Las Vegas—In 2011, the FDA warned clinicians against using the fibrate gemfibrozil with simvastatin because of an increased risk for cardiomyopathy and rhabdomyolysis in patients taking the combination therapy. Some health systems have responded by issuing a universal ban on all fibrate–statin combination treatment. Others have incorporated a hard stop into their clinical decision support systems when these two drugs are co-prescribed.

Regardless of the approach, experts say that safety protocols to monitor lipids and replace gemfibrozil with an appropriate alternative or switch to another statin must be part of the mix to guard against adverse drug reactions. Several efforts to accomplish those medication management goals were in evidence at the American Society of Health-System Pharmacists (ASHP) Midyear Clinical Meeting.

An Algorithm-Based Approach

In response to the gemfibrozil–simvastatin contraindication, the Pharmacy and Therapeutics Committee at the Ralph H. Johnson Veterans Affairs Medical Center (RHJ VAMC), in Charleston, S.C., has developed a treatment algorithm based on patients’ low-density lipoprotein (LDL) cholesterol and triglyceride levels. The algorithm calls for patients whose LDL is “at goal” (<130 mg/dL for primary prevention patients and <100 mg/dL for secondary prevention patients) and whose triglycerides are less than 150 mg/dL to remain on simvastatin but be taken off gemfibrozil with no alternative therapy. Fish oil supplementation is given as an alternative to patients with LDL at goal and triglycerides of 150-249 mg/dL. Niacin is given to patients with LDL at goal and triglycerides of 250-499 mg/dL. Patients whose LDL is not at goal receive an increased dose of simvastatin (20 or 40 mg), and those with a history of pancreatitis or triglycerides of 500 mg/dL or greater are kept on gemfibrozil but converted to rosuvastatin (Crestor, AstraZeneca) or pravastatin (Pravachol, Bristol-Myers Squibb) at an equivalent or higher dose, as indicated by their LDL level. (Pravastatin and rosuvastatin are less likely to interact with gemfibrozil.)

“We wanted to outline [the algorithm] for the physicians to make it as easy as possible so they would have to make as few benchmark decisions as possible,” said Molly Haselden, PharmD. In doing so, patients “wouldn’t get lost under the radar or get an inappropriate combination.”

The protocol also stresses individualized care, added Thomas J. Worrall, PharmD, BCPS, an ambulatory care clinical pharmacy specialist at RHJ VAMC. The physician and patient work together to come up with the best plan based on history and risk factors, he said. “Anytime a medication is changed for lipids or cholesterol, we always monitor it and make additional changes if needed.”

A study of the new algorithm’s effect on a subset of patients, presented by Dr. Haselden and her colleagues at the ASHP meeting, showed a statistically but not clinically significant change in pre- and post-intervention triglycerides (107.5 vs. 159.5 mg/dL; P<0.001) and LDL (81.2 vs. 75.0 mg/dL; P=0.01) among 81 patients whose LDL and triglyceride levels were at goal (150 mg/dL or lower) when they were removed from gemfibrozil in response to the FDA contraindication. The increase in triglycerides “was not clinically significant, as additional therapy would not be added for a triglyceride level of 159 mg/dL,” said Dr. Worrall.

An additional eight patients whose LDL levels were not at goal at baseline had a significant increase in triglycerides post-intervention (107.6 vs. 156.1 mg/dL; P=0.01); mean LDL did not change significantly (119.6 vs. 119.1 mg/dL; P=0.82).

Mean total cholesterol, high-density lipoprotein (HDL) and the ratio of aspartate aminotransferase to alanine aminotransferase did not change across the total group of 89 patients. Analyses of patients receiving alternative therapies such as fish oil or niacin, or different statins with gemfibrozil, are under way.

Another study presented at the meeting suggested that fish oil might offer an effective alternative to gemfibrozil. In a retrospective chart review of 248 patients on background simvastatin therapy, researchers identified 39 patients who were converted to fish oil supplementation from gemfibrozil during June to December 2011. Triglycerides and LDL decreased (12.5% and 16.7%, respectively) among these patients (mean age, 66.2 years), reported Christine Huber, PharmD, BCPS, a clinical pharmacy specialist in primary care, and Haley J. Morrill, PharmD, a resident at Providence VA Medical Center, in Providence, R.I.

Although the findings were not significant, “it was surprising for us because normally you would expect the LDL to go up,” Dr. Huber said. All patients in the study received the over-the-counter fish oil supplied by the VA pharmacy.

Most of the patients—27 of 39—were prescribed the recommended daily dose of 4,000 mg. “I was surprised that the primary care physicians had selected a recommended dose,” Dr. Huber said, adding that she expected the physicians would start with lower doses. Doses ranged from 1,000 to 4,000 mg. A subanalysis revealed that patients taking 4,000 mg daily achieved better triglyceride control, she said.

For Fish Oil, Rx Is Best?

Robert DiDomenico, PharmD, a cardiovascular clinical pharmacist at the University of Illinois at Chicago College of Pharmacy, noted in an interview that prescription fish oil supplements (Lovaza omega-3-acid ethyl esters, Reliant Pharmaceuticals) may be preferable to over-the-counter products as an alternative to gemfibrozil because they are regulated by the FDA. “If you’re identifying a patient who clearly has hypertriglyceridemia or low HDL and you are purposely trying to raise HDL with one of these products, I might be more inclined to use a brand-name product,” he said. “The alternative is to use the over-the-counter product and follow the patient closely, and if you don’t see the response you want, switch to the brand.”

Dr. DiDomenico added that the current emphasis on taking patients off gemfibrozil and providing an alternative may be “the wrong side of the coin.” The focus may instead need to shift toward replacing simvastatin with another statin, he noted. Simvastatin’s availability as a generic has led to its widespread use, he said, but “are we focusing on the right drug to switch out?”

He said a good candidate for such a switch is atorvastatin calcium (Lipitor, Pfizer). In addition to being a cost saver—the statin recently became available as a generic—it is slightly more potent than simvastatin and “doesn’t have as many of the hard-and-fast contraindications that simvastatin has.”

C. Michael White, PharmD, a professor and the chair of the Department of Pharmacy Practice at the University of Connecticut, in Storrs, and the author of numerous papers on statins, has his own prescription for managing patients on the lipid-lowering medications—avoiding rash cessations of therapy. “A protocol that just takes someone with a high risk of pancreatitis due to high triglycerides off gemfibrozil would not be smart,” Dr. White said. Better therapeutic options, he noted, include keeping the patient on gemfibrozil but switching their statin to pravastatin or rosuvastatin, given the latter drug’s lower risk for interacting with gemfibrozil, or keeping the patient on simvastatin but using high-dose fish oil, niacin or fenofibrate (Tricor, Abbott Laboratories) instead of gemfibrozil.

Drs. Haselden, Worrall, Huber and White reported that they had no relevant financial conflicts of interest. Dr. DiDomenico reported that he has served on Roche’s advisory board.