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

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

3. 27 June 2000Victor 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

4. 27 June 2000Victor 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

5. 27 June 2000Victor 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

6. 27 June 2000Victor F. C. Raczkowski, M.D.6 Lotronex Labeling: Anticipated Principal Changes Indications and Usage Contraindications Warnings Precautions Adverse Events Patient Package Insert

7. 27 June 2000Victor 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

8. 27 June 2000Victor 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

9. 27 June 2000Victor 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

10. 27 June 2000Victor 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

11. 27 June 2000Victor 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

12. 27 June 2000Victor 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

13. 27 June 2000Victor 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)

14. 27 June 2000Victor 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

15. 27 June 2000Victor 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?

16. 27 June 2000Victor F. C. Raczkowski, M.D.16 Communications and Educational 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

17. 27 June 2000Victor F. C. Raczkowski, M.D.17 Communications and Educational 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

18. 27 June 2000Victor F. C. Raczkowski, M.D.18 Communications and Educational 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

19. 27 June 2000Victor F. C. Raczkowski, M.D.19 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 the name of the drug only are not permitted for drugs with a Boxed Warning

20. 27 June 2000Victor 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

21. 27 June 2000Victor F. C. Raczkowski, M.D.21 Withdrawal Cessation of Marketing –Voluntary Withdrawal by the sponsor –Withdrawal of Approval/Imminent Hazard

22. 27 June 2000Victor F. C. Raczkowski, M.D.22 Conclusion Many options are available to help manage risk for Lotronex interventions would be considered.

23. 27 June 2000Victor 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)