2023-27015. Bayer HealthCare Pharmaceuticals Inc., et al.; Withdrawal of Approval of CIPRO (Ciprofloxacin Hydrochloride) Oral Tablet, Equivalent to 100 Milligrams Base, and Five Generic Ciprofloxacin Hydrochloride, Oral Tablet, Equivalent to 100 ...

AGENCY:

Food and Drug Administration, HHS.

ACTION:

Notice.

SUMMARY:

The Food and Drug Administration (FDA or the Agency) is withdrawing the approval of CIPRO (ciprofloxacin hydrochloride (HCl)) oral tablet, equivalent to (EQ) 100 milligrams (mg) base under new drug application (NDA) 019537 and five generic ciprofloxacin HCl, oral tablet, EQ 100 mg base products which referenced it as their basis of submission. The holders of the applications requested withdrawal of the 100 mg strength products and waived their opportunity for a hearing.

DATES:

Approval is withdrawn as of December 8, 2023.

FOR FURTHER INFORMATION CONTACT:

Ayako Sato, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 51, Rm. 6206, Silver Spring, MD 20993–0002, 240–402–4191.

SUPPLEMENTARY INFORMATION:

On October 22, 1987, FDA approved NDA 019537 for CIPRO (ciprofloxacin HCl) oral tablet, EQ 250 mg, 500 mg, and 750 mg base. On April 8, 1996, FDA approved a supplement to NDA 019537 to add the oral 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. FDA approved the following generic ciprofloxacin HCl, oral tablet, EQ 100 mg base products under section 505(j) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) which identified as their reference listed drug (RLD) the 100 mg strength tablet approved in NDA 019537: ^[1]

• ANDA 075593 approved on June 9, 2004;
• ANDA 075817 approved on June 25, 2007;
• ANDA 075939 approved on March 3, 2005;
• ANDA 076794 approved on February 10, 2005; and
• ANDA 076912 approved on February 18, 2005.

On May 18, 2005, FDA approved labeling revisions for NDA 019537, including updates to reflect that the 100 mg oral tablet product was no longer being marketed. Subsequently, the Agency made a safety and effectiveness determination that CIPRO (ciprofloxacin HCl) oral 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, oral 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) oral tablet, EQ 100 mg base for the treatment of acute uncomplicated cystitis was removed from the product labeling in 2005. The effectiveness of CIPRO (ciprofloxacin HCl) oral tablet, EQ 100 mg base and ciprofloxacin HCl, oral tablet, EQ 100 mg base for the treatment of acute uncomplicated cystitis is not supported by the current ciprofloxacin Susceptibility Test Interpretive Criteria (STIC) (a.k.a., breakpoints),^[2] established by the Clinical and Laboratory Standards Institute and recognized by FDA on June 10, 2019.^[3] Recent pharmacokinetic/pharmacodynamic analyses conducted by FDA indicated that the dosage regimen of ciprofloxacin HCl oral 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 twice daily or 500 mg extended-release tablet daily. A literature search produced no studies comparing the efficacy of ciprofloxacin 100 mg twice daily versus ciprofloxacin 250 mg 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.^[4] Given that the safe and effective use of ciprofloxacin hydrochloride tablets, 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, FDA believes that the potential problems associated with ciprofloxacin hydrochloride tablets, 100 mg are sufficiently serious that the product should be removed from the market under § 314.150(d) (21 CFR 314.150(d)).

On June 16, 2023, the Agency notified Bayer HealthCare Pharmaceuticals Inc. that it believes the potential problems associated with the drug are sufficiently serious that the 100 mg strength product should be removed from the market pursuant to § 314.150(d). Bayer requested in a letter dated July 7, 2023, that FDA withdraw approval of the 100 mg strength product in NDA 019537 under § 314.150(d) and waived its opportunity for a hearing.

FDA also notified abbreviated new drug applications (ANDAs) 075593, 075817, 075939 and 076794 on June 16, 2023, and 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 oral tablet, EQ 100 mg base, and to waive their opportunity for a hearing. In a letter dated June 26, 2023, Rising Pharma Holdings, Inc., requested that FDA withdraw approval of the 100 mg strength product in ANDA 075817 under § 314.150(d) and waived its opportunity for a hearing. In a letter dated June 30, 2023, Amneal Pharmaceuticals, LLC requested that FDA withdraw approval of the 100 mg strength product in ANDA 075939 under § 314.150(d) and waived its opportunity for a hearing. In separate letters dated July 7, 2023, Dr. Reddy's Laboratories and Watson Laboratories, Inc. requested that FDA withdraw approval of their 100 mg strength products in ANDA 075593 and in ANDA 076794, respectively, under § 314.150(d) and waived their opportunity for a hearing. In a letter dated July 12, 2023, Taro Pharmaceutical Industries, Ltd., requested that FDA withdraw approval of the 100 mg strength product in ANDA 076912 under § 314.150(d) and waived its opportunity for a hearing.

For the reasons discussed above, which Bayer and the ANDA holders do not dispute in their withdrawal request letters, and pursuant to the applicants' requests, FDA is withdrawing approval of the 100 mg strength product from one NDA and from the five ANDAs listed in the table below under § 314.150(d). This notice is limited to CIPRO (ciprofloxacin HCl) oral tablet, EQ 100 mg base and ciprofloxacin HCl, oral tablet, EQ 100 mg base for the treatment of acute uncomplicated cystitis. Other products approved in NDA 019537 for CIPRO (ciprofloxacin HCl) oral tablet or related ANDAs for ciprofloxacin HCl, oral tablet ( e.g., the 250 mg base, 500 mg base, or 750 mg base strength products) remain approved. Distribution of CIPRO (ciprofloxacin HCl) oral tablet, EQ 100 mg base and ciprofloxacin HCl, oral tablet, EQ 100 mg base in interstate commerce without an approved application is illegal and subject to regulatory action (see sections 505(a) and 301(d) of the FD&C Act (21 U.S.C. 355(a) and 331(d)).

Application No.	Drug	Applicant
NDA 019537	CIPRO (ciprofloxacin HCl) oral tablet, EQ 100 mg base	Bayer Healthcare Pharmaceuticals Inc., 100 Bayer Blvd., P.O. Box 915, Whippany, NJ 07981–0915.
ANDA 075593	Ciprofloxacin HCl, oral tablet, EQ 100 mg base	Dr. Reddy's Laboratories Ltd., 107 College Rd. East, 2nd Floor Princeton, NJ 08540.
ANDA 075817	Ciprofloxacin HCl, oral tablet, EQ 100 mg base	Rising Pharma Holdings, Inc., 2 Tower Center Blvd., Suite 1401A, East Brunswick, NJ 08816.
ANDA 075939	Ciprofloxacin HCl, oral tablet, EQ 100 mg base	Amneal Pharmaceuticals, LLC, 50 Horseblock Rd., Brookhaven, NY 11719.
ANDA 076794	Ciprofloxacin HCl, oral tablet, EQ 100 mg base	Watson Laboratories, Inc., 400 Interpace Pkwy., Building A, Parsippany, NJ 07054.
ANDA 076912	Ciprofloxacin HCl, oral tablet, EQ 100 mg base	Taro Pharmaceutical Industries, Ltd., 1600 Stewart Ave., Suite 604, Westbury, NY 11590.

Dated: December 5, 2023.

Lauren K. Roth,

Associate Commissioner for Policy.

Footnotes

1.  ANDA 076426 for ciprofloxacin HCl, oral tablet, EQ 100 mg was approved on June 15, 2005. In the Federal Register of October 4, 2016, FDA announced it was withdrawing the approval of ANDA 076426 upon request by the applicant under 21 CFR 314.150(c) (see 81 FR 68427, October 4, 2016).

2.  See Ciprofloxacin Oral, Injection products, available at https://www.fda.gov/​drugs/​development-resources/​ciprofloxacin-oral-injection-products. Note E. coli is within the family of Enterobacteriaceae.

3.  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 67354–55, recognizing on June 10, 2019, updated standard susceptibility test interpretive criteria for ciprofloxacin.

4.  Fluoroquinolone Antimicrobial Drugs Information, available at https://www.fda.gov/​drugs/​information-drug-class/​fluoroquinolone-antimicrobial-drugs-information#:~:text=​Fluoroquinolones%20are%20drugs%20approved%20for,such%20as%20colds%20or%20flu.