1. Risk Assessment / Risk Management of EXANTA ® (ximelagatran) Liver Injury Kate Gelperin, M.D., M.P.H. Medical Officer Division of Drug Risk Evaluation Office of Drug Safety September 10, 2004 Kate Gelperin, M.D., M.P.H. Medical Officer Division of Drug Risk Evaluation Office of Drug Safety September 10, 2004 Center for Drug Evaluation and Research

2. Cardiovascular and Renal Drugs Advisory Committee September 10, 2004 2 Overview Assessment of risk of severe or fatal liver injury with ximelagatran Evaluation of sponsor’s proposed Risk Management Plan Brief regulatory history: risk management of hepatotoxic drugs Assessment of risk of severe or fatal liver injury with ximelagatran Evaluation of sponsor’s proposed Risk Management Plan Brief regulatory history: risk management of hepatotoxic drugs

3. Cardiovascular and Renal Drugs Advisory Committee September 10, 2004 3 Relationship Between Risk Assessment and Risk Management Risk Management Plan must address specific risks and have clear goals Ximelagatran risk may differ for Short term exposure Long term exposure Risk Management Plan must address specific risks and have clear goals Ximelagatran risk may differ for Short term exposure Long term exposure

4. Cardiovascular and Renal Drugs Advisory Committee September 10, 2004 4 Proposed Indications & Exposures Short term use after TKR –Duration: 7 – 12 days Long term use for atrial fibrillation or 2° prevention VTE –Duration: months - years Short term use after TKR –Duration: 7 – 12 days Long term use for atrial fibrillation or 2° prevention VTE –Duration: months - years

5. Cardiovascular and Renal Drugs Advisory Committee September 10, 2004 5 Definition of Severe Liver Injury Used in This Review Concurrent increase of total bilirubin (TBL) >2x ULN within 30 days of alanine aminotransferase (ALT) >3x ULN Concurrent increase of total bilirubin (TBL) >2x ULN within 30 days of alanine aminotransferase (ALT) >3x ULN

6. Cardiovascular and Renal Drugs Advisory Committee September 10, 2004 6 Identified Liver Related Risks Short Term Use Mild liver injury pattern in surgical population; potential delayed injury? Potential for extension of use beyond 12 days in some surgical patients with higher risk of thromboembolic complications Mild liver injury pattern in surgical population; potential delayed injury? Potential for extension of use beyond 12 days in some surgical patients with higher risk of thromboembolic complications

7. Cardiovascular and Renal Drugs Advisory Committee September 10, 2004 7 Identified Liver Related Risks Long Term Use Mean ximelagatran exposure in Long Term Experience (LTE) population = 357 days Substantial risk of severe liver injury seen in LTE population 1 in 200 ximelagatran-treated patients (0.5%) experienced severe liver injury Fatal liver injuries also occurred Mean ximelagatran exposure in Long Term Experience (LTE) population = 357 days Substantial risk of severe liver injury seen in LTE population 1 in 200 ximelagatran-treated patients (0.5%) experienced severe liver injury Fatal liver injuries also occurred

8. Cardiovascular and Renal Drugs Advisory Committee September 10, 2004 8 Ximelagatran Severe Liver Injury in LTE Trials 37/6948 (0.5%) ximelagatran group versus 5/6230 (0.08%) comparator Relative risk 6.6 (95% CI 2.6 – 16.9) 37/6948 (0.5%) ximelagatran group versus 5/6230 (0.08%) comparator Relative risk 6.6 (95% CI 2.6 – 16.9)

9. Cardiovascular and Renal Drugs Advisory Committee September 10, 2004 9 Other Data Cuts Still Show Significant Relative Risk Relative risk for drug-related cases including less severe liver injury cases (ALT >3x ULN with TBL >1.5x ULN) is significant: –45/6948 ximelagatran group vs. 5/6230 comparator –Relative risk 8.1 (95% CI 3.2 – 20.3) Relative risk for drug-related cases including less severe liver injury cases (ALT >3x ULN with TBL >1.5x ULN) is significant: –45/6948 ximelagatran group vs. 5/6230 comparator –Relative risk 8.1 (95% CI 3.2 – 20.3)

10. Cardiovascular and Renal Drugs Advisory Committee September 10, 2004 10 Time-To-Event Analysis ALT >3x ULN (LTE Pool)

11. Cardiovascular and Renal Drugs Advisory Committee September 10, 2004 11 Initial Signs of Liver Injury in Ximelagatran-treated LTE Patients Who Developed Severe Injury Days to ALT >3x ULN Cases (N)Related Cases (N) 1-711 8-1510 16-3043 31-4544 46-90117 >90164 Total3719

12. Cardiovascular and Renal Drugs Advisory Committee September 10, 2004 12 Sponsor Attribution of Severe Liver Injury Cases Causally related: 19/6948 ximelagatran group versus 2/6230 comparator Relative risk 8.5 (95% CI 2.0 – 36.6) Causally related: 19/6948 ximelagatran group versus 2/6230 comparator Relative risk 8.5 (95% CI 2.0 – 36.6)

13. Cardiovascular and Renal Drugs Advisory Committee September 10, 2004 13 Severe Liver Injury Cases Compliance and Tempo of Injury Compliance 14/36 patients (39%) failed to discontinue study drug as specified in algorithm Rapid tempo of liver injury In some cases: –near normal ALT rose to very high levels in <30 days –rise of bilirubin occurred after stopping drug Compliance 14/36 patients (39%) failed to discontinue study drug as specified in algorithm Rapid tempo of liver injury In some cases: –near normal ALT rose to very high levels in <30 days –rise of bilirubin occurred after stopping drug

14. Cardiovascular and Renal Drugs Advisory Committee September 10, 2004 14 Fatal Liver Injury Case

15. Cardiovascular and Renal Drugs Advisory Committee September 10, 2004 15 “Hy’s Law” Instances (even very few of them) of transaminase elevation accompanied by elevated bilirubin (even if obvious jaundice was not present) have been associated with, and have often predicted, post- marketing serious liver injuries (fatal or requiring transplant) 1 No evidence of biliary obstruction 1 Zimmerman HJ. Drug-induced liver disease. In: Hepatotoxicity The Adverse Effects of Drugs and Other Chemicals on the Liver. Appleton-Century-Crofts, New York, 1978, 1999. Instances (even very few of them) of transaminase elevation accompanied by elevated bilirubin (even if obvious jaundice was not present) have been associated with, and have often predicted, post- marketing serious liver injuries (fatal or requiring transplant) 1 No evidence of biliary obstruction 1 Zimmerman HJ. Drug-induced liver disease. In: Hepatotoxicity The Adverse Effects of Drugs and Other Chemicals on the Liver. Appleton-Century-Crofts, New York, 1978, 1999.

16. Cardiovascular and Renal Drugs Advisory Committee September 10, 2004 16 “Hy’s Law” Drug-induced hepatocellular jaundice is a serious lesion. Estimated mortality at least 10%. Explanation: hepatocellular injury great enough to interfere with bilirubin excretion must involve a large fraction of the liver cell mass. Drug-induced hepatocellular jaundice is a serious lesion. Estimated mortality at least 10%. Explanation: hepatocellular injury great enough to interfere with bilirubin excretion must involve a large fraction of the liver cell mass.

17. Cardiovascular and Renal Drugs Advisory Committee September 10, 2004 17 Projected Severe Liver Injury Based on LTE Trials Assumes monitoring compliance in controlled trials as “best case”, so expected rate ≥0.5% For 100,000 similar patients who receive one year of ximelagatran treatment: –500 patients will develop severe liver injury –≥10% (or 50 patients) likely to progress to liver failure, transplant, or death Consistent with this prediction, three liver related deaths were noted in long term trials = one fatal liver injury in 2,300 patients Assumes monitoring compliance in controlled trials as “best case”, so expected rate ≥0.5% For 100,000 similar patients who receive one year of ximelagatran treatment: –500 patients will develop severe liver injury –≥10% (or 50 patients) likely to progress to liver failure, transplant, or death Consistent with this prediction, three liver related deaths were noted in long term trials = one fatal liver injury in 2,300 patients

18. Cardiovascular and Renal Drugs Advisory Committee September 10, 2004 18 Categories of RiskMAP Tools Targeted education and outreach –educational materials for HCP and/or patients Reminder systems –stickers, informed consent, limited supply Performance-Linked Access Systems (PLAS) –selected groups able to prescribe, dispense, use –often mandatory use of reminder-like systems Targeted education and outreach –educational materials for HCP and/or patients Reminder systems –stickers, informed consent, limited supply Performance-Linked Access Systems (PLAS) –selected groups able to prescribe, dispense, use –often mandatory use of reminder-like systems

19. Cardiovascular and Renal Drugs Advisory Committee September 10, 2004 19 Sponsor’s Proposed RMP Short term use: –No RMP proposed by sponsor for short term use –Assumes intended treatment duration not to exceed 12 days Long term use: –RMP comprised of baseline and monthly serum ALT monitoring based on algorithms used in LTE trials –Algorithm was changed due to occurrence of fatal liver failure during clinical program Short term use: –No RMP proposed by sponsor for short term use –Assumes intended treatment duration not to exceed 12 days Long term use: –RMP comprised of baseline and monthly serum ALT monitoring based on algorithms used in LTE trials –Algorithm was changed due to occurrence of fatal liver failure during clinical program

20. Cardiovascular and Renal Drugs Advisory Committee September 10, 2004 20 Sponsor’s Proposed RMP for Long Term Use Baseline ALT; if <2x ULN, may initiate drug Monthly ALT –If <2x ULN, continue to screen monthly for 6 months and periodically thereafter –If >2x ULN, monitor ALT weekly; stop drug if: ALT >3x ULN after 4 weeks ALT >5x ULN at anytime Symptoms of hepatic injury (e.g. jaundice w/o obvious cause) Baseline ALT; if <2x ULN, may initiate drug Monthly ALT –If <2x ULN, continue to screen monthly for 6 months and periodically thereafter –If >2x ULN, monitor ALT weekly; stop drug if: ALT >3x ULN after 4 weeks ALT >5x ULN at anytime Symptoms of hepatic injury (e.g. jaundice w/o obvious cause)

21. Cardiovascular and Renal Drugs Advisory Committee September 10, 2004 21 Sponsor’s Proposed Monitoring RMP for Long Term Use Success of RMP Based on assumption that progression to severe injury can be minimized by monitoring ALT at a specified interval. Must consider: 1.Tempo of liver injury 2.Compliance with monitoring < 100% 3.Reversibility of injury if drug stopped. Success of RMP Based on assumption that progression to severe injury can be minimized by monitoring ALT at a specified interval. Must consider: 1.Tempo of liver injury 2.Compliance with monitoring < 100% 3.Reversibility of injury if drug stopped.

22. Cardiovascular and Renal Drugs Advisory Committee September 10, 2004 22 Sponsor’s Proposed Monitoring RMP for Long Term Use Observed compliance with ALT monitoring in clinical trials reflects “best” case performance. In practice, expect lower compliance. Anticipate that rate of severe liver injury postmarketing would be similar to or higher than rate observed in LTE trials. Observed compliance with ALT monitoring in clinical trials reflects “best” case performance. In practice, expect lower compliance. Anticipate that rate of severe liver injury postmarketing would be similar to or higher than rate observed in LTE trials.

23. Cardiovascular and Renal Drugs Advisory Committee September 10, 2004 23 FDA Experience with Hepatotoxins FDA experience with drugs that cause idiosyncratic liver injury –Currently no RM tools proven to prevent the risk for rapidly progressive severe injury Caveat: limiting the usage of the drug on a population basis has been associated with a marked decrease in reports of liver failure postmarketing (e.g., trovafloxacin, pemoline) FDA experience with drugs that cause idiosyncratic liver injury –Currently no RM tools proven to prevent the risk for rapidly progressive severe injury Caveat: limiting the usage of the drug on a population basis has been associated with a marked decrease in reports of liver failure postmarketing (e.g., trovafloxacin, pemoline)

24. Cardiovascular and Renal Drugs Advisory Committee September 10, 2004 24 REZULIN ® (troglitazone) Rapidly Progressive Liver Injury In response to reports of liver failure received after approval in 1997, several “Dear HCP” letters warned about severe liver injury and recommended monthly transaminase monitoring. Despite this, monthly monitoring was not regularly performed (~5% compliance rate) Troglitazone was withdrawn from the US market in March 2000, after 94 cases of drug-induced liver failure had been reported. In response to reports of liver failure received after approval in 1997, several “Dear HCP” letters warned about severe liver injury and recommended monthly transaminase monitoring. Despite this, monthly monitoring was not regularly performed (~5% compliance rate) Troglitazone was withdrawn from the US market in March 2000, after 94 cases of drug-induced liver failure had been reported.

25. Cardiovascular and Renal Drugs Advisory Committee September 10, 2004 25 REZULIN ® (troglitazone) Rapidly Progressive Liver Injury FDA analysis of 94 reports of liver failure: Progression to irreversible liver injury occurred within less than one month interval in 19 patients. Casts doubt on the value of monthly monitoring. A key issue in effective intervention to prevent fatal liver injury is “recoverability” at time of sign or symptom onset. FDA analysis of 94 reports of liver failure: Progression to irreversible liver injury occurred within less than one month interval in 19 patients. Casts doubt on the value of monthly monitoring. A key issue in effective intervention to prevent fatal liver injury is “recoverability” at time of sign or symptom onset.

26. Cardiovascular and Renal Drugs Advisory Committee September 10, 2004 26 “Hy’s Law” with REZULIN ® In the NDA database (n=2510): –No cases of liver failure –1.9% had ALT >3x ULN, –0.2% (5 patients) had ALT >30x ULN (two with jaundice). Consideration of marketed experience with troglitazone may be relevant to risk assessment of ximelagatran. In the NDA database (n=2510): –No cases of liver failure –1.9% had ALT >3x ULN, –0.2% (5 patients) had ALT >30x ULN (two with jaundice). Consideration of marketed experience with troglitazone may be relevant to risk assessment of ximelagatran.

27. Cardiovascular and Renal Drugs Advisory Committee September 10, 2004 27 DURACT ® (bromfenac) Extended Use Despite Labeling for Short Term Use Approved July ‘97 for short term use but withdrawn June ‘98 due to reports of liver failure Single dose acute pain studies (n=1000) and 1-week studies (n=500): no safety concerns –0.4% ALT >3x ULN Chronic OA and RA studies (n=830): –2.8% ALT >3x ULN –0.5% ALT >8x ULN Approved July ‘97 for short term use but withdrawn June ‘98 due to reports of liver failure Single dose acute pain studies (n=1000) and 1-week studies (n=500): no safety concerns –0.4% ALT >3x ULN Chronic OA and RA studies (n=830): –2.8% ALT >3x ULN –0.5% ALT >8x ULN

28. Cardiovascular and Renal Drugs Advisory Committee September 10, 2004 28 DURACT ® (bromfenac) Postmarketing Reports Rx recommended 4 weeks 12 deaths and/or liver transplants, all but one with >10 days use Black Box Warning and Dear HCP did not prevent extended periods of use with unacceptable level of severe liver injury Rx recommended 4 weeks 12 deaths and/or liver transplants, all but one with >10 days use Black Box Warning and Dear HCP did not prevent extended periods of use with unacceptable level of severe liver injury

29. Cardiovascular and Renal Drugs Advisory Committee September 10, 2004 29 Track Record: Transaminase Monitoring Generally, the effectiveness of transaminase monitoring in preventing severe drug-induced liver injury has not been convincingly demonstrated. Rapid acceleration of liver injury in some individuals limits protective value of standardized periodic transaminase monitoring. Requirement: time interval between onset of liver chemistry abnormality and subsequent liver injury must exceed the screening interval. Generally, the effectiveness of transaminase monitoring in preventing severe drug-induced liver injury has not been convincingly demonstrated. Rapid acceleration of liver injury in some individuals limits protective value of standardized periodic transaminase monitoring. Requirement: time interval between onset of liver chemistry abnormality and subsequent liver injury must exceed the screening interval.

30. Cardiovascular and Renal Drugs Advisory Committee September 10, 2004 30 Proposed RiskMAP Summary Concern: unlikely that long term hepatotoxicity risk will be adequately minimized by sponsor’s proposed RMP of monitoring. Sponsor has not demonstrated that: –Compliance with monitoring postmarketing would protect patients. –Even if full compliance achieved, that ALT monitoring can prevent serious liver injury with this drug. Sponsor has not proposed a strategy to prevent prolonged use after total knee replacement. Concern: unlikely that long term hepatotoxicity risk will be adequately minimized by sponsor’s proposed RMP of monitoring. Sponsor has not demonstrated that: –Compliance with monitoring postmarketing would protect patients. –Even if full compliance achieved, that ALT monitoring can prevent serious liver injury with this drug. Sponsor has not proposed a strategy to prevent prolonged use after total knee replacement.

31. Cardiovascular and Renal Drugs Advisory Committee September 10, 2004 31 ConclusionsConclusions Ximelagatran can cause severe, and even fatal liver injury in some patients Initial signs in patients who developed severe liver injury were noted during the first month of ximelagatran use in 6 LTE patients Ability of transaminase monitoring to minimize risk of severe or fatal liver injury remains unproven for ximelagatran Ximelagatran can cause severe, and even fatal liver injury in some patients Initial signs in patients who developed severe liver injury were noted during the first month of ximelagatran use in 6 LTE patients Ability of transaminase monitoring to minimize risk of severe or fatal liver injury remains unproven for ximelagatran

32. Cardiovascular and Renal Drugs Advisory Committee September 10, 2004 32 AcknowledgementsAcknowledgements ODS Review Team –Mark Avigan, MD, CM, Director, Division of Drug Risk Evaluation –Jeanine Best, RN, PNP, Patient Product Information Specialist –Allen Brinker, MD, MPH, Epidemiologist Team Leader –Gerald Dal Pan, MD, MHS, Director, Division of Surveillance, Research and Communication Support (DSRCS) –Mary Dempsey, Project Management Officer –Claudia Karwoski, PharmD, Scientific Coordinator of RMP –Quynh Nguyen, PharmD, Project Manager –David Moeney, RPh, Drug Use Specialist –Toni Piazza-Hepp, PharmD, Deputy Director, DSRCS –John Senior, MD, Hepatology Expert, OPaSS –Judy Staffa, PhD, RPh, Epidemiology Team Leader –Anne Trontell, MD, MPH, Deputy Director, Office of Drug Safety –Leslie Wheelock, MS, RN, Associate Director, DSRCS ODS Review Team –Mark Avigan, MD, CM, Director, Division of Drug Risk Evaluation –Jeanine Best, RN, PNP, Patient Product Information Specialist –Allen Brinker, MD, MPH, Epidemiologist Team Leader –Gerald Dal Pan, MD, MHS, Director, Division of Surveillance, Research and Communication Support (DSRCS) –Mary Dempsey, Project Management Officer –Claudia Karwoski, PharmD, Scientific Coordinator of RMP –Quynh Nguyen, PharmD, Project Manager –David Moeney, RPh, Drug Use Specialist –Toni Piazza-Hepp, PharmD, Deputy Director, DSRCS –John Senior, MD, Hepatology Expert, OPaSS –Judy Staffa, PhD, RPh, Epidemiology Team Leader –Anne Trontell, MD, MPH, Deputy Director, Office of Drug Safety –Leslie Wheelock, MS, RN, Associate Director, DSRCS