BETHESDA, MD 13 Aug 2014—Recent changes to the risk evaluation and mitigation strategy (REMS) for rosiglitazone-containing products have eliminated the access restrictions that had been in place since 2011.
The restrictions, along with strong warnings in the products' labeling, were previously instituted over concerns that rosiglitazone may increase the risk of cardiovascular events and death [see August 15, 2010, AJHP News].
But those concerns have since waned, partially in response to a reanalysis of data from a pivotal study of the antidiabetic medication [see July 15, 2013, AJHP News]. A panel of experts last June, after reviewing the reanalyzed data, had advised FDA to ease the REMS requirements and labeled warnings for rosiglitazone.
One of those panelists was Marjorie Shaw Phillips, clinical research pharmacist at the Georgia Regents Medical Center in Atlanta.
Phillips, interviewed this past July, recalled that the reanalysis had reassured most panel members that there are no strong signals of excess cardiovascular risk associated with rosiglitazone.
"There's certainly not any evidence to warrant the...very strong restrictions that had been put in place" for the drug, she said.
Those restrictions had included registration and training requirements for prescribers, an enrollment program for patients, and distribution of the medications through a small number of specially certified mail-order pharmacies. FDA had also required that the medications be prescribed only to patients who were already using them or new patients whose diabetes could not be controlled by other drugs.
The intent of the revised REMS, according to the program's documentation, is "to provide training to likely prescribers of rosiglitazone medicines about the current state of knowledge concerning the cardiovascular risks of these medicines."
Specifically, according to the REMS documentation, data from a meta-analysis of "mostly short-term trials" of rosiglitazone versus a placebo suggest that the antidiabetic drug may increase the risk of myocardial infarction. But data from long-term, prospective, randomized controlled clinical trials comparing rosiglitazone with metformin or sulfonylureas found no between-group differences in the occurrence of major adverse cardiovascular events.
Phillips said it was challenging to evaluate "reams and reams of evidence" from the variety of studies that examined the safety of rosiglitazone.
"You have to look at corroborating evidence, and the way the different studies are designed, and how the information is collected to determine how meaningful it is. And it's very hard to do that without looking at the quality of the original data," Phillips said.
The revised rosiglitazone REMS consists of a website (http://rosiglitazonerems.com), a 14-page online voluntary training module for prescribers, and a communication plan targeting prescribers and healthcare professional societies, including ASHP. The communication plan is part of the "elements to assure safe use" section of the REMS.
An FDA-required Medication Guide for rosiglitazone must be provided to patients when they have a prescription filled, but the document is part of the labeling for the drug and not a REMS component.
The Medication Guide is intended to warn patients and prescribers about the potential risk of new or worsening heart failure in patients who are treated with rosiglitazone, especially in combination with insulin.
GlaxoSmithKline announced May 7 that the revised REMS permits any physician to prescribe rosiglitazone to any suitable patient. The company stated that its rosiglitazone-containing products will continue to be available through the existing mail-order pharmacy network, but other pharmacies can also carry the drugs.
Rosiglitazone is indicated, in conjunction with diet and exercise, to improve glycemic control in adults with type 2 diabetes mellitus.
GlaxoSmithKline markets the rosiglitazone maleate–containing product Avandia and two combination products, Avandamet and Avandaryl. Generic rosiglitazone-containing products are also available, and the revised REMS program applies to all versions of the drugs.
Delia Charest Carias, clinical pharmacist in medication–use policy at St. Jude Children's Research Hospital in Memphis, Tennessee, said FDA's decision to ease the REMS restrictions in response to clinical data was reassuring.
"I think that it showed that REMS programs are working," Carias said. "It's showing that FDA is continuing to review these REMS programs and . . . working to make them more meaningful and less burdensome."
Carias said rosiglitazone is rarely used at her pediatric hospital, but it's possible that more rosiglitazone prescriptions will be written for adults now that the REMS restrictions have been eased.
Pharmacy sales of rosiglitazone-containing products peaked at about 13 million dispensed prescriptions in 2006 before falling to less than 13,000 prescriptions dispensed to 665 patients in 2012, according to data presented by FDA last June. More than 1 million prescriptions were written in 2012 for pioglitazone, the only other FDA-approved thiazolidinedione drug, according to the agency's estimates.
Phillips said rosiglitazone was taken off her hospital's formulary when concerns began to emerge about the drug's cardiovascular risks. She said pioglitazone is on the formulary instead, and it's not likely that rosiglitazone will take its place at this time.
The boxed warnings for both drugs are now similar and emphasize the risk of heart failure that is associated with the use of thiazolidinediones.
"If I was asked [about the drugs] by a patient, I would be concerned with the general class warnings . . . for edema and weight gain and provoking heart failure," Phillips said, adding that thiazolidinediones aren't considered first-line agents.
"I think in any of our discussions with patients, as pharmacists, we need to put the risks in context. No drug is truly safe or risk free," Phillips said. "In the context of diabetes care, weight management, diet, and exercise may limit your need for any of these medications."