Risk-Management Options

1. Risk-Management Options Victor F. C. Raczkowski, M.D., M.S. Gastrointestinal Drugs Advisory Committee 27 June 2000 Victor F. C. Raczkowski, M.D.

2. Risk-Management Options for Marketed Drugs • Labeling • Communications and Educational Programs • Advertising • Packaging • Restricted Distribution • Withdrawal Victor F. C. Raczkowski, M.D.

3. Labeling Components • Labels • Immediate container • Outer package • Package insert for prescription drugs • Professional labeling • Patient Package Insert • Medication Guides Victor F. C. Raczkowski, M.D.

4. Patient Package Inserts (PPI) • Extension of professional labeling • Can be distributed to patients when drug dispensed • Important information about the drug in lay language • Lotronex currently has a PPI Victor F. C. Raczkowski, M.D.

5. Medication Guides for Prescription Drugs • Information leaflet for patients • FDA can require one: 21 CFR 208 • Must be distributed to patients when drug dispensed • May be used with unit-of-use packaging to enforce its distribution Victor F. C. Raczkowski, M.D.

6. Lotronex Labeling: Anticipated Principal Changes • Indications and Usage • Contraindications • Warnings • Precautions • Adverse Events • Patient Package Insert Victor F. C. Raczkowski, M.D.

7. Warnings • Describes serious adverse reactions and potential safety hazards • Describes limitations in use imposed by serious adverse reactions • Describes steps that should be taken if serious adverse reactions occur Victor F. C. Raczkowski, M.D.

8. Warnings • Reasonable evidence of an association of a serious hazard with drug • Causal relationship need not have been proved Victor F. C. Raczkowski, M.D.

9. Boxed Warnings • Special problems, particularly those that may lead to death or serious injury • Increases prominence of warning • Can be required by FDA • Ordinarily based on clinical data Victor F. C. Raczkowski, M.D.

10. Boxed Warnings • May be based on serious animal toxicity • Specify frequency of serious adverse reactions and, if known, approximate mortality and morbidity rates from reaction • Advertising consequence: No reminder ads Victor F. C. Raczkowski, M.D.

11. Boxed Warnings: How Used? • Adverse reaction serious in proportion to potential benefit • Benefit-risk should be considered before drug is prescribed Victor F. C. Raczkowski, M.D.

12. Boxed Warnings: How Used? • Serious adverse reaction, preventable or decreased in frequency or severity by: • Appropriate patient selection • Careful monitoring (e.g., LFTs for hepatotoxicity) • Avoiding certain concomitant therapy • Avoiding use in specific clinical situation Victor F. C. Raczkowski, M.D.

13. Boxed Warnings: How Used? • Contraindicated situations • Important risk/benefit information about a drug (e.g., drug is the only one in class to have a particular risk that makes it inappropriate for first-line therapy) Victor F. C. Raczkowski, M.D.

14. Boxed Warning for Lotronex? • Constipation: • Clear causal relationship with Lotronex • Constipation reported as serious adverse event in 7 patients taking Lotronex • 6 patients hospitalized • 3 patients underwent surgery Victor F. C. Raczkowski, M.D.

15. Boxed Warning for Lotronex? • Ischemic colitis: • Causal relationship to Lotronex suggested in clinical trials and confirmed after marketing • Ischemic colitis reported as serious adverse event in 12 patients taking Lotronex • 8 patients hospitalized • Remaining 4 patients required endoscopy • Lack of serious sequelae (e.g., colectomy, death) reassuring? Victor F. C. Raczkowski, M.D.

16. Communications andEducational Programs • Communications to health care practitioners and consumers • Dear Healthcare Practitioner letter & mailing by the sponsor • Press Releases and Talk Papers for the Press and posting in the FDA Website • Health Advisories to communicate serious health risks Victor F. C. Raczkowski, M.D.

17. Communications andEducational Programs • Communications to health care practitioners and consumers • Educational Programs by sponsors directed to healthcare practitioners to ensure optimal prescribing and implementation of necessary precautions Victor F. C. Raczkowski, M.D.

18. Communications andEducational Programs • Educational Programs by sponsors for the public/patients through toll free numbers, internet sites, newsletters, and collaborative efforts with patient advocacy groups • Sales force outreach Victor F. C. Raczkowski, M.D.

19. Advertising • Advertising • Voluntary restriction to journal type • Voluntary restriction of direct to consumer ads • Ads must present a brief, accurate and balanced representation of adverse reactions, contraindications, and effectiveness • Reminder ads that call attention to thename of the drug only are not permitted for drugs with a Boxed Warning Victor F. C. Raczkowski, M.D.

20. Packaging and Restricted Distribution • Packaging - Unit of Dose packaging used with patient package insert/med guide • Restricted Distribution - Mechanism to ensure safer use and availability of drug of benefit over existing treatments to treat serious or life threatening conditions • Restricted Distribution may be voluntary Victor F. C. Raczkowski, M.D.

21. Withdrawal • Cessation of Marketing • Voluntary Withdrawal by the sponsor • Withdrawal of Approval/Imminent Hazard Victor F. C. Raczkowski, M.D.

22. Conclusion • Many options are available to help manage risk for Lotronex • interventions would be considered. Victor F. C. Raczkowski, M.D.

23. Discussion Points • Discuss which risk-management tools should be used for Lotronex • Specify next steps if goals of a risk-management program for Lotronex are not being realized • Discuss when additional risk-management tools should be implemented (e.g., thresholds) Victor F. C. Raczkowski, M.D.