access to information regarding a specific drug’s effects on renal and hepatic function, as well as safety in pregnancy. This will help encourage prescribers to be more aware of their patients’ renal and hepatic function and take those factors into consideration when deciding on drug doses. This, in turn, will help to decrease adverse effects of the medications and, ultimately, reduce the number of emergency room visits and hospitalizations caused by drug toxicity. The RMP code also will play an important role in preventing worsening of renal and hepatic function.
There are some challenges, however, in implementing RMP labeling. It likely will be difficult to establish RMP codes for each drug, in part because the process may need to be coordinated with the FDA—a process that may raise significant regulatory and logistical issues. Moreover, at this point, we are not able to calculate an exact dose for liver function; however, knowing what percentage of a drug is eliminated by the liver allows clinicians to adjust medication doses along with their clinical experience. Becoming familiar with the various stages of liver disease4 and how they affect drug metabolism can help promote more responsible drug dosing and prescribing.
Despite these challenges, we are confident that the considerable efforts required to get RMP labeling off the ground will pay off based on improved patient outcomes. In fact, this initiative literally can be a lifesaver.
Examples of RMP Codes
This drug induces hepatic enzymes that increase metabolism of other drugs. It is excreted in the urine.
||Data not available
||Data not available
||This drug needs renal adjustment in patients with CrCl <30 mL/min
||No adjustments are needed
||Category D in first and second trimesters
- National Kidney Foundation. KDOQI Clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. 2002. http://www.kidney.org/professionals/KDOQI/guidelines_ckd. Accessed March 3, 2014.
- Bachmann KA, Lewis JD, Fuller MA, Bonfiglio MF. Drug Interactions Handbook, 2nd ed. Hudson, Ohio: Lexi-Comp, Inc.;2004.
- William DJ, Fuller MA, Goldman MP, et al. Drug Information Handbook, 22nd ed. Hudson, Ohio: Lexi-Comp, Inc.;2013.
- American Liver Foundation. The progression of liver disease. http://www.liverfoundation.org/abouttheliver/info/progression. Accessed March 24, 2014.