[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Not Withdrawn From Sale for Reasons of Safety or Effectiveness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(mg)/milliliter (mL) and 250 mg/mL, was not withdrawn from sale for 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