1. Anti-Infective Drugs Advisory Committee Meeting September 12, 2006 1 Andrew Mosholder, M.D., M.P.H. Medical Officer Division of Drug Risk Evaluation Office of Surveillance and Epidemiology, FDA Review of post-marketing safety of Factive (gemifloxacin)

2. Anti-Infective Drugs Advisory Committee Meeting September 12, 2006 2 OutlineOutline Extent of use of gemifloxacin Overview of AERS data for gemifloxacin Non-skin adverse event reporting data Skin adverse events Special review of serious skin reports Conclusions Extent of use of gemifloxacin Overview of AERS data for gemifloxacin Non-skin adverse event reporting data Skin adverse events Special review of serious skin reports Conclusions

3. Anti-Infective Drugs Advisory Committee Meeting September 12, 2006 3 Extent of Use of Gemifloxacin Approved in 2003, launched in 2004 Large number of drug samples given to patients makes estimations difficult Oscient’s estimate of exposure –U.S. 760,000 patients –Outside U.S. 205,000 patients Verispan LLC Vector One –Total Patient Tracker estimates approximately 332,114 pts filled prescriptions* –Physician Drug and Diagnosis Audit estimates approximately 1.2 million uses** Drug samples given to patients may account for some of discrepancy Approved in 2003, launched in 2004 Large number of drug samples given to patients makes estimations difficult Oscient’s estimate of exposure –U.S. 760,000 patients –Outside U.S. 205,000 patients Verispan LLC Vector One –Total Patient Tracker estimates approximately 332,114 pts filled prescriptions* –Physician Drug and Diagnosis Audit estimates approximately 1.2 million uses** Drug samples given to patients may account for some of discrepancy * Verispan Total Patient Tracker, Year 2002 - June 2006 Aggregate Time, Extracted 8-23-06 ** Verispan, Physician Drug and Diagnosis Audit (PDDA), Years 2004 - June 2006, Extracted 8-23-06

4. Anti-Infective Drugs Advisory Committee Meeting September 12, 2006 4 Postmarketing Data from AERS Voluntary, spontaneous reports collected through MedWatch system Useful for detecting rare but significant adverse drug reactions in the population post-marketing Subject to usual limitations of spontaneous reporting systems Under-reporting (see next slide) Biases in reporting Variable quality of information in reports Spontaneous reports entered in FDA’s Adverse Event Reporting System (AERS) database On the MedWatch form, “serious” cases are those designated by the reporter as fatal, life-threatening, involving hospitalization, causing disability, involving a congenital anomaly, requiring intervention to prevent permanent impairment, or “other” (fill in blank) Voluntary, spontaneous reports collected through MedWatch system Useful for detecting rare but significant adverse drug reactions in the population post-marketing Subject to usual limitations of spontaneous reporting systems Under-reporting (see next slide) Biases in reporting Variable quality of information in reports Spontaneous reports entered in FDA’s Adverse Event Reporting System (AERS) database On the MedWatch form, “serious” cases are those designated by the reporter as fatal, life-threatening, involving hospitalization, causing disability, involving a congenital anomaly, requiring intervention to prevent permanent impairment, or “other” (fill in blank)

5. Anti-Infective Drugs Advisory Committee Meeting September 12, 2006 5 Under-reporting of severe cutaneous reactions In Canada over a five year period, 250 cases of toxic epidermal necrolysis were admitted to hospital burn units, but only 25 of these were reported to the Canadian postmarketing surveillance system Mittman et al. Drug Saf 2004;27:477-87 In Canada over a five year period, 250 cases of toxic epidermal necrolysis were admitted to hospital burn units, but only 25 of these were reported to the Canadian postmarketing surveillance system Mittman et al. Drug Saf 2004;27:477-87

6. Anti-Infective Drugs Advisory Committee Meeting September 12, 2006 6 Overview of AERS reports for gemifloxacin (Aug 2006) Total # of reports:960 # of serious reports:84 (8.5%) Origin:957 US, 3 non-US Gender distribution:589 F, 257 M Age distribution:207 ≤ 40, 319>40 Leading System Organ Class: Skin and Subcutaneous Tissue Disorders (n=783, 82% of total) Total # of reports:960 # of serious reports:84 (8.5%) Origin:957 US, 3 non-US Gender distribution:589 F, 257 M Age distribution:207 ≤ 40, 319>40 Leading System Organ Class: Skin and Subcutaneous Tissue Disorders (n=783, 82% of total)

7. Anti-Infective Drugs Advisory Committee Meeting September 12, 2006 7

8. Anti-Infective Drugs Advisory Committee Meeting September 12, 2006 8 Gemifloxacin AERS data Non-cutaneous reports Selected events (As of August 2006) Non-cutaneous reports Selected events (As of August 2006)

9. Anti-Infective Drugs Advisory Committee Meeting September 12, 2006 9 Summary of non- skin reports August 2006 Approximately 20% (184) of all AERS reports were not a cutaneous reaction 43 with serious outcome Majority of the serious reports were in adult patients Approximately 20% (184) of all AERS reports were not a cutaneous reaction 43 with serious outcome Majority of the serious reports were in adult patients

10. Anti-Infective Drugs Advisory Committee Meeting September 12, 2006 10 Summary of non- skin reports with Serious Outcome (n=43) Indication for (n=28) bronchitis 9, sinusitis 9, pneumonia 7 Most frequently reported serious AEs: –Allergic phenomena (anaphylaxis, allergic reactions) Total = 16 serious allergic event reports including both cutaneous and non- cutaneous –Clostridium difficile infection, 7 –Bleeding/increased INR with warfarin, 6 Indication for (n=28) bronchitis 9, sinusitis 9, pneumonia 7 Most frequently reported serious AEs: –Allergic phenomena (anaphylaxis, allergic reactions) Total = 16 serious allergic event reports including both cutaneous and non- cutaneous –Clostridium difficile infection, 7 –Bleeding/increased INR with warfarin, 6

11. Anti-Infective Drugs Advisory Committee Meeting September 12, 2006 11 Reports with fatal outcomes August 2006 –74 yo m died with C. difficile colitis, toxic megacolon and sepsis, one week after completing gemifloxacin treatment for bronchitis –47 yo m died after one dose; pt had renal failure and was candidate for dialysis; no autopsy –33 yo m died from hemophagocytic syndrome of unknown etiology (also had mild rash) –44 yo m with dilated cardiomyopathy; hx seizures –66 yo f with hives, photosensitivity died months later during a surgical procedure Of the above, the death from C. difficile colitis can be reasonably attributed to gemifloxacin treatment –74 yo m died with C. difficile colitis, toxic megacolon and sepsis, one week after completing gemifloxacin treatment for bronchitis –47 yo m died after one dose; pt had renal failure and was candidate for dialysis; no autopsy –33 yo m died from hemophagocytic syndrome of unknown etiology (also had mild rash) –44 yo m with dilated cardiomyopathy; hx seizures –66 yo f with hives, photosensitivity died months later during a surgical procedure Of the above, the death from C. difficile colitis can be reasonably attributed to gemifloxacin treatment

12. Anti-Infective Drugs Advisory Committee Meeting September 12, 2006 12 Events of Interest Cardiac events6 Hepatic events12 Clostridium colitis10 Drug ineffective31 Drug Interactions10 Thrombocytopenia 3 Cardiac events6 Hepatic events12 Clostridium colitis10 Drug ineffective31 Drug Interactions10 Thrombocytopenia 3

13. Anti-Infective Drugs Advisory Committee Meeting September 12, 2006 13 Cardiac Events (n=6) QT prolongation N=1 –46 yo F, hosp. with respiratory failure, hypokalemic Tachycardia N=5 –One supraventricular tachycardia –no ventricular tachycardia QT prolongation N=1 –46 yo F, hosp. with respiratory failure, hypokalemic Tachycardia N=5 –One supraventricular tachycardia –no ventricular tachycardia

14. Anti-Infective Drugs Advisory Committee Meeting September 12, 2006 14 Hepatic events (n=12) Liver failure/hemophagocytic syndrome* N=1 Cholestasis/Liver necrosis* N=1 Hepatic steatosis* N=1 Acute cholecystitis* N=1 Elevation of liver enzymes N=8 * = Confounded by other drugs, prior history or disease Liver failure/hemophagocytic syndrome* N=1 Cholestasis/Liver necrosis* N=1 Hepatic steatosis* N=1 Acute cholecystitis* N=1 Elevation of liver enzymes N=8 * = Confounded by other drugs, prior history or disease

15. Anti-Infective Drugs Advisory Committee Meeting September 12, 2006 15 Clostridium colitis (n=10) Clostridium colitis infection was reported in 10 patients 6/10 were females 40% had a positive culture or toxin, or had the diagnosis confirmed by biopsy One patient died of megacolon and sepsis Clostridium colitis infection was reported in 10 patients 6/10 were females 40% had a positive culture or toxin, or had the diagnosis confirmed by biopsy One patient died of megacolon and sepsis

16. Anti-Infective Drugs Advisory Committee Meeting September 12, 2006 16 Drug Interactions (n=10) 7 out of 10 gemifloxacin + warfarin –Increased PT or INR –Some with bleeding 7 out of 10 gemifloxacin + warfarin –Increased PT or INR –Some with bleeding

17. Anti-Infective Drugs Advisory Committee Meeting September 12, 2006 17 Gemifloxacin AERS data Cutaneous manifestations reports

18. Anti-Infective Drugs Advisory Committee Meeting September 12, 2006 18 BackgroundBackground Strong signal for rash in clinical trials data –Rash in 32% of patients treated in special study 344 (enriched for susceptibility to rash) –Rashes designated serious by investigator in ~1 in 1200 patients treated in clinical trials Purpose of postmarketing data review: to expand upon the clinical picture of gemifloxacin cutaneous toxicity observed in clinical trials Strong signal for rash in clinical trials data –Rash in 32% of patients treated in special study 344 (enriched for susceptibility to rash) –Rashes designated serious by investigator in ~1 in 1200 patients treated in clinical trials Purpose of postmarketing data review: to expand upon the clinical picture of gemifloxacin cutaneous toxicity observed in clinical trials

19. Anti-Infective Drugs Advisory Committee Meeting September 12, 2006 19 Initial AERS Skin Events Review AERS Data cutoff: May 31, 2006 N=799 total reports –Crude count, may include duplicates 83% of all AERS reports listed a skin adverse event 73% of skin events were in females 6% of skin events listed a serious outcome N=799 total reports –Crude count, may include duplicates 83% of all AERS reports listed a skin adverse event 73% of skin events were in females 6% of skin events listed a serious outcome

20. Anti-Infective Drugs Advisory Committee Meeting September 12, 2006 20 Age and Gender Females: where age/gender stated (n=247), 42% of skin event reports from ≤ 40 years age group. Approximate drug use (prescriptions) for this age group accounted for 21%*. Males: (n=93), 45% of skin events were reported from ≤ 40 years age group. Approximate drug use (prescriptions) for this age group accounted for 23%*. Females: where age/gender stated (n=247), 42% of skin event reports from ≤ 40 years age group. Approximate drug use (prescriptions) for this age group accounted for 21%*. Males: (n=93), 45% of skin events were reported from ≤ 40 years age group. Approximate drug use (prescriptions) for this age group accounted for 23%*. * Verispan Vector One®: National, 2002-2006, data extracted July-2006

21. Anti-Infective Drugs Advisory Committee Meeting September 12, 2006 21 Time to onset of Rash Subset review of n=291 cases coded with the MedDRA term “Rash” –Median time to onset (when data provided) = 4 d Subset review of n=291 cases coded with the MedDRA term “Rash” –Median time to onset (when data provided) = 4 d

22. Anti-Infective Drugs Advisory Committee Meeting September 12, 2006 22 Serious Outcome Cases Death cases already discussed Hospitalized cases required treatments including steroids, antihistamines, oxygen, and intravenous fluids Medically important cases with hypersensitivity component: “urticaria”, “swelling of face”, “allergic vasculitis” etc. needed intervention with epinephrine, steroids and antihistamines Some with previous FQ use, history of drug allergy Death cases already discussed Hospitalized cases required treatments including steroids, antihistamines, oxygen, and intravenous fluids Medically important cases with hypersensitivity component: “urticaria”, “swelling of face”, “allergic vasculitis” etc. needed intervention with epinephrine, steroids and antihistamines Some with previous FQ use, history of drug allergy

23. Anti-Infective Drugs Advisory Committee Meeting September 12, 2006 23 Crude US AERS Reporting rates for serious skin event cases (5/2006) Product (Approval) Moxifloxacin (1999) Gatifloxacin (1999) Gemifloxacin (2003) Cefditoren (2001) Telithromycin (2004) Estimated Rx (in 1000s)* 538682373633605340 # of AERS serious cutaneous reports 226141385109 Reporting rates Per million RX 42171051420 * Verispan Vector One™: National, 1996-2006, data extracted July-2006; First two and a half years for telithromycin and gemifloxacin; first three years for moxifloxacin and gatifloxacin; and first 4 years for cefditoren (only 1,000 prescriptions were dispensed in 2001)

24. Anti-Infective Drugs Advisory Committee Meeting September 12, 2006 24 Addendum Review Data cutoff: August 2, 2006

25. Anti-Infective Drugs Advisory Committee Meeting September 12, 2006 25 Addendum Review Individual review and analysis of U.S. AERS skin disorder reports with serious outcomes (8-2-06) Special attention to cases that might represent known severe drug reactions –Stevens-Johnson syndrome (SJS) –Toxic epidermal necrolysis (TEN) –Allergic/hypersensitivity reactions Exclusions –Cases designated “serious” by reporter but which did not seem to warrant that classification on review (e.g., “severe rash”) –Cases in which the only skin events were not relevant to assessment of cutaneous drug reactions (e.g., petechiae) Drugs: –Gemifloxacin –Cefditoren Individual review and analysis of U.S. AERS skin disorder reports with serious outcomes (8-2-06) Special attention to cases that might represent known severe drug reactions –Stevens-Johnson syndrome (SJS) –Toxic epidermal necrolysis (TEN) –Allergic/hypersensitivity reactions Exclusions –Cases designated “serious” by reporter but which did not seem to warrant that classification on review (e.g., “severe rash”) –Cases in which the only skin events were not relevant to assessment of cutaneous drug reactions (e.g., petechiae) Drugs: –Gemifloxacin –Cefditoren

26. Anti-Infective Drugs Advisory Committee Meeting September 12, 2006 26 Individual review of serious skin events: Results Drug 2002- 6/2006 TPT* total patients PDDA* uses 2002- 6/2006 Numbers of U.S. AERS reports per manual review Definite SJS Possible SJS Serious allergic skin Other serious skin All serious skin Gemifloxacin332,1141,183,000 0391224 Cefditoren512,1561,412,000 00303 * Verispan Total Patient Tracker, Year 2002 - June 2006 Aggregate Time, Extracted 8-23-06 ** Verispan, Physician Drug and Diagnosis Audit (PDDA), Years 2004 - June 2006, Extracted 8-23-06

27. Anti-Infective Drugs Advisory Committee Meeting September 12, 2006 27 Selected case descriptions 37 yo M completed 5 d treatment for sinusitis/bronchitis. On day 6: morbilliform rash, sore throat, periorbital swelling, fever; hospitalized and received antihistamine therapy. Dx dermatitis medicamentosus 40 yo M after one dose for sinusitis: anaphylaxis with difficulty breathing, rash, facial and oral swelling, cough, dyspnea, hives, light headed; treated in ER with epinephrine, antihistamines, prednisone 44 yo M completed 5 d treatment for sinusitis; day 6: dyspnea, trouble swallowing, confusion, progressive macular rash; hospitalized and treated with IV steroid and antihistamine 20s F, one day after completing 5 day treatment for unspecified respiratory tract infection, was hospitalized for rash. Treatment and outcome = ?. 37 yo M completed 5 d treatment for sinusitis/bronchitis. On day 6: morbilliform rash, sore throat, periorbital swelling, fever; hospitalized and received antihistamine therapy. Dx dermatitis medicamentosus 40 yo M after one dose for sinusitis: anaphylaxis with difficulty breathing, rash, facial and oral swelling, cough, dyspnea, hives, light headed; treated in ER with epinephrine, antihistamines, prednisone 44 yo M completed 5 d treatment for sinusitis; day 6: dyspnea, trouble swallowing, confusion, progressive macular rash; hospitalized and treated with IV steroid and antihistamine 20s F, one day after completing 5 day treatment for unspecified respiratory tract infection, was hospitalized for rash. Treatment and outcome = ?.

28. Anti-Infective Drugs Advisory Committee Meeting September 12, 2006 28 U.S. AERS reports of serious cutaneous events per million PDDA occurrences, by drug (as of 8/2/06) Drug Possible SJS Serious allergic rash Other serious skin All serious skin Gemifloxacin2.53.45.111.0 Cefditoren02.10

29. Anti-Infective Drugs Advisory Committee Meeting September 12, 2006 29 Addendum review of AERS serious skin reports: Comments In the postmarketing environment, as in the clinical trials, gemifloxacin is associated with serious skin adverse events –Serious allergic responses with cutaneous manifestations –Rashes requiring hospital treatment (even without meeting criteria for SJS or TEN) –Possible SJS cases? Many reports lacked critical clinical information that might have permitted more definitive classification In the postmarketing environment, as in the clinical trials, gemifloxacin is associated with serious skin adverse events –Serious allergic responses with cutaneous manifestations –Rashes requiring hospital treatment (even without meeting criteria for SJS or TEN) –Possible SJS cases? Many reports lacked critical clinical information that might have permitted more definitive classification

30. Anti-Infective Drugs Advisory Committee Meeting September 12, 2006 30 Addendum review of AERS serious skin reports: Comments, cont. Serious skin events in the U.S. were reported at a higher rate for gemifloxacin than for the comparator drug cefditoren, in both the initial crude reporting rate analysis and the analysis following individual case review Such comparisons must be made very cautiously because of uncertainties in both the numerator and denominator Serious skin events in the U.S. were reported at a higher rate for gemifloxacin than for the comparator drug cefditoren, in both the initial crude reporting rate analysis and the analysis following individual case review Such comparisons must be made very cautiously because of uncertainties in both the numerator and denominator

31. Anti-Infective Drugs Advisory Committee Meeting September 12, 2006 31 Review of Postmarketing Data for Gemifloxacin: Conclusions Cefditoren has been marketed in Japan since 1994 and has been associated with SJS and TEN in foreign postmarketing data Slightly more U.S. patients have used cefditoren compared to gemifloxacin Thus, absence of U.S. reports of definite SJS/TEN with gemifloxacin provides only limited reassurance, given similar absence of U.S. reports for cefditoren to date Cefditoren has been marketed in Japan since 1994 and has been associated with SJS and TEN in foreign postmarketing data Slightly more U.S. patients have used cefditoren compared to gemifloxacin Thus, absence of U.S. reports of definite SJS/TEN with gemifloxacin provides only limited reassurance, given similar absence of U.S. reports for cefditoren to date

32. Anti-Infective Drugs Advisory Committee Meeting September 12, 2006 32 Review of Postmarketing Data for Gemifloxacin: Conclusions ~ 1 mil or fewer patients exposed to gemifloxacin to date Because of short duration of exposure with a typical course of treatment, even a single case of SJS would be more than expected ~ 1 mil or fewer patients exposed to gemifloxacin to date Because of short duration of exposure with a typical course of treatment, even a single case of SJS would be more than expected

33. Anti-Infective Drugs Advisory Committee Meeting September 12, 2006 33 ConclusionsConclusions Important adverse events associated with gemifloxacin in the postmarketing environment thus far include: –Serious allergic reactions –Clostridium colitis –Rashes which require hospitalization –Others SJS? Increased INR with coumadin? Thrombocytopenia? Important adverse events associated with gemifloxacin in the postmarketing environment thus far include: –Serious allergic reactions –Clostridium colitis –Rashes which require hospitalization –Others SJS? Increased INR with coumadin? Thrombocytopenia?

34. Anti-Infective Drugs Advisory Committee Meeting September 12, 2006 34 Conclusions continued Post-marketing data do not give us assurance that our concerns regarding cutaneous toxicity should be any less when larger patient populations are exposed. The magnitude of the benefit gained from the use of gemifloxacin for the indication under discussion (Acute Bacterial Sinusitis) needs to be clearly defined to weigh against the magnitude of this risk associated with gemifloxacin. Post-marketing data do not give us assurance that our concerns regarding cutaneous toxicity should be any less when larger patient populations are exposed. The magnitude of the benefit gained from the use of gemifloxacin for the indication under discussion (Acute Bacterial Sinusitis) needs to be clearly defined to weigh against the magnitude of this risk associated with gemifloxacin.

35. Anti-Infective Drugs Advisory Committee Meeting September 12, 2006 35 AcknowledgementsAcknowledgements Evelyn R. Farinas, R.Ph., M.G.A. Melissa Truffa, R.Ph. Syed Rizwanuddin Ahmad, M.D., M.P.H. Allen Brinker, M.D., M.S. Lois La Grenade, M.D., M.P.H. Brenda Marques, Pharm.D. Laura A. Governale, Pharm.D., MBA Vicky Borders-Hemphill, Pharm.D. Carol Pamer, R.Ph. Rosemary Johann-Liang, M.D. Evelyn R. Farinas, R.Ph., M.G.A. Melissa Truffa, R.Ph. Syed Rizwanuddin Ahmad, M.D., M.P.H. Allen Brinker, M.D., M.S. Lois La Grenade, M.D., M.P.H. Brenda Marques, Pharm.D. Laura A. Governale, Pharm.D., MBA Vicky Borders-Hemphill, Pharm.D. Carol Pamer, R.Ph. Rosemary Johann-Liang, M.D.