# Presentation: 511678

## Telithromycin-Associated Hepatotoxicity

**Allen Brinker, MD, MS**
**Epidemiology Team Leader**
**Division of Drug Risk Evaluation (DDRE)**
**Office of Surveillance and Epidemiology (OSE)**

## Telithromycin-Associated Acute Liver Failure (ALF) and Clinically Significant Liver Injury

**Outline of Speakers**
**Allen Brinker, MD (FDA)**
**Case material / DDRE signal assessment**
**Leonard Seeff, MD**
**Expert Consultant for FDA**
**Principles of ALF causality assessment**
**William Lee, MD**
**Expert Consultant for FDA**
**Telithromycin ALF causality assessment**

## Telithromycin-Associated ALFOverview

**Summarize DDRE review**
**Methods**
**spontaneous adverse event (MedWatch) reports**
**Analysis of cases**
**Pharmacoepidemiology**
**Reporting rates**
**Two supporting ALF reporting rate analyses**
**Telithromycin ALF reporting rate analysis**
**Conclusions and status as of September 2006**

## Summary of DDRE AnalysisTelithromycin-Associated ALF

**Spectrum of injury**
**Per FDA review, 12 cases of telithromycin-associated ALF “clinically remarkable”**
**Short time-to-onset (median 4 days)**
**One case following first dose**
**Profound hepatic injury**
**4 deaths**
**1 transplant**
**Patients appeared healthy and with few confounding factors**

## Summary of DDRE AnalysisTelithromycin-Associated ALF

**Reporting rate for telithromycin-associated ALF similar ALF reporting rates for selected comparators (moxi-, gatifloxacin) given variation inherent in spontaneous adverse event reporting**

## Summary of DDRE AnalysisTelithromycin-Associated ALF

**Recommended regulatory actions consistent with actions advanced for the fluoroquinolones**
***Review of this analysis included***
**DDRE recommendations realized with addition of WARNING for ALF within approved labeling for telithromycin - June 2006**

## Summary of DDRE AnalysisTelithromycin-Associated ALF

**Set a reporting rate level (bar) for further regulatory action for telithromycin**
**based on experience with trovafloxacin-associated ALF**
***Review of this analysis included***

## MethodsSpontaneous Adverse Event Reports

##      Spontaneous Adverse Event Reports

**“****MedWatch reports”**
**Designed to detect**
**Rare**
**Serious**
**Unexpected**
**Substantial variation in quality and information report to report**

## Spontaneous Adverse Event Reports

**Fraction of incident adverse events attributable to a selected drug AND reported is unknown**
**Estimates of 1% to 10% commonly cited**
**These are likely to be overestimates**
**Assume variation between products**

## Spontaneous Adverse Event Reports

**Three DDRE reviews of antibiotic-associated ALF**
**Separated in time and by authors**
**Utilized generally similar case definitions**
**Totality of information could not exclude telithromycin as a factor in liver injury**
**Typical for FDA case series**
**Inclusion “case” criteria**
**Exclusion “confounding” criteria**

## DDRE review of telithromycin-Associated ALF

**Conducted January - May 2006**
**Ron Wassel and Allen Brinker**
**Telithromycin market appearance - July 2004**

## DDRE Review of Telithromycin-Associated ALF

**Ongoing review**
**Initial review (June 2005)**
**Continued monitoring**
***Annals of Internal Medicine***
**January 2006**
**Three patients who experienced serious liver toxicity following administration of telithromycin**
**Concern for hepatotoxicity observed in controlled clinical trials**

## DDRE Review of Telithromycin-Associated ALF

**Identified cases of:**
**Acute Liver Failure (ALF)**
**Acute Serious Liver Injury (ASLI)**

## DDRE review of telithromycin-associated ALF

**Acute Liver Failure (ALF)  defined as a report describing:**
**diagnosis of acute “liver failure,” or**
**acute and severe liver injury with encephalopathy, or**
**liver transplant following acute illness, or**
**death in the setting of acute severe liver injury**

## DDRE Review of Telithromycin-Associated ALF

**Acute Serious Liver Injury (ASLI) defined as a report of:**
**hepatic transaminase elevations, or**
**hyperbilirubinemia, or**
**clinical jaundice**
**leading to hospitalization**

## DDRE Review of Telithromycin-Associated ALF

**Exclusion criteria included:**
**“****Hearsay” reports**
**Infectious hepatitis**
**Sepsis**
**Pancreatitis**
**Rhabdomyolysis**
**Cancer**
**Selected concomitant therapies**

## DDRE Review of Telithromycin-Associated ALF

**110 unduplicated, domestic reports of liver injury in association with telithromycin**
**Excluded 31 as confounded or hearsay reports**
**Excluded 44 as minor liver injury**
**23 cases of Acute Serious Liver Injury**
**12 cases of Acute Liver Failure**

## DDRE Review of Telithromycin-Associated ALF

**Causality assessment project**
**2 FDA + 3 expert consultants**
**Review of 109 unduplicated, domestic reports of liver injury with telithromycin by Seeff**
**38 cases as very likely, possible or probable**
**12 cases “ALF” or “ASLI” per DDRE review**
**3 cases from DILIN network**
**Reviewed 53 cases in total**

## Slide 20

| Clinical characteristics of domestic (US) ALF cases (n=12) reported in association with telithromycin  (through April 2006) |  |
| --- | --- |
| Age | Median—52 years
Range—26 to 85 years |
| Gender  | Female (9), Male (3)  |
| Indication for use (verbatim from report)  | Sinusitis—5
Pneumonia—2
URI—2
Bronchitis/pneumonia—1
Bronchitis—1
RTI—1 |

## Slide 21

| Clinical characteristics of domestic (US) ALF cases (n=12) reported in association with telithromycin  through April 2006.  |  |
| --- | --- |
| continued |  |
| Latency (time to onset of symptoms from initiation of treatment)  | Median—4 days 
Range—1 to 20 days |
| Jaundice reported at Dx  | 8  |
| Highest reported bilirubin (mg/dL) | Median—18.3
Range—1.7 to 24.3 |
| Highest reported AST (IU/L) | Median—3638
Range—812 to 34,423 |
| Highest reported ALT (IU/L) | Median—2489
Range—833 to 19,888 |
| Death / transplant  | 4 / 1  |

## DDRE Review of Telithromycin-Associated ALF

**AERS # 4892304-3****	****	****51 year old female**
**	****	****	****	****	****(North Carolina)**
**PMHx-Non significant; Current meds-ASA, MVit, Vit E**
**no prior hx of liver disease**
**social drinker (up to 2-3 glasses wine/day)**
**	****Received telithromycin after presentation to her PCP with 2 wk h/o symptoms c/w URI. Developed icterus and elevated liver enzymes, bilirubin, and PT 7 days after initiation of therapy with telithromycin; alk phos only mildly elevated. Negative for hepatitis A, B, and C.  Abdominal US that showed a small, echogenic liver with ascites. One month later bili increased; listed for liver transplant. Subsequently pt readmitted with systemic symptoms and underwent liver transplant.  Explanted liver was small and remarkable for massive necrosis on histologic examination.**
****As published within: Clay KD, Hanson JS, Pope SD, et al. Brief communication: severe hepatotoxicity of telithromycin: three case reports and literature review. Ann Intern Med 2006;144(6):415-20.**

## DDRE Review of Telithromycin-Associated ALF

## DDRE Review of Telithromycin-Associated ALF

**Case material sufficient for addition of serious liver injury including ALF to telithromycin label**
**What is risk compared to similar agents?**
**Reporting rates**
**Two supporting analyses**

## Pharmacoepidemiology

**Reporting rates**
**Drug-against-drug comparisons**
**Observed versus expected comparisons**

## Pharmacoepidemiology

**Reporting rates calculated as:**
**	****	****	****Spontaneous cases of selected event**
**	****	****	****-----------------------------------------------------------**
**	****	****	****exposure or utilization**
**Expressed as:**
**Cases per million Rx, per 10 million Rx**
**Incidence density (cases per unit person-time)**
**Typically restricted to cases that arise during oral (ambulatory) therapy.**

## Pharmacoepidemiology

**Spontaneous reports data offer limited insight into population risk**
**Reporting rates are not incidence rates**
**Have been used in addition to other data to support previous regulatory actions by the agency**
**Large differences in reporting rate ratios may support differential in risk**

## Pharmacoepidemiology

**Drug-against-drug reporting rate comparisons require very similar drug products**
**time on market**
**Assumption that reporting practices are similar for similar drug products over the observed reporting period.**

## Relevant Case Studies Including Reporting Rate Comparisons and Regulatory Recommendations

**ALF in association with trovafloxacin**
**ALF in association with moxifloxacin, gatifloxacin, and levofloxacin**

## Acute Liver Failure in Association with Trovafloxacin 

**July 1999**
**David Graham and Sarah Singer**
**Analysis included drug-against-drug reporting rate comparisons**
**trovafloxacin**
**levofloxacin**

## ALF in Association with Trovafloxacin: Reporting Rate Analysis

| 
Drug | US market
appear-ance | US
cases | Onset  
median (days) | Rxs*
(in millions) | Reporting
rate
(per 10 million Rx) |
| --- | --- | --- | --- | --- | --- |
| 
Levo | Jan 
1997 | 
1 | 
--- | 
6.868 | 
1.5 |
| 
Trova | Jan
1998 | 
12 | 
25 | 
2.073 | 
58 |

- *IMS Health, National Prescription Audit PlusTM, Years 1997 and 1998, Hardcopy book.

## Acute Liver Failure in Association with Trovafloxacin

**Absolute ratio in case counts**
**12:1**
**Adjusted ratio in case counts**
**	****(reporting rate ratio)**
**39:1**

## Acute Liver Failure in Association with Trovafloxacin

**Regulatory action: June 1999**
**Trovafloxacin restricted to initial therapy for in-hospital use for treatment of life and limb-threatening infections**

## Acute Liver Failure in Association with Moxifloxacin, Gatifloxacin, and Levofloxacin 

**August 2004**
**Sarah Singer and Allen Brinker**
**Analysis included drug-against-drug reporting rate comparisons**
**levofloxacin**
**moxifloxacin**
**gatifloxacin**

## ALF with Moxi-, Gati-, and Levofloxacin:Reporting Rate Comparison

| 
Drug | US market appear-ance | US
Cases | Onset
median
(days) | Rxs*
(millions) | Reporting rate
(cases per 10 mil Rx) |
| --- | --- | --- | --- | --- | --- |
| Levo | Jan
1997 | 12 | 7.0 | 57.436 | 2.1 |
| Gati | Dec 1999 | 6 | 4.0 | 10.068 | 6.0 |
| Moxi | Dec 1999 | 5 | 2.5 | 7.563 | 6.6 |

- IMS Health, National Prescription Audit *Plus*TM, Years 1997 through September 2003, extracted July 2004.

## Acute Liver Failure in Association with Moxifloxacin, Gatifloxacin, and Levofloxacin 

**Absolute ratio in case counts**
**About 2:1**
**Adjusted ratio in case counts**
**	****(reporting rate ratio)**
**About 3:1**

## Acute Liver Failure in Association with Moxifloxacin, Gatifloxacin, and Levofloxacin 

**Observed ALF reporting rates for these three agents appeared similar**
**DDRE recommended addition of ALF as a WARNING within product labeling for all fluoroquinolones**

## Telithromycin-Associated ALF:Reporting Rate Comparison

| 
Drug | US market appear-ance | US
Cases | Onset
Median
(days) | Rxs
(in
millions) | Reporting rate
(Per 10 million Rx) |
| --- | --- | --- | --- | --- | --- |
| Gati | Dec 99 | 6 | 4.0 | 10.068* | 6.0 |
| Moxi | Dec 99 | 5 | 2.5 | 7.563* | 6.6 |
| Teli | July 04 | 12
(Apr 06) | 4.0 | 5.198** | 23 |

- *IMS Health, National Prescription Audit *Plus*TM, Years 1997 through September 2003, extracted July 2004.
- **Verispan Vector One®:National, months May 2004-April 2006, extracted May 2006.

## DDRE Review of Telithromycin-Associated ALF

**Absolute ratio in case counts**
**About 2:1**
**Adjusted ratio in case counts**
**	****(reporting rate ratio)**
**About 4:1 (April 2006)**

## DDRE Review of Telithromycin-Associated ALF

**Observed reporting rates generally similar**
**Not consistent with trovafloxacin analysis**
**Absolute ratio of case count not ~12:1**
**Adjusted ratio of case count not ~39:1**
**Recommended regulatory actions similar to that advanced for the recent ALF-FQ review**

## DDRE Review of Telithromycin-Associated ALF

**Also noted rising trend in the cumulative telithromycin-ALF reporting rate**
**12 per 10 million Rx through Dec 2005**
**17 per 10 million Rx through February 2006**
**23 per 10 million Rx through April 2006**
**Liver injury was a concern pre-approval**
**to be addressed within Study 3014**

## DDRE Review of Telithromycin-Associated ALF

**DDRE recommended a “bar” for further regulatory actions based on ALF-reporting rate for trovafloxacin (58 per 10 million Rx)**
**Would not wait until:**
**Absolute ratio of case counts ~12:1, or**
**Adjusted ratio of case counts ~39:1**
**As seen with ALF with trovafloxacin**

## DDRE Review of Telithromycin-Associated ALF - Update

**13****th**** case added in 2 QTR 06**
**Reporting rate for telithromycin-associated ALF through September 2006 with:**
**13 cases / 5,650,000 Rx***
**23 per 10 million Rx**
**Unchanged from RR observed in April 2006**

- *Verispan Vector One®:National, months May 2004-September 2006, extracted Nov 2006.

## Sanofi-Aventis Population-Based Epidemiology Studies

**Received completed studies last week    (early December 2006)**
**Pharmetrics**
**i3 drug safety**
**Review ongoing**
**Comments at this time preliminary**

## Sanofi-Aventis Population-Based Epidemiology Studies

**Comments (preliminary)**
**Both studies appear underpowered for both drug-associated ALF and serious liver injury**
**Medical record validation required**
**Done in i3 study; not done in Pharmetrics study**

## Sanofi-Aventis Population-Based Epidemiology Studies

**Comments (preliminary)**
**The point estimate for severe liver injury observed in the i3 study is consistent with an elevated risk for serious liver injury with telithromycin in comparison to clarithromycin.**
**The finding in the i3 study of an elevated risk of serious liver injury with sequential use of telithromycin and clarithromycin **
**deserves attention (further study) but based on 3 cases.**

## DDRE Review of Telithromycin-Associated ALF

**End of**
**Presentation**
**Acknowledgements**
**Jenna Lyndly, RN**
**Ron Wassel, PharmD**
**Melissa Truffa, PharmD**
**Mark Avigan, MD, CM**

## Back-up Slides

- _[Return to agenda](file:///../final%20version%202%20meeting%20slides%20fda,oph,questions%20main.ppt#4. Slide 4)_

## Crude Assessment of Agreement on ALF “Case” Status between 3 Disparate DDRE Reviews of Antibiotic-Associated ALF

| Drug | Crude count
(“serious”) | “Cases” after review | Percent |
| --- | --- | --- | --- |
| Trova | 115 | 14 | 12 |
| Levo | 107 | 19 | 18 |
| Gati | 55 | 9 | 16 |
| Moxi | 49 | 6 | 12 |
| Teli | 66 | 12 | 18 |

## Rx Versus Person-Time Reporting Rate Comparison

**Rx-based comparisons preferred by this reviewer as:**
**1 Rx = 1 Pt (in most cases)**
**Time to onset falls within typical treatment course for most cases**
**Rx-based reporting rates**
**Absolute difference in case counts**
**About 2:1**
**Adjusted difference (reporting rate ratio)**
**About 4:1**

## Rx Versus Person-Time Reporting Rate Comparison

**Person-time reporting rates**
**Transformation based on typical treatment courses of:**
**10 days for moxifloxacin and gatifloxacin**
**5 days for telithromycin**
**Results in incidence density for moxi- or gati associated ALF of ~22 per million person years**
**Results in incidence density for telithromycin-associated ALF of 168 per million person-years**
**Background (expected) rate of idiosyncratic ALF in the general population ~1 per million person-years.**

## Rx Versus Person-Time Reporting Rate Comparison

**Person-time reporting rates**
**Absolute difference in case counts**
**About 2:1 (unchanged)**
**Adjusted difference (incidence ratio)**
**About 8:1 fold (increased from 4:1)**
**Trovafloxacin**
**Absolute difference in case counts:**
**12:1**
**Adjusted difference (reporting rate ratio):**
**39:1**

## Return

**                **_**[Return to agenda](file:///../final%20version%202%20meeting%20slides%20fda,oph,questions%20main.ppt#4. Slide 4)**_