,
`
`z
`
`sicor~
`
`SICOR Pharmaceuticals, Inc.
`A Subsidiary of TEVA Pharmaceuticals USA
`19 Hughes
`Irvine, CA 92618-1902
`Phone : 800 .806 .4226
`Fax: 949.855 .8210
`
`April 28, 2006
`
`Dockets Management Branch
`Food and Drug Administration
`Department of Health and Human Services
`Room 1061, HFA-305
`5630 Fishers Lane
`Rockville, Maryland 20852
`
`" ANDA Suitability Petition
`
`RE : ANDA Suitability Petition
`Methotrexate Injection, USP (100 mglmL)
`
`The undersigned submits this Suitability Petition (the "Petition") under the provisions of the
`Federal Food, Drug and Cosmetic Act, Section 505(j)(2)(c) and 21 CFR 314.93 to request the
`Commissioner of Food and Drugs to allow submission of an abbreviated new drug application
`(ANDA) for Methotrexate Injection, USP in a strength of 1,000 mg/lOmL (100 mg/mL) in a
`lOmL single use vial .
`
`A. Action Requested
`
`The Petitioner requests that the Commissioner of Food and Drugs permits a change in (a) dosage
`form (lyophilized powder to ready to use liquid) and (b) final drug concentration to allow for
`submission of an abbreviated new drug application (ANDA) for Methotrexate Injection in a
`strength of 1,000 mg/lOmL (100 mg/mL) in a 10 mL single use vial . The basis of the Petition is
`the reference listed drug product, Methotrexate Preservative Free for Injection, USP marketed by
`Bedford Laboratories, which is available in a single-use vial containing 1,000 mg of
`Methotrexate as Methotrexate Sodium for Injection with instructions to reconstitute with
`19 .4 mL of 0.9% Sodium Chloride Injection or Dextrose 5% in Water to a concentration of
`50 mg/mL. Bedford Laboratories received approval of Methotrexate Preservative Free for
`Injection, USP under ANDA 40-632 on August 12, 2005 .
`
`7 7-
`
`1
`
`Medac Exhibit 2021
`Koios Pharmaceuticals v. Medac
`IPR2016-01370
`Page 00001
`
`

`

`~ P C H Methotrexate Injection, USP
`1, 000 mg/10 m1,
`
`ANDA Suitability Petition
`
`"
`
`B. Statement of Grounds
`
`The subject of the Petition is to request Food and Drug Administration (FDA) permission to
`implement a change in (a) dosage form (lyophilized powder to ready to use liquid) and (b) final
`drug concentration for Methotrexate for Injection, USP. The reference listed drug product,
`Methotrexate Preservative Free for Injection, USP marketed by Bedford Laboratories is available
`in a single-use vial containing 1,000 mg of Methotrexate as Methotrexate Sodium for Injection
`with instructions to reconstitute with 19 .4 ml, of 0.9% Sodium Chloride Injection or Dextrose
`5% in Water to a concentration of 50 mg/mL.
`
`PCH's proposed drug product would contain 1,000 mg Methotrexate as Methotrexate Sodium
`USP at a concentration of 100 mg/mL in a fill volume of 10 ml, in a 10 mL single use vial. The
`proposed concentration is twice that set forth in the package insert for Methotrexate Preservative
`Free for Injection, USP, the reference listed drug product, after reconstitution with 19 .4 ml, of a
`suitable diluent.
`
`Product
`
`Dosage Form
`
`Route of
`Administration
`
`"
`
`' Bedford s
`
`Methotrexate Preservative
`Free for Injection USP
`
`Lyophilized
`Powder
`
`Intravenous
`
`PCH' S
`PROPOSED
`Methotrexate Injection, USP
`
`Liquid
`
`Intravenous
`
`Strength
`1,000 mg at 50 mg/mL
`when reconstituted with
`19.4 mL of a suitable diluent
`in a 20 mL single use vial
`
`1,000 mg at 100 mg/mL
`in a 10 mL single use vial
`
`Methotrexate is indicated in the treatment of several neoplastic diseases including gestational
`choriocarcinoma, chorioadenoma destruens and hydatidiform mole. In acute lymphocytic
`leukemia, methotrexate is indicated in the prophylaxis of meningeal leukemia and is used in
`maintenance therapy in combination with other chemotherapeutic agents. Methotrexate is also
`indicated in the treatment of meningeal leukemia. Methotrexate is used alone or in combination
`with other anticancer agents in the treatment of breast cancer, epidermoid cancers of the head and
`neck, advanced mycosis fungoides (cutaneous T cell lymphoma), and lung cancer, particularly
`squamous cell and small cell types. Methotrexate is also used in combination with other
`chemotherapeutic agents in the treatment of advanced stage non-Hodgkin's lymphomas .
`
`Methotrexate in high doses followed by leucovorin rescue in combination with other
`chemotherapeutic agents is effective in prolonging relapse-free survival in patients with non-
`metastatic osteosarcoma who have undergone surgical resection or amputation for the primary
`tumor.
`
`Page 00002
`
`

`

`~ P C H Methotrexate Injection, LISP
`1, 000 mg/10 mL
`
`ANDA Suitability Petition
`
`Methotrexate is indicated in the symptomatic control of severe, recalcitrant, disabling psoriasis
`that is not adequately responsive to other forms of therapy.
`
`Methotrexate is indicated in the management of selected adults with severe, active rheumatoid
`arthritis (ACR criteria), or children with active polyarticular-course juvenile rheumatoid arthritis,
`who have had an insufficient therapeutic response to, or are intolerant of, an adequate trial of
`first-line therapy including full dose nonsteroidal anti-inflammatory agents (NSAIDs).
`
`The proposed dosage form and concentration contains Methotrexate in an amount recommended
`in the approved labeling for dilution with 5% Dextrose Injection, USP or 0.9% Sodium Chloride
`Injection, USP.
`
`Methotrexate Preservative Free far Injection, USP is currently approved in one configuration:
`1,000 mg in a 20 mL vial for reconstitution with 19.4 mL of a suitable diluent.
`
`The Dosage and Administration section of the approved labeling describes the following IM and
`IV dosage regimens:
`
`Choriocarcinoa and similar Trophoblastic Diseases
`15 mg to 30 mg daily
`
`Leukemia
`Induction Regimen
`Maintenance Regimen 1
`Maintenance Regimen 2
`
`3.3 Mg/M2 daily
`30 Mg/M2 total dose per week in two divided doses
`2 .5 mg/kg every 14 days
`
`Meningeal Leukemia
`12 mg/m2 every 2 to 5 days
`
`Osteosarcoma
`High Dose Regimen
`
`Arthritis
`10 Mg/M2 every week
`
`Psoriasis
`10 mg to 25 mg per week
`
`12 grams/m2 up to 15 grams/m2
`
`Based on information included in the approved labeling, it is presumed that the 1,000 mg size is
`used exclusively for preparing the High Dose Regimen.
`
`
`
`. When preparing the High Dose Regimen, the calculated dose must be diluted in a suitable
`
`Page 00003
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`

`

`~ P C H Methotrexate Injection, USP
`1, 000 mg/10 mL
`
`ANDA Suitability Petition
`
`"
`
`infusion solution. It is recommended that Methotrexate administered via the High Dose Regimen
`be infused over 4 hours.
`
`Based on Average Body Surface Area of 1 .7 m2, patients receiving the High Dose Regimen
`would require starting doses of 20.4 grams to 25.5 grams.
`
`In preparing such a dose, the practitioner would be required to reconstitute 20 to 26 vials of
`Methotrexate Preservative Free for Injection, USP. The total reconstituted volume would be
`400 mL to 520 mL.
`
`The proposed configuration, 1,000 mg of Methotrexate as a ready to use preservative free liquid
`at a concentration of 100 mg/mL would provide practitioners with a convenient alternative to the
`currently approved form. A copy of the medical rationale is provided in Attachment 1 .
`
`The proposed strength would allow for more convenient preparation of approved doses for
`patients with Average Body Surface Area both less than and greater than 1 .7 m2 . Because the
`total volume of drug in liquid form would be half of that compared to the reference listed drug, a
`practitioner would have greater flexibility in preparing the infusion solution.
`
`The proposed product clearly conforms to the dosage modifications and administration
`u
`recommendations listed in the approved package insert of the reference listed drug.
`
`Although the number of vials required to prepare a specific dose would not change, the proposed
`drug product would minimize the potential for contamination resulting from the handling of the
`product, such as blood borne pathogens from cut fingers and glass particles because it would not
`require reconstitution.
`
`The proposed presentation would also provide a reduction in hazardous waste disposal and cost
`for the course of therapy.
`
`The proposed drug is intended for use only as described in the Indications and Dosage and
`Administration sections of the approved labeling of the RLD. Draft labeling is provided in
`Attachment 2.
`
`Included in Attachment 3 is the package insert for Methotrexate Preservative Free for Injection
`USP marketed by Bedford Laboratores. The labeling for the proposed drug is identical to that of
`Bedford's Methotrexate Preservative Free for Injection USP, but differs only with respect to the
`product name, dosage preparation, final concentration and volume, the how-supplied statement,
`and the specific manufacturer's information.
`
`The proposed strength (1,000 mg/ 10 mL) does not pose a question of safety or efficacy because
`the uses, the doses, and the route of administration are the same as those of the RLD. The only
`
`Page 00004
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`

`

`~ P C H Methotrexate Ir jection, LISP
`1, 000 mg/10 mI
`
`ANDA Suitability Petition
`
`difference between the proposed products and the RLD is the dosage form (ready to use liquid
`versus lyophilized powder) and the final concentration of the drug (100 mg/mL versus 50 mg/mL
`when reconstituted with 19.4 mL of a suitable diluent). The proposed doses axe reflected in the
`approved labeling of the RLD. For the above reasons, the undersigned requests that the
`Commissioner approve this petition and find that an application for Methotrexate Injection, USP,
`1,000 mg/20mL (100 mg/mL) is suitable for submission as an ANDA.
`
`C. Environmental Impact
`
`In accord with 21 CFR 25 .24(c)(1), an Environmental Impact Analysis Statement is not required
`if there is a determination that Methotrexate Injection is suitable for ANDA status.
`
`D. Certification
`
`The undersigned certifies that, to the best knowledge and belief of the undersigned, this Petition
`includes all information and views on which the Petition relies, and that it includes representative
`data and information known to the Petitioner, which are unfavorable to the Petition.
`
`" We trust you will find the information in the Petition to be satisfactory for your review and
`approval. If there are any questions concerning this amendment, please do not hesitate in
`contacting me at (949) 457-2808 or Tania Hoffman, Project Specialist, Regulatory Affairs, at
`(949) 455-4728. We can also be contacted by facsimile at (949) 583-7351 .
`
`Sincerely,
`
`Rosalie A. Lowe
`Authorized Agent, Regulatory Affairs
`
`"
`
`Page 00005
`
`