[Federal Register Volume 65, Number 17 (Wednesday, January 26, 2000)]
[Notices]
[Pages 4253-4256]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-1787]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 79N-0113; DESI 2847]


Pediatric Parenteral Multivitamin Products; Drug Efficacy Study 
Implementation; Announcement of Marketing Conditions

AGENCY:  Food and Drug Administration, HHS.

ACTION:  Notice.

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SUMMARY:  The Food and Drug Administration (FDA) is announcing that 
pediatric parenteral multivitamin drug products that are formulated as 
set forth in this document are effective for treating certain vitamin 
deficiencies. FDA is further announcing the conditions for the approval 
and marketing of the drug products for the indications for which they 
are now regarded as effective.

DATES:  Supplements to the conditionally approved new drug application 
(NDA) must be submitted by March 27, 2000.

ADDRESSES:  Communication in response to this notice should be 
identified with the reference number DESI 2847 and directed to the 
attention of the appropriate office named below.
    Supplements to the conditionally approved NDA (identify with NDA 
number): Division of Metabolic and Endocrine Drug Products (HFD-510), 
Center for Drug Evaluation and Research, Food and Drug Administration, 
5600 Fishers Lane, Rockville, MD 20857.
    Original abbreviated new drug applications (ANDA's): Office of 
Generic Drugs (HFD-600), Center for Drug Evaluation and Research, Food 
and Drug Administration, 7500 Standish Pl., Rockville, MD 20855.
    Requests for opinion of the applicability of this notice to a 
specific product: Division of Prescription Drug Compliance and 
Surveillance (HFD-330), Center for Drug Evaluation and Research, Food 
and Drug Administration, 7500 Standish Pl., Rockville, MD 20855.

FOR FURTHER INFORMATION CONTACT:  Mary E. Catchings, Center for Drug 
Evaluation and Research (HFD-7), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-594-2041.

SUPPLEMENTARY INFORMATION:

I. Background

    In a notice published in the Federal Register of July 27, 1972 (37 
FR 15027), FDA announced its evaluations of reports received from the 
National Academy of Sciences/National Research Council Drug Efficacy 
Study Group on certain parenteral multivitamin drug products. The 
agency stated that the products, as then formulated, lacked substantial 
evidence of effectiveness for their claimed indications. The conclusion 
was not based on any individual vitamin's lack of effectiveness; 
rather, certain essential vitamins in the available formulations were 
either not included or included in too great or too small amounts.
    In a followup notice published in the Federal Register of December 
14, 1972 (37 FR 26623), FDA granted parenteral multivitamin products a 
temporary exemption (paragraph XIV, category 11) from the time limits 
imposed for the implementation of the Drug Efficacy Study. The 
temporary exemption was based primarily on the recognized critical 
medical importance of

[[Page 4254]]

parenteral multivitamin therapy and the lack of alternative drugs. The 
agency allowed these products to remain on the market as then 
formulated, while complex technical and medical problems were being 
resolved and rational formulations were being developed and tested.
    To facilitate the determination of rational multivitamin 
formulations and their evaluation, FDA accepted the assistance offered 
by the American Medical Association (AMA). In December 1975, the AMA 
submitted its ``Guidelines for Multivitamin Preparations for Parenteral 
Use,'' which recommended specific amounts of individual vitamins and 
procedures for evaluating the stability, safety, and effectiveness of 
the formulations.
    The AMA report stressed that the guideline formulations were 
estimated from the existing Recommended Daily Allowance, which in turn 
is based on dietary population surveys. The assumptions applied by the 
AMA to correlate the established dietary allowances of the essential 
vitamins to the parenteral administration of vitamins to patients in 
various disease states required that clinical trials be conducted to 
evaluate the guideline formulations.
    FDA accepted the AMA guidelines with minor reservations and, 
subsequently, in a Federal Register notice published July 13, 1979 (44 
FR 40933), amended the terms of the December 1972 paragraph XIV 
temporary exemption to require conditional approval of an NDA or 
supplemental NDA within specific time frames as a condition for the 
continued marketing of a parenteral multivitamin drug product. The 
agency agreed not to initiate regulatory proceedings against these 
products under the following requirements: (1) Reformulation in accord 
with the AMA guidelines as to the number and quantities of vitamins in 
the formulation; (2) an outline of proposed studies along the lines set 
forth in the AMA report, to evaluate the stability and biological 
availability of the reformulated preparations; and (3) a plan or 
protocol for clinical effectiveness studies in accord with the AMA 
guidelines. A reformulated product could be marketed in place of the 
previous formulation after agency review and conditional approval of 
the submission. This procedure allowed continued marketing of 
parenteral multivitamins while clinical testing and evaluation of the 
AMA guideline formulations were being carried out.
    After evaluating available data, FDA classified the AMA guideline 
adult formulations as effective in the Federal Register of September 
17, 1984 (49 FR 36446). That notice also revoked the paragraph XIV 
exemption of all products listed in the notice, including the following 
pediatric product conditionally approved under the terms of the July 
13, 1979, notice (in accordance with current labeling practice, amounts 
previously listed in United States Pharmacopeia units have been 
converted to weights):
    NDA 18-920; M.V.I. Pediatric (lyophilized), each vial containing 
vitamin A (retinol) 0.7 milligrams (mg)/vial, vitamin D 
(ergocalciferol) 10 micrograms (g)/vial, vitamin E (dl-alpha 
tocopherol acetate) 7 mg/vial, vitamin C (ascorbic acid) 80 mg/vial, 
folic acid 140 g/vial, niacin (niacinamide) 17.0 mg/vial, 
vitamin B2 (riboflavin-5'-phosphate sodium) 1.4 mg/vial, 
vitamin B1 (thiamine hydrochloride) 1.2 mg/vial, vitamin 
B6 (pyridoxine hydrochloride) 1.0 mg/vial, vitamin 
B12 (cyanocobalamin) 1 g/vial, dexpanthenol (d-
pantothenyl alcohol) 5.0 mg/vial, biotin 20 g/vial, vitamin K 
(phytonadione) 200 g/vial; Astra Zeneca, 50 Otis St., 
Westborough, MA 01581 (formerly held by Armour Pharmaceutical Co., P.O. 
Box 511, Kankakee, IL 60901).
    The September 17, 1984, notice stated that further evaluation of 
pediatric parenteral multivitamin formulations containing vitamin E was 
required. The notice went on to state that until the time that such 
evaluation was completed, pediatric multivitamin products could be 
marketed only under the terms and conditions of the July 13, 1979, 
Federal Register notice.
    The effectiveness of the AMA guideline pediatric formulations was 
considered by an AMA-FDA committee in the Workshop on Multivitamin 
Preparations for Parenteral Use on August 21, 1985, and by FDA's 
Endocrinologic and Metabolic Drugs Advisory Committee on March 3 and 4, 
1986. Based on a review of the committees' recommendations and other 
available material, the Director of the Center for Drug Evaluation and 
Research has determined that the 1975 AMA guideline pediatric 
formulations are effective multivitamin preparations.
    It should be noted, however, that although the intravenous 
preparation is properly formulated in composition and dosage amount of 
essential vitamins, it supplies inadequate amounts of vitamin A, 
particularly to low birth weight infants. In addition, the issue of 
whether the solubilizers used in pediatric preparations contribute to 
toxicity remains unresolved. Further study of the pediatric 
formulations is needed to determine a vehicle for administration of 
multivitamins to low birth weight infants that will provide adequate 
amounts of vitamin A and avoid possible toxicity associated with the 
use of solubilizers employed in pediatric preparations. Future approval 
of a more appropriate formulation for low birth weight infants may 
restrict the labeling of the current formulation to use in infants 
weighing more than 3 kilograms (kg).
    The continuing exemption announced in the September 17, 1984, 
notice for pediatric parenteral multivitamin products is hereby 
revoked. These products are regarded as new drugs under section 201(p) 
of the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 
321(p)). Therefore, a fully approved NDA is required to market them. 
M.V.I. Pediatric (NDA 18-920) received conditional approval under the 
terms of the July 13, 1979, notice. A supplemental NDA is now required 
for M.V.I. Pediatric to revise the labeling and to update its 
conditionally approved NDA.
    In addition to the product specifically named above, this notice 
applies to any product that is not the subject of an approved 
application and is identical or, under 21 CFR 310.6, is related or 
similar to M.V.I. Pediatric. It is the responsibility of all drug 
manufacturers and distributors to review this notice to determine 
whether it covers any drug product that they manufacture or distribute. 
Any person may request an opinion of the applicability of this notice 
to a specific drug product by writing to the Division of Prescription 
Drug Compliance and Surveillance (address above).

II. Conditions for Approval and Continued Marketing of Formulations 
Evaluated as Effective

A. Effectiveness Classification

    FDA has reviewed all available evidence and concludes that 
pediatric parenteral drug products formulated as listed below are 
effective for the applicable indication set forth in the labeling 
conditions below.

B. Conditions for Approval and Marketing

    FDA is prepared to approve ANDA's and supplements to the 
conditionally approved NDA named above under conditions described here.
1. Form of Drug
    (a) Intravenous multivitamin preparations. The preparation is an 
aqueous solution or lyophilized powder suitable for reconstitution and/
or secondary dilution prior to intravenous

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infusion and contains the specified amounts of the following individual 
vitamins, either as the moiety listed below or as the chemically 
equivalent salt or ester.
    (i) Pediatric formulation (intended for infants and children under 
age 11)1

 
------------------------------------------------------------------------
             Ingredient                      Amount per unit dose
------------------------------------------------------------------------
Fat-Soluble Vitamins
 
A (retinol)                          0.7 mg
D (ergocalciferol or                 10 g
 cholecalciferol)
E (alpha-tocopherol)                  7 mg
K1 (phytonadione)                     200 g
 
Water-Soluble Vitamins
 
C (ascorbic acid)                    80 mg
Folic acid                            140 g
Niacin                               17 mg
B2 (riboflavin)                      1.4 mg
B1 (thiamine)                        1.2 mg
B6 (pyridoxine)                      1.0 mg
B12 (cyanocobalamin)                  1.0 g
Pantothenic acid                     5.0 mg
Biotin                               20.0 g
------------------------------------------------------------------------
\1\ For infants weighing less than 1 kg the daily dose is 30 percent of
  the indicated formulation. Do not exceed this daily dose. For infants
  weighing 1 to 3 kg the daily dose is 65 percent of the indicated
  formulation.

    (b) Intramuscular multivitamin preparations. The preparation is a 
sterile solution suitable for intramuscular injection.
    (i) Pediatric formulation. The vitamin composition of the pediatric 
intramuscular formulation shall be that of the pediatric intravenous 
preparation named above without the fat-soluble vitamins.
2. Labeling Conditions
    (a) The label bears the statement ``Caution: Federal law prohibits 
dispensing without prescription.''
    (b) The drug is labeled to comply with all requirements of the act 
and regulations, and the labeling bears adequate information for safe 
and effective use of the drug. The indication is as follows:
    (i) Intravenous Pediatric Multivitamin Preparations. This 
formulation is indicated as a daily multivitamin maintenance dosage for 
infants and children up to 11 years of age receiving parenteral 
nutrition.
    It is also indicated in other situations where administration by 
the intravenous route is required. Such situations include surgery, 
extensive burns, fractures and other trauma, severe infectious 
diseases, and comatose states, which may provoke a ``stress'' situation 
with profound alterations in the body's metabolic demands and 
consequent tissue depletion of nutrients.
    The physician should not await the development of clinical signs of 
vitamin deficiency before initiating vitamin therapy.
    This product (administered in intravenous fluids under proper 
dilution) contributes intake of these necessary vitamins toward 
maintaining the body's normal resistance and repair processes.
    Patients with multiple vitamin deficiencies or with markedly 
increased requirements may be given multiples of the daily dosage for 
two or more days as indicated by the clinical status.
    (ii) Intramuscular Pediatric Multivitamin Preparations. This 
product is indicated for infants and children up to ll years of age for 
conditions in which: (1) Intake or absorption of the water-soluble 
vitamins is inadequate and oral intake must be supplemented; or (2) 
there is a known or suspected serious depletion of the water-soluble 
vitamins, and immediate treatment by the intramuscular route is 
advisable.
    Conditions that may require parenteral administration of water-
soluble vitamins may include disorders that can affect oral intake, 
gastrointestinal absorption, or utilization. Such conditions include 
comatose states, persistent vomiting, prolonged fever, severe 
infectious diseases, major surgery, extensive burns, fractures and 
other traumas, diarrhea, achlorhydria, or liver disease.
    The physician should not await the development of clinical signs of 
vitamin deficiency before initiating therapy because there are few 
specific or pathognomonic signs of early vitamin deficiencies.
    (c) CONTRAINDICATIONS: Known hypersensitivity to any of the 
vitamins or excipients in this product or a preexisting 
hypervitaminosis.
    Allergic reaction has been known to occur following intravenous 
administration of thiamine and vitamin K. The formulation is 
contraindicated prior to blood sampling for detection of megaloblastic 
anemia, as the folic acid and the cyanocobalamin in the vitamin 
solution can mask serum deficits.
    (d) PRECAUTIONS: (The following paragraph should appear in bold 
type)
    Caution should be exercised when administering this multivitamin 
formulation to patients on warfarin sodium-type anticoagulant therapy. 
In such patients, periodic monitoring of prothrombin time is essential 
in determining the appropriate dosage of anticoagulant therapy.
    Adequate blood levels of vitamin E are achieved when this product 
is given to infants at the recommended dosage. Larger doses or 
supplementation with oral or parenteral vitamin E are not recommended 
because elevated blood levels of vitamin E may result.
    Studies have shown that vitamin A may adhere to plastic, resulting 
in inadequate vitamin A administration in the doses recommended with 
this product. Additional vitamin A supplementation may be required, 
especially in low birth weight infants.
3. Marketing Status
    (a) Marketing of the drug product that is now the subject of a 
conditionally approved NDA may be continued

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provided that on or before March 27, 2000, the holder of the 
application has submitted: (i) A supplement for revised labeling 
necessary to be in accord with the labeling conditions described in 
this notice, and complete container labeling if current container 
labeling has not been submitted; and (ii) a supplement to provide 
updated information with respect to the composition, manufacture, and 
specifications of the drug substance and the drug product as described 
in 21 CFR 314.50(d)(1)(i) and (d)(1)(ii). FDA will evaluate the 
submitted material and, if the material is adequate, will grant full 
approval to the conditionally approved NDA.
    (b) Approval of an ANDA must be obtained in accordance with section 
505(j) of the act (21 U.S.C. 355(j)) before marketing such products. 
Marketing prior to approval of an ANDA will subject such products, and 
those persons who caused the products to be marketed, to regulatory 
action.
    This notice is issued under the Federal Food, Drug, and Cosmetic 
Act (secs. 502, 505 (21 U.S.C. 352, 355)) and under authority delegated 
to the Director, Center for Drug Evaluation and Research (21 CFR 5.70).

    Dated: January 4, 2000.
Janet Woodcock,
Director, Center for Drug Evaluation and Research.
[FR Doc. 00-1787 Filed 1-25-00; 8:45 am]
BILLING CODE 4160-01-F