# Presentation: 511679

## Review of post-marketing safety of Factive (gemifloxacin)

- 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)**

## Outline

- 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

**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

## 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)**

## 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**

## 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)**

## Slide 7

## Gemifloxacin AERS data

**Non-cutaneous reports **
**Selected events**
**(As of August 2006)**

## 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**

## 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**

## 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  **

## Events of Interest

**Cardiac events****	****	****	****6**
**Hepatic events****	****	****	****12**
**Clostridium colitis****	****	****10**
**Drug ineffective****	****	****	****31**
**Drug Interactions****	****	****10**
**Thrombocytopenia****	****	**** 3**

## 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**

## 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**

## 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**

## Drug Interactions (n=10)

** **
**7 out of 10 gemifloxacin + warfarin  **
**Increased PT or INR**
**Some with bleeding**
** **

## Gemifloxacin AERS data

**Cutaneous manifestations reports**

## Background 

**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**

## 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**

## 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%*.**

- * Verispan Vector One®: National, 2002-2006, data extracted July-2006

**Notes:**
Clinical trial data found a higher incidence of rash in patients receiving gemifloxacin than
in those receiving comparator antibiotics, and a 2003 Advisory Committee presentation
on gemifloxacin 4 identified female gender, age <40, planned duration of treatment >7
days, and hormone replacement therapy in women >40 years of age as risk factors for
rash development. Postmarketing data from AERS showed the propensity of
gemifloxacin to be associated with cutaneous adverse events predominately in females.
AERS data for gemifloxacin also indicated that the proportions of cutaneous adverse
event reports were greater in the ≤ 40 of age group for both females and males in
comparison to the amount of drug use in that same age bracket.

## 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**
**        **

**Notes:**
Clinical trial data of
cutaneous safety4 showed that 2/3 of rash in gemifloxacin patients began after day 7 of
therapy. However, in our postmarketing analyses, time-to-event was shorter with AERS
reports of cutaneous events coded as rash having a median time-to-event onset at 4 days.
One-quarter and 1/3 of the serious skin adverse event reports listed previous
fluoroquinolone use or history of drug allergy, respectively. Further, many of the serious
outcome cases reported an allergic/hypersensitivity component to the cutaneous events
with numerous cases reporting significant morbidity.

## 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**

## 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)* | 5386 | 8237 | 363 | 360 | 5340 |
| # of AERS serious cutaneous reports | 226 | 141 | 38 | 5 | 109 |
| Reporting rates
Per million RX | 42 | 17 | 105 | 14 | 20 |

-  * Verispan Vector OneTM: 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)

## Addendum Review

**Data cutoff: August 2, 2006**

## 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 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 |
| Gemifloxacin | 332,114 | 1,183,000 | 0 | 3 | 9 | 12 | 24 |
| Cefditoren | 512,156 | 1,412,000 | 0 | 0 | 3 | 0 | 3 |

- * 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

## 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 = ?.**

| 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 |
| Gemifloxacin | 2.5 | 3.4 | 5.1 | 11.0 |
| Cefditoren | 0 | 2.1 | 0 | 2.1 |

## 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**

## 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**

## 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**

## 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**

## Conclusions

**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?**

## 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.**

## Acknowledgements

**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.**