[Federal Register Volume 89, Number 153 (Thursday, August 8, 2024)]
[Notices]
[Pages 64921-64923]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2024-17650]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2024-N-3510]


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Equivalent to 100 Milligrams Base, Was Withdrawn From Sale for Reasons 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.

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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equivalent to (EQ) 100 milligrams (mg) base, was withdrawn from sale 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FDA determines that the listed drug was withdrawn from sale for reasons 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 (Sec.  314.162 (21 CFR 314.162)).

[[Page 64922]]

    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 
(Sec.  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\
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    \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.
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    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 Sec.  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 Sec.  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 Sec.  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\
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    \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 Sec.  314.150(c), effective November 3, 
2016 (81 FR 68427).
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    After reviewing Agency records and based on the information we have 
at this time, FDA has determined under Sec.  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 Sec.  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

[[Page 64923]]

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.
[FR Doc. 2024-17650 Filed 8-7-24; 8:45 am]
BILLING CODE 4164-01-P