P&T News: May 2003
Kevin Bebout, R.Ph.
Peer Review Status: Internally Peer Reviewed by
Joel V. Weinstock, Professor and Head, Division of Gastroenterology
-- Hepatology, Department of Internal Medicine
During this one-year time frame, the nine most frequently reported agents associated with an adverse drug reaction were: warfarin, phenytoin, levofloxacin, vancomycin, morphine, amiodarone, IVIG, nafcillin, and tirofiban (see Figure 1 for a summary of all agents associated with ADRs). Drugs that affect the central nervous system and anti-infective agents were associated with nearly half the ADR reports. Within these two therapeutic drug classes, it should also be noted that non-steroidal anti-inflammatory agents (NSAIDs) including the COX-2 inhibitors were identified 21 times, cephalosporins 20 times, penicillins 17 times, and opioids 17 times.
The Important Role of Health Care Professionals
Clinical trials effectively assess efficacy and risk-benefit ratios, but they are generally not large enough to provide all the information on a new drug's safety. The FDA reports that in recent years the time from submission to the FDA to the marketing of a new drug product has been reduced from a two- to three-year period to about 12 months. This more rapid approval is due in part to the passage of the Prescription Drug User Fee Act that allows the FDA to collect fees from drug companies to add reviewers and scientific equipment to expedite drug approval process. All health care professionals must perform vigilant post-marketing surveillance in order to continue the necessary monitoring after new agents reach the market. New data are used to update the prescribing information of recently approved agents and, in some cases, drug entities that have been marketed for years.
Whenever you become aware of an adverse drug reaction (whether in the inpatient or ambulatory care environments), please complete and forward a "Suspected Adverse Drug Reaction" card (Form 158a) to the Drug Information Center (C 108-B GH); these yellow cards may be found in patient care areas throughout the UIHC. Alternatively, staff who wish to report an adverse drug reaction may telephone the Drug Information Center.
Recent Drug Safety Warnings
In recent months, the FDA and/or drug manufacturers have distributed new nationwide safety warnings and instituted labeling changes on various prescription drug products prompted by submission of adverse drug event reports to the MedWatch Program and because of findings in post-marketing safety studies. New warnings and revised product labeling, which are summarized below, have been issued for palivizumab, sirolimus, and pergolide.
Palivizumab
The manufacturer of palivizumab (Synagis, MedImmune, Inc.) has revised the prescribing information for this product to provide clarification on the risk of anaphylaxis. Following the marketing of palivizumab, two patients with anaphylaxis have been reported. Both patients made a full recovery with appropriate therapy; but because the risk of anaphylaxis changed from theoretical when the drug was first approved to actual, the Warnings section of the product label was modified to read:
"Very rare cases of anaphylaxis (<1 case per 100,000 patients) have been reported following re-exposure to Synagis (palivizumab) [see Adverse Reactions, Post-Marketing Experience]. Rare severe acute hypersensitivity reactions have also been reported on initial exposure or re-exposure to palivizumab. If a severe hypersensitivity reaction occurs, therapy with palivizumab should be permanently discontinued. If milder hypersensitivity reactions occur, caution should be used on readministration of palivizumab. If anaphylaxis or severe allergic reactions occur, administer appropriate medications (e.g., epinephrine) and provide supportive care as required." |
Additionally, upon review of the post-marketing data for patient exposure beyond five doses in a single RSV season, the manufacturer found that adverse events after a sixth or greater dose of Synagis (palivizumab) are similar in character and frequency to those after the initial five doses. Therefore, the following statement was added to the Adverse Reactions, Post Marketing Experience section of the labeling:
"Limited information from post-marketing reports suggests that, within a single RSV season, adverse events after a sixth or greater dose of Synagis (palivizumab) are similar in character and frequency to those after the initial five doses." |
"Dear Healthcare Professional" Letter
MedImmune, Inc.
November 26, 2002
Sirolimus
Wyeth, the manufacturer of sirolimus (Rapamune), revised the package labeling for this product in de novo lung transplant patients based on post-marketing reports of bronchial anastomotic dehiscence, including fatal cases, in patients treated with sirolimus in combination with tacrolimus and corticosteroids. Sirolimus, typically used in a regimen with cyclosporine and corticosteroids, is indicated for the prophylaxis of organ rejection in patients receiving renal transplants. Sirolimus is not FDA labeled as immuno-suppressive therapy in lung transplant patients. Two centers reported bronchial anastomotic dehiscence in lung transplant recipients in whom this immunosuppressive regimen was initiated at the time of transplantation. At one center, four of fifteen patients enrolled in an investigator-sponsored study developed this serious adverse event; a fatal outcome was identified in three of these four patients. The second center reported two cases of bronchial anastomotic dehiscence, one of which was fatal.
The boxed Warnings section of the prescribing information was revised to read as follows (the new wording are in blue):
|
Liver Transplantation -- Excess Mortality, Graft Loss, and Hepatic Artery Thrombosis (HAT): The use of sirolimus in combination with tacrolimus was associated with excess mortality and graft loss in a study in de novo liver transplant recipients. Many of these patients had evidence of infection at or near the time of death. In this and another study in de novo liver transplant recipients, the use of sirolimus in combination with cyclosporine or tacrolimus was associated with an increase in HAT; most cases of HAT occurred within 30 days post-transplantation and most led to graft loss or death. Lung Transplantation -- Bronchial Anastomotic Dehiscence: Cases of bronchial anastomotic dehiscence, most fatal, have been reported in de novo lung transplant patients when Rapamune has been used as part of an immunosuppressive regimen. The safety and efficacy of Rapamune (sirolimus) as immunosuppressive therapy have not been established in liver or lung transplant patients and therefore, such use is not recommended. |
"Dear Healthcare Professional" Letter
Wyeth
February 2003
Pergolide
Since its initial marketing in the United States in 1989, Eli Lilly and Company and the FDA have received a number of reports cardiac valvulopathy involving one or more valves associated with pergolide (Permax‚) therapy. Based on Lilly's safety data and scientific publications, the pathological assessment of valves that were surgically removed was consistent with the valvulopathy associated with carcinoid syndrome and with the use of other ergot alkaloid drugs. While a clear causal relationship between pergolide and the valvulopathy seen in these patients has not been established, given the nature of the lesions and known similar effects of other ergots, the Warnings section of the package insert for Permax was modified to reflect these reports (the new wording is in blue):
Serous Inflammation and Fibrosis--There have been rare reports of pleuritis, pleural effusion, pleural fibrosis, pericarditis, pericardial effusion, cardiac valvulopathy involving one or more valves, or retroperitoneal fibrosis in patients taking pergolide. In some cases, symptoms or manifestations of cardiac valvulopathy improved after discontinuation of pergolide. Pergolide should be used with caution in patients with a history of these conditions, particularly those patients who experienced the events while taking ergot derivatives. Patients with a history of such events should be carefully monitored clinically and with appropriate radiographic and laboratory studies while taking pergolide. |
"Dear Healthcare Professional" Letter
Eli Lilly and Company
February 2003
Ongoing ADR Vigilance
It obviously requires the ongoing vigilance of all health care providers to monitor for, document, and report all suspected adverse drug reactions experienced by patients so that rare or unusual events can be analyzed and, when indicated, drug product labeling appropriately updated. Ultimately, the goal of this process is to reduce the number of patients who experience similar adverse reactions in the future.
Additional information about recent safety alerts for drugs, biologics, medical devices, and dietary supplements may be viewed on the FDA's web site at: http://www.fda.gov/medwatch/SAFETY/2003/safety03.htm#drugs.
Prepared by Kevin Bebout, Administrative Pharmacist for Regulatory Affairs, Department of Pharmaceutical Care.