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U.S. Department of Health and Human Services

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Food and Drug Administration 09 June 1999 Trovan (Trovafloxacin / Alatrofloxacin Mesylate)

INTERIM RECOMMENDATIONS

Trovan (trovafloxacin / alatrofloxacin) was approved by FDA in 1997 for the treatment of a wide variety of infections.

Based on new safety data related to serious liver injury, described below, the Food and Drug Administration is today advising physicians that the drug Trovan should be reserved for use ONLY in the treatment of patients who meet ALL of the following treatment criteria:

  • Have at least one of the following infections that is judged by the treating physician to be serious and life- or limb-threatening:
  • nosocomial pneumonia,
  • community acquired pneumonia,
  • complicated intra-abdominal infections (including post-surgical infections)
  • gynecologic and pelvic infections, or
  • complicated skin and skin structure infections, including diabetic foot infections;
  • Receive their initial therapy in an in-patient health care facility (i.e., hospital or long-term nursing care facility); and
  • The treating physician believes that, even given the new safety information, the benefit of the product for the patient outweighs the potential risk.

In most cases, it is expected that therapy in these patients would begin with the intravenous formulation of Trovan. Due to the bioavailability of oral Trovan, patients who have stabilized clinically on IV therapy may be switched to oral Trovan to complete their course of therapy, if deemed appropriate by the treating physician. In some patients with these kinds of serious and life- or limb-threatening infections, oral Trovan may be considered appropriate initial therapy. Use of oral Trovan to treat less serious infections is not warranted.

Therapy with Trovan beyond 14 days duration generally should not be used, because the risk of liver injury may increase substantially with exposure beyond 14 days. Trovan should be discontinued prior to 14 days of therapy if the patient experiences any clinical signs or symptoms of liver dysfunction, including fatigue, anorexia, yellowing of the skin and eyes, severe stomach pain with nausea and vomiting, or dark urine.

NEW SAFETY DATA

No reports of hepatic failure, liver transplant, or death due to possible hepatic etiology were reported in the 7000 patients in the pre-marketing clinical trials database exposed to Trovan. It is estimated that approximately 2,500,000 patients have received Trovan since approval for marketing. Following marketing of Trovan in the United States in February 1998, FDA began receiving reports of patients who experienced serious hepatic reactions in association with the use of the product. In July of 1998, FDA had worked with Trovan’s manufacturer to add information about hepatic toxicity to the Precautions section of Trovan’s package insert.

Since that time, FDA has received reports of over 100 cases of clinically symptomatic liver toxicity in patients receiving Trovan. Some of these patients developed serious liver injury leading to liver transplant and/or death. At present, FDA is aware of 14 cases of acute liver failure that are strongly associated with Trovan exposure. Four of these patients required liver transplant (one of whom subsequently died). Five additional patients died of liver-related illness. Three patients recovered without transplantation, and the final outcome is still pending on two patients. These numbers of patients with acute liver failure, although few, represent a rate that appears to be significantly higher than would be expected to occur idiopathically in the general population - despite the under-reporting of cases that generally occurs to our post-marketing surveillance system.

Trovan-associated liver failure appears to be unpredictable. It has been reported with both short-term (as little as 2 days exposure) and longer-term drug exposure; therefore the efficacy of liver function monitoring in acceptably managing this risk is uncertain.

Trovan use exceeding 2 weeks duration appears to be associated with a substantially increased risk of acute liver failure.

Liver failure has also been reported following Trovan re-exposure.

These uncommon but very serious adverse reactions are typical of drug toxicities which, because of their rarity, may not always be detectable in clinical trials databases. However, such toxicities may become apparent after marketing when the product is used in a significantly broader population. As such, these adverse reactions are the types of important, new safety information the post-marketing spontaneous reporting system is designed to detect, as it did in this case.

CONCLUSIONS

FDA does not wish to deprive patients and physicians of access to effective antimicrobials, if the risks associated with these drugs can be managed successfully by other means. Based on the new safety data presently available to the agency and based on the availability of alternative products to treat other less serious indications for which this product was originally approved, FDA is issuing the interim recommendations outlined above.

FDA and Pfizer have agreed to a program that will limit the distribution of Trovan to in-patient health care facilities (hospitals and long-term nursing care facilities). Pfizer will be communicating in the near future with appropriate pharmacies to provide directions concerning possible return of their present inventories of Trovan.

FDA believes that this risk management program will better ensure that Trovan is used in clinical situations in which its benefits can be expected to outweigh its presently known risks. In this manner, FDA believes that Trovan can continue to be made available to those patients who may need it for treatment of serious and life- or limb-threatening infections, while minimizing other patients’ risk of exposure to the product.

FDA advises patients presently taking Trovan NOT to discontinue their therapy until they have discussed their treatment options with their physician.

FDA and the manufacturer will continue to collect and evaluate data on Trovan’s safety and will continue to assess the drug’s benefit/risk profile. As further information or recommendations about Trovan become available, FDA will continue to inform the health care and patient communities.

FDA requests that any suspected adverse events thought associated with Trovan be reported to the agency through MedWatch, FDA’s adverse event reporting system. Reports may be submitted to FDA by telephone (800-332-1088), by fax (800-332-0178) or by mail to MedWatch, HF-2, FDA, 5600 Fishers Lane, Rockville, Maryland 20857. Reports can also be filed via the Internet at www.fda.gov/medwatch. Reports may also be filed directly to the manufacturer.

 

Murray M. Lumpkin, M.D.
Deputy Center Director (Review Management)
Center for Drug Evaluation and Research
Food and Drug Administration
Rockville, Maryland