Drug Information

Lotronex Tablets
(alosetron hydrochloride):
Questions and Answers

Lotronex (LOW-trah-nex) Tablets (alosetron hydrochloride)

1. What are the Food and Drug Administration (FDA) and GlaxoSmithKline (GSK) announcing today?
2. What are the restrictions for marketing Lotronex?
3. What is Lotronex?
4. Who should take Lotronex?
5. Why did GSK stop marketing Lotronex?
6. What is ischemic colitis?
7. Why is Lotronex being made available now?
8. Why is Lotronex not being made available under an Investigational New Drug application (IND)?
9. Does FDA believe the risks of Lotronex are manageable?
10. Can FDA say which patients taking Lotronex would be at the most risk?
11. What is involved in the risk management program to allow for the safe use of Lotronex?
12. Are there other measures to ensure safe use?
13. What are the goals of the risk management program with Lotronex?
14. Does FDA have any new information on the safety and efficacy of Lotronex?
15. How can I report a serious side effect with Lotronex to FDA?
16. When will Lotronex be available again in the pharmacy?
17. Why has this process of reconsidering Lotronex taken so long?
18. Where can I get copies of the labeling, Physician Agreement, Medication Guide, and Patient-Physician Agreement for Lotronex?
19. What if I have other questions about Lotronex?

1. What are the Food and Drug Administration (FDA) and GlaxoSmithKline (GSK) announcing today?

FDA and GSK are announcing FDA's decision to approve GSK's application to make the prescription drug Lotronex (alosetron) available again in the near future. Because of serious safety concerns, Lotronex will only be available through a restricted marketing program. Lotronex is only approved for women with severe diarrhea-predominant irritable bowel syndrome (d-IBS) who meet certain criteria. It is estimated that only 5% of IBS patients have severe IBS, and fewer have severe diarrhea-predominant IBS.

2. What are the restrictions for marketing Lotronex?

GSK has agreed to implement a Prescribing Program for Lotronex. Physicians enrolled in the program must attest to having certain qualifications and agree to fulfill specific responsibilities. Physicians enrolled in the Prescribing Program for Lotronex will agree to inform patients of the risks and benefits of Lotronex and to have patients sign a Patient-Physician Agreement indicating that they understand these risks and benefits. Enrolled physicians will then affix a sticker, which identifies the physician as a participant in the Prescribing Program for Lotronex, to each Lotronex prescription. This sticker will allow the pharmacist to identify that the prescription was written by a physician enrolled in the Prescribing Program for Lotronex.

3. What is Lotronex?

Lotronex is a medicine that slows the movement of stools through the bowels. Lotronex does not cure IBS and it will not help every person who takes it. For those who are helped, Lotronex reduces lower abdominal (stomach area) pain, abdominal discomfort, urgency (sudden need to have a bowel movement), and diarrhea of IBS. Patients who stop taking Lotronex may experience return of their IBS symptoms within 1 or 2 weeks.

4. Who should take Lotronex?

Lotronex is only approved for women with severe diarrhea-predominant IBS.

The following should be true for patients who take Lotronex:

• The main IBS problem is diarrhea
• IBS has gone on for a long time, 6 months or longer
• A physician has informed the patient that symptoms are not due to other medical problems
• Other IBS treatments have been tried and none has helped

IBS is thought to be very bad if a patient has one or more of the following problems:

• Lots of painful stomach cramps or bloating
• Inability to control the need to have a bowel movement or have "accidents" where underwear gets dirty from diarrhea or bowel movement (stools)
• Inability to lead a normal home or work life because of the need to be near a bathroom

Unless all of these things are true, Lotronex should not be considered for use.

Women whose main IBS problem is constipation should not use Lotronex. Lotronex has not been shown to help men with IBS.

5. Why did GSK stop marketing Lotronex?

Lotronex was voluntarily withdrawn from the market by GSK on November 28, 2000, after discussions with FDA concerning the severity and number of adverse reactions resulting from the use of Lotronex. Lotronex has been associated with reports of serious intestinal conditions, including severe constipation and ischemic colitis. These conditions can lead to hospitalization, blood transfusions, surgery, and even death.

6. What is ischemic colitis?

Ischemic colitis is a condition resulting from reduced blood flow to the intestines, which causes serious intestinal damage, and sometimes death. Some of the signs and symptoms of ischemic colitis are new or worsening abdominal pain, fever, vomiting, bloody diarrhea, rectal bleeding and low back pain.

7. Why is Lotronex being made available now?

The FDA is aware of the need to balance between access to effective therapies (particularly when conditions are serious, debilitating, or life threatening, and when no satisfactory alternative therapy exists) and protection of the public from serious drug-related adverse events. Since the withdrawal of Lotronex, the FDA and GSK have received numerous emails, letters and telephone calls from patients who related how their IBS symptoms were not responsive to any therapy other than Lotronex, and how their quality of life was adversely affected by its withdrawal. FDA has determined that in some patients the benefits of Lotronex outweigh the risks associated with the use of the drug. To assure that only those patients who are most likely to benefit from using Lotronex receive this drug, FDA and GSK agreed to work together to develop a risk management program to permit the reintroduction of Lotronex for use by women suffering from severe diarrhea-predominant disabling IBS.

8. Why is Lotronex not being made available under an Investigational New Drug application (IND)?

An Investigational New Drug (IND) application is a regulatory process through which FDA oversees clinical research and use of investigational drugs involving patients. GSK declined to make Lotronex available under an IND. However, GSK has agreed to narrow the drug's indication and implement a comprehensive risk management program to assure the safe use of the drug. At this time, many of the provisions of an IND program, such as informed consent for the patient, have been adapted to the risk management program.

9. Does FDA believe the risks of Lotronex are manageable?

FDA believes that the benefits of Lotronex outweigh the possible risks in women with severe diarrhea-predominant IBS who have exhausted all available therapeutic alternatives. Although data from clinical trials and post-marketing experience have identified complications of constipation and ischemic colitis as possible risks following Lotronex treatment, these risks must be assessed against the substantial benefits provided to appropriate patients who have not responded to conventional IBS therapy and, therefore, do not have therapeutic alternatives.

Physicians are essential in determining the benefits and managing the risks for the individual patient for whom the drug is prescribed. Ultimately, the patient, once informed, is the definitive decision-maker concerning the benefit-risk balance.

10. Can FDA say which patients taking Lotronex would be at the most risk?

All medicines carry some level of risk. However, the risk management program puts controls in place to allow appropriate and informed patients access to Lotronex while managing the risks.

At this point we have no identifiable risk factors to say who is at the most risk. For that reason, the FDA and GSK have agreed it is best to limit access to individual patients whose IBS is severe, such that the benefit for them outweighs the risk.

11. What is involved in the risk management program to allow for the safe use of Lotronex?

The risk management program for Lotronex brings together active participation of the physician, the patient, and the pharmacist. The risk management program provides a balance between allowing access by appropriate patients and managing the potential for serious risks. FDA and GSK have carefully crafted the details of a risk management program.

The Lotronex risk management program includes:

Changes in the labeling (physicians' package insert) for Lotronex [PDF]

Labeling is a primary source of information for physicians prescribing prescription drugs, and for pharmacists dispensing prescription drugs. The modified Lotronex labeling presents new safety information, including a black box warning emphasizing that:

• serious gastrointestinal events, some fatal, have been reported in association with the use of Lotronex
• only physicians enrolled in the GSK Prescribing Program for Lotronex should write prescriptions for Lotronex
• Lotronex is indicated only for women with severe diarrhea-predominant IBS who have not responded to conventional therapy
• Lotronex should be discontinued immediately in patients who develop constipation or symptoms of ischemic colitis

A Physician Attestation

This agreement is a way for GSK to ensure that physicians prescribing Lotronex are aware of the risks of Lotronex and the type of patients in which use of Lotronex may be appropriate. By enrolling in GSK's Prescribing Program for Lotronex, the physician states that he/she:

• is qualified to diagnose and treat IBS
• is qualified to diagnose and manage ischemic colitis
• is qualified to diagnose and manage constipation and complications of constipation
• understands the risks and benefits of Lotronex treatment for diarrhea-predominant IBS
• agrees to educate the patient about risks and benefits of Lotronex, confirms that the patient has signed a Patient-Physician Agreement, and gives the patient a copy of that agreement and of the Medication Guide
• will report serious adverse events to GSK or FDA.

The physician will attest to meeting the above qualifications and send the agreement to GSK. Additionally, the physician will agree to place the qualification sticker on all Lotronex prescriptions.

Changes in the Medication Guide for Lotronex

Medication Guides present important information enabling patients to take a more active role in their drug therapy, particularly when that drug therapy involves a risk of serious side effects. The Medication Guide for Lotronex is modified to give new safety information for patients taking Lotronex. Physicians enrolled in the GSK Prescribing Program for Lotronex agree to provide the patient a copy of the Medication Guide at the time the first prescription is written. The pharmacist will also provide a Medication Guide to the patient each time a prescription is filled.

A Patient Agreement document

It is important for patients to understand the benefits and risks associated with Lotronex use. Once informed, patients will make decisions regarding treatment. Most importantly, patients need to be able to recognize important signs and symptoms requiring immediate action, which may include stopping treatment and seeking medical attention.

This patient agreement is a way for FDA and GSK to ensure that patients prescribed Lotronex:

• have read, understood, and agreed to the points in the Medication Guide in order to gain a better understanding about the severity of potential risks and the balance between the risks and benefits of treatment.
• agree to treatment with Lotronex.
• will not take Lotronex if they are constipated, and if they become constipated, will immediately stop taking Lotronex and contact their physician.
• will stop taking Lotronex and call their physician if Lotronex does not control IBS symptoms after 4 weeks.

12. Are there other measures to ensure safe use?

Yes, FDA and GSK have agreed on several steps to monitor the risk management program. GSK will conduct several programs to monitor prescribing patterns with a goal of assuring that only enrolled physicians prescribe Lotronex. GSK will monitor databases to follow the use of Lotronex and survey patients to ensure they understand the risks, benefits, and warning signs for adverse events associated with the drug. Adverse events will be monitored closely. Gastrointestinal disease experts, GSK, and FDA will meet periodically to review adverse events and the risk management program.

Additional studies will be conducted to investigate safer ways to dose or use the drug and to study its long-term risks. Other studies will investigate what may be causing ischemic colitis and what risk factors may be associated with it.

13. What are the goals of the risk management program with Lotronex?

The risk management program seeks to limit access to Lotronex to appropriate patients and to minimize risks. The risk management program is a way to allow informed patient access to Lotronex under the supervision of a qualified physician.

FDA and GSK anticipate there will be patients who experience serious adverse events and it is possible that patients may die while taking Lotronex. At this point we have no identifiable risk factors to say who is at the most risk and it is not yet known either how to prevent ischemic colitis or when constipation may become serious and lead to intestinal blockage.

However, the overall goals of the risk management program are to ensure that:

• patients and physicians are fully informed of the risks and possible benefits of Lotronex.

• only patients with severe, debilitating, diarrhea-predominant IBS, in whom benefits of the drug may exceed risks, are the target population for Lotronex.

• only physicians with certain qualifications and who agree to accept certain responsibilities prescribe Lotronex.

14. Does FDA have any new information on the safety and efficacy of Lotronex?

Since the withdrawal of Lotronex, substantial amounts of new information about the drug have become available. On December 7, 2001, GSK submitted new information to FDA about the safety and efficacy of Lotronex. This information included data from clinical trials that were ongoing (and were terminated) when the drug was withdrawn from the market and data from adverse events reported while the drug was being marketed.

The primary purpose of reviewing the new data was to have a comprehensive safety database for an updated benefit-risk assessment. New study data confirm the efficacy of Lotronex in patients with debilitating IBS symptoms. This new information is key to a revised safety assessment for the patient population for whom the benefit-risk balance is believed to be most favorable, namely, women with severely diarrhea-predominant IBS who have not responded to conventional therapy.

About 1 woman out of 1,000 women who take Lotronex may get serious constipation problems. These constipation problems can lead to hospitalization, blood transfusions, or even death.

About 1 woman out of 350 women who take Lotronex over a 6-month period may get ischemic colitis. The risk of ischemic colitis when Lotronex is taken for more than 6 months is unknown. Ischemic colitis can lead to hospitalization, blood transfusions, or even death.

15. How can I report a serious side effect with Lotronex to FDA?

FDA encourages anyone aware of a serious side effect, including consumers, to make a MedWatch report.

You can report an adverse event in two ways:

• Visit www.fda.gov/medwatch and click on "How to Report"
• Call 1-800-FDA-1088

16. When will Lotronex be available again in the pharmacy?

It is our understanding that supplies of Lotronex must be manufactured by GSK. GSK has said it would take the company approximately 6 months to have enough supplies for marketing. FDA has no control over when products are available in pharmacies after FDA approval for re-introduction to the market. The decision on availability is made by the company marketing the product. For further information, consumers should contact GSK directly.

17. Why has this process of reconsidering Lotronex taken so long?

Since January 2001, representatives of FDA and GSK have held numerous discussions to explore options that might allow for the re-introduction of Lotronex under a mutually acceptable risk management program. The benefit-risk issues surrounding Lotronex are complex. Last year FDA and GSK worked on aspects of revising labeling, the Medication Guide, and Patient-Physician Agreement forms, but no agreement was made on the overall risk management program. FDA then requested all clinical trial data be submitted for FDA's review to better understand risks of the drug. Finally, we felt that holding an Advisory Committee meeting with outside experts and others would offer an open public forum for discussion and advice on whether an appropriate risk management program could be established for Lotronex, and if so, what the specific characteristics of such a program should be.

It is by working through all the aspects of an appropriate and effective risk management program, with all interested parties, that FDA and GSK have come to agreement that with restricted access and proper safeguards in place, Lotronex can be marketed to certain appropriate patients.

18. Where can I get copies of the labeling, Physician Agreement, Medication Guide, and Patient-Physician Agreement for Lotronex?

The labeling [PDF], Physician Agreement, Medication Guide, and Patient-Physician Agreement for Lotronex are available at:

• the FDA's Lotronex web page at: http://www.fda.gov/cder/drug/infopage/lotronex/lotronex.htm
• by calling GSK at 888-825-5249

19. What if I have other questions about Lotronex?

If you have further questions regarding the program for the safe use of Lotronex, please contact the Center for Drug's Division of Drug Information at: 888-INFO.FDA (888-463-6332), or email us at: druginfo@fda.hhs.gov.

You can contact GSK directly at 888-825-5249.

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FDA/Center for Drug Evaluation and Research
Last Updated: June 7, 2002
Originator: OTCOM/DDI
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