[Federal Register Volume 75, Number 51 (Wednesday, March 17, 2010)]
[Notices]
[Pages 12760-12761]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2010-5748]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2009-P-0318]


Determination That CERNEVIT-12 (Multivitamins for Infusion) Was 
Withdrawn From Sale for Reasons of Safety or Effectiveness

AGENCY:  Food and Drug Administration

ACTION:  Notice

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SUMMARY:  The Food and Drug Administration (FDA) has determined that 
CERNEVIT-12, multivitamins for infusion (retinol palmitate 
corresponding to retinol (Vitamin A) 3500 international units (I.U.), 
cholecalciferol (Vitamin D3) 200 I.U., DL alpha-tocopherol 
10.2 milligrams (mg) corresponding to alpha-tocopherol (Vitamin E) 11.2 
I.U., ascorbic acid (Vitamin C) 125 mg, nicotinamide (Vitamin 
B3) 46 mg, dexpanthenol 16.15 mg corresponding to 
pantothenic acid (Vitamin B5) 17.25 mg, pyridoxine 
hydrochloride 5.5 mg corresponding to pyridoxine (Vitamin 
B6) 4.53 mg, riboflavin sodium phosphate 5.67 mg 
corresponding to riboflavin (Vitamin B2) 4.14 mg, 
cocarboxylase tetrahydrate 5.8 mg corresponding to thiamine (Vitamin 
B1) 3.51 mg, folic acid 414 micrograms (mcg), D-biotin 60 
mcg, and cyanocobalamin (Vitamin B12) 5.5 mcg), (hereinafter 
CERNEVIT-12 (multivitamins for infusion)), was withdrawn from sale for 
reasons of safety or effectiveness. FDA therefore will not accept or 
approve abbreviated new drug applications (ANDAs) for CERNEVIT-12 
(multivitamins for infusion).

FOR FURTHER INFORMATION CONTACT:  Nancy Hayes, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 51, rm. 6354, 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 No. 98-
417 (the 1984 Amendments), which authorized the approval of duplicate 
versions of drug products approved under an ANDA procedure. ANDA 
sponsors 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. Sponsors of ANDAs 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)(A) of the 
Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355(j)(7)(A)) (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 generally is known as the 
``Orange Book.'' Under FDA regulations (part 314 (21 CFR part 314)), 
drugs are removed from the list if the agency withdraws or suspends 
approval of the drug's NDA or ANDA (Sec.  314.162(a)(1)) or if FDA 
determines that the listed drug was withdrawn from sale for reasons of 
safety or effectiveness (Sec.  314.162(a)(2)).
    Under Sec.  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

[[Page 12761]]

that refers to that listed drug may be approved. FDA may not approve an 
ANDA that references a listed drug that the agency has determined was 
withdrawn for reasons of safety or effectiveness (Sec.  
314.127(a)(11)).
    CERNEVIT-12 (multivitamins for infusion) is the subject of NDA 20-
924, held by Baxter Health Corp. (Baxter). FDA approved the NDA on 
April 6, 1999, as an application under section 505(b)(2) of the act (21 
U.S.C. 355(b)(2)), relying in part upon literature and the agency's 
prior findings of safety and efficacy for a listed parenteral 
multivitamin drug product. CERNEVIT-12 (multivitamins for infusion) is 
indicated as a daily multivitamin maintenance dosage for adults and 
children age 11 years and older receiving parenteral nutrition, and for 
situations in which administration by the intravenous route is 
required.
    Adult parenteral multivitamin drug products were reviewed for 
efficacy under the Drug Efficacy Study Implementation (DESI) program. 
Under this program, implemented in response to the 1962 amendments to 
the act requiring demonstration of effectiveness (The Kefauver-Harris 
Amendments, Public Law No. 87-781 (1962)), the National Academy of 
Sciences-National Research Council (NAS-NRC) undertook a study of some 
4,000 drug formulations for the express purpose of assessing the 
efficacy of the products. Upon consideration of the findings and 
recommendations of the NAS-NRC, FDA set forth in the Federal Register 
its conclusions and assessment of whether and under what circumstances 
a drug product is considered ``effective'' for use as required by the 
act.
    In the initial DESI notice of July 27, 1972, addressing parenteral 
multivitamin preparations, FDA announced its conclusion that parenteral 
multivitamin preparations as then formulated lacked substantial 
evidence of effectiveness because they did not contain certain 
essential vitamins, or they contained certain vitamins in doses that 
were too high or too low (37 FR 15027, July 27, 1972). Because of the 
critical medical importance of these preparations and the lack of 
alternative drug products, FDA notified manufacturers and distributors 
of parenteral multivitamin products in December 1972 that the agency 
would allow these products to remain on the market pending the 
development and testing of new formulations and the resolution of 
complex technical and medical issues (37 FR 26623, December 14, 1972).
    On September 17, 1984, FDA announced the parenteral multivitamin 
formulations the agency had determined to be effective and the 
conditions for marketing those products (49 FR 36446, September 17, 
1984). The agency subsequently modified the conditions for marketing an 
effective adult parenteral multivitamin drug product in 2000 (65 FR 
21200, April 20, 2000). In that ``upgrade'' notice, FDA announced 
several changes to the product formulation including increases in the 
dosage amounts of Vitamins B1, B6, C, and folic 
acid, and amended portions of the ``Conditions for Marketing and 
Approval'' for parenteral multivitamin products set forth in the 
September 17, 1984, notice to reflect the changes (Id. at 21201).
    In the Federal Register of August 18, 2003, FDA announced that it 
was withdrawing approval of NDA 20-924 in response to Baxter's 
withdrawal request dated December 18, 2002 (68 FR 49481, August 18, 
2003). As a result, CERNEVIT-12 (multivitamins for infusion) was moved 
to the ``Discontinued Drug Product List'' section of the Orange Book.
    Strides Arcolab Limited submitted a citizen petition under Sec.  
314.161(b) of the regulations (Docket No. FDA-2009-P-0318) requesting 
that FDA determine whether the NDA for CERNEVIT-12 (multivitamins for 
infusion) had been withdrawn from sale for reasons of safety or 
effectiveness. After considering the citizen petition and reviewing 
agency records, FDA has determined that CERNEVIT-12 (multivitamins for 
infusion) was withdrawn from sale for reasons of safety or 
effectiveness.
    Specifically, we have carefully reviewed our files for records 
concerning the withdrawal of CERNEVIT-12 (multivitamins for infusion), 
including the NDA file for this product. We also have independently 
evaluated relevant literature and data for possible postmarketing 
adverse event reports. Agency records did not contain any clinical 
reviews describing safety issues associated with CERNEVIT-12 
(multivitamins for infusion), and postmarketing safety reports did not 
raise any safety concerns.
    FDA has determined, however, that CERNEVIT-12 (multivitamins for 
infusion) was not reformulated to comply with the April 20, 2000, 
Federal Register upgrade notice before it was withdrawn from the 
market. As described in that notice, adult parenteral multivitamin drug 
products must contain higher doses of Vitamins B1, 
B6, C, and folic acid than the dosages contained in 
CERNEVIT-12 (multivitamins for infusion) (65 FR 21201).
    Because CERNEVIT-12 (multivitamins for infusion) is not in 
compliance with current FDA standards for adult parenteral multivitamin 
drug products, the agency has determined under Sec.  314.161 that 
CERNEVIT-12 (multivitamins for infusion) was withdrawn from sale for 
reasons of safety or efficacy. (57 FR 17950 at 17956, April 28, 1992) 
(``if the NDA or ANDA holder fails to comply with [the DESI upgrade] 
notice, the NDA or ANDA product is not considered to be approved for 
effectiveness and cannot be a listed drug''). The Discontinued Drug 
Product List delineates, among other items, products that have been 
discontinued from marketing for reasons other than safety or 
effectiveness. Therefore, CERNEVIT-12 (multivitamins for infusion) will 
be removed from the Discontinued Drug Product List section of the 
Orange Book (Sec.  314.162(a)(2)). In addition, FDA will not accept or 
approve ANDAs that refer to CERNEVIT-12 (multivitamins for infusion) 
(21 CFR 314.127(a)(11)).

    Dated: March 11, 2010.
Leslie Kux,
Acting Assistant Commissioner for Policy.
[FR Doc. 2010-5748 Filed 3-16-10; 8:45 am]
BILLING CODE 4160-01-S