Glaxo Wellcome's withdrawal of Lotronex suggests that hurdles remain in FDA's efforts to expand the use of risk management programs for approved products.

Glaxo chose to withdraw the irritable bowel syndrome drug after the company and FDA could not agree on a risk management program.

The agency and Glaxo have been discussing an appropriate response to reports of gastrointestinal adverse events, including ischemic colitis, associated with alosetron since shortly after it was launched.

From FDA's point of view, the risk management program presented an opportunity for patients severely in need of Lotronex to continue to receive the product while Glaxo conducted additional research to define the appropriate indication. From Glaxo's perspective, the program may have resembled a return to IND status without any prospect of a commercial return.

FDA is emphasizing risk-management programs as a new tool to strengthen its post-marketing surveillance efforts.

Lotronex was among the first products to which FDA applied the risk management concept. Following reports of gastrointestinal adverse events, FDA held a follow-up advisory committee meeting in June to discuss risk-management options.

In keeping with the committee's recommendations, FDA made Lotronex the first product to include a mandatory consumer Medication Guide (¹ [A#00620350000]).

As of Nov. 10, FDA had received reports of 49 cases of ischemic colitis and 21 cases of severe constipation, the agency said. Of the 70 cases, 34 resulted in hospitalization without surgery, 10 resulted in surgical procedures and three resulted in death.

FDA received two additional reports of death that the agency did not classify as being cases of ischemic colitis or severe complications of constipation.

The decision to withdraw the drug came after a Nov. 28 meeting during which FDA presented Glaxo with two choices: withdrawing Lotronex or accepting a limited distribution program proposed by the agency.

The proposed program included a physician certification component, FDA said. Physicians would be authorized to prescribe Lotronex only after demonstrating they could identify the correct patient population, recognize the side effects associated with Lotronex, and monitor and manage those side effects.

FDA also would have required a registry of Lotronex patients and prescribers.

Patients seeking to take Lotronex under the program would have been required to have a documented discussion with their physician on the risks and benefits associated with the product.

Under FDA's limited distribution plan, Lotronex would only have been available through Glaxo, rather than through pharmacies, the company pointed out. In addition, Glaxo would have been required to monitor Lotronex prescriptions, and would have had responsibility for ejecting physicians from the program who prescribed outside the specified indication.

Glaxo would not have been able to add new patients to therapy, except under an IND. FDA envisioned studies designed to identify a more narrow indication for Lotronex.

Lotronex was indicated for the treatment of women with diarrhea-predominant IBS. Language added in August explains that the condition is characterized by "at least three months of continuous or recurrent symptoms of abdominal pain or discomfort with either urgency, an increase in frequency of stool, or diarrhea not attributable to organic disease."

FDA outlined its objectives from the limited access program in a Nov. 28 "Talk Paper."

"The restricted drug distribution program would provide 1) safe use of Lotronex in appropriately informed patients, 2) continued access to Lotronex by severely debilitated IBS patients under closely monitored conditions, and 3) continued clinical research into the benefits, risks and safe and appropriate use of Lotronex," FDA said.

However, "at the conclusion of today's meeting, Glaxo Wellcome informed FDA that it will voluntarily withdraw Lotronex from the market," rather than implement the proposed program, FDA said.

"FDA recognized that the other available treatments for IBS may offer inadequate relief from a condition that can be severely incapacitating for some patients," the agency added. Novartis' irritable bowel syndrome therapy Zelmac is pending at FDA. The drug targets constipation-predominant IBS, and has been "approvable" since August (² Also see "Novartis Zelmac Well Tolerated In Alternating IBS, Study Suggests" - Pink Sheet, 4 December, 2000.)

Glaxo said it offered alternative risk management plans for Lotronex to FDA, but apparently none were acceptable to the agency.

The company's recommendations included a limited distribution program that Glaxo said is not as restrictive as that proposed by FDA. Glaxo also suggested convening an independent medical review board to review adverse event reports as they come in.

The company's proposals included labeling changes, patient education, and new clinical and epidemiological research, Glaxo said.

The company also asked FDA for another advisory committee review for Lotronex, a request Glaxo said the agency refused. FDA said it was open to the idea of another committee review, but did not want any further delay in implementing restricted distribution.

In announcing the withdrawal, Glaxo did not acknowledge FDA's proposal for stopping short of total product withdrawal. After summarizing its proposals to the agency, Glaxo said FDA "disagrees as to the adequacy of these proposals and has requested that Glaxo Wellcome voluntarily withdraw Lotronex from the market."

Glaxo explained that it considers FDA's proposal to be so restrictive as to be tantamount to withdrawal and characterized the agency plan as more limited than the distribution program for Johnson & Johnson's Propulsid, which was withdrawn in March (³ Also see "J&J Propulsid Compassionate IND Program Expands To Allow Emergency Use" - Pink Sheet, 4 December, 2000.).

FDA viewed its proposals as different than the Propulsid program. From FDA's point of view, Propulsid was withdrawn and remains available only via an IND. The agency felt its proposal was not such a drastic step for Glaxo.

The prescriber registration and certification agreements are similar to provisions included in the risk management program established by FDA for the abortifacient Mifeprex (mifepristone, RU-486).

Glaxo said it has no plans for additional studies or any other efforts to resume marketing of Lotronex. The company is withdrawing its marketing application for Lotronex in the EU, and will cancel plans to launch the drug in Argentina, Mexico and South Korea, where it has been approved but is not yet marketed.

The company has instituted a pharmacy-level recall of Lotronex, and is sending letters to pharmacists requesting returns of the product. Physicians will be asked to destroy any unused product samples.

Lotronex was given a priority review at FDA, although the agency points out that the review was extended to seven months to allow the agency extra time to examine reported cases of ischemic colitis.

In FDA's post mortem report for Warner-Lambert's type 2 diabetes drug Rezulin (troglitazone), issued Nov. 8, FDA employees suggested that the agency should evaluate the criteria used to assign priority reviews (⁴ Also see "Priority Review Criteria Reassessment Called For In FDA Rezulin Report" - Pink Sheet, 4 December, 2000.).

Lotronex is the eighth product approved under Prescription Drug User Fee Act review procedures to be withdrawn or severely restricted due to side effect concerns. All eight of the actions have occurred since September 1997, when Wyeth/Interneuron's Redux was pulled (⁵ see chart: Product Withdrawals Under User Fees).

In addition, Propulsid and the non-sedating antihistamines Seldane and Hismanal have been withdrawn for safety reasons during that period, although all three were pre-PDUFA NDAs.

Lotronex is the second Glaxo product pulled in the past 13 months: the antibiotic Raxar was withdrawn in October 1999.

Burroughs Wellcome withdrew the antidepressant Wellbutrin (buproprion) in 1986 due to an increased risk of seizures reported in a study of bulimic patients. The product was reintroduced in 1989, and the anti-smoking formulation (Zyban) remains a significant product for Glaxo.

Glaxo was involved in the troglitazone withdrawal in Europe, where it marketed the antidiabetic as Romozin.

Glaxo Lotronex Withdrawal Follows Failed Risk Management Negotiations

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