Bernard Schwetz, Ph.D, D.V.M.
Acting Principal Deputy Commissioner
Food and Drug Administration
5600 Fishers Lane
Rockville, MD 20857
Dear Dr. Schwetz:
We have just obtained, through the Freedom of Information Act (FOIA), a memo from FDA’s Office of Post-marketing Drug Risk Assessment (OPDRA) (pdf) dated November 16, 2000, that confirms and extends the dangers of the drug Lotronex (alosetron) for the treatment of Irritable Bowel Syndrome (IBS). In addition, we have obtained from the FDA’s Adverse Event Reporting System (AERS) information about further cases of ischemic colitis and severe constipation in people using Lotronex. Thus, our data include information not available to OPDRA at the time of its memo.
According to the OPDRA memo, which was written two weeks before the drug’s withdrawal on November 29, 2000, there were already 49 cases of ischemic colitis and 21 cases of severe constipation. The updated AERS data we obtained, which extend through the end of calendar year 2000, now include a total of 63 people with ischemic colitis and 75 people with severe constipation (see graphs below). Thirty-eight of the ischemic colitis patients (60%) and 58 of the patients with constipation (77%) required hospitalization. Furthermore, three patients had mesenteric occlusion (blockage of the blood vessels supplying the colon) for a total of 141 cases of severe gastrointestinal complications of the drug, twice as many as in early November before the drug was withdrawn. As of the end of 2000, there were a total of 5 deaths related to adverse gastrointestinal reactions in people using Lotronex.
In its November 16, 2000 memo, OPDRA presented a comprehensive analysis of the seriousness of the cases of constipation and ischemic colitis that led to the withdrawal of Lotronex two weeks later. OPDRA concluded that “there are no known risk factors to predict either ischemic colitis or severe constipation” and that “Early warning of the dire side effects of this drug is clearly not feasible” (italics added). We know of no new information available since that memo that would change these conclusions.
Yet, the FDA, responding to pressure from industry and patient groups, is now considering reversing its decision and putting Lotronex back on the market. Public Citizen feels strongly that this now increased number of serious cases of ischemic colitis and severe constipation coupled with the inability to determine which individuals are at risk for drug complications, argues strongly that only a carefully monitored and restricted patient population should have access to this dangerous drug. Thus, we recommend an active monitoring program with rigorous data collection in those carefully selected patients who were previous users and who did not suffer any adverse reactions.
Public Citizen has been concerned about the safety of using Lotronex since the Gastrointestinal Drugs Advisory Committee meeting held on June 27, 2000 which examined the emerging GI adverse events. Our letters to then-FDA Commissioner Dr. Jane Henney (August 31, 2000 and October 30, 2000) pointed out the seriousness of the cases of ischemic colitis and severe constipation seen in the clinical trials along with the increasing number of cases that were being reported post-approval. We asked for the drug’s withdrawal.
A more thorough and more recent analysis was presented by OPDRA in its November 16, 2000 memo. The table below summarizes their analysis:
Severe Adverse Event Cases Referable to the GI System (based on 11/16 memo)
Outcome of Lotronex Use
|Phase of Use
|Phase III clinical trials
(March 2000 to November 2000)
|49 (30 hosp)
|21 (14 hosp)
*Data from clinical trials plus 36 weeks of post-marketing (through November 10, 2000)
As evident from the table and noted by OPDRA, “Much has changed since the June 27, 2000 AC (Advisory Committee) meeting”: there was an increase in the number of reported cases of ischemic colitis and severe constipation as well as 5 deaths (none had appeared in the clinical trials). Also included in their memo were a number of important observations, which appear designed to counter industry claims:
Ischemic colitis is not a class effect (that is, other drugs with a similar structure and function do not cause ischemic colitis): “NO cases of ischemic colitis were identified with other 5-HT3 receptor antagonists, including Zofran (odansetron), Kytril (granisetron), and Anzemet (dolasetron).” (emphasis in original)
Ischemic colitis is not an adverse effect of other drugs used for IBS: “NO cases of ischemic colitis were identified for any other drugs used off-label’ to treat IBS, including Imodium, Lomotil, Valium, Librium, Levsin, and Levsinex.” (emphasis in original)
IBS does not, by itself, cause severe injury: “IBS does not lead to surgery, does not shorten the life span and does not cause death.” Therefore, risks acceptable for life-saving drugs are not acceptable for IBS drugs.
Ischemic colitis cannot be predicted: “The warning signs and symptoms of ischemic colitis or colonic ischemia are not always clear, not always typical, and do not always occur.” “The sponsor has not identified a subset of women who will respond to Lotronex therapy safely.”
GlaxoWellcome’s contention that the identification and management of constipation could prevent ischemic colitis was refuted by OPDRA’s analysis of the data: 1) only 9 of the 49 patients with ischemic colitis had complained of constipation at the time of the event; and 2) only 2 of 10 surgical cases of ischemic colitis had constipation as a symptom upon arrival at the emergency room.
No risk management plan is feasible: “A restricted distribution plan will not manage the risk, but will only decrease the number of patients exposed . . .” “any management strategy that focuses on the patient’s age or the management of constipation will fail to manage the risk in the majority of patients exposed to Lotronex”.
Public Citizen is concerned that the FDA might, having withdrawn Lotronex, now allow largely unrestricted resumption of its marketing. However, since “there are no known risk factors to predict either ischemic colitis or severe constipation”, according to OPDRA, GlaxoWellcome needs to closely monitor its use in those for whom it already appears to have been used safely, and, in so doing, gain further safety information. Until and unless there is a way to reliably predict who is at risk for ischemic colitis and severe constipation, there is no way to prescribe Lotronex safely for the population at large: Lotronex should not be placed back on the market.
The following restrictions and monitoring systems need to be in place for the drug to be allowed even in an experimental, investigational (IND or investigational new drug) setting with use restricted as follows:
1) The IND use will be limited to patients who have previously used the drug and
a) have not experienced constipation from it and
b) have not had bleeding or severe abdominal pain from the drug.
2) There should be a written informed consent sheet pointing out that ischemic colitis occurs in as many as one in 300 patients using alosetron and including other information about its risks such as the conclusions described in the November 16th memo. They should be instructed to contact their physician if constipation or severe abdominal pain or gastrointestinal bleeding occur.
3) A registry of all patients and their physicians participating in this system should be kept so that periodic monitoring/assessment could be made and data collected concerning the clinical status.
Director Dr. Janet Woodcock and others in CDER such as Dr. Lilia Talarico, Director of the Gastrointestinal Drugs Division to whom the November 16th memo was addressed, are aware of significant opposition within CDER to the idea of any availability other than tightly restricted and monitored investigational use of Lotronex. If anything other than this approach is used, the toll of needless deaths and serious injuries and the repeat ban that will inevitably occur will be on the hands of those FDA officials responsible for such a reckless remarketing.
Elizabeth Barbehenn, Ph.D.
Peter Lurie, M.D.
Sidney M. Wolfe, M.D.
Public Citizen’s Health Research Group
Cc: Senator Edward Kennedy
Congressman Henry Waxman