An FDA notice contained in the Federal Register (FR) notice prepublication pages today (here) has put the final kibosh on the use of ciprofloxacin 100mg tablets due to current evidence demonstrating that the increased resistance of Escherichia coli (E. coli) to the low strength of ciprofloxacin makes it no longer effective for treatment of acute uncomplicated cystitis.

From a historical perspective “[O]n May 18, 2005, FDA approved labeling revisions for NDA 019537 [the innovator product], including updates to reflect that the 100mg oral tablet product was no longer being marketed. Subsequently, the Agency made a safety and effectiveness determination that CIPRO (ciprofloxacin HCl) oral tablet, EQ 100mg base was not discontinued for reasons of safety or effectiveness, which was later published in the Federal Register on October 1, 2019 (84 FR 52113). Since the Agency’s initial safety and effectiveness determination, new information related to the safe and effective use of ciprofloxacin HCl, oral tablet, EQ 100mg base for its indication has become available.”

The notice also states that “significant adverse reactions associated with the use of fluoroquinolones, including ciprofloxacin HCl, have been identified. Given that the safe and effective use of ciprofloxacin hydrochloride tablets, 100mg twice daily for three (3) days for the treatment of acute uncomplicated cystitis is not supported by its current STIC [the current ciprofloxacin Susceptibility Test Interpretive Criteria], and considering the risks of serious adverse reactions along with the increased resistance of E. coli to ciprofloxacin, FDA believes that the potential problems associated with ciprofloxacin hydrochloride tablets, 100mg are sufficiently serious that the product should be removed from the market under § 314.150(d) (21 CFR 314.150(d)).”

The internal FDA review of this issue led the Agency to write letters to the holder of the approved NDA on June 16, 2023, and ANDA holders a bit later in June requesting the 100mg product’s withdrawal. All the holders of the previously approved applications for the 100mg strength requested withdrawal of their application and all waived the opportunity for a hearing within a month of receiving the FDA’s initial communications.

It is important to note that the higher strengths of ciprofloxacin (e.g., the 250mg base, 500mg base, or 750mg base strength products) are still approved and are not subject to this notice. Thus, the FDA considers the 100mg strength product to have been withdrawn for safety and/or efficacy and the Agency will no longer accept applications for the 100mg strength. Marketing of a 100mg strength ciprofloxacin without an approved application is illegal and subject to immediate regulatory action.

This is another example of microbiological resistance developing over time and is one of the reasons that it is imperative to continue the development of new antibiotics. Remember, the little things (microbial agents) can be more dangerous than the big things.