[Federal Register Volume 88, Number 235 (Friday, December 8, 2023)]
[Notices]
[Pages 85636-85638]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2023-27015]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2023-N-4973]


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 Milligrams Base Drug Products

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA or the Agency) is

[[Page 85637]]

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DATES: Approval is withdrawn as of December 8, 2023.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\
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    \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).
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     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 Sec.  314.150(d) (21 CFR 
314.150(d)).
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    \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,s
uch%20as%20colds%20or%20flu.
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    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 Sec.  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 Sec.  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 Sec.  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 Sec.  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 Sec.  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 Sec.  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 Sec.  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 Sec.  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

[[Page 85638]]

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)).

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     Application No.               Drug                 Applicant
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NDA 019537...............  CIPRO                Bayer Healthcare
                            (ciprofloxacin       Pharmaceuticals Inc.,
                            HCl) oral tablet,    100 Bayer Blvd., P.O.
                            EQ 100 mg base.      Box 915, Whippany, NJ
                                                 07981-0915.
ANDA 075593..............  Ciprofloxacin HCl,   Dr. Reddy's Laboratories
                            oral tablet, EQ      Ltd., 107 College Rd.
                            100 mg base.         East, 2nd Floor
                                                 Princeton, NJ 08540.
ANDA 075817..............  Ciprofloxacin HCl,   Rising Pharma Holdings,
                            oral tablet, EQ      Inc., 2 Tower Center
                            100 mg base.         Blvd., Suite 1401A,
                                                 East Brunswick, NJ
                                                 08816.
ANDA 075939..............  Ciprofloxacin HCl,   Amneal Pharmaceuticals,
                            oral tablet, EQ      LLC, 50 Horseblock Rd.,
                            100 mg base.         Brookhaven, NY 11719.
ANDA 076794..............  Ciprofloxacin HCl,   Watson Laboratories,
                            oral tablet, EQ      Inc., 400 Interpace
                            100 mg base.         Pkwy., Building A,
                                                 Parsippany, NJ 07054.
ANDA 076912..............  Ciprofloxacin HCl,   Taro Pharmaceutical
                            oral tablet, EQ      Industries, Ltd., 1600
                            100 mg base.         Stewart Ave., Suite
                                                 604, Westbury, NY
                                                 11590.
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    Dated: December 5, 2023.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2023-27015 Filed 12-7-23; 8:45 am]
BILLING CODE 4164-01-P