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6/12/2002

Lotronex Returns to Market

Donna Young

A controversial medication used to treat irritable bowel syndrome (IBS) has become the first drug that was withdrawn from the market for safety reasons to receive Food and Drug Administration (FDA) approval to be allowed back on the market.

Last Friday, FDA approved a supplemental new drug application that permits restricted marketing of alosetron hydrochloride (Lotronex).

Alosetron manufacturer GlaxoSmithKline voluntarily withdrew the drug from the market in November 2000—nine months after the product was first approved—after reports of serious cases of ischemic colitis and other complications that led to more than 100 hospitalizations and at least four patient deaths.

Alosetron is regulated under an FDA program that requires restricted marketing of certain products approved for the treatment of serious or life-threatening illnesses, according to FDA officials. Four other drug products—mifepristone (Mifeprex, Danco Laboratories) bosentan (Tracleer, Actelion Ltd.), fentanyl citrate oral transmucosal (Actiq, Cephalon Inc.) and thalidomide (Thalomid, Celgene Corp.)—are also regulated under this program.

Joyce Korvick, a physician and deputy director of gastrointestinal and coagulation drug products at FDA’s Center for Drug Evaluation and Research (CDER), said FDA will require Glaxo to implement a risk-management plan for alosetron that includes a prescriber education program. The drug’s newly approved labeling includes a black-box warning that states that only physicians who have enrolled in the education program should prescribe alosetron. The black-box warning also requires patients to read and sign a patient–physician agreement form before receiving a prescription for alosetron.

The prescriber program is similar to one used by F. Hoffmann-La Roche Ltd. for its acne-control medication isotretinoin, which pharmacists dispense only after they receive a prescription that bears a special yellow sticker.

Florence Houn, a physician and director of CDER’s Office of Drug Evaluation III, said that a sticker on an alosetron prescription will likewise alert pharmacists that the prescriber meets specific qualifications and has agreed to educate patients about risks associated with the drug and to report adverse events.

To obtain the alosetron stickers, copies of the alosetron medication guide, and patient-physician agreement forms, prescribers must submit a physician agreement form to Glaxo, Houn said. "Doctors will not get stickers unless they enroll in the [prescriber] program, and pharmacists are directed not to fill prescription[s] unless they have such stickers," she noted.

Eric Carter, a physician and Glaxo’s vice president of gastrointestinal clinical development and medical affairs, said his company is also developing educational "activities" specifically for pharmacists.

As Glaxo and FDA work through the details of the prescribing program, Carter said, the groups will "ensure that there is no confusion between their program and Roche’s program."

"We will make sure that whatever we do, we will not confuse our [stickers] with Roche’s," he said.

Carter said he does not expect many alosetron prescriptions to be filled by health-system pharmacists. "Patients generally start this therapy outside the hospital setting," he said.

Although the Roche prescriber program for isotretinoin is voluntary, Houn said, the prescriber program for alosetron is not.

Houn said that FDA has greater control over the alosetron program than the prescriber program used for isotretinoin. She noted that the agency can rapidly withdraw alosetron from the market if the newly approved regulations are not followed. In addition, Houn said, Glaxo must conduct postmarketing studies of the drug, and FDA must approve all promotional materials before they are released.

Glaxo has decided to not market alosetron directly to consumers, according to FDA officials.

Under the prescriber program for alosetron, Korvick said, physicians must "attest that they are knowledgeable in the treatment of irritable bowel syndrome." If a patient has severe IBS symptoms and might benefit from alosetron therapy, Korvick said, the physician and patient should "engage in a dialogue...to make sure the information is complete, so the patient can make an informed decision."

FDA will evaluate how the drug is dispensed, according to officials at the agency. But it will be up to state boards of pharmacy to enforce whether pharmacies fill only those prescriptions that bear a sticker.

Carter said Glaxo is "working out the details" of the prescribing process with each state board of pharmacy.

The drug cannot be prescribed over the Internet, fax, or telephone, FDA officials said.

FDA has narrowed the drug’s indication for use by women with severe diarrhea-predominant IBS, a condition that FDA officials said affects 185,000 women in the United States.

"However, if a physician, in consultation and discussion with the patient who is a male, feels that it is appropriate in the practice of medicine to prescribe this drug for that patient with serious disease, that is a decision and choice that’s left up to the health care provider and the patient," Korvick said.

Houn noted that alosetron is not contraindicated in men.

"Given the circumstances, patients and physicians need to…decide if they are willing to take risks with the drug depending on how severe their disease is and how desperate they are for therapy," she said.

The recommended dosage of alosetron has been reduced from 1 mg twice daily to 1 mg daily, according to FDA officials.

But, according to the drug’s new labeling, if the 1-mg daily dosage is well tolerated but does not adequately control IBS symptoms after four weeks, the dosage can be increased to 1 mg twice a day—the dosage established in previous clinical trials of alosetron.

"Because the drug’s risks are very well-known, and because of the current malpractice environment...and the kinds of patients this drug is indicated for, we think that doctors who want to prescribe this drug will take it seriously, and it will not be prescribed casually because of all these pressures and constraints," Houn said.