Risk Assessment / Risk Management of EXANTA ® (ximelagatran) Liver Injury Kate Gelperin, M.D.,...

Risk Assessment / Risk Risk Assessment / Risk Management of EXANTAManagement of EXANTA® ®

(ximelagatran) Liver Injury(ximelagatran) Liver Injury

Risk Assessment / Risk Risk Assessment / Risk Management of EXANTAManagement of EXANTA® ®

(ximelagatran) Liver Injury(ximelagatran) Liver Injury

Kate Gelperin, M.D., M.P.H. Kate Gelperin, M.D., M.P.H.

Medical OfficerMedical OfficerDivision of Drug Risk EvaluationDivision of Drug Risk Evaluation

Office of Drug SafetyOffice of Drug SafetySeptember 10, 2004September 10, 2004

Kate Gelperin, M.D., M.P.H. Kate Gelperin, M.D., M.P.H.

Medical OfficerMedical OfficerDivision of Drug Risk EvaluationDivision of Drug Risk Evaluation

Office of Drug SafetyOffice of Drug SafetySeptember 10, 2004September 10, 2004

Center for Drug Evaluation and ResearchCenter for Drug Evaluation and Research

2Cardiovascular and Renal Drugs Advisory Committee Cardiovascular and Renal Drugs Advisory Committee September 10, 2004September 10, 2004

OverviewOverview

• 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


Relationship Between Risk Relationship Between Risk Assessment and Risk Assessment and Risk

ManagementManagement

Relationship Between Risk Relationship Between Risk Assessment and Risk Assessment and Risk

ManagementManagement

• 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


Proposed Indications & ExposuresProposed Indications & ExposuresProposed Indications & ExposuresProposed 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


Definition of Severe Liver Injury Definition of Severe Liver Injury Used in This ReviewUsed in This Review

Definition of Severe Liver Injury Definition of Severe Liver Injury Used in This ReviewUsed 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


Identified Liver Related RisksIdentified Liver Related RisksShort Term UseShort Term Use

Identified Liver Related RisksIdentified Liver Related RisksShort Term UseShort 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


Identified Liver Related RisksIdentified Liver Related RisksLong Term UseLong Term Use

Identified Liver Related RisksIdentified Liver Related RisksLong Term UseLong 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


XimelagatranXimelagatranSevere Liver Injury in LTE TrialsSevere Liver Injury in LTE Trials

XimelagatranXimelagatranSevere Liver Injury in LTE TrialsSevere 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)


Other Data Cuts Still Show Other Data Cuts Still Show Significant Relative RiskSignificant Relative Risk

Other Data Cuts Still Show Other Data Cuts Still Show Significant Relative RiskSignificant 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)


Time-To-Event AnalysisTime-To-Event AnalysisALT >3x ULN (LTE Pool)ALT >3x ULN (LTE Pool)Time-To-Event AnalysisTime-To-Event AnalysisALT >3x ULN (LTE Pool)ALT >3x ULN (LTE Pool)


Initial Signs of Liver Injury in Ximelagatran-treated Initial Signs of Liver Injury in Ximelagatran-treated LTE Patients Who Developed Severe InjuryLTE Patients Who Developed Severe Injury

Initial Signs of Liver Injury in Ximelagatran-treated Initial Signs of Liver Injury in Ximelagatran-treated LTE Patients Who Developed Severe InjuryLTE Patients Who Developed Severe Injury

Days to ALT >3x ULN

Cases (N) Related Cases (N)

1-7 1 1

8-15 1 0

16-30 4 3

31-45 4 4

46-90 11 7

>90 16 4

Total 37 19


Sponsor Attribution of Severe Sponsor Attribution of Severe Liver Injury CasesLiver Injury Cases

Sponsor Attribution of Severe Sponsor Attribution of Severe Liver Injury CasesLiver 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)


Severe Liver Injury CasesSevere Liver Injury CasesCompliance and Tempo of InjuryCompliance and Tempo of Injury

Severe Liver Injury CasesSevere Liver Injury CasesCompliance and Tempo of InjuryCompliance 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


Fatal Liver Injury CaseFatal Liver Injury CaseFatal Liver Injury CaseFatal Liver Injury Case


““Hy’s Law”Hy’s Law”““Hy’s Law”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.


““Hy’s Law”Hy’s Law”““Hy’s Law”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.


Projected Severe Liver Injury Projected Severe Liver Injury Based on LTE TrialsBased on LTE Trials

Projected Severe Liver Injury Projected Severe Liver Injury Based on LTE TrialsBased 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


Categories of RiskMAP ToolsCategories of RiskMAP ToolsCategories of RiskMAP ToolsCategories 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


Sponsor’s Proposed RMPSponsor’s Proposed RMPSponsor’s Proposed RMPSponsor’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


Sponsor’s Proposed RMP for Long Sponsor’s Proposed RMP for Long Term UseTerm Use

Sponsor’s Proposed RMP for Long Sponsor’s Proposed RMP for Long Term UseTerm 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)


Sponsor’s Proposed Monitoring Sponsor’s Proposed Monitoring RMP for Long Term UseRMP 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 injury2. 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 injury2. Compliance with monitoring < 100%3. Reversibility of injury if drug stopped.




• 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.


FDA Experience with HepatotoxinsFDA Experience with HepatotoxinsFDA Experience with HepatotoxinsFDA 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)


REZULINREZULIN®® (troglitazone) (troglitazone)Rapidly Progressive Liver InjuryRapidly 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.




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.


““Hy’s Law” with REZULINHy’s Law” with REZULIN®®““Hy’s Law” with REZULINHy’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.


DURACTDURACT® ® (bromfenac)(bromfenac)Extended Use Despite Labeling for Extended Use Despite Labeling for

Short Term UseShort Term Use

DURACTDURACT® ® (bromfenac)(bromfenac)Extended Use Despite Labeling for Extended Use Despite Labeling for

Short Term UseShort 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


DURACTDURACT®® (bromfenac) (bromfenac)Postmarketing ReportsPostmarketing ReportsDURACTDURACT®® (bromfenac) (bromfenac)Postmarketing ReportsPostmarketing Reports

• Rx recommended <10 days and transaminase monitoring if >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 <10 days and transaminase monitoring if >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


Track Record:Track Record:Transaminase MonitoringTransaminase Monitoring

Track Record:Track Record:Transaminase MonitoringTransaminase 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.


Proposed RiskMAPProposed RiskMAPSummarySummary

Proposed RiskMAPProposed RiskMAPSummarySummary

• 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.


ConclusionsConclusionsConclusionsConclusions

• 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


AcknowledgementsAcknowledgementsAcknowledgementsAcknowledgements

• 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

Risk Assessment / Risk Management of EXANTA ® (ximelagatran) Liver Injury Kate Gelperin, M.D.,...

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