[Federal Register Volume 75, Number 122 (Friday, June 25, 2010)]
[Notices]
[Pages 36419-36421]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2010-15416]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA-2006-P-0089 (formerly Docket No. 2006P-0144)]
Determination That DELALUTIN (hydroxyprogesterone caproate)
Injection, 125 Milligrams/Milliliter and 250 Milligrams/Milliliter, Was
Not Withdrawn From Sale for Reasons of Safety or Effectiveness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) has determined that
DELALUTIN (hydroxyprogesterone caproate) injection, 125 milligrams
(mg)/milliliter (mL) and 250 mg/mL, was not withdrawn from sale for
reasons of safety or effectiveness. This determination will allow FDA
to approve abbreviated new drug applications (ANDAs) for
hydroxyprogesterone caproate injection, 125 mg/mL and 250 mg/mL, if all
other legal and regulatory requirements are met. However, in
considering whether to file an ANDA for hydroxyprogesterone caproate,
future applicants are advised that they may not be able to obtain
DELALUTIN (hydroxyprogesterone caproate) injection, 125 mg/mL and 250
mg/mL, for bioequivalence testing because the product has not been
commercially available for a number of years. An ANDA applicant who is
unable to obtain DELALUTIN (hydroxyprogesterone caproate) injection,
125 mg/mL and 250 mg/mL, for bioequivalence testing should contact the
Office of Generic Drugs for a determination of what is necessary to
show bioavailability and same therapeutic effect.
FOR FURTHER INFORMATION CONTACT: Nam Kim, Center for Drug Evaluation
and Research, Food and Drug Administration, 10903 New Hampshire Ave.,
Bldg. 51, rm. 6320, Silver Spring, MD 20993-0002, 301-796-3601.
SUPPLEMENTARY INFORMATION: In 1984, Congress enacted the Drug Price
Competition and Patent Term Restoration Act of 1984 (Public Law 98-417)
(the 1984 amendments), which authorized the approval of duplicate
versions of drug products approved under an ANDA procedure. ANDA
applicants must, with certain exceptions, show that the drug for which
they are seeking approval contains the same active ingredient in the
same strength and dosage form as the ``listed drug,'' which is a
version of the drug that was previously approved. ANDA applicants do
not have to repeat the extensive clinical testing otherwise necessary
to gain approval of a new drug application (NDA). The only clinical
data required in an ANDA are data to show that the drug that is the
subject of the ANDA is bioequivalent to the listed drug.
The 1984 amendments include what is now section 505(j)(7) of the
Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355(j)(7)) (the act),
which 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 generally known as the
``Orange Book.'' Under FDA regulations, drugs are withdrawn 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 (21 CFR 314.162). Under Sec. 314.161(a)(1) (21 CFR
314.161(a)(1)), the agency must determine whether a listed drug was
withdrawn from sale for reasons of safety or effectiveness before an
ANDA that refers to that listed drug may be approved. FDA may not
approve an ANDA that does not refer to a listed drug.
DELALUTIN (hydroxyprogesterone caproate) injection, 125 mg/mL and
250 mg/mL, is the subject of NDA 10-347 and NDA 16-911 held by Bristol-
Myers Squibb Company (BMS). According to the latest version of the
approved labeling for DELALUTIN (hydroxyprogesterone caproate)
injection, DELALUTIN is indicated in non-pregnant women: for the
treatment of advanced adenocarcinoma of the uterine corpus (Stage III
or IV); in the management of amenorrhea (primary and secondary) and
abnormal uterine bleeding due to hormonal imbalance in the absence of
organic pathology, such as submucous fibroids or uterine cancer; as a
test for endogenous estrogen production (``Medical D and C''); and for
the production of secretory endometrium and desquamation.
FDA originally approved NDA 10-347 for DELALUTIN
(hydroxyprogesterone caproate) injection based on a finding of safety
in 1956. The indications section of the original labeling approved in
1956 states that DELALUTIN appears to be useful in conditions generally
responding to progestogens and provided suggested dosing and
administration for the following indications: primary and secondary
amenorrhea; metropathia hemorrhagica
[[Page 36420]]
(functional uterine bleeding) not associated with genital malignancy;
infertility with inadequate corpus luteum function; production of
secretory endometrium and desquamation during estrogen therapy;
premenstrual tension; dysmenorrhea; cyclomastopathy, mastodynia,
adenosis, chronic cystic mastitis; habitual and threatened abortion;
postpartum after-pains; test for endogenous estrogen production; and
test for continuous endogenous progesterone production. In 1970, a
supplement to NDA 10-347 was submitted for the additional indication of
treatment of advanced adenocarcinoma of the uterine corpus (Stage III
or IV). FDA reviewed this supplement as an original NDA (NDA 16-911)
because it proposed a new indication, and approved it as both safe and
effective in 1972. Both NDA 10-347 and NDA 16-911 reference the same
drug product and utilize the same labeling.
The indications for DELALUTIN (hydroxyprogesterone caproate)
injection, other than the indication for treatment of advanced
adenocarcinoma of the uterine corpus (Stage III or IV), were reviewed
for efficacy under the Drug Efficacy Study Implementation (DESI)
program. In the Federal Register of September 9, 1971 (36 FR 18115),
FDA announced that preparations containing hydroxyprogesterone caproate
are effective for use in amenorrhea and abnormal uterine bleeding due
to hormonal imbalance in the absence of organic pathology, such as
submucous fibroids or uterine cancer; as a presumptive test for
pregnancy; as a test for continuous endogenous progesterone production;
and for production of secretory endometrium and desquamation--as a test
for endogenous estrogen production (medical D and C). FDA also
announced that preparations containing hydroxyprogesterone caproate are
probably effective for habitual and threatened abortion and
cyclomastopathies (mastodynia, adenosis, chronic cystic mastitis) and
possibly effective for use in premenstrual tension and dysmenorrhea and
disturbances of the menstrual cycle (hypomenorrhea, oligomenorrhea,
irregular cycles). In addition, FDA announced that hydroxyprogesterone
caproate lacks substantial evidence of effectiveness for use in
postpartum afterpains and, when used alone, in deficiency syndromes
(castration, primary ovarian failure, menopause, senile vaginitis, and
pruritis vulvae). The notice announced that FDA was prepared to approve
NDAs and supplements to previously approved NDAs under the conditions
described in the notice, including the condition that the revised
labeling include only the indications for which the drug was classified
as effective or probably effective.
In the Federal Register of October 10, 1973 (38 FR 27947), FDA
announced that it was modifying its prior conclusions with respect to
the indications for DELALUTIN (hydroxyprogesterone caproate) injection
that were determined to be probably effective and possibly effective.
FDA stated that the additional information submitted by BMS to support
use of DELALUTIN in threatened and habitual abortion does not
constitute substantial evidence of effectiveness. In addition, the
notice stated that data had become available which suggested a possible
association of prenatal hormonal treatment of mothers with congenital
heart defects in the offspring. The notice stated that the potential
risk of teratogenic effects is considered high enough to warrant
removal of pregnancy-related indications from the labeling of
progestins currently marketed for systemic use, which are as follows:
(1) Presumptive test for pregnancy, (2) treatment of threatened and
habitual abortion, and (3) treatment of any abnormalities of pregnancy,
including pregnancy complicating diabetes. The notice concluded that
the labeling section given in the September 9, 1971, announcement for
hydroxyprogesterone caproate should be amended to read as follows:
``This drug is indicated in amenorrhea; abnormal uterine bleeding due
to hormonal imbalance in the absence of organic pathology, such as
submucous fibroids or uterine cancer; for production of secretory
endometrium and desquamation; and as a test for endogenous estrogen
production (Medical D & C).''
In the Federal Register of July 22, 1977 (42 FR 37646), FDA stated
that reports during the past several years had indicated that the use
of sex hormones during early pregnancy may seriously damage the
offspring. FDA stated that in view of the adverse effects on the fetus
that may be associated with its exposure to pregestational hormones,
the labeling for all progestational drug products except those for use
as contraceptives should be revised to include an additional
contraindication and warning regarding the use of progestational agents
during pregnancy. In the Federal Register of October 13, 1978 (43 FR
47178), FDA published a final rule requiring the labeling of
progestational drug products to include warnings informing patients of
an increased risk of birth defects associated with the use of these
drugs during the first 4 months of pregnancy. In the Federal Register
of January 12, 1989 (54 FR 1243), FDA published revised guideline texts
for professional and patient labeling for prescription progestational
drug products not including progestogen-containing oral contraceptive
drug products. The notice revised the guideline texts by: (1) Deleting
the warning about possible congenital heart defects and limb reduction
defects, and (2) adding a warning stating that the use of
progestational drugs in pregnancy may cause certain genital
abnormalities.
In the Federal Register of November 16, 1999 (64 FR 62110), FDA
revoked its regulation requiring such patient labeling for
progestational drug products because it concluded, based on a review of
the scientific data, that such labeling for all progestogens was not
warranted. In the notice, FDA stated that the diversity of drugs that
can be described as progestational and the diversity of conditions
these drugs may be used to treat make it inappropriate to consider
these drugs a single class for labeling purposes.
By letter dated September 13, 1999, BMS requested withdrawal of NDA
10-347 for DELALUTIN (hydroxyprogesterone caproate) injection and
stated that the drug product had not been marketed for several years.
In the Federal Register of September 13, 2000 (65 FR 55264), FDA
announced that it was withdrawing approval of NDA 10-347 and NDA 16-
911, effective September 30, 2000.
CUSTOpharm, Inc., submitted a citizen petition dated March 27, 2006
(Docket No. FDA-2006-P-0089), under 21 CFR 10.30, requesting that the
agency determine whether DELALUTIN (hydroxyprogesterone caproate)
injection was withdrawn from sale for reasons of safety or
effectiveness and therefore is suitable for submission in an ANDA.
After considering the citizen petition (including comments submitted)
and reviewing agency records, FDA has determined that DELALUTIN
(hydroxyprogesterone caproate) injection, 125 mg/mL and 250 mg/mL, was
not withdrawn from sale for reasons of safety or effectiveness. The
petitioner identified several publications discussing the potential
teratogenic properties of DELALUTIN (hydroxyprogesterone caproate)
injection over the years but asserts that recent studies indicate that
with proper administration (beginning in the second trimester) in high
risk patients these risks are minimal or not evident. In view of these
studies, the petitioner
[[Page 36421]]
seeks a determination that DELALUTIN (hydroxyprogesterone caproate)
injection was not withdrawn for reasons of safety or efficacy. FDA has
reviewed the information submitted by petitioner and has independently
evaluated relevant literature and data for adverse event reports for
DELALUTIN (hydroxyprogesterone caproate) injection. Based on its
evaluation, FDA does not consider this information to indicate that
DELALUTIN (hydroxyprogesterone caproate) injection, 125 mg/mL and 250
mg/mL, was withdrawn for reasons of safety or effectiveness.
For the reasons outlined in this document, FDA determines that
DELALUTIN (hydroxyprogesterone caproate) injection, 125 mg/mL and 250
mg/mL, was not withdrawn from sale for reasons of safety or
effectiveness. Accordingly, the agency will continue to list DELALUTIN
(hydroxyprogesterone caproate) injection, 125 mg/mL and 250 mg/mL, in
the ``Discontinued Drug Product List'' section of the Orange Book. The
``Discontinued Drug Product List'' delineates, among other items, drug
products that have been discontinued from marketing for reasons other
than safety or effectiveness. ANDAs that refer to DELALUTIN
(hydroxyprogesterone caproate) injection, 125 mg/mL and 250 mg/mL, may
be approved by the agency as long as they meet all relevant legal and
regulatory requirements for approval of ANDAs. If FDA determines that
labeling for these drug products should be revised to meet current
standards, the agency will advise ANDA applicants to submit such
labeling.
In considering whether to file an ANDA for this drug product,
future applicants should be advised that they may not be able to obtain
DELALUTIN (hydroxyprogesterone caproate) injection, 125 mg/mL and 250
mg/mL, for bioequivalence testing because the product has not been
commercially available for a number of years. An ANDA applicant who is
unable to obtain DELALUTIN (hydroxyprogesterone caproate) injection,
125 mg/mL and 250 mg/mL, for bioequivalence testing should contact the
Office of Generic Drugs for a determination of what showing is
necessary to satisfy the requirements of section 505(j)(2)(A)(iv) of
the act. If an ANDA is approved without a showing of bioequivalence,
the approved product will not be considered therapeutically equivalent
(i.e., granted an AB rating) in the Orange Book.
Dated: June 21, 2010.
Leslie Kux,
Acting Assistant Commissioner for Policy.
[FR Doc. 2010-15416 Filed 6-24-10; 8:45 am]
BILLING CODE 4160-01-S