[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DATES: Approval is withdrawn as of December 8, 2023.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