Determination That DELALUTIN (hydroxyprogesterone caproate) Injection, 125 Milligrams/Milliliter and 250 Milligrams/Milliliter, Was Not Withdrawn From Sale for Reasons of Safety or Effectiveness, 36419-36421 [2010-15416]
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Federal Register / Vol. 75, No. 122 / Friday, June 25, 2010 / Notices
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[FR Doc. 2010–15423 Filed 6–24–10; 8:45 am]
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BILLING CODE 4165–16–P
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16:23 Jun 24, 2010
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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Withdrawn From Sale for Reasons of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.
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was not withdrawn from sale for reasons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
PO 00000
Frm 00074
Fmt 4703
Sfmt 4703
36419
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 § 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
E:\FR\FM\25JNN1.SGM
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mstockstill on DSKH9S0YB1PROD with NOTICES
36420
Federal Register / Vol. 75, No. 122 / Friday, June 25, 2010 / Notices
(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 afterpains; 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
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16:23 Jun 24, 2010
Jkt 220001
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
PO 00000
Frm 00075
Fmt 4703
Sfmt 4703
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 progestogencontaining 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
E:\FR\FM\25JNN1.SGM
25JNN1
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Federal Register / Vol. 75, No. 122 / Friday, June 25, 2010 / Notices
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.
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16:23 Jun 24, 2010
Jkt 220001
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
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA–2010–D–0283]
Draft Guidance for Industry on
Chemistry, Manufacturing, and
Controls Postapproval Manufacturing
Changes Reportable in Annual
Reports; Availability
AGENCY:
Food and Drug Administration,
HHS.
ACTION:
Notice.
SUMMARY: The Food and Drug
Administration (FDA) is announcing the
availability of a draft guidance for
industry entitled ‘‘CMC Postapproval
Manufacturing Changes Reportable in
Annual Reports.’’ This draft guidance
provides recommendations to holders of
new drug applications (NDAs) and
abbreviated new drug applications
(ANDAs) regarding the types of changes
that may be reported in annual reports.
Specifically, the draft guidance
describes chemistry, manufacturing, and
controls (CMC) postapproval
manufacturing changes that FDA has
determined will likely present minimal
potential to have adverse effects on
product quality and, therefore, may be
reported by applicants in an annual
report. (The draft guidance excludes
positron emission tomography (PET)
drug products.)
DATES: Although you can comment on
any guidance at any time (see 21 CFR
10.115(g)(5)), to ensure that the agency
considers your comment on this draft
guidance before it begins work on the
final version of the guidance, submit
either electronic or written comments
on the draft guidance by September 23,
2010.
ADDRESSES: Submit written requests for
single copies of the draft guidance to the
Division of Drug Information, Center for
Drug Evaluation and Research, Food
and Drug Administration, 10903 New
Hampshire Ave., Bldg. 51, rm. 2201,
Silver Spring, MD 20993–0002. Send
one self-addressed adhesive label to
assist that office in processing your
requests. See the SUPPLEMENTARY
INFORMATION section for electronic
access to the draft guidance document.
Submit electronic comments on the
draft guidance to https://
PO 00000
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Fmt 4703
Sfmt 4703
36421
www.regulations.gov. Submit written
comments, including comments
regarding the proposed collection of
information, to the Division of Dockets
Management (HFA–305), Food and Drug
Administration, 5630 Fishers Lane, rm.
1061, Rockville, MD 20852.
FOR FURTHER INFORMATION CONTACT: Jon
Clark, Center for Drug Evaluation and
Research, Food and Drug
Administration, Bldg. 51, rm. 4178,
10903 New Hampshire Ave., Silver
Spring, MD 20993–0002, 301–796–2400.
SUPPLEMENTARY INFORMATION:
I. Background
FDA is announcing the availability of
a draft guidance for industry entitled
‘‘CMC Postapproval Manufacturing
Changes Reportable in Annual Reports.’’
This draft guidance provides
recommendations to holders of NDAs
and ANDAs regarding the types of CMC
postapproval manufacturing changes
that FDA has determined will likely
present minimal potential to have
adverse effects on product quality, and
therefore, may be reported by applicants
in an annual report under § 314.70 (21
CFR 314.70).
In its September 2004 final report,
‘‘Pharmaceutical Current Good
Manufacturing Practices (CGMPs) for
the 21st Century—A Risk-Based
Approach’’ (Pharmaceutical Product
Quality Initiative, https://www.fda.gov/
Drugs/DevelopmentApprovalProcess/
Manufacturing/QuestionsandAnswerson
CurrentGoodManufacturing
PracticescGMPforDrugs/
ucm137175.htm), FDA stated that to
keep pace with the many advances in
quality management practices in
manufacturing and to enable the agency
to more effectively allocate its limited
regulatory resources, FDA would
implement a cooperative, risk-based
approach for regulating pharmaceutical
manufacturing. As part of this approach,
FDA determined that to provide the
most effective public health protection,
its CMC regulatory review should be
based on an understanding of product
risk and how best to manage this risk.
The number of CMC manufacturing
supplements for NDAs and ANDAs has
continued to increase over the last
several years. In connection with FDA’s
Pharmaceutical Product Quality
Initiative and its risk-based approach to
CMC review, FDA has evaluated the
types of changes that have been
submitted in CMC postapproval
manufacturing supplements and
determined that many of the changes
being reported present very low risk to
the quality of the product and do not
need to be submitted in supplements.
E:\FR\FM\25JNN1.SGM
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Agencies
[Federal Register Volume 75, Number 122 (Friday, June 25, 2010)]
[Notices]
[Pages 36419-36421]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2010-15416]
-----------------------------------------------------------------------
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.
-----------------------------------------------------------------------
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