NAVINTA LLC Fax:

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1 AVITA LLC Fax: ! 2011 FEB - 8 A 10: 2q February 7, 2011 VIA OVERIGHT DELIVERY Division of Documents Management Food and Drug Administration Department of Health and Human Services 5630 Fishers Lane Room 1061 Rockville, MD CITIZE PETITIO The undersigned submits this petition under Section 505 of the Federal Food, Drug, and Cosmetic Act (FDC Act), 21 U.S.C. 355, to request the Commissioner of Food and Drugs to refrain from approving any pending or new applications [submitted under 5050) or 505(b)(2)] of Iron Sucrose Injection drug prodilct therapeutically equivalent to the Reference Listed Drug product (RLD) Venofer (Iron sucrose injection). A. Action Requested This petition is submitted by avinta LLC (avinta) and requests that the Food and Drug Administration (FDA) refrain from granting final approval of any pending or new applications [submitted under 505(j) or 505(b)(2)] of Iron Sucrose Injection drug product, therapeutically equivalent to Venofer@ and do not exhibit pharmaceutical equivalence to Venofer with respect to the Sodium COlltent as described within the scope of this petition. -;:::OIJ c}d11 p. cx>? 1499 Lower Ferry Rd., Ewing, J Page 1 of6 d

2 Dr. Paokaj Dave AVITA LLC Fax: B. Statement of Grounds Iron sucrose Injection (DA ) was approved by the agency on ov 06, 2000 and currently it is marketed in the US as a Reference Listed Drug (RLD) under the trade name "Venofer ". Venofer (Iron Sucrose Injection, USP) is a brown, sterile, aqueous, complex of polynuclear iron (III)-hydroxide in sucrose for intravenous use. Iron sucrose injection has a molecular weight of approximately 34,000-60,000 daltons and a proposed structural formula: here, n is the degree of iron polymerization and m is the number of sucrose molecules associated with the iron (III)-hydroxide. Each ml of injection contains 20 mg elemental iron as iron sucrose in water for injection. Venofer is available in 5 ml single dose vials (100 mg elemental iron per 5 ml) and 10 ml single dose vials (200 mg elemental iron per 10 ml). The drug product contains approximately 30% sucrose w/v (300 mglml) and has a ph of The product contains no preservatives. The Osmolarity ofthe injection is 1250 mosmolll as provided in physician's inert labeling for Venofer (Exhibit A) Lower Ferry Rd., Ewing, J Page 2 of6

3 AVITA LLC Viee President Phone: Fax: Additionally, United States phannacopoeia (USP) has a monograph for Iron sucrose injection (Exhibit B), which describes that Iron sucrose injection is a sterile, colloidal solution of ferric hydroxide in complex with sucrose in water for injection. It contains not less than 95.0 percent and not more than percent ofthe labeled amount of iron. Sodium hydroxide may be added to adjust the ph. It contains no antimicrobial agent, chelating agent, dextran, gluconate, or other added substances. Elemental Components in Venofer : As described in the molecular formula of Iron sucrose complex printed in the Venofer Label, one can infer that Iron sucrose molecule contains Ferric Iron as polynuclear Iron(III) hydroxide, Sodium and Sucrose. USP monograph has defined specific tests for the control on content of Iron and content of Sucrose in the drug product, whereas a specific control on the content of sodium was not provided, even though sodium has been described as part of the Iron sucrose molecule (Ref: Venofer Label). As stated in the USP monograph, sodium hydroxide may be added to adjust the ph. This process of adding sodium hydroxide would introduce additional sodium level into the drug product. Alkalinity Test: USP monograph for Iron sucrose injection has a test for alkalinity, specifying that each ml of Iron sucrose injection should consume not less than 0.5 ml and not more than 0.8 ml of 0.1 Hydrochloric acid to bring down the ph to 7.4. Assuming the USP monograph test "Alkalinity" is 1499 Lower Ferry Rd., Ewing, J Page 3 of6

4 AVITA LLC Fax: intended to control the amount of sodium present in the Iron sucrose injection, the amount of sodium equivalent to 0.5 ml and 0.8 ml of 0.1 Hydrochloric acid would be correspondingly 1.15 mg/ml and 1.84 mg/ml of injection. Sodium Content: In order to verify the sodium content present in Venofer, three lots were tested for sodium content by ICPMS system using a validated analytical method. The sodium results obtained with three lots ofvenofer are provided in the Table 1. Table 1: Observed Sodium Content in Venofer (Iron Sucrose Injection) Venofer Lot o. Exp. Date Content of Sodium, mglml I 9500 July August August As evident from the sodium content data reported in Table 1, the values for sodium content are significantly higher than the sodium equivalent to the USP alkalinity test specification. This proves that significant amount of sodium is present in the drug product which did not contribute to the test for alkalinity, meaning this could be the sodium bound to the molecule and hence not neutralized during the titration against 0.1 hydrochloric acid as given in the test for alkalinity described in USP monograph Lower Ferry Rd., Ewing, J Page 4 of6

5 AVITA LLC Fax: Therefore, it is essential to have a control on the total sodium content in the Iron sucrose injection product so as to ensure phannaceutical equivalence of composition of a 505(j) and/or 505(b)(2) application drug product to that ofvenofer. Based on the sodium content data (about 5.7 mg/ml) observed in Venofer, the agency shall refrain from approving any pending or new applications referencing to Venofer if the sodium content is not within a proposed range ofbetween 5.1 mg/ml and 6.6 mg/ml ofdrug product. For the scientific reasons stated within the scope of this petition, all pending or new applications [submitted under 505(j) or 505(b)(2)] of Iron Sucrose Injection drug product], before being eligible to receive tentative or final approvals, besides meeting the USP monograph specification for Iron sucrose injection, shall be required to submit evidence to show the amount of sodium present in the respective drug product is similar to that found in Venofer at a proposed specification of between 5.1 mg/ml and 6.6 mg/ml of injection. c. Environmental Impact The relief requested by this petition is categorically exempt from the requirement for an environmental assessment under 21 C.F.R and D. Economic Impact Information regarding economic impact will be submitted upon request Lower Ferry Rd., Ewing, J Page 50f6

6 AVITA LLC Fax: E. Certification I certify that, to my best knowledge and belief: (a) this petition includes all information and views upon which the petition relies; (b) this petition includes representative data and/or information known to the petitioner which are unfavorable to the petition; and (c) I have taken reasonable steps to ensure that any representative data and/or information which are unfavorable to the petition were disclosed to me. If I received or expect to receive payments, including. cash and other forms of consideration, to file this information or its contents, I received or expect to receive those payments from the following persons or organizations: one, other than my usual salary and benefits as an employee ofavinta. I verify under penalty ofperjury that the foregoing is true and correct as ofthe date ofthe submission ofthis petition. Respectfully submitted, aj Dave, PhD. V President, a inta LLC 1499 Lower Ferry Road Ewing, J (609) Lower Ferry Rd., Ewing, J Page 60f6

7 ",-- l '.-,III _- DR.PAKAI DAVE AVITA, LLC. 0.5 LBS LTR 1 OF LO!R. Pl!RRY RD. EIG J SHIP TO: DMSIO OF DOCUMETS MAAGEMET FOOD AD DRUG ADMIISTRATIO DMSIO OF DOCUMETS MAAGEMET DEPT. OF HEALTH & HUMA SERVICES 5630 FISHERS LAE, ROOM# 1061 ROCKVILLE MD MD S: F '0.l> V. '0 II " UPS EXT DAY AIR I TRACKIG #: 1Z E BIUJG: PIP lim '" V"IS 12.OA * L i '".[ (:, I - CD.-:!.. 00 r.. '0.I>