# Determination That CIPRO (Ciprofloxacin Hydrochloride) Tablet, Equivalent to 100 Milligrams Base, Was Withdrawn From Sale for Reasons of Safety or Effectiveness
**AGENCY:**
Food and Drug Administration, HHS.
**ACTION:**
Notice.
**SUMMARY:**
The Food and Drug Administration (FDA or Agency) has determined that CIPRO (ciprofloxacin hydrochloride (HCl)) tablet, equivalent to (EQ) 100 milligrams (mg) base, was withdrawn from sale for reasons of safety or effectiveness. The Agency will not accept or approve abbreviated new drug applications (ANDAs) for ciprofloxacin HCl tablet, EQ 100 mg base.
**FOR FURTHER INFORMATION CONTACT:**
Ayako Sato, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 51, Rm. 6238, Silver Spring, MD 20993-0002, 240-402-4191, *[email protected].*
**SUPPLEMENTARY INFORMATION:**
Section 505(j) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 355(j)) allows the submission of an ANDA to market a generic version of a previously approved drug product. To obtain approval, the ANDA applicant must show, among other things, that the generic drug product: (1) has the same active ingredient(s), dosage form, route of administration, strength, conditions of use, and (with certain exceptions) labeling as the listed drug, which is a version of the drug that was previously approved and (2) is bioequivalent to the listed drug. ANDA applicants do not have to repeat the extensive clinical testing otherwise necessary to gain approval of a new drug application (NDA).
Section 505(j)(7) of the FD&C Act requires FDA to publish a list of all approved drugs. FDA publishes this list as part of the “Approved Drug Products With Therapeutic Equivalence Evaluations,” which is known generally as the “Orange Book.” Under FDA regulations, drugs are removed from the list if the Agency withdraws or suspends approval of the drug's NDA or ANDA for reasons of safety or effectiveness or if FDA determines that the listed drug was withdrawn from sale for reasons of safety or effectiveness (§ 314.162 (21 CFR 314.162)).
A person may petition the Agency to determine, or the Agency may determine on its own initiative, whether a listed drug was withdrawn from sale for reasons of safety or effectiveness. This determination may be made at any time after the drug has been withdrawn from sale but must be made prior to approving an ANDA that refers to the listed drug (§ 314.161 (21 CFR 314.161)). FDA may not approve an ANDA that does not refer to a listed drug.
On October 22, 1987, FDA approved NDA 019537 for CIPRO (ciprofloxacin HCl) tablet, EQ 250 mg base, 500 mg base, and 750 mg base. On April 8, 1996, FDA approved a supplement to NDA 019537 to add the tablet, EQ 100 mg base, to treat acute uncomplicated cystitis in adult females to be supplied as a cystitis pack containing six 100 mg oral tablets with a dosing regimen of 100 mg twice daily for 3 days.
On May 18, 2005, FDA approved labeling revisions for NDA 019537, including updates to reflect that the 100 mg tablet drug product was no longer being marketed. CIPRO (ciprofloxacin HCl) tablet, EQ 100 mg base, was moved from the “Prescription Drug Product List” to the “Discontinued Drug Product List” section of the Orange Book. Subsequently, the Agency made a safety and effectiveness determination that CIPRO (ciprofloxacin HCl) tablet, EQ 100 mg 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 tablet, EQ 100 mg base, for its indication has become available.
The resistance of *Escherichia coli* ( *E. coli* ), the main causative pathogen for acute uncomplicated cystitis, to ciprofloxacin has been increasing since CIPRO (ciprofloxacin HCl) tablet, EQ 100 mg base, for the treatment of acute uncomplicated cystitis was removed from the labeling in 2005. The effectiveness of CIPRO (ciprofloxacin HCl) tablet, EQ 100 mg base, and ciprofloxacin HCl tablet, EQ 100 mg base, for the treatment of acute uncomplicated cystitis is not supported by the current ciprofloxacin susceptibility test interpretive criteria (STIC) (also known as break points), [^1] established by the Clinical and Laboratory Standards Institute and recognized by FDA on June 10, 2019. [^2] Recent pharmacokinetic/pharmacodynamic analyses conducted by FDA indicated that the dosage regimen of ciprofloxacin HCl tablet, 100 mg twice daily for 3 days may not be effective for the treatment of acute uncomplicated cystitis. A review of published literature also showed that more contemporary studies of the treatment of acute uncomplicated cystitis with ciprofloxacin were conducted with the dosage of 250 mg tablet twice daily or 500 mg extended-release tablet daily. A literature search produced no studies comparing the efficacy of ciprofloxacin 100 mg tablet twice daily versus ciprofloxacin 250 mg tablet twice daily or 500 mg extended-release tablet daily in treatment of acute uncomplicated cystitis. Finally, significant adverse reactions associated with the use of fluoroquinolones, including ciprofloxacin HCl, have been identified. [^3]
[^1] See Ciprofloxacin Oral, Injection products, available at *https://www.fda.gov/drugs/development-resources/ciprofloxacin-oral-injection-products.* Note *E. coli* is within the order of Enterobacterales.
[^2] 21st Century Cures Act: Annual Compilation of Notices of Updates from the Susceptibility Test Interpretive Criteria web page; Request for Comments (85 FR 67353 at 67354 to 67355, October 22, 2020), recognizing on June 10, 2019, updated standard STIC for ciprofloxacin.
[^3] Fluoroquinolone Antimicrobial Drugs Information, available at *https://www.fda.gov/drugs/information-drug-class/fluoroquinolone-antimicrobial-drugs-information.*
On June 16, 2023, the Agency notified Bayer HealthCare Pharmaceuticals Inc. (Bayer) that it believed the potential problems associated with the drug product are sufficiently serious that the EQ 100 mg base strength product should be removed from the market pursuant to § 314.150(d) (21 CFR 314.150(d)). Bayer requested in a letter dated July 7, 2023, that FDA withdraw approval of the EQ 100 mg base strength product in NDA 019537 under § 314.150(d) and waived its opportunity for a hearing. FDA also notified application holders for ANDAs 075593, 075817, 075939, and 076794 on June 16, 2023, and for ANDA 076912 on June 21, 2023. FDA asked the ANDA holders to request withdrawal of approval under § 314.150(d) of the generic versions of ciprofloxacin HCl tablet, EQ 100 mg base, and to waive their opportunity for a hearing.
Consistent with requests from the relevant application holders, in the *Federal Register* of December 8, 2023 (88 FR 85636), FDA announced that it was withdrawing approval of the EQ 100 mg base strength product from NDA 019537 and ANDAs 075593, 075817, 075939, 076794, and 076912 for the treatment of acute uncomplicated cystitis, effective December 8, 2023. The Agency further noted that the withdrawal of approval is limited to CIPRO (ciprofloxacin HCl) tablet, EQ 100 mg base, and ciprofloxacin HCl tablet, EQ 100 mg base, for the treatment of acute uncomplicated cystitis and that other products approved in NDA 019537 for CIPRO (ciprofloxacin HCl) tablet or related ANDAs for ciprofloxacin HCl tablet ( *e.g.,* the EQ 250 mg base, 500 mg base, or 750 mg base strength products) remain approved. Accordingly, the Agency has withdrawn approval of the EQ 100 base mg strength product from NDA 019537 and ANDAs 075593, 075817, 075939, 076794, and 076912 for the treatment of acute uncomplicated cystitis. [^4]
[^4] Previously, a decade earlier, in a letter dated June 10, 2013, Plivia Inc., subsidiary of Teva Pharmaceuticals USA Inc., notified FDA that ciprofloxacin HCl tablet, EQ 100 mg base, EQ 250 mg base, EQ 500 mg base, and EQ 750 mg base, the subject of ANDA 076426, was being voluntarily withdrawn from the market and FDA moved the drug products to the “Discontinued Drug Product List” section of the Orange Book. In the *Federal Register* of October 4, 2016, FDA announced it was withdrawing from approval ANDA 076426, held by Plivia Inc., under § 314.150(c), effective November 3, 2016 (81 FR 68427).
After reviewing Agency records and based on the information we have at this time, FDA has determined under § 314.161 that CIPRO (ciprofloxacin HCl) tablet, EQ 100 mg base, for the treatment of acute uncomplicated cystitis was withdrawn for reasons of safety or effectiveness. We have carefully reviewed our files for records concerning the withdrawal of CIPRO (ciprofloxacin HCl) tablet, EQ 100 mg base, for the treatment of acute uncomplicated cystitis from sale. We have also independently evaluated relevant literature and data. We have reviewed the available evidence. Given that the safe and effective use of ciprofloxacin HCl tablet, 100 mg twice daily for 3 days for the treatment of acute uncomplicated cystitis is not supported by its current STIC and considering the risks of serious adverse reactions along with the increased resistance of *E. coli* to ciprofloxacin, we have determined that CIPRO (ciprofloxacin HCl) tablet, EQ 100 mg base, would not be considered safe and effective if it were introduced to the market today in the absence of new clinical studies to address relevant effectiveness concerns identified during our review.
Accordingly, under § 314.162 the Agency will remove Bayer's NDA 019537 for CIPRO (ciprofloxacin HCl) tablet, EQ 100 mg base, for the treatment of acute uncomplicated cystitis from the list of drug products published in the Orange Book. FDA will not accept or approve ANDAs that refer to this drug product. Likewise, the Agency will remove from the list of drug products published in the Orange Book, those drug products in ANDAs that used NDA 019537 CIPRO (ciprofloxacin HCl) tablet, EQ 100 mg base as their reference listed drug; these are Amneal Pharmaceuticals, LLC's ciprofloxacin HCl tablet, EQ 100 mg base, in ANDA 075939; Dr. Reddy's Laboratories' ciprofloxacin HCl tablet, EQ 100 mg base, in ANDA 075593; Watson Laboratories, Inc.'s ciprofloxacin HCl tablet, EQ 100 mg base, in ANDA 076794; Rising Pharma Holdings, Inc.'s ciprofloxacin HCl tablet, EQ 100 mg base, in ANDA 075817; Taro Pharmaceutical Industries Ltd.'s ciprofloxacin HCl tablet, EQ 100 mg base, in ANDA 076912; and Pliva Inc.'s ciprofloxacin HCl tablet, EQ 100 mg base, in ANDA 076426.
Dated: August 5, 2024.
Lauren K. Roth,
Associate Commissioner for Policy.