208400Orig1s000 208400Orig2s000 OTHER …...Page 5 Version: January 2015 Name of drug(s) described...

CENTER FOR DRUG EVALUATION AND RESEARCH

APPLICATION NUMBER:

208400Orig1s000 208400Orig2s000

OTHER REVIEW(S)

1For 505(b)(2) applications that rely on a listed drug(s), bridging studies are often BA/BE studies comparing the proposed product to the listed drug(s) Other examples include: comparative physicochemical tests and bioassay; preclinical data (which may include bridging toxicology studies); pharmacokinetic/pharmacodynamic (PK/PD) data; and clinical data (which may include immunogenicity studies) A bridge may also be a scientific rationale that there is an adequate basis for reliance upon FDA’s finding of safety and effectiveness of the listed drug(s) For 505(b)(2) applications that rely upon literature, the bridge is an explanation of how the literature is scientifically sound and relevant to the approval of the proposed 505(b)(2) product

Page 3 Version: January 2015

RELIANCE ON PUBLISHED LITERATURE 4) (a) Regardless of whether the applicant has explicitly stated a reliance on published literature

to support their application, is reliance on published literature necessary to support the approval of the proposed drug product (i.e., the application cannot be approved as labeled without the published literature)?

YES NO If “NO,” proceed to question #5.

(b) Does any of the published literature necessary to support approval identify a specific (e.g., brand name) listed drug product?

YES NO If “NO”, proceed to question #5.

If “YES”, list the listed drug(s) identified by name and answer question #4(c).

(c) Are the drug product(s) listed in (b) identified by the applicant as the listed drug(s)? YES NO

Reference ID: 4089265


RELIANCE ON LISTED DRUG(S) Reliance on published literature which identifies a specific approved (listed) drug constitutes

reliance on that listed drug. Please answer questions #5-9 accordingly.

5) Regardless of whether the applicant has explicitly cited reliance on listed drug(s), does the application rely on the finding of safety and effectiveness for one or more listed drugs (approved drugs) to support the approval of the proposed drug product (i.e., the application cannot be approved without this reliance)?

If “NO,” proceed to question #10. 6) Name of listed drug(s) relied upon, and the NDA #(s). Please indicate if the applicant

explicitly identified the product as being relied upon (see note below):

Name of Listed Drug NDA # Did applicant specify reliance on the product? (Y/N)

Methotrexate Tablets NDA 008085 Yes

Applicants should specify reliance on the 356h, in the cover letter, and/or with their patent

certification/statement. If you believe there is reliance on a listed product that has not been explicitly identified as such by the applicant, please contact the (b)(2) review staff in the

Immediate Office, Office of New Drugs. 7) If this is a (b)(2) supplement to an original (b)(2) application, does the supplement rely upon

the same listed drug(s) as the original (b)(2) application? N/A YES NO

If this application is a (b)(2) supplement to an original (b)(1) application or not a supplemental application, answer “N/A”.

If “NO”, please contact the (b)(2) review staff in the Immediate Office, Office of New Drugs.

8) Were any of the listed drug(s) relied upon for this application: a) Approved in a 505(b)(2) application?

YES NO If “YES”, please list which drug(s).

Name of drug(s) approved in a 505(b)(2) application:

b) Approved by the DESI process? YES NO

If “YES”, please list which drug(s). Name of drug(s) approved via the DESI process: DESI 8085 for the oncology indication

c) Described in a final OTC drug monograph?

YES NO If “YES”, please list which drug(s).

YES NO



Name of drug(s) described in a final OTC drug monograph:

d) Discontinued from marketing?

YES NO If “YES”, please list which drug(s) and answer question d) i. below.

If “NO”, proceed to question #9. Name of drug(s) discontinued from marketing:

i) Were the products discontinued for reasons related to safety or effectiveness? YES NO

(Information regarding whether a drug has been discontinued from marketing for reasons of safety or effectiveness may be available in the Orange Book. Refer to section 1.11 for an explanation, and section 6.1 for the list of discontinued drugs. If a determination of the reason for discontinuation has not been published in the Federal Register (and noted in the Orange Book), you will need to research the archive file and/or consult with the review team. Do not rely solely on any statements made by the sponsor.)

9) Describe the change from the listed drug(s) relied upon to support this (b)(2) application (for example, “This application provides for a new indication, otitis media” or “This application provides for a change in dosage form, from capsule to solution”). The application provides for a new oral solution dosage form for methotrexate, and the application is limited to the indications of ALL and pJIA in pediatric patients.

The purpose of the following two questions is to determine if there is an approved drug product that is equivalent or very similar to the product proposed for approval that should be referenced as a listed drug in the pending application. The assessment of pharmaceutical equivalence for a recombinant or biologically-derived product and/or protein or peptide product is complex. If you answered YES to question #1, proceed to question #12; if you answered NO to question #1, proceed to question #10 below. 10) (a) Is there a pharmaceutical equivalent(s) to the product proposed in the 505(b)(2)

application that is already approved (via an NDA or ANDA)?

(Pharmaceutical equivalents are drug products in identical dosage forms intended for the same route of administration that: (1) contain identical amounts of the identical active drug ingredient, i.e., the same salt or ester of the same therapeutic moiety, or, in the case of modified release dosage forms that require a reservoir or overage or such forms as prefilled syringes where residual volume may vary, that deliver identical amounts of the active drug ingredient over the identical dosing period; (2) do not necessarily contain the same inactive ingredients; and (3) meet the identical compendial or other applicable standard of identity, strength, quality, and purity, including potency and, where applicable, content uniformity, disintegration times, and/or dissolution rates. (21 CFR 320.1(c), FDA’s “Approved Drug Products with Therapeutic Equivalence Evaluations” (the Orange Book)).

Note that for proposed combinations of one or more previously approved drugs, a pharmaceutical equivalent must also be a combination of the same drugs.



YES NO

If “NO” to (a) proceed to question #11. If “YES” to (a), answer (b) and (c) then proceed to question #12.

(b) Is the pharmaceutical equivalent approved for the same indication for which the 505(b)(2) application is seeking approval?

YES NO

(c) Is the listed drug(s) referenced by the application a pharmaceutical equivalent? N/A YES NO

If this application relies only on non product-specific published literature, answer “N/A” If “YES” to (c) and there are no additional pharmaceutical equivalents listed, proceed to question #12. If “NO” or if there are additional pharmaceutical equivalents that are not referenced by the application, list the NDA pharmaceutical equivalent(s); you do not have to individually list all of the products approved as ANDAs, but please note below if approved approved generics are listed in the Orange Book. Please also contact the (b)(2) review staff in the Immediate Office, Office of New Drugs. Pharmaceutical equivalent(s):

11) (a) Is there a pharmaceutical alternative(s) already approved (via an NDA or ANDA)?

(Pharmaceutical alternatives are drug products that contain the identical therapeutic moiety, or its precursor, but not necessarily in the same amount or dosage form or as the same salt or ester. Each such drug product individually meets either the identical or its own respective compendial or other applicable standard of identity, strength, quality, and purity, including potency and, where applicable, content uniformity, disintegration times and/or dissolution rates. (21 CFR 320.1(d)) Different dosage forms and strengths within a product line by a single manufacturer are thus pharmaceutical alternatives, as are extended-release products when compared with immediate- or standard-release formulations of the same active ingredient.) Note that for proposed combinations of one or more previously approved drugs, a pharmaceutical alternative must also be a combination of the same drugs.

YES NO

If “NO”, proceed to question #12.

(b) Is the pharmaceutical alternative approved for the same indication for which the 505(b)(2) application is seeking approval? YES NO

(c) Is the approved pharmaceutical alternative(s) referenced as the listed drug(s)?

N/A YES NO If this application relies only on non product-specific published literature, answer “N/A” If “YES” and there are no additional pharmaceutical alternatives listed, proceed to question #12.



If “NO” or if there are additional pharmaceutical alternatives that are not referenced by the application, list the NDA pharmaceutical alternative(s); you do not have to individually list all of the products approved as ANDAs, but please note below if approved generics are listed in the Orange Book. Please also contact the (b)(2) review staff in the Immediate Office, Office of New Drugs.

Pharmaceutical alternative(s): NDA 204824, NDA 205776, ANDA 040632, A089341, A040632, A089342, A089343, A089340, A040263, A040716, A040768, A040767, A040385

PATENT CERTIFICATION/STATEMENTS

12) List the patent numbers of all unexpired patents listed in the Orange Book for the listed drug(s) for which our finding of safety and effectiveness is relied upon to support approval of the (b)(2) product.

Listed drug/Patent number(s):

No patents listed proceed to question #14 13) Did the applicant address (with an appropriate certification or statement) all of the unexpired

patents listed in the Orange Book for the listed drug(s) relied upon to support approval of the (b)(2) product?

YES NO If “NO”, list which patents (and which listed drugs) were not addressed by the applicant.

Listed drug/Patent number(s):

14) Which of the following patent certifications does the application contain? (Check all that apply and identify the patents to which each type of certification was made, as appropriate.)

No patent certifications are required (e.g., because application is based solely on published literature that does not cite a specific innovator product)

21 CFR 314.50(i)(1)(i)(A)(1): The patent information has not been submitted to

FDA. (Paragraph I certification)

21 CFR 314.50(i)(1)(i)(A)(2): The patent has expired. (Paragraph II certification)

Patent number(s):

21 CFR 314.50(i)(1)(i)(A)(3): The date on which the patent will expire. (Paragraph

III certification)

Patent number(s): Expiry date(s): 21 CFR 314.50(i)(1)(i)(A)(4): The patent is invalid, unenforceable, or will not be

infringed by the manufacture, use, or sale of the drug product for which the application is submitted. (Paragraph IV certification). If Paragraph IV certification was submitted, proceed to question #15.



21 CFR 314.50(i)(3): Statement that applicant has a licensing agreement with the

NDA holder/patent owner (must also submit certification under 21 CFR 314.50(i)(1)(i)(A)(4) above). If the applicant has a licensing agreement with the NDA holder/patent owner, proceed to question #15.

21 CFR 314.50(i)(1)(ii): No relevant patents.

21 CFR 314.50(i)(1)(iii): The patent on the listed drug is a method of use patent and the labeling for the drug product for which the applicant is seeking approval does not include any indications that are covered by the use patent as described in the corresponding use code in the Orange Book. Applicant must provide a statement that the method of use patent does not claim any of the proposed indications. (Section viii statement)

Patent number(s): Method(s) of Use/Code(s):

15) Complete the following checklist ONLY for applications containing Paragraph IV certification and/or applications in which the applicant and patent holder have a licensing agreement:

(a) Patent number(s): (b) Did the applicant submit a signed certification stating that the NDA holder and patent

owner(s) were notified that this b(2) application was filed [21 CFR 314.52(b)]? YES NO

If “NO”, please contact the applicant and request the signed certification.

(c) Did the applicant submit documentation showing that the NDA holder and patent owner(s) received the notification [21 CFR 314.52(e)]? This is generally provided in the form of a registered mail receipt.

YES NO If “NO”, please contact the applicant and request the documentation.

(d) What is/are the date(s) on the registered mail receipt(s) (i.e., the date(s) the NDA holder

and patent owner(s) received notification):

Date(s): Note, the date(s) entered should be the date the notification occurred (i.e., delivery date(s)), not the date of the submission in which proof of notification was provided

(e) Has the applicant been sued for patent infringement within 45-days of receipt of the notification listed above?

Note that you may need to call the applicant (after 45 days of receipt of the notification) to verify this information UNLESS the applicant provided a written statement from the notified patent owner(s) that it consents to an immediate effective date of approval.

YES NO Patent owner(s) consent(s) to an immediate effective date of



approval


---------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signedelectronically and this page is the manifestation of the electronicsignature.---------------------------------------------------------------------------------------------------------/s/----------------------------------------------------

SADAF NABAVIAN04/25/2017


DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service

Division of Pediatric and Maternal HealthOffice of New Drugs

Center for Drug Evaluation and Research Food and Drug Administration

Silver Spring, MD 20993Tel 301-796-2200FAX 301-796-9744

Division of Pediatric and Maternal Health Review

Date: March 20, 2017 Date consulted: December 9, 2016

From: Christos Mastroyannis, M.D., Medical Officer, Maternal Health Division of Pediatric and Maternal Health (DPMH)

Through: John J Alexander, MD, Division Deputy DirectorDivision of Pediatric and Maternal Health

To: Office of Hematology and Oncology Products (OHOP)/ Division of Hematology Products (DHP) and Division of Pulmonary, Allergy, and Rheumatology Products (DPARP)

Drug: Xatmep [Methotrexate (MTX) Oral Solution]

Pharmacological Dihydrofolate inhibitor (folate analog metabolic Class: inhibitor)

Indications: Acute Lymphoblastic Leukemia (ALL)

Methotrexate Oral Solution is indicated for the treatment of pediatric patients with acute lymphoblastic leukemia (ALL) as part of a multi-phase, combination chemotherapy maintenance regimen.

Polyarticular Juvenile Idiopathic Arthritis (pJIA)Methotrexate Oral Solution is indicated in the management of children with active polyarticular juvenile idiopathic arthritis (pJIA).

NDA: 208400

Applicant: Silvergate Pharmaceuticals Inc. (Silvergate)


Subject: Pregnancy and Lactation Labeling

Materials Reviewed: December 9, 2016, combined DHP and DPARP consult request to

DPMH, DARRTS Reference ID 4025466 October 25, 2016, applicant’s resubmitted package for Methotrexate

Oral Solution, NDA 208400 (Original-1 and Original-2)o NDA 208400/Original-1 – Treatment of pediatric patients

with acute lymphoblastic leukemia (ALL) as part of a combination regimen.

o NDA 208400/Original-2 – Management of children with active polyarticular juvenile idiopathic arthritis (pJIA), who have had an insufficient therapeutic response to, or are intolerant of, an adequate trial of first-line therapy including full dose non-steroidal antiinflammatory agents (NSAIDs).

June 29, 2016, Complete Response (CR) for deficiencies in the manufacturing facility of the

June 20, 2016, Xatmep (Methotrexate) oral solution labeling review by Carol H. Kasten, M.D., DARRTS Reference ID 3948391

August 31, 2015, Original Submission for Methotrexate Oral Solution, NDA 208400.

Consult Question:

DHP and DPARP request DPMH input with Pregnancy and Lactation Labeling Rule (PLLR) for this NDA.


(b) (4)

INTRODUCTION

On August 31, 2015, Silvergate Pharmaceuticals Inc. (the applicant) submitted the New Drug Application for Xatmep (Methotrexate) oral solution, NDA 208400 Original-1 for the treatment of pediatric patients with acute lymphoblastic leukemia (ALL) as part of a combination regimen and Original-2 for the management of children with active polyarticular juvenile idiopathic arthritis (pJIA), who have had an insufficient therapeutic response to, or are intolerant of, an adequate trial of first-line therapy including full dose non-steroidal anti-inflammatory agents (NSAIDs). During that review cycle, a CR was issued for deficiencies in the manufacturing facility of the

In the same letter, the applicant was informed that the proposed prescribing information (PI) was not in compliance with PLLR (and PLR) labeling regulations (21 CFR 201.56(d) and 201.57) and not consistent with PLLR and PLR labeling guidances. The applicant was informed that in order to comply, they should submit a comprehensive, integrated review of the published literature sufficient to support the basis for the warnings related to methotrexate exposure during the periconceptional and prenatal periods, as well as the risk of infertility for females and males or reproductive potential following methotrexate exposure. Therefore, they should provide:

1. A comprehensive, integrated review of the published literature to support the Warnings and Precautions related to:

a. Embryo-fetal toxicity/fetal death/congenital anomaliesb. Effects on fertility and its duration

2. Propose labeling language for the Human Data sub-heading under Section 8.1 Pregnancy of the full prescribing information.

On October 25, 2016, Silvergate submitted the response to CR stating that deficiencies had been corrected and provided proposed prescribing information (PI) in PLLR format as per labeling regulations [21 CFR 201.56(d) and 201.57] and responded to the Division’s recommendation to provide a comprehensive, integrated review of the published literature regarding methotrexate and pregnancy and lactation and its effects on fertility in association with an upgraded to PLLR labeling and a safety update.

DHP and DPARP consulted the Division of Pediatric and Maternal Health (DPMH) on December 9, 2016, to provide input for appropriate labeling of the pregnancy and lactation subsections of the Xatmep labeling and to ensure compliance with the Pregnancy and Lactation Labeling Rule formatting requirements.

This review provides recommended revisions and structuring of information related to the Pregnancy, Lactation, and Females and Males of Reproductive Potential sections in labeling in order to provide clinically relevant information for prescribing decisions and to comply with current PLLR regulatory requirements.

REGULATORY HISTORY

December 7, 1953: NDA 008085 (tablet) was approved as a new molecular entity for: Neoplastic Diseases

The treatment of gestational choriocarcinoma, chorioadenoma destruens and hydatidiform mole.

Maintenance therapy in combination with other chemotherapeutic agents.


(b) (4)

(b) (4)

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.

PsoriasisMethotrexate is indicated in the symptomatic control of severe, recalcitrant, disabling psoriasis that is not adequately responsive to other forms of therapy, but only when the diagnosis has been established, as by biopsy and/or after dermatologic consultation. It is important to ensure that a psoriasis “flare” is not due to an undiagnosed concomitant disease affecting immune responses.

Rheumatoid Arthritis including Polyarticular-Course Juvenile Rheumatoid Arthritis 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).

August 10, 1959, NDA 011719 (injectable formulations) was approved for:1,2

Neoplastic Diseases The treatment of gestational choriocarcinoma, chorioadenoma destruens and

hydatidiform mole. In acute lymphocytic leukemia, in the prophylaxis of meningeal leukemia and is

used in maintenance therapy in combination with other chemotherapeutic agents. 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.

PsoriasisIn the symptomatic control of severe, recalcitrant, disabling psoriasis that is not adequately responsive to other forms of therapy, but only when the diagnosis has been established, as by biopsy and/or after dermatologic consultation. It is important to ensure that a psoriasis “flare” is not due to an undiagnosed concomitant disease affecting immune responses.

1 Clinical pharmacology online©, www.clinicalpharmacology-ip.com Elsevier. Gold Standard.Revision date: August 12, 2014. Accessed March 27, 2016.2 Drugs @FDA


Rheumatoid Arthritis including Polyarticular-Course Juvenile Rheumatoid ArthritisIn 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 non-steroidal anti-inflammatory agents (NSAIDs).

May 28, 2015: Orphan Drug Designation (ODD) granted for treatment of ALL in pediatric patients (0 to 16 years of age) for NDA 208400. August 31, 2015: Original submission of NDA 008085, a 505(b)(2) application by Silvergate that relies on the Agency’s previous findings of safety and effectiveness for a reference listed drug (RLD), Methotrexate Sodium Tablets, manufactured by DAVA Pharmaceuticals. Complete Response action was taken on June 29, 2016. October 25, 2016: Resubmission

BACKGROUND

Methotrexate Drug CharacteristicsMethotrexate (formerly Amethopterin) Oral Solution is an antimetabolite used in the treatment of pediatric patients with Acute Lymphoblastic Leukemia (ALL) and Polyarticular Juvenile Idiopathic Arthritis (pJIA). It belongs to the class of folate analog metabolic inhibitors. Half-life for low dose MTX is from 3 to 10 hours [for patients receiving treatment for psoriasis, or rheumatoid arthritis or low dose antineoplastic therapy (less than 30 mg/m2)], and for high doses is 8-15 hours [most clinicians reserve the term high-dose MTX (HDMTX) for doses ≥500 mg/m2 for oncology patients]. Some MTX may persist in tissues for extended periods of time. It is approximately 50% protein bound and has bioavailability approximately 60%. Its molecular weight is 454.45 Daltons.3

Methotrexate inhibits dihydrofolic acid reductase. Therefore, it interferes with DNA synthesis, repair, and cellular replication. Actively proliferating tissues such as malignant cells, bone marrow, fetal cells, buccal and intestinal mucosa, and cells of the urinary bladder are in general more sensitive to this effect of methotrexate.

Acute Lymphocytic Leukemia and Pregnancy (ALL)4

ALL is a rare disease with a peak incidence in children four to five years of age. The incidence drops gradually with a smaller peak incidence in adults over the age of 50 years.5 In childhood, ALL represents about 80% of the acute leukemias in the pediatric population. The etiology of ALL is unknown, although chromosomal translocations in utero have been suggested by some. ALL has been described in pregnant women (rare diagnosis).6,7

3 Existing MTX labeling4 Kasten, CH, Xatmep Labeling review in DARRTS , June 20, 2016. Reference ID 39483915 Jabbour E, Fullmer A, Faderl S. Chapter 1. Acute Lymphoblastic Leukemia. In: Kantarjian HM, WolffRA, Koller CA. eds. The MD Anderson Manual of Medical Oncology, 2e. New York, NY: McGraw-Hill;2011.6 Ali R, Özkalemka F, et al., Maternal and fetal outcomes in pregnancy complicated with acute leukemia: asingle institutional experience with 10 pregnancies at 16 years. Leukemia Research 27:381–385;20037 Nakajima Y, Hattori Y, et al. Acute leukemia during pregnancy: an investigative survey of the past 11years. Int Jnl Lab Hem 37:174–180;2015


Juvenile Idiopathic Arthritis (JIA) and PregnancyJIA is a heterogeneous group of diseases with an onset before age 16 years of age. It is the most prevalent rheumatologic disease affecting children, ranging from 16 to 150 affected children per 100,000 children.8 Lower doses of MTX are reported to be used to treat JIA compared to doses used to treat ALL. Despite the lower exposures, increased incidences of spontaneous abortions and congenital malformations have been reported among women with rheumatic diseases treated with MTX during pregnancy at doses less than or equal to 30 mg weekly.9,10

Methotrexate is used off label as an abortifacient (medical abortion) and as medical treatment of ectopic pregnancy.

Pregnancy and Lactation Labeling Rule (PLLR)On June 30, 2015, the “Content and Format of Labeling for Human Prescription Drug and Biological Products; Requirements for Pregnancy and Lactation Labeling,”11 also known as the Pregnancy and Lactation Labeling Rule (PLLR) went into effect. The PLLR requirements include a change to the structure and content of labeling for human prescription drug and biologic products with regard to pregnancy and lactation and create a new subsection for information with regard to females and males of reproductive potential. Specifically, the pregnancy categories (A, B, C, D and X) are removed from all prescription drug and biological product labeling and a new format is required for all products that are subject to the 2006 Physicians Labeling Rule12 format to include information about the risks and benefits of using these products during pregnancy and lactation.

RLD Methotrexate Sodium (Tablet) Labeling There is no previously approved labeling for Xatmep [Methotrexate (MTX) Oral Solution] because this manufacturer’s drug product has not been approved. See the applicant’s proposed labeling in Appendix 1. The existing labeling for Methotrexate Sodium Tablets, USP, dated January 2016, states:

BOXED WARNING

WARNINGS: Methotrexate has been reported to cause fetal death and/or congenital anomalies. Therefore, it is not recommended for women of childbearing potential unless there is clear medical evidence that

8 Rochette E, Duché P, Merlin E. Juvenile idiopathic arthritis and physical activity: Possible inflammatoryand immune modulation and tracks for interventions in young populations. Autoimmunity Reviews14:726–734;20159 Rheumatic diseases included rheumatoid arthritis, psoriasis/psoriatic arthritis, systemic lupuserythematosus, inflammatory bowel disease, ankylosing spondylitis/Bechterew’s disease10 Weber-Schoendorfer C, Chambers C, et al., Pregnancy Outcome After Methotrexate Treatment forRheumatic Disease Prior to or During Early Pregnancy. Arthritis & Rheumatology 66:1101 – 1110.;201411 Content and Format of Labeling for Human Prescription Drug and Biological Products, Requirements for Pregnancy and Lactation Labeling (79 FR 72063, December 4, 2014).12 Requirements on Content and Format of Labeling for Human Prescription Drug and Biological Products, published in the Federal Register (71 FR 3922; January 24, 2006).


the benefits can be expected to outweigh the considered risks. Pregnant women with psoriasis or rheumatoid arthritis should not receive methotrexate (see CONTRAINDICATIONS).

CONTRAINDICATIONS:Methotrexate can cause fetal death or teratogenic effects when administered to a pregnant woman. Methotrexate is contraindicated in pregnant women with psoriasis or rheumatoid arthritis and should be used in the treatment of neoplastic diseases only when the potential benefit outweighs the risk to the fetus. Women of childbearing potential should not be started on methotrexate until pregnancy is excluded and should be fully counseled on the serious risk to the fetus (see PRECAUTIONS) should they become pregnant while undergoing treatment. Pregnancy should be avoided if either partner is receiving methotrexate; during and for a minimum of three months after therapy for male patients, and during and for at least one ovulatory cycle after therapy for female patients (see BOXED WARNINGS).Because of the potential for serious adverse reactions from methotrexate in breast fed infants, it is contraindicated in nursing mothers.

PRECAUTIONS:Carcinogenesis, Mutagenesis, Impairment of FertilityNo controlled human data exist regarding the risk of neoplasia with methotrexate. Methotrexate has been evaluated in a number of animal studies for carcinogenic potential with inconclusive results. Although there is evidence that methotrexate causes chromosomal damage to animal somatic cells and human bone marrow cells, the clinical significance remains uncertain. Non-Hodgkin’s lymphoma and other tumors have been reported in patients receiving low-dose oral methotrexate. However, there have been instances of malignant lymphoma arising during treatment with low-dose oral methotrexate, which have regressed completely following withdrawal of methotrexate, without requiring active anti-lymphoma treatment. Benefits should be weighed against the potential risk before using methotrexate alone or in combination with other drugs, especially in pediatric patients or young adults. Methotrexate causes embryotoxicity, abortion, and fetal defects in humans. It has also been reported to cause impairment of fertility, oligospermia and menstrual dysfunction in humans, during and for a short period after cessation of therapy.

PregnancyPsoriasis and rheumatoid arthritis: Methotrexate is in Pregnancy Category X (see CONTRAINDICATIONS).

Nursing Mothers(see CONTRAINDICATIONS).

REVIEWPREGNANCYAnimal DataNo new nonclinical studies have been initiated with Methotrexate Oral Solution since the initial


submission of NDA 208400 on August 31, 2015. During this original submission, the applicant states that FDA agreed to Silvergate’s proposal to reference the nonclinical sections of the DAVA package insert for labeling of their 505(b)(2) NDA. The applicant provided a literature search of nonclinical effects of MTX exposure on pregnancy. Embryonic toxicity has been observed in cats, and embryonic toxicity and teratogenicity has been observed in rats, mice, and rabbits.13 Embryonic and fetal toxicity and congenital defects have been observed in different species. MTX was determined to be highly embryotoxic, but not teratogenic.14 Monkeys receiving MTX at different doses and durations (gestation days 17 to 45) showed evidence of embryonic toxicity with observations of abnormal ossification of long bones and thoracic vertebrae.13 For more detailed review of animal data, the reader is referred to the information request (IR) response by the applicant of June 22, 2016. DHP and DPARP nonclinical teams have concluded that animal data will not be added to labeling because a large body of human data is available from published references and because there are no animal data that meet current standards for nonclinical developmental toxicity studies.4

Human DataReview of LiteratureThe applicant conducted a literature search in PubMed and the following search topics were evaluated through June 3, 2016. The search was limited to literature published in English and literature associated with clinical trials and case reports. Methotrexate and pregnancy and pregnancy registry Methotrexate and embryonic toxicity Methotrexate and fetal toxicity Methotrexate and fetal death Methotrexate and congenital abnormalities/anomalies and birth defects Methotrexate and reproduction Methotrexate and infertility Methotrexate and fertility Methotrexate and breast milk Methotrexate and lactationThe applicant states that of the 2170 articles identified, 2070 were removed from further consideration because: General relevance Duplication (i.e., same article appearing in results from more than 1 search term) No substantive data or information (ie, no specific pregnancy, lactation, or reproductive potential results were provided within the article) Irrelevant indication (methotrexate for off label use) Methotrexate administered in combination with other therapies and methotrexate monotherapy was not included/discussed.

DPMH also searched PubMed, Embase, ReproTox and TERIS databases for information regarding MTX and use during pregnancy.

In humans, MTX has been reported to produce abnormalities referred to as the

13 Lloyd ME , Carr M , McElhatton P, Hall GM, Hughes RA. The Effects of Methotrexate on Pregnancy, Fertility and Lactation. QJM 92 (10), 551-563, 199914 Gastrol-Lewinska L:Evaluation of toxicity and teratogenicity of drugs. Pol. J. Pharm. Pharmacol, 25,327-339;1973


aminopterin/methotrexate syndrome and are similar to those observed in animals. The most characteristic features of the syndrome include growth deficiency, dysmorphic faces, multiple skull and limb skeletal abnormalities, and less frequently, central nervous system abnormalities and congenital heart defects. Recently, developmental disabilities and mental retardation have been described in children or adults after in utero exposure.15,16,17,18 The incidence of these effects, approximately 6%, is higher than the normal background rate of 2% to 4% observed in the general population.19 Methotrexate is widely distributed within the body (kidneys, gallbladder, spleen, liver, and skin) with half-life up to 15 hours. Prolonged presence of methotrexate (reported up to 116 days after exposure) in the liver creates an inherent risk in infants of mothers who have received methotrexate at any dose prior to conception.20 A prospective study evaluated data from the Organization of Teratogen Information Services (OTIS) and the European Network of Teratology Information Services (ENTIS) registries to assess pregnancy outcome in women on low-dose methotrexate prior to conception. The study reported on 21 prospectively ascertained cases, 9 pregnancies exposed to methotrexate within 1 year prior to conception, 5 exposures occurred during pregnancy and 7 exposures occurred prior to 1 year of conception (the last seven were excluded from the analysis). Of the 9 pregnancies exposed to methotrexate within 1 year prior to conception, 4 resulted in first trimester spontaneous abortions and 5 resulted in full term healthy infants of which 1 had a cavernous hemangioma, while of the 5 exposures during pregnancy, all delivered healthy term newborns (4 were exposed during the first trimester, and 1 in third trimester).21 Feldkamp and Carey (1993) identified 20 first trimester maternal exposures to methotrexate with varied timing and dosage. Of those liveborn infants (N=17), three had congenital malformations identified as “aminopterin/methotrexate syndrome”.22 In another trial of 445 women treated with MTX or MTX plus one additional agent for gestational trophoblastic disease, 49% of all women studied conceived and 86% had at least one live birth. Among the 281 live births and stillbirths in the study there was no statistically significant excess of congenital malformations. No increase incidence of miscarriages was observed.23

Prenatal exposure to MTX in the first trimester may lead to fetal death and/or create an increased risk of developing fetal aminopterin/ methotrexate syndrome (FMS).18 Several clinical reports evaluating methotrexate during the first trimester of pregnancy report the critical timeframe for methotrexate-induced teratogenicity as 6 to 10 weeks after conception (ie, 8 to 10 weeks of gestation).16,20,21

Methotrexate use in late pregnancy is also contraindicated due to its inherent risk of spontaneous

15 Lewden B, Vial T, Elefant E, Nelva A,et.al: Low Dose Methotrexate in the First Trimester of Pregnancy: Results of a French Collaborative Study. The Journal of Rheumatology 31 :12:2360-65,200416Backley LM, Bullaboy CA, Leichtman L, Marquez M. Multiple congenital anomalies associated with weekly low-dose methotrexate treatment of the mother. Arthritis Rheum ;40:971-3, 199717Boley EV, Conard JV, Weiss L. Adult and two children with fetal methotrexate syndrome. Teratology;57:51-5, 1998.18 Del Campo M, Kosaki K, Bennett FC, Jones KL. Developmental delay in fetal aminopterin/methotrexate syndrome. Teratology. 60:10-2,1990.19 Visser K, Katchamart W, Loza E, et al. Multinational evidence-based recommendations for the use of methotrexate in rheumatic disorders with a focus on rheumatoid arthritis: integrating systematic literature research and expert opinion of a broad international panel of rheumatologists in the 3E Initiative. Ann Rheum Dis. 68:1086-1093;200920 Charache S, Condit PT, Humprheys SR. Studies on the folic acid vitamins – IV. The persistence of aminopterin in mammalian tissues. Cancer. 13:236-240;1960.21 Donnenfeld AE. Methotrexate exposure prior to and during pregnancy. Teratology.49:79-81;199422 Feldkamp, M., and J .C. Carey. Clinical teratology counseling and consultation case report: Low dose methotrexate in the early weeks of pregnancy. Teratology, 47:533-539;1993.23 Rustin GJS, Booth M, Dent J, et al. Pregnancy after cytotoxic chemotherapy for gestationaltrophoblastic tumours. BMJ;288:103-106;1984


abortion, fetal growth retardation, and functional abnormalities in the exposed.13

Pregnancy outcome in women taking methotrexate ≤ 30 mg per week for rheumatic diseases either after conception or within 12 weeks before conception was compared to pregnancy outcome in women who did not receive methotrexate. The study sample consisted of 324 methotrexate-exposed pregnancies (188 exposed post-conception, 136 exposed preconception), 459 disease matched comparators, and 1,107 comparators without autoimmune disease. In the post-conception cohort, the cumulative incidence of spontaneous abortion was 42.5% (95% confidence interval [95% CI] 29.2, 58.7), which was significantly greater than either comparator group (22.5% in disease-matched comparators and 17.3% in nonautoimmune disease comparators)24 while Visser et al, reported that the rate of miscarriages was greater in women treated with methotrexate (approximately 24%) than in healthy women (12% to 16%).25

Reprotox25 states “Methotrexate increases the incidence of congenital anomalies in experimental animals and appears to do so in humans as well. A critical period for exposure of 6-8 weeks after fertilization and a critical dose of 10 mg/week have been described, although not universally accepted. A controlled study of human exposures up to 30 mg/week suggested an approximate doubling of the malformation risk”. In a review of case reports, authors have suggested that the maternal methotrexate dose that is associated with developmental anomalies is more than 10 mg per week, and a critical period for exposure was described as 6 through 8 weeks after conception.21 Reprotox states that given the small number of available case reports, the limited details on the timing of methotrexate exposures in some cases and the existence of case reports suggesting congenital abnormalities in pregnancies involving exposure at 20 mg/week,13,26,27 any delineation of a narrow critical period for exposure (6 to 8 weeks) and a consistently safe threshold dose is considered tentative. Some authors have recommended that women who stop taking methotrexate during gestation be offered folinic acid for at least 5 months to minimize possible adverse effects on the fetus.13

The National Birth Defects Prevention Study found that 0.06% (16 cases) of women having live-born infants with major birth defects reported exposure to MTX between 3 months before conception through the end of pregnancy.28 The percentage of women having a live-born infant without a birth defect who were exposed to methotrexate was 0.04%. Eleven of the 16 case infants had a congenital heart defect (CHD) including atrial and ventricular septal defect, total anomalous pulmonary venous return, tetralogy of Fallot (1 case), valvular pulmonic stenosis (1 case), and double-inlet left ventricle with transposition of the great arteries (1 case). Exposure timing for cases with CHD varied. All cases that were exposed during the preconceptional period and the case exposed in the second trimester had at least one CHD, while five of 10 cases exposed during the first trimester had CHD. The non-cardiac cases had cleft palate, hypospadias, congenital diaphragmatic hernia, or

24 Weber-Schoendorfer C, Chambers C, Wacker E, et al. Pregnancy outcome after methotrexate treatment for rheumatic disease prior to or during early pregnancy. Arthritis Rheumatol. a;66(5):1101-1110;2014.25 Truven Health Analytics, Micromedex Solutions26 Buckley LM, Bullaboy CA, Leichtman L, Marquez M: Multiple congenital anomalies associated with weekly low-dose methotrexate treatment of the mother. Arthritis Rheum 40:971-973, 199727 Martin MC, Barbero P, Groisman B, Aguirre MA, Koren G: Methotrexate embryopathy after exposure to low weekly doses in early pregnancy. Reprod Toxicol;43, 26-29. http://dx.doi.org/10.1016/j.reprotox.2013.10.005;201428 Dawson AL, Riehle-Colarusso T, Reefhuis J, Arena JF, and the National Birth Defects Prevention Study. Maternal exposure to methotrexate and birth defects: a population-based study. Am J Med Genet Part A. 164A: 2212-2216;2014.


craniosynostosis. The authors suggested a possible association between gestational methotrexate use and congenital heart defects.

Review of pharmacovigilance databaseThe drug has not yet been approved; therefore, there are no postmarketing cases; however, review of clinical trials across the Xatmep clinical program, reported no pregnancies. The applicant did not conduct studies with Xatmep [Methotrexate (MTX) Oral Solution] in pregnant women.

SummaryThere are no clinical data from trials the applicant performed that contribute to any safety conclusions about the effects of Xatmep during pregnancy. From review of the literature, it appears that the risk associated with maternal Xatmep treatment during pregnancy may be substantial, causing embryo-fetal toxicity, including fetal death. Xatmep use in patients with pJIA should be contraindicated during pregnancy. When prescribing Xatmep to a pregnant patient with ALL, the benefits and risks of Xatmep should be evaluated and discussed with the pregnant woman.

LACTATIONAnimal DataThere is no nonclinical experience with methotrexate (MTX) Oral Solution and lactation provided by the applicant.

Human DataReview of literatureReview of the literature (14 publications) provided by the applicant indicates the transfer of methotrexate to breast milk is limited, and low concentrations have been observed within 24 hours postdose.32,33

DPMH conducted a search of Medications and Mother’s Milk29,30, the Drugs and Lactation Database (LactMed)31, Micromedex, and of published literature in PubMed using the search terms “methotrexate (MTX) Oral Solution and lactation” and “methotrexate (MTX) Oral Solution and breastfeeding.”

Following administration of 22.5 mg of methotrexate per day, orally, methotrexate was detectable in the milk within 2 hours and the peak concentration (5.0 X 10-9 M) was reached by 10 hours postdose.32 The cumulative excretion of methotrexate in milk within 12 hours postdose was 0.32 µg, and 98% of this was in the lipid insoluble form. Following weekly administration of 25 mg

29 Nice, F and Luo, Amy. Medications and breast-feeding: Current Concepts. Journal of the AmericanPharmacists Association. 2012;30 Hale, Thomas (2012) Medications and Mothers’ Milk. Amarillo, Texas Hale Publishing,31 http://toxnet nlm nih.gov/cgi-bin/sis/htmlgen?LACT. The LactMed database is a National Library of Medicine (NLM) database with information on drugs and lactation geared toward healthcare practitioners and nursing women. The LactMed database provides information when available on maternal levels in breast milk, infant blood levels, any potential effects in the breastfed infants if known, alternative drugs that can be considered and the American Academy of Pediatrics category indicating the level of compatibility of the drug with breastfeeding32 Johns DG, Rutherford LD, Leighton PC, et al. Secretion of methotrexate into human milk. Am JObstet Gynecol.;112(7):978-80;1972.


methotrexate, concentrations in breast milk were detectable, but below the quantifiable limit at 2, 12, and 24 hours postdose. The estimated dose for the breastfed infant was 3.4 µg/kg/day.33 Briggs34 acknowledges the maximum milk:plasma (M:P) ratio of 0.08 would indicate that the breastfeeding infant of a woman treated with MTX would have low MTX exposure; similarly, the weight-adjusted maternal dose of 1% indicates the MTX exposure to the breastfed infant would be low. However, the Briggs review raises a concern that MTX may accumulate in infant tissue.

LactMed states that chemotherapy may adversely affect the normal microbiome and chemical makeup of breastmilk.35 An abstinence period of at least 1 week after chemotherapy doses of MTX has been suggested.36 Because low levels of MTX has been observed in milk, some authors consider that low single or weekly doses are of low risk to the breastfed infant,37,38,39,40 although some expert opinion warns against this use.41,42,43

Reviewer CommentIf breastfeeding during long-term, low-dose MTX use is undertaken, monitoring of the infant's complete blood count and differential could be considered.

Micromedex/Reprotox states that “Although the amount of methotrexate ingested daily through milk would be less than 0.5% of the pediatric therapeutic dose of this drug (0.12 mg/kg),44 the possible accumulation of this agent in neonatal tissues is a concern that has led the American Academy of Pediatrics to list methotrexate among cytotoxic drugs that “may interfere with cellular metabolism” in a nursing infant.13,45 The WHO Working Group on Drugs and Human Lactation did not recommend breastfeeding during the maternal use of this drug unless no alternative was available”.44 A

33 Thorne JC, Nadarajah T, Moretti M, et al. Methotrexate use in a breastfeeding patient withrheumatoid arthritis. Rheumatol;41(11):2332;201434 Briggs, G, Freeman, R. Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and NeonatalRisk, 10th ed. Philadelphia, Pa.: Lippincott Williams & Wilkins, 201535 Urbaniak C, McMillan A, Angelini M et al. Effect of chemotherapy on the microbiota and metabolome of human milk, a case report. Microbiome. 2:24;201436 Pistilli B, Bellettini G, Giovannetti E et al. Chemotherapy, targeted agents, antiemetics and growth-factors in human milk: How should we counsel cancer patients about breastfeeding? Cancer Treat Rev. 39:207-11;201337 Johns DG, Rutherford LD et al. Secretion of methotrexate in human milk. Am J Obstet Gynecol. 112:978-80;197238 Moretti ME, Lee A, Ito S. Which drugs are contraindicated during breastfeeding? Can Fam Physician. 46:1753-7;200039 Tanaka T, Walsh W, Verjee Z et al. Methotrexate use in a lactating woman with an ectopic pregnancy. Birth Defects Res A Clin Mol Teratol. 85:494;2009. Abstract.40 Thorne JC, Nadarajah T, Moretti M, Ito S. Methotrexate use in a breastfeeding patient with rheumatoid arthritis. J Rheumatol. 41:2332;201441 Nguyen GC, Seow CH, Maxwell C et al. The Toronto Consensus Statements for the Management of IBD in Pregnancy. Gastroenterology. 150:734-57;201642 Mahadevan U, Matro R. Care of the pregnant patient with inflammatory bowel disease. Obstet Gynecol. 126:401-12;201543 Kavanaugh A , Cush JJ, Ahmed MS et al. Proceedings from the American College of Rheumatology Reproductive Health Summit: The management of fertility, pregnancy, and lactation in women with autoimmune and systemic inflammatory diseases. Arthritis Care Res (Hoboken). 67:313-25.;201544 The WHO Working Group, Bennet PN (ed).: Drugs and Human Lactation. Elsevier, Amsterdam, New York, Oxford, pp. 369-70;1988.45 Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human breast milk. Pediatrics 108:776-89, 2001


recommendation to avoid breastfeeding during methotrexate therapy was included among the 2016 Toronto Consensus Statements for the Management of Inflammatory Bowel Disease in Pregnancy.46

Review of pharmacovigilance databaseThe applicant provided no information.

Summary:Limited published literature report the presence of methotrexate in human milk in low amounts. The highest breast milk to plasma concentration ratio demonstrated was 0.08:1. No information is available on the effects of methotrexate on a breastfed infant or on milk production.

The effects on the breastfed infant are unknown. Because of the potential for serious adverse reactions, including myelosuppression, from methotrexate in breastfed infants, DPMH agrees with the applicant’s recommendation not to breastfeed during treatment with Xatmep therapy.

FEMALES AND MALES OF REPRODUCTIVE POTENTIALInfertilityNonclinical ExperienceNo dedicated fertility studies have been performed with methotrexate oral solution. There are no animal data that meet current standards for nonclinical studies. Therefore, nonclinical information will not be reported in the labeling.

Review of Literature

FemaleTreatment with methotrexate does not appear to negatively affect female fertility.13,47

Three randomized trials in women with ectopic pregnancies treated with methotrexate or surgery found equivalent preservation of fertility between the 2 treatment arms.48,49,50

Another study of 445 women treated with methotrexate treatment for gestational trophoblastic disease found that 97% of the women who wanted to become pregnant post-treatment had conceived and 86% had at least 1 live birth.22

DPMH’s search of published literature in PubMed and Embase and Micromedex regarding MTX and its effects on fertility showed forty-five pregnancies conceived within 6 months of methotrexate

46 Nguyen GC, Seow CH, Maxwell C, et al; IBD in Pregnancy Consensus Group. The Toronto Consensus Statements for the Management of Inflammatory Bowel Disease in Pregnancy. Gastroenterology. 150(3):734-757.e1;201647 Janssen NM, Genta MS. The effects of immunosuppressive and anti-inflammatory medications on fertility, pregnancy, and lactation. Arch Intern Med.160(5):610-9;200048 Dias Pereira G, Hajenius PJ, Mol BW, et al. Fertility outcome after systemic methotrexate andlaparoscopic salpingostomy for tubal pregnancy. Lancet.353:724-725;199949 Fernandez H, Capmas P, Lucot JP, Resch B, Panel P, Bouyer J. Fertility after ectopic pregnancy: the DEMETER randomized trial. Hum Reprod. 28:1247-1253;201350 rag Moeller LB, Moeller C, Thomsen SG, et al. Success and spontaneous pregnancy rates following systemic methotrexate versus laparoscopic surgery for tubal pregnancies: a randomized trial. Acta Obstet Gynecol Scand. 88:1331-1337.;2009


treatment were not found to have outcomes different from the outcome of 80 pregnancies conceived more than 6 months after therapy.51 A 2014 study investigated a possible adverse relationship between MTX use for childhood-onset systemic lupus erythematosus and adult ovarian reserve evaluated by FSH, LH, estradiol, anti-Müllerian hormone and antral follicle count.52 Fifty-seven adult female patients with childhood-onset systemic lupus erythematosus (c-SLE) and 21 healthy controls were evaluated for anti-corpus luteum antibodies (anti-CoL) and ovarian reserve. High cumulative methotrexate dosing was proposed as a possible cause of subclinical ovarian dysfunction in adult lupus patients because 19 patients in the study, treated only with methotrexate, showed a negative correlation between cumulative methotrexate dose and anti-Müllerian hormone concentrations.

MaleRegarding male fertility, overall no adverse outcomes of pregnancies have been reported among fathers who were exposed to methotrexate prior to conception53 and no long-term effects on fertility have been observed in men receiving methotrexate.13 Toxic effects of methotrexate on gonadal function are inferred from studies in which this agent, along with other agents used for cancer therapy, was associated with azoospermia or oligospermia in men and amenorrhea in women. In several cases, the testicular and ovarian abnormalities were reversible.54,55,56 There have also been reports of normal children born to men and women treated with methotrexate-containing regimens.49,57,58 It is not known how often methotrexate treatment is compatible with normal reproduction; the rate might depend on whether other chemotherapeutic agents or radiation have been co-administered.

Review of Pharmacovigilance DatabaseThe applicant provided no information.

ContraceptionDue to the potential for adverse developmental outcomes, females of reproductive potential should use effective contraception during treatment with Methotrexate (MTX) Oral Solution. Overall, the recommendations in the literature state that women should discontinue methotrexate at least 3 months13,25,47 before attempting to conceive, and that men should wait at least 3 months after

51 Svirsky R, Rozovski U, Vaknin Z, Pansky M, Schneider D, Halperin R. The safety of conception occurring shortly after methotrexate treatment of an ectopic pregnancy. Reprod Toxicol 27:85-87;200952de Araujo DB, Yamakami LY, Aikawa NE, Bonfa E, Viana VS, Pasoto SG, Pereira RM, Serafin PC, Borba EF, Silva CA. Ovarian reserve in adult patients with childhood-onset lupus: a possible deleterious effect of methotrexate. Scand J Rheumatol 43(6): 503-511;2014 53 French AE, Koren G. Effect of methotrexate on male fertility. Can Fam Physician. 49:577-578;200354 Evenson DP et al: Male reproductive capacity may recover following drug treatment with the L-10 protocol for acute lymphocytic leukemia. Cancer 53:30-6, 1984.55 Shamberger RC et al: Effects of high-dose methotrexate and vincristine on ovarian and testicular functions in patients undergoing postoperative adjuvant treatment of osteosarcoma. Cancer Treat Rep 65:739-46, 1981.56 Longhi A, Macchiagodena M, Vitali G, Bacci G: Fertility in male patients treated with neoadjuvant chemotherapy for osteosarcoma. J Pediatr Hematol Oncol 25(4):292-6;200357 Wallenius M, Lie E, Daltvelt AK, Salvesen KA, Skomvoll JF, Kalstad S, Lexberg AS, Mikkelsen K, Kvien TK, Ostensen M. No excess risks in offspring with paternal preconception exposure to disease-modifying antirheumatic drugs. Arthritis Rheumatol 67(1): 296-301;201558 Weber-Schoendorfer C, Hoeltzenbein M, Wacker E, Meister R, Schaefer C. No evidence for an increased risk of adverse pregnancy outcome after paternal low-dose methotrexate: an observational cohort study. 53(4): 757-763;2014


methotrexate cessation before attempting to conceive. 25,59

Reviewer CommentBecause MTX has a likelihood of embryofetal toxicity, this reviewer recommends that females of reproductive potential use effective contraception during treatment and for 6 months following completion of treatment because of the potential for adverse fetal and infant effects from maternal exposure (for cytotoxic drugs: 6 x terminal half-life plus extra time because MTX may persist in tissues for extended period). Males with female partners of reproductive potential should use effective contraception during and for 3 months after the final methotrexate dose [3 months (one spermatogenesis cycle) for cytotoxic drugs with short half-life (less than 10 days)].

Summary

In general, it appears that MTX does not affect female or male fertility. Because toxic effects of methotrexate on gonadal function are inferred from studies in which this agent, along with other agents used for cancer therapy, was associated with azoospermia or oligospermia in men and amenorrhea in women, females and males of reproductive potential should be advised that Xatmep may cause impairment of fertility. It is not known if infertility may be reversed in all affected individuals.

CONCLUSIONSThe Pregnancy, Lactation, and Females and Males of Reproductive Potential subsections of Xatmep labeling were structured to be consistent with the PLLR as follows:

Pregnancy, Section 8.1

The “Pregnancy” section of Xatmep labeling was formatted in the PLLR format to include “Risk Summary” and “Data” subsections. 60

Lactation, Section 8.2

The “Lactation” subsection of Xatmep labeling was formatted in the PLLR format to include the “Risk Summary” subsection. 61

Females and Males of Reproductive Potential, Section 8.3

The “Females and Males of Reproductive Potential” subsection of Xatmep labeling was formatted in the PLLR format to include the headings:

o Pregnancy testing

59 Morris LF, Harrod MJ, Menter MA, Silverman AK. Methotrexate and reproduction in men: casereport and recommendations. J Am Acad Dermatol. 29:913-916;199360 Guidance for Industry: Pregnancy, Lactation, and Reproductive Potential: Labeling for Human Prescription Drug and Biological Products-Content and Format. December 2014. Part IV Specific Subsection A-8.1 Pregnancy, 2-Risk Summary

61 Guidance for Industry: Pregnancy, Lactation, and Reproductive Potential: Labeling for Human Prescription Drug and Biological Products-Content and Format. December 2014. Part IV Specific Subsection, B- 8.2 Lactation, 1- Risk Summary


o Contraception o Infertility (Females and males)

Patient Counseling Information, Section 17

The “Patient Counseling Information” section of Xatmep labeling was updated to correspond with changes made to sections 5.9, 8.1, 8.2 and 8.3 of labeling.

RECOMMENDATIONS

The below recommendations include DPMH revised sections 5.9, 8.1, 8.2, 8.3 and 17 of Xatmep labeling for compliance with the PLLR and agreed upon by DHP and DPARP during the labeling meeting of February 21, 2017. DPMH refers to the final NDA action for final labeling.


HIGHLIGHTS OF PRESCRIBING INFORMATION

WARNING: SEVERE TOXIC REACTIONS, INCLUDING EMBRYO-FETAL TOXICITY

See full prescribing information for complete boxed warning.

Methotrexate can cause embryo-fetal toxicity and fetal death. Use in polyarticular juvenile idiopathic arthritis is contraindicated in pregnancy (4). Consider the benefits and risks of XATMEP and risks to the fetus when prescribing XATMEP to a pregnant patient with a neoplastic disease. Advise patients to use effective contraception during and after treatment with XATMEP (5.9, 8.1, 8.3).

-------------------------CONTRAINDICATIONS-------------------------Pregnancy (patients with pJIA) (4)

----------------WARNINGS AND PRECAUTIONS-------------Effects on reproduction: May cause impairment of fertility, oligospermia and menstrual dysfunction (5.11, 8.3).

----------------

USE IN SPECIFIC POPULATIONS------------------Lactation: Advise women not to breastfeed. (8.2).

FULL PRESCRIBING INFORMATION: CONTENTS 8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy8.2 Lactation8.3 Females and Males of Reproductive Potential

FULL PRESCRIBING INFORMATION4 CONTRAINDICATIONSXATMEP is contraindicated in the following:Pregnancy: in patients with non-malignant diseases. XATMEP can cause embryo-fetal toxicity and fetal death when administered during pregnancy [see Warnings and Precautions (5.9), Use in Specific Populations (8.1)].


5 WARNINGS AND PRECAUTIONS5.9 Embryo-fetal Toxicity

Based on published reports and methotrexate’s mechanism of action, methotrexate can cause embryo-fetal toxicity and fetal death when administered to a pregnant woman. In pregnant women with non-malignant diseases, methotrexate is contraindicated. Consider the benefits and risks of XATMEP and risks to the fetus when prescribing XATMEP to a pregnant patient with a neoplastic disease. Advise females of reproductive potential to use effective contraception during therapy and for 6 months after the final dose. Advise males of reproductive potential to use effective contraception during and for at least 3 months after the final methotrexate dose [see Contraindications (4), Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)].

5.11 Effects on Reproduction

Based on published reports, methotrexate can cause impairment of fertility, oligospermia, and menstrual dysfunction. It is not known if the infertility is reversible in affected patients. Discuss the risk of effects on reproduction with female and male patients [see Use in Specific Populations (8.3)].

8 USE IN SPECIFIC POPULATIONS8.1 PregnancyRisk SummaryBased on published reports and methotrexate’s mechanism of action, methotrexate is a teratogen that can cause embryo-fetal toxicity and fetal death when administered to a pregnant woman [see Data and Clinical Pharmacology (12.1)]. In pregnant women with non-malignant disease, XATMEP is contraindicated. Consider the benefits and risks of XATMEP and risks to the fetus when prescribing XATMEP to a pregnant patient with a neoplastic disease.

The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

DataHuman Data Published data from cases, literature reviews, and observational studies report that methotrexate exposure during pregnancy is associated with an increased risk of embryo-fetal toxicity and fetal death. Methotrexate exposure during the first trimester of pregnancy is associated with an increased incidence of spontaneous abortions and multiple adverse developmental outcomes, including skull anomalies, facial dysmorphism, central nervous system abnormalities, limb abnormalities, and sometimes cardiac anomalies and intellectual impairment. Adverse outcomes associated with exposure during second and third trimesters of pregnancy include intrauterine growth restriction and functional abnormalities. Because methotrexate is widely distributed and persists in the body for a prolonged period, there is a potential risk to the fetus from preconception methotrexate exposure.

A prospective multicenter study by U.S. and European teratology information services evaluated


pregnancy outcomes in women taking methotrexate less than or equal to 30 mg/week after conception. The rate of spontaneous abortion/miscarriage in pregnant women exposed to methotrexate was 42.5% (95% confidence interval [95% CI] 29.2-58.7), which was higher than in unexposed autoimmune disease comparators (22.5%, 95% CI 16.8-29.7) and unexposed nonautoimmune disease comparators (17.3%, 95% CI 13-22.8). Of the live births, the rate of major birth defects in pregnant women exposed to methotrexate after conception was higher than in autoimmune disease comparators (adjusted odds ratio (OR) 1.8 [95% CI 0.6-5.7]) and nonautoimmune disease comparators (adjusted OR 3.1 [95% CI 1.03-9.5]). Major birth defects associated with pregnancies exposed to methotrexate after conception were not always consistent with methotrexate-associated adverse developmental outcomes.

8.2 LactationRisk SummaryLimited published literature report the presence of methotrexate in human milk in low amounts. The highest breast milk to plasma concentration ratio demonstrated was 0.08:1. No information is available on the effects of methotrexate on a breastfed infant or on milk production. Because of the potential for serious adverse reactions from methotrexate in breast fed infants, including myelosuppression, advise women not to breastfeed during XATMEP therapy.

8.3 Females and Males of Reproductive PotentialPregnancy TestingTest for pregnancy prior to initiating therapy with XATMEP. Methotrexate can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

ContraceptionFemalesXATMEP can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during and for 6 months after the final methotrexate dose.MalesMethotrexate can cause chromosomal damage to sperm cells. Advise males with female partners of reproductive potential to use effective contraception during and for 3 months after the final methotrexate dose.

InfertilityFemalesBased on published reports of female infertility after therapy with methotrexate, advise females of reproductive potential that XATMEP can cause impairment of fertility and menstrual dysfunction during and after cessation of therapy. It is not known if the infertility may be reversed in all affected females. MalesBased on published reports of male infertility after therapy with methotrexate, advise males of reproductive potential that XATMEP can cause oligospermia or infertility during and after cessation of therapy. It is not known if the infertility may be reversed in all affected males.


17 PATIENT COUNSELING INFORMATION

Embryo-Fetal Toxicity

Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy [see Boxed Warning, Contraindications (4), Warnings and Precautions (5.9), Use in Specific Populations (8.1)].

Advise females of reproductive potential to use effective contraception during XATMEP therapy and for 6 months after the final dose [see Use in Specific Populations (8.3)].

Advise males of reproductive potential to use effective contraception during XATMEP therapy and for 3 months after the final dose [see Use in Specific Populations (8.3)].

Infertility

Advise patients of reproductive potential that XATMEP may cause impairment of fertility, oligospermia, and menstrual dysfunction [see Warnings and Precautions (5.11), Use in Specific Populations (8.3)].

Lactation

Advise females not to breastfeed during therapy with XATMEP [see Use in Specific Populations (8.2)].


5 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this page


CHRISTOS MASTROYANNIS04/13/2017

JOHN J ALEXANDER04/13/2017Signing for Drs. Johnson and Yao


1

****Pre-decisional Agency Information****

Memorandum Date: 03/21/17 To: Michael Gwathmey, Regulatory Project Manager

Division of Hematology Products (DHP) Sadaf Nabavian, Regulatory Health Project Manager Division of Pulmonary, Allergy, and Rheumatology Products (DPARP)

From: Rachael Conklin, Regulatory Review Officer

Kyle Snyder, Regulatory Review Officer Office of Prescription Drug Promotion (OPDP) Subject: Comments on draft labeling (Package Insert) for XATMEP

(methotrexate) oral solution NDA 208400 In response to your labeling consult request dated December 9, 2016, we have reviewed the draft Package Insert for XATMEP (methotrexate) oral solution (Xatmep). This review is based upon the version of the draft PI emailed to OPDP on March 17, 2017. OPDP previously provided comments on this label on June 8, 2016, and we do not have any additional comments on the PI at this time. OPDP acknowledges and concurs with the February 10, 2017, review of the container labeling by the Division of Medication Error Prevention and Analysis (DMEPA) and has no additional comments on the container labeling. If you have any questions, please contact Rachael Conklin at (240) 402‐8189 or [email protected] or Kyle Snyder at (240) 402‐8792 or [email protected]

FOOD AND DRUG ADMINISTRATION Center for Drug Evaluation and Research Office of Prescription Drug Promotion


22 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page


RACHAEL E CONKLIN03/21/2017

KYLE SNYDER03/21/2017


Division of Hematology Products (DHP) Labeling Review

Application Number NDA 208400

Application Type 505(b)(2)

Proprietary Name

(nonproprietary name)

XATMEP (methotrexate oral solution)

Receipt Date 10/25/16 (Class 2 Resubmission)

PDUFA Goal Date 04/25/17

Review Classification Standard

Proposed Indication (or current

indication if unchanged)

XATMEP is a folate analog metabolic inhibitor indicated for the:

Treatment of pediatric patients with acute lymphoblastic leukemia (ALL) as a component of a combination maintenance therapy regimen.

Management of children with active polyarticular juvenile idiopathic arthritis (pJIA) who are intolerant of or had an inadequate response to first-line therapy.

Dosing Regimen The recommended dose of XATMEP, in multi-agent combination

chemotherapy maintenance regimens, is mg/m2 given

weekly

The recommended starting dose of XATMEP for pJIA is 10 mg/m2

given once weekly.

From Virginia Kwitkowski, MS, ACNP-BC

Associate Director for Labeling, DHP

Background of Application:

In this review, I propose labeling recommendations and edits in the XATMEP (methotrexate oral solution)

labeling to ensure that the prescribing information is a useful communication tool for healthcare

providers and uses clear, concise language; is based on regulations and guidances; and conveys the

essential scientific information needed for the safe and effective use of XATMEP (methotrexate oral

solution).

At the time the labeling edits below were semi-final, we were awaiting the consult response from

the Division of Pediatric and Maternal Health Staff with regards to their recommendations on

Section 8 (Use in Specific Populations) for the PLLR labeling revisions.



(b) (4)(b) (4)


VIRGINIA E KWITKOWSKI03/07/2017


1

LABEL AND LABELING MEMORANDUMDivision of Medication Error Prevention and Analysis (DMEPA)

Office of Medication Error Prevention and Risk Management (OMEPRM)Office of Surveillance and Epidemiology (OSE)

Center for Drug Evaluation and Research (CDER)

*** This document contains proprietary information that cannot be released to the public***

Date of This Review: 10 February 2017

Requesting Office or Division: Division of Hematology Products (DHP)

Application Type and Number: NDA 208400

Product Name and Strength: Xatmep (methotrexate) oral solution,

300 mg per 120 mL bottle; 2.5 mg per mL

Product Type: Single Ingredient

Rx or OTC: Rx

Applicant/Sponsor Name: Silvergate Pharmaceuticals, Inc.

Submission Date: 6 February 2017

OSE RCM #: 2016-2616 and 2016-2799

DMEPA Pediatric Medication

Safety Advisor:

Rhiannon Leutner, PharmD, MPH, MBA

DMEPA Team Leader: Hina Mehta, PharmD


2

1 PURPOSE OF MEMOThe Division of Hematology Products (DHP) requested we review the revised container label (Appendix A) for Xatmep (methotrexate) oral solution NDA 208400 to determine if it is acceptable from a medication error perspective. Silvergate Pharmacueticals, Inc. submitted a response to the Complete Response on 25 October 2016. The revisions are in response to recommendations that we made in previous label and labeling reviews.1,2

2 REGULATORY HISTORYSilvergate Pharmaceuticals, Inc. submitted NDA 208400 for Xatmep (methotrexate) oral solution on 31 August 2015. The Application received a Complete Response on 29 June 2016 due to facility deficiencies.

3 CONCLUSIONS

The revised container label for Xatmep is acceptable from a medication error perspective. We have no further recommendations at this time.

1 Leutner RM. Label and Labeling Review for Xatmep (NDA 208400). Silver Spring (MD): Food and Drug Administration, Center for Drug Evaluation and Research, Office of Surveillance and Epidemiology, Division of Medication Error Prevention and Analysis (US); 2016 FEB 16. 6 p. OSE RCM No.: 2015-2288.

2 Leutner RM. Label and Labeling Memorandum for Xatmep (NDA 208400). Silver Spring (MD): Food and Drug Administration, Center for Drug Evaluation and Research, Office of Surveillance and Epidemiology, Division of Medication Error Prevention and Analysis (US); 2016 MAR 28. 3 p. OSE RCM No.: 2015-2288-1.


1 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this page


RHIANNON LEUTNER02/10/2017

HINA S MEHTA02/10/2017


2

INTRODUCTION

Silvergate Pharmaceuticals, Inc. submitted a 505(b)(2) for a new formulation of Xatmep,

methotrexate (MTX) oral solution on August 31, 2015, with the following proposed

indications:

NDA 208-400-1 (Original-1) indicated for the treatment of Acute Lymphoblastic

Leukemia (ALL) assigned to the Division of Hematology Products (DHP); and

NDA 208-400-2 (Original-2) indicated of polyarticular Juvenile

Idiopathic Arthritis (pJIA) assigned to the Division of Pulmonary, Allergy,

Rheumatology (DPARP)

The reference listed drug (RLD) for this application is methotrexate sodium tablets

manufactured by Dava Pharmaceuticals, Inc., NDA 8085 approved in December, 1953.

The nonclinical data for this NDA is that from the RLD. DPARP and DHP consulted the

Division of Pediatric and Maternal Health Staff - Maternal Health Team (DPMH) to

review and provide labeling recommendations for Warnings and Precautions (Section 5),

Pregnancy (Subsection 8.1), Lactation (Subsection 8.2) and Females and Males of

Reproductive Potential (Subsection 8.3) for Xatmep.

REGULATORY HISTORY

1953: Approved tablet and injectable formulations1

May 28, 2015: Orphan Drug Designation (ODD) granted for treatment of ALL in

pediatric patients.

August 28, 2015: ODD granted for management of oligoarticular and pJIA.

August 31, 2015: Application NDA 208-400 received

March 26, 2016: Response to Agency Information Request for review of human

data to support PLLR labeling.

BACKGROUND

Acute Lymphocytic Leukemia and Pregnancy

ALL is a rare disease with a peak incidence in children four to five years of age. The

incidence drops gradually with a smaller peak incidence in adults over the age of 50

years.2 In childhood, ALL represents about 80% of the acute leukemias in the pediatric

population. The etiology of ALL is unknown, although chromosomal translocations in

utero have been suggested by some. One of the two indicated populations for this drug is

pregnant females with ALL.3,4

While very rare, there are many reports of pregnant

women diagnosed with ALL. These reports do not often describe the chemotherapy used

1 Clinical pharmacology online©, www.clinicalpharmacology-ip.com Elsevier. Gold Standard.

Revision date: August 12, 2014. Accessed March 27, 2016. 2 Jabbour E, Fullmer A, Faderl S. Chapter 1. Acute Lymphoblastic Leukemia. In: Kantarjian HM, Wolff

RA, Koller CA. eds. The MD Anderson Manual of Medical Oncology, 2e. New York, NY: McGraw-Hill;

2011. http://accessmedicine.mhmedical.com/content.aspx?bookid=379&Sectionid=39902022 . Accessed

June 13, 2016. 3 Ali R, Özkalemka F, et al., Maternal and fetal outcomes in pregnancy complicated with acute leukemia: a

single institutional experience with 10 pregnancies at 16 years. Leukemia Research 2003; 27:381–385. 4 Nakajima Y, Hattori Y, et al. Acute leukemia during pregnancy: an investigative survey of the past 11

years. Int Jnl Lab Hem 2015; 37:174–180.


(b) (4)

3

and this reviewer has not found a report in which a pregnant woman with ALL was

treated with MTX.

Juvenile Idiopathic Arthritis (JIA) and Pregnancy

JIA is a heterogeneous group of diseases with an onset before age 16 years of age. It is

the most prevalent rheumatologic disease affecting children ranging from 16 to 150

affected children per 100,000 children.5 Lower doses of MTX are reported to be used to

treat JIA compared to doses used to treat ALL. Despite the lower exposures, increased

incidences of spontaneous abortions and congenital malformations have been reported

among women with rheumatic diseases6 treated with MTX during pregnancy at doses less

than or equal to 30 mg weekly.7

Drug Characteristics8

Drug class: folate analog metabolic inhibitor

Half-life:

o multi-phase elimination, some MTX may persist in tissues for extended

period9

o low dose MTX10

ranges from 3 to 10 hours

% Protein bound: approximately: 50%

Bioavailability: approximately 60%

Molecular weight: 454.45

MTX is present in human milk11,12

Methotrexate Mechanism of Action

MTX blocks the conversion of folic acid to reduced folate cofactors such as

tetrahydrofolate via competitive inhibition of dihydrofolate reductase. Reduced folate

cofactors are required for many one carbon unit transfers in biochemistry such as the

synthesis of purine nucleotides and thymidylate. 13

By blocking purine synthesis, MTX

blocks DNA synthesis, repair and cell replication which is thought to be the mechanism

by which MTX is active against malignancies.14

5 Rochette E, Duché P, Merlin E. Juvenile idiopathic arthritis and physical activity: Possible inflammatory

and immune modulation and tracks for interventions in young populations. Autoimmunity Reviews

2015;14:726–734. 6 Rheumatic diseases included rheumatoid arthritis, psoriasis/psoriatic arthritis, systemic lupus

erythematosis, inflammatory bowel disease, ankylosing spondylitis/Bechterew’s disease. 7 Weber-Schoendorfer C, Chambers C, et al., Pregnancy Outcome After Methotrexate Treatment for

Rheumatic Disease Prior to or During Early Pregnancy. Arthritis & Rheumatology 2014;66:1101 – 1110. 8 Data from Xatmep labeling downloaded May 14, 2016, unless otherwise indicated. 9 See Clinical Pharmacology Online. 10 Low dose methotrexate is less than 30 mg/m2 11 See Clinical pharmacology online. 12 Johns D, Rutherford L, et al. Secretion of methotrexate into human milk. Am J Obstet Gynecol

1973;112:978-980. 13 See Clinical pharmacology online. 14 Reprotext®, Micromedex, Accessed March 4, 2016.

http://www micromedexsolutions.com/micromedex2/librarian/CS/362043/ND PR/evidencexpert/ND P/ev

idencexpert/


4

Overview of MTX and Pregnancy, Lactation and Infertility

MTX is a teratogen which induces a set of malformations known as the Methotrexate

Embryopathy characterized by fetal growth retardation, craniosynostosis, brain

anomalies, intellectual disability and skeletal defects.15,16

MTX activity as a folate analog

metabolic inhibitor has been used clinically as an abortifacient in the first trimester to

induce non-surgical abortions in ectopic pregnancies.17,18,19,20,21

MTX doses administered

to induce abortion differ depending on the institution or practice protocol.22

In instances

when there is a failed termination following MTX administration, infants born with

severe malformations have been reported.23,24,25,26,27,28

MTX has been measured in

human breast milk and breastfeeding during treatment with MTX is contraindicated.

MTX is also known to induce infertility in both females and males. The duration and

reversibility of the infertility appears to vary by age at exposure, duration of exposure and

dose used.

Pregnancy and Lactation Labeling

On June 30, 2015, the “Content and Format of Labeling for Human Prescription Drug

and Biological Products; Requirements for Pregnancy and Lactation Labeling,” also

known as the Pregnancy and Lactation Labeling Rule (PLLR), went into effect. The

15 TERIS is the TERatology Information Service located at University of Washington. Accessed March 4,

2016. http://www.micromedexsolutions.com/micromedex2/librarian/ND T/evidencexpert/ND PR/evidencexpert/CS/ 16 Nurmohamed L, Moretti M, et al.,Outcome following high-dose methotrexate in pregnancies

misdiagnosed as ectopic. Am J Obstet Gynecol 2011;205:533.e1-3. 17 See Nurmohamed. 18 Hoffman BL, Schorge JO, Schaffer JI, Halvorson LM, Bradshaw KD, Cunningham F, Calver LE.

Chapter 7. Ectopic Pregnancy. In: Hoffman BL, Schorge JO, Schaffer JI, Halvorson LM, Bradshaw KD,

Cunningham F, Calver LE. eds. Williams Gynecology, 2e. New York, NY: McGraw-Hill; 2012.

http://accessmedicine.mhmedical.com/content.aspx?bookid=399&Sectionid=41722295. Accessed May 23,

2016. 19 Hoffman BL, Schorge JO, Schaffer JI, Halvorson LM, Bradshaw KD, Cunningham F, Calver LE.

Chapter 7. Ectopic Pregnancy. In: Hoffman BL, Schorge JO, Schaffer JI, Halvorson LM, Bradshaw KD,

Cunningham F, Calver LE. eds. Williams Gynecology, 2e. New York, NY: McGraw-Hill; 2012.

http://accessmedicine.mhmedical.com/content.aspx?bookid=399&Sectionid=41722295.Accessed May 20, 2016 20 McLaren J, Burney R, et al. Effect of methotrexate exposure on subsequent fertility in women

undergoing controlled ovarian stimulation. Fertil Steril 2009;92:515–519. 21 Cunningham F, Leveno KJ, Bloom SL, Spong CY, Dashe JS, Hoffman BL, Casey BM, Sheffield JS.

Teratology, Teratogens, and Fetotoxic Agents. In: Cunningham F, Leveno KJ, Bloom SL, Spong CY,

Dashe JS, Hoffman BL, Casey BM, Sheffield JS. eds. Williams Obstetrics, Twenty-Fourth Edition. New

York, NY: McGraw-Hill; 2013. Accessed May 20, 2016.

http://accessmedicine.mhmedical.com/content.aspx?bookid=1057&Sectionid=59789150 22 See Hoffman. 23 Feldkamp M, Carey J: Clinical teratology counseling and consultation case report: low dose methotrexate

exposure in early weeks of pregnancy. Teratology 47(6):533-539, 1993 24

Lloyd M, Carr M, et al: The effects of methotrexate on pregnancy, fertility and lactation. QJM

1999;92:551- 563. 25 Donoway T, Mandeville J, Gauer R: When a fetus survives methotrexate exposure. J Fam Pract

61(3):E1-E4, 2012. 26

MacDonald K, Norman WV, Popescu O: New anomalies due to methotrexate and misoprostol exposure

in early pregnancy. Int J Gynaecol Obstet 122(3):267-268, 2013. 27

Martin MC, Barbero P, Groisman B, Aguirre MA, Koren G: Methotrexate embryopathy after exposure

to low weekly doses in early pregnancy. Reprod Toxicol 43:26-29, 2014. 28 See Nurmohamed.


5

PLLR requirements include a change to the structure and content of labeling for human

prescription drug and biologic products with regard to pregnancy and lactation, and

create a new subsection for information with regard to females and males of reproductive

potential. Specifically, the pregnancy categories (A, B, C, D and X) will be removed

from all prescription drug and biological product labeling and a new format will be

required for all products that are subject to the 2006 Physicians Labeling Rule format to

include information about the risks and benefits of using these products during pregnancy

and lactation.

REVIEW

PREGNANCY

Nonclinical Experience

This is a 505(b)(2) application for which the RLD is NDA 8085. There are no

nonclinical data in the labeling for NDA 8085. The DPARP and DHP Nonclinical teams

determined that animal data will not be added to labeling because a large body of human

data is available from published references.

Review of Pregnancy Literature

The applicant completed a literature search for publications on methotrexate and

pregnancy; however, the applicant limited their searches to references published from

2009 to the present. The applicant noted that labeling for the RLD was last revised in

2009.

Viktil, 201229

This publication provided by the applicant describes data collected from 2004 to 2007 by

the Medical Birth Registry of Norway (MBRN) that was linked to the Norwegian

Prescription Database. There were 154,976 singleton births during the study period. Of

those, 1461 Women (0.9%) and 1198 Men (0.8%) were exposed to any of seven anti-

inflammatory drugs. MBRN patients were treated with: non-steroidal anti-inflammatory

drugs, n= 723; Prednisolone, n = 633; sulfasalazine, n = 119; azathioprine, n = 101;

hydroxychloroquine, n = 58; etanercept, n = 37; MTX, n = 8; adalumimab, n = 3; and

leflunomide, n =2.

Conclusions: These population-based data demonstrate that in the study period eight

women in Norway were exposed to MTX during pregnancy. This number of pregnancy

exposures is too low to draw a clear conclusion about potential risks with use of MTX

during pregnancy.

Reviewer’s Comment

The review of the literature (2009 to present) provided by the applicant did not include

information that would serve as the basis for the labeling in the Boxed Warning,

Contraindications (4), Warnings and Precautions (5.11, 5.13) and Pregnancy (8.1).

There were no data describing the Methotrexate Embryopathy or the malformations

29 Viktil K, Engeland A, Furu K. Outcomes after anti-rheumatic drug use before and during pregnancy: a

cohort study among 150 000 pregnant women and expectant fathers, Scandinavian Journal of

Rheumatology 2012;41:3, 196-201, DOI: 10.3109/03009742.2011.6264


6

reported after failed non-surgical terminations of ectopic pregnancies. Following

discussions with DHP and DPARP, a further information request was sent to the

applicant on May 31, 2016 requesting the following:

“…a comprehensive, integrated review of the published literature sufficient to

support the basis for the warnings related to methotrexate exposure during the

periconceptional and prenatal periods, as well as the risk of infertility for females

and males or reproductive potential following methotrexate exposure.

1. Provide a comprehensive, integrated review of the published literature to

support the Warnings and Precautions related to:

a. Embryo-fetal toxicity/fetal death/ Congenital anomalies

b. Effects on fertility and its duration

2. Propose labeling language for the Human Data sub-heading under Section

8.1 Pregnancy of the full prescribing information. Refer to the PLLR

guidance for additional information.”

DPMH Review of Pregnancy Literature

This Reviewer found one publication which is representative of the adverse effects of

prenatal MTX exposure.

Martin, 201430

This was a prospective, observational study of 18 pregnant Argentinian women who were

being treated with ‘low dose’ MTX for an autoimmune disorder31

and who had contacted

the Argentine Teratogenic Information Service “Fetal Health” for prenatal MTX

exposure information. All the women had been treated with MTX during pregnancy

(n=8) or within six months prior to conception (n=10). All the women were enrolled in

the study prior to receiving information of the pregnancy outcome. Of the 8 women

prenatally exposed to MTX, one had an infant with features of MTX embryopathy (MTX

oral dose = 7.5 mg weekly), six women delivered healthy infants and the eighth mother

had an infant with Down syndrome (not reported if the infant had trisomy 21 or an

unbalanced translocation). In the second group of women who were treated with MTX

up to 6 months prior to conception, one woman had an intrauterine fetal death at 18

weeks (MTX oral dose = 10 mg weekly) without obvious fetal malformations; another

woman had a miscarriage at 10 weeks (MTX IM32

dose = 20 mg). Three women had

healthy newborns (MTX oral dose= 7.5 or 20 mg, or IM dose = 12.5 mg) and one was

still pregnant at the time of publication with no evidence of abnormalities on ultrasound.

The remaining four women in the second group were lost to follow-up.

Conclusions: (1) An infant prenatally exposed to a ‘low dose’ of MTX (7.5 mg oral)

during the first trimester of pregnancy had multiple malformations at birth which

appeared similar to the MTX embryopathy; (2) the effect of only pre-conception MTX

exposure on female reproductive outcomes is not clear from the data presented and no

30 Martín M, Barberoa P, et al. Methotrexate embryopathy after exposure to low weekly doses in early

pregnancy. Reproductive Toxicology 2014; 43:26– 29. 31 Patients in prenatal exposure group had rheumatoid arthritis, systemic lupus erythematosus (SLE) or

scleroderma; patients in pre-conception only exposure had rheumatoid arthritis, anti-phospholipid

antibodies, SLE and scleroderma 32 IM = intramuscular


7

conclusion may be drawn regarding possible persistent adverse effects of that exposure;

and (3) the small number of prenatally exposed women (n=8) in this study demonstrated

that there may be a teratogenic risk from oral doses of MTX as low as 7.5 mg weekly.

Review of Pregnancy Pharmacovigilance Database

This is a 505(b)(2) application for which the applicant has no pharmacovigilance

information from clinical trials or postmarketing.

Summary

MTX is a known teratogen which may produce a characteristic set of malformations at a

dose as low as 7.5 mg weekly. Because the applicant’s proposed labeling was not

supported by a review of the literature that would serve as the basis for the labeling in the

Boxed Warning, Contraindications (4), Warnings and Precautions (5.11, 5.13) and

Pregnancy (8.1), additional information request was requested of the applicant to better

describe the known risks of MTX to the developing fetus.

The applicant’s response to the information request was received June 16, 2016, which

was extremely late in the current review cycle. The data submitted by the sponsor will be

reviewed with the Complete Response submission and any changes to PLLR labeling will

be included at that time.

LACTATION


There are no nonclinical data for this 505(b)(2) application or the RLD. As noted above,

the Divisions’ Nonclinical teams have determined that animal data will not be added to

labeling because a large body of human data is available from published references. .


There are very few publications which provide data on MTX in breast milk. The

applicant reviewed three publications which described two case reports of women treated

with MTX.

Johns, 197233

This 1972 publication described the use of oral MTX in a one month postpartum woman

in Kampala, Uganda diagnosed with choriocarcinoma. Bottle feeding was rare in that

region and therefore, a limited study was completed. The highest milk:plasma

concentration ratio (M:P ratio) measured was 0.08 and occurred at 10 hours after

administration of 22.5 mg of MTX. The authors’ summary stated “the kinetics of the

MTX secretion process correspond to those which would be anticipated for a weak

organic acid transferred from plasma to milk by passive diffusion of the non-ionized

form.”34

33 Johns D, Rutherford L, et al., Secretion of methotrexate into human milk. Am J Obstet Gynecol

1972;112:978-980. 34 See Johns.


8

Thorne, 201435

There is one other publication that the applicant provided which described a study of

MTX levels in a lactating woman with rheumatoid arthritis (RA). The woman had

frequent flares of her RA requiring treatment with oral steroids and MTX. The mother

was lactating at the time of an RA flare and did not wish to stop breastfeeding to be

treated. A limited study to monitor MTX levels in breast milk was completed. The

lactating woman was administered 25 mg SC and maternal serum and breast milk were

collected for the next 24 hours and levels were measured using liquid chromatography –

mass spectrometry. The infant’s oral dose of MTX was calculated to be 3.4 µg/kg/day or

about 1% of the maternal weight-adjusted dose. The infant continued to breastfeed for an

additional 9 months and no abnormalities during that time period were described by the

author in the publication.

DPMH review of literature

There are very few publications which provide data on MTX in breast milk. This

reviewer searched PubMed using the search terms methotrexate and lactation or

breastfeed using filters for human and English language publications and found 36

publications. Only two of the references contained data on MTX levels measured in

breast milk and these were the same two references cited by the applicant.

A key reference guide, Briggs36

acknowledged the maximum M:P ratio of 0.08 would

indicate that the breastfeeding infant of a woman treated with MTX would have a low

MTX exposure; similarly, the weight-adjusted maternal dose of 1% indicates the MTX

exposure would be low. However, the Briggs review raises a concern that MTX may

accumulate in infant tissue. Another reference, Clinical Pharmacology Online, also states

that MTX may accumulate in tissues for an extended period of time.

The LactMed37

database noted both the Johns and Thorne references and the MTX

exposure in breastmilk and stated “Most sources consider breastfeeding to be

contraindicated during maternal high-dose antineoplastic drug therapy with MTX.” The

LactMed review also references some authors who state that “low single or weekly doses,

such as those used for ectopic pregnancy or RA, are of low risk to the breastfed infant.”

The review concludes with the statement, “If breastfeeding during long-term, low-dose

MTX use is undertaken, monitoring of the infant’s complete blood count and differential

could be considered.”

Review of Lactation Pharmacovigilance Database

This is a 505(b)(2) application for which the applicant provided no information.

35 Thorne J. Methotrexate Use in a Breastfeeding Patient with Rheumatoid Arthritis. Journal of

Rheumatology 2014; 41:11. 36 Briggs, G, Freeman, R. Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal

Risk, 10th ed. Philadelphia, Pa.: Lippincott Williams & Wilkins, 2015. 37 LACTMED®: The LactMed database is a National Library of Medicine database with information on

drugs and lactation geared toward healthcare practitioners and nursing women. LactMed Record

Number:466; Last Revision: April 1, 2016. Accessed May 23, 2016.


9

Summary

Review of the literature by the applicant and this reviewer yielded the same key

references relevant to describe MT levels in breast milk. These data from two women are

limited and no measurements of MTX levels in breastfeeding infants have been reported.

An assessment of the risk posed based on these data is unclear. Methotrexate causes

severe toxicity in adults and may accumulate over time in tissues in breastfeeding infants.

Therefore, breastfeeding an infant while being treated with MTX poses an unknown risk

and should be avoided.

FEMALES AND MALES OF REPRODUCTIVE POTENTIAL


There are no nonclinical data for this original application or the RLD. As noted above,

the Divisions’ Nonclinical teams have determined that animal data will not be added to

labeling because a large body of human data is available from published references.


The applicant completed literature searches for publications on methotrexate and

infertility; however, the applicant limited their searches to references published from

2009 to the present.

Reviewer’s Comment

The applicant’s review of the literature did not include high quality publications

reviewing the incidence and duration of the infertility following MTX or describe the

mechanism of infertility in females and males following treatment. The literature review

did not support the labeling in Warnings and Precautions regarding Infertility (5.13) as

well as in Females and Males of Reproductive Potential (8.3). As noted in the Pregnancy

section of this review, after a discussion with the Divisions, an information request was

sent to the applicant on May 31, 2016 requesting additional information. The applicant’s

response to the information request was received June 16, 2016, which was extremely

late in the current review cycle. The data submitted by the sponsor will be reviewed with

the Complete Response submission and any changes to PLLR labeling will be included at

that time.

Review of Pharmacovigilance Database

The applicant provided no information.

Summary

The publications provided by the applicant do not include sufficient information to

determine the severity or the duration of infertility following exposure to MTX or the

mechanism by which females and males treated with MTX become infertile. This

information has been requested from the applicant as noted above.

CONCLUSIONS

The Xatmep labeling has been converted to PLLR format. However, the sponsor

submitted additional data extremely late in the current review cycle. The data submitted


10

by the sponsor will be reviewed with the Complete Response submission and any

additional changes to PLLR labeling will be included at that time (e.g., changes to the

Boxed Warning, Contraindications (4), Warnings and Precautions (5.11, 5.13),

Pregnancy (8.1), Lactation (8.2) and Females and Males of Reproductive Potential (8.3)).

RECOMMENDATIONS

Pending review of the applicant’s response to the information request.

DPMH Proposed Pregnancy and Lactation Labeling

HIGHLIGHTS

XATMEP (methotrexate) oral solution

Initial U.S. Approval: 1953

Boxed Warning

WARNING: SEVERE TOXIC REACTIONS, INCLUDING EMBRYO-FETAL

TOXICITY and DEATH

• Methotrexate can cause fetal death and/or congenital anomalies and is

contraindicated during pregnancy for arthritis patients. (4, 5.x, 8.1)

• Advise patients treated for neoplasia to use effective contraception after therapy.

(4, 5.x, 8.1, 8.3)

-------------------------------CONTRAINDICATIONS------------------------------

• Pregnancy in arthritis patients (4)

-----------------------WARNINGS AND PRECAUTIONS------------------------

• Effects on reproduction: May cause impairment of fertility, oligospermia and

menstrual dysfunction (5.3, 8.3).

-----------------------USE IN SPECIFIC POPULATIONS------------------------

• Lactation: Advise women to discontinue breastfeeding (8.2)

FULL PRESCRIBING INFORMATION

BOXED WARNING

WARNING: SEVERE TOXIC REACTIONS, INCLUDING EMBRYO-FETAL

TOXICITY and DEATH

Methotrexate can cause fetal death and/or congenital anomalies. Use in

arthritis patients JIA is contraindicated in pregnancy. Advise patients to use

effective contraception [see Contraindications (4), Warnings and Precautions

(5.11, 5.13) and Use in Specific Populations (8.1, 8.3)].

1 INDICATIONS AND USAGE

1.1 Acute Lymphoblastic Leukemia

XATMEP is indicated for the treatment of pediatric patients with acute lymphoblastic

leukemia (ALL) as part of a multi-phase, combination chemotherapy maintenance

regimen.

1.2 Polyarticular Juvenile Idiopathic Arthritis

XATMEP is indicated in the management of children with active polyarticular juvenile

idiopathic arthritis (pJIA).


12

8.2 Lactation

Risk Summary

Limited published literature report the presence of methotrexate in human milk in low

amounts. The highest breast milk to plasma concentration ratio demonstrated was 0.08.

No information is available on the effects of methotrexate on a breastfed infant or on

milk production. Because of the potential for serious adverse reactions from methotrexate

in breast fed infants, advise women to during

XATMEP therapy.

8.3 Females and Males of Reproductive Potential

Pregnancy Testing

Pregnancy prior to initiating therapy with XATMEP.

Contraception

Females

XATMEP can cause fetal harm when administered to a pregnant woman [see Use in

Specific Populations (8.1)]. Advise females of reproductive potential to use effective

contraception during and for 6 months after the final dose.

Males

advise males of reproductive potential to use

effective contraception during and for 3 months after the final dose.

Infertility

Females

Based on published reports of female infertility after therapy with methotrexate, advise

females of reproductive potential that XATMEP can cause impairment of fertility and

menstrual dysfunction during and after cessation of methotrexate therapy. It is not

known if the infertility may be reversed in all affected females.

Males

Based on published reports of male infertility after therapy with methotrexate, advise

males of reproductive potential that XATMEP can cause oligospermia or infertility

during and after cessation of therapy. It is not known if the infertility may

be reversed in all affected males.


Embryo-Fetal Toxicity

Advise females of reproductive potential of the potential risk to a fetus and to

inform their healthcare provider a known or suspected pregnancy [see Boxed

Warning, Contraindications (4), Warnings and Precautions (5.11) and Use in

Specific Populations 8.1)].

Advise females of reproductive potential to use effective contraception during


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13

therapy and for 6 months after the final dose [see Use in Specific

Populations (8.3)].

Advise males of reproductive potential to use effective contraception during

XATMEP therapy and for 3 months after the final dose [see Use in

Specific Populations (8.3)].

Infertility

Advise patients of reproductive potential that XATMAP may cause impairment of

fertility, oligospermia, and menstrual dysfunction [see Warnings and Precautions

(5.13) Use In Specific Populations (8.3)].

Lactation

Advise during therapy with

XATMEP [see Use in Specific Populations (8.2)].


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CAROL H KASTEN06/20/2016

TAMARA N JOHNSON06/20/2016

LYNNE P YAO06/20/2016


1

****Pre-decisional Agency Information****

Memorandum Date: June 8th, 2016 To: Jessica Boehmer, Regulatory Health Project Manager Division of Hematology Products (DHP) Sadaf Nabavian, Regulatory Health Project Manager

Division of Pulmonary, Allergy, and Rheumatology Products (DPARP)

From: Rachael Conklin, Regulatory Review Officer Roberta Szydlo, Regulatory Review Officer

Office of Prescription Drug Promotion (OPDP) Through: Kathleen Davis, Team Leader, OPDP Subject: Comments on draft labeling (Package Insert, Container Label) for

XATMEP (methotrexate) oral solution NDA 208400 In response to your labeling consult request dated January 14, 2016, we have reviewed the draft Package Insert (PI) and Container Label for XATMEP (methotrexate) oral solution. This review is based upon the version of the draft PI and Container Label accessed in Sharepoint on June 1, 2016. Package Insert

Section Statement from Draft (if applicable)

OPDP Comment

HIGHLIGHTS OF PRESCRIBING INFORMATION: ADVERSE REACTIONS

“Most common adverse reactions are: ulcerative stomatitis, leukopenia, nausea, and abdominal distress. Other frequently reported adverse

are malaise, fatigue, chills and fever, dizziness and decreased resistance to infection. (6).”

If available, the criteria used to determine inclusion (e.g., frequency cutoff rate) should be included here in order to be consistent with the recommendation in the Guidance for Industry, Labeling for Human Prescription Drug and Biological Products—Implementing the PLR Content and Format Requirements, dated February 2013.

For example: “most common adverse reactions observed in at least x% of patients treated with XATMEP

FOOD AND DRUG ADMINISTRATION Center for Drug Evaluation and Research Office of Prescription Drug Promotion


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. . .”

We note that the term is called “fatigue” in the list of adverse reactions in section 6.1. OPDP suggests deleting the word from the Highlights section, both to be consistent with section 6.1 and because, from a promotional perspective, such a non‐specific term could be used to minimize the level of fatigue experienced by those taking this drug.

OPDP also questions whether it would be appropriate to include “elevated liver function tests” in this section as we note that they occurred at an approximate rate of 14% in pediatric patients with JIA.

HIGHLIGHTS OF PRESCRIBING INFORMATION: Drug Interactions

“Probenecid: May increase methotrexate exposure.

Antibiotics: increase

Monitor patients accordingly. (7.2)

Theophylline: may reduce clearance

Monitor theophylline levels

(7.3).”

OPDP recommends revising this section in order to be consistent with section 7 of the FPI. For example, the Highlights includes

5.4 Gastrointestinal

Toxicity

“Unexpectedly severe and fatal gastrointestinal toxicity can occur with concomitant administration of XATMEP (primarily at high dosage) and nonsteroidal anti‐inflammatory drugs (NSAIDs) [see Drug Interactions (7.2)].” (emphasis added)

OPDP is concerned that the phrasing “primarily at high dosage” is vague and may be used promotionally to minimize this risk. Is there data regarding the specific incidence rates of and dosages at which severe/fatal GI toxicity has occurred with concomitant administration of XATMEP and NSAIDs? If so, OPDP recommends that this information be included.

5.8 Secondary Malignancies

“Lymphoproliferative disease associated with low‐dose oral methotrexate

In promotion, the current wording of this section may be used to minimize this serious risk and provide an overly comforting perspective on methotrexate‐


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OPDP notes that this recommendation is made; however, as the referenced patient labeling is not included as part of the SCPI, we are uncertain as to whether or not there is patient labeling for this drug. If there is not patient labeling, OPDP suggests deleting this sentence. If there is patient labeling, OPDP suggests that DMPP and OPDP be consulted regarding the patient labeling.

Container Labeling: OPDP acknowledges and concurs with the March 28, 2016, review of the container labeling by the Division of Medication Error Prevention and Analysis (DMEPA) and has no additional comments on the container labeling. If you have any questions, please contact Rachael Conklin at (240) 402‐8189 or [email protected] or Roberta Szydlo at 301‐796‐5389 or [email protected].



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RACHAEL E CONKLIN06/08/2016

ROBERTA T SZYDLO06/08/2016


1

LABEL AND LABELING MEMORANDUMDivision of Medication Error Prevention and Analysis (DMEPA)




Date of This Review: 28 March 2016






Rx or OTC: Rx


Submission Date: 22 March 2016

OSE RCM #: 2015-2288-1


Safety Advisor:


DMEPA Team Leader: Yelena Maslov, PharmD


2

1 PURPOSE OF MEMOThe Division of Hematology Products (DHP) requested we review the revised container label (Appendix A) to determine if it is acceptable from a medication error perspective. The revisions are in response to recommendations that we made in a previous label and labeling review.1

2 CONCLUSIONSWe have reviewed the proposed container label revisions submitted on 22 March 2016 and note opportunities to improve the safe use of this product. Previously, DMEPA recommended removal of the “Ready-to-Use” statement from the container label.1 Silvergate has responded with their intent to retain this statement on their container label. If the firm is intent to retain this statement, we recommend the modifications noted below to ensure the safe use of this product.

2.1 RECOMMENDATIONS FOR SILVERGATE PHARMACEUTICALS

The “Ready-to-Use” statement, as depicted on the revised container label submitted 22 March 2016, is displayed with similar prominence as the name of the product, given the bold font and capital letters. If the firm is intent to retain this “Ready-to-Use” statement, we recommend the following changes to the revised container label to improve the safe use of this product.

1. Move the “Ready-to-Use” statement to follow the “For Oral Use Only” statement, thus increasing the white space on the principal display panel which improves the readability of important prescribing information such as product name, strength, and route of administration.

2. Decrease the prominence of the “Ready-to-Use” statement, so as to not draw attention away from important product information (such as product name, strength, and route of administration) by the following means:

a. Remove bold;b. Change font color from

1 Leutner RM. Label and Labeling Review for Xatmep (NDA 208400). Silver Spring (MD): Food and Drug Administration, Center for Drug Evaluation and Research, Office of Surveillance and Epidemiology, Division of Medication Error Prevention and Analysis (US); 2016 FEB 16. 6 p. OSE RCM No.: 2015-2288.


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APPENDIX A. REVISED CONTAINER LABEL

Silvergate Pharmaceuticals submitted the revised container label below on 22 March 2016.


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YELENA L MASLOV03/28/2016



SHILA S NKAH03/07/2016


1

LABEL AND LABELING REVIEWDivision of Medication Error Prevention and Analysis (DMEPA)




Date of This Review: 16 February 2016






Rx or OTC: Rx


Submission Date: 31 August 2015 4 December 2015 23 December 2015

OSE RCM #: 2015-2288


Safety Advisor:


DMEPA Team Leader: Yelena Maslov, PharmD


2

1 REASON FOR REVIEWAs part of the NDA approval process for Xatmep (methotrexate oral solution), the Division of Hematology Products (DHP) requested we review the proposed label and labeling for areas that may lead to medication errors.

2 MATERIALS REVIEWED We considered the materials listed in Table 1 for this review. The Appendices provide the methods and results for each material reviewed.

Table 1. Materials Considered for this Label and Labeling Review

Material Reviewed Appendix Section (for Methods and Results)

Product Information/Prescribing Information A

Previous DMEPA Reviews B

Human Factors Study C – N/A

ISMP Newsletters D – N/A

FDA Adverse Event Reporting System (FAERS)* E – N/A

Other F – N/A

Labels and Labeling G

N/A=not applicable for this review*We do not typically search FAERS for label and labeling reviews unless we are aware of medication errors through our routine postmarket safety surveillance

3 OVERALL ASSESSMENT OF THE MATERIALS REVIEWEDWe reviewed the applicant submitted label and labeling for this NDA for Methotrexate Oral Solution on 31 August 2015. The applicant submitted revised prescribing information and container labels on 4 December 2015 and 23 December 2015, respectively. We performed a risk assessment of the container labels along with the prescribing information for any areas that may lead to medication errors. We have found certain aspects of the label and prescribing information that could be revised to increase clarity of this labeling, thus promoting safe use of this product. We provide recommendations to the Division and Silvergate Pharmaceuticals in sections 4.1 and 4.2.

4 CONCLUSION & RECOMMENDATIONSWe recommend changes to the submitted labels and prescribing information to improve clarity and understanding for safe use of this product.

4.1 RECOMMENDATIONS FOR THE DIVISION

Prescribing Information, Section 2, Dosage and Administration:


3

1. Remove trailing the trailing zero (e.g. 1.0 mg) to avoid a ten-fold misinterpretation.1,2 The polyarticular juvenile idiopathic arthritis dosing (section 2.3) states that

20 to 30 mg/m2/wk (0.65 to 1.0 mg/kg/wk) may have better absorption and fewer gastrointestinal side effects if methotrexate is administered

4.2 RECOMMENDATIONS FOR SILVERGATE PHARMACEUTICALS

We recommend the changes below be implemented prior to approval of this NDA.

Container Label:

1. Consider revising the presentation of the proprietary name so only the first letter in the proprietary name is capitalized. Words written in all-capital letters are less legible than words written in mixed case letters.3 Example: Xatmep

2. Harmonize the font size for the words “Oral” and “Solution” on the principal display panel, so that are in equal font size and appear at the same prominence.

3. Remove the text, “READY-TO-USE” as this statement does not provide any useful information and does not contribute to safe use of the product.

4. Consider providing the route of administration on the principal display panel because there are other routes of administration of methotrexate. Example: For Oral Use Only

5. We recommend revising usual dosage statement in accordance with 21 CFR 201.55. Example: Usual Dose: See prescribing information

6. Relocate “KEEP THIS AND ALL MEDICATIONS OUT OF REACH OF CHILDREN” from the principal display panel to side panel. Only the most important information (e.g., proprietary and established names of the product, route of administration, strength,) should be retained on the principal display panel.

1 Guidance for Industry: Safety considerations for container labels and carton labeling design to minimize medication errors (Draft Guidance). April 2013.

2 Institute of Safe Medication Practices (ISMP). ISMP’s List of Error-Prone Abbreviations, Symbols, and Dose Designations. http://www.ismp.org/tools/errorproneabbreviations.pdf



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7. We recommend decreasing the overall size of the manufacturer trademark or move the trademark to the side panel to prevent taking the readers’ attention away from important information such as proprietary names and strength.4

8. Revise and bold the statement refrigeration statement to increase the prominence of this important information and minimize the risk of this storage information being overlooked. Example: Must be refrigerated, store at 2°- 8°C (36°- 46°F).

9. The after dispensing statement does not have a 60 day storage limitation stated on the container as the prescribing information suggests. Consider adding the 60 day storage limitation to container labeling to ensure consistency between the prescribing information and the container labeling. Example: After dispensing, may be stored at room temperature 15°-30° (59°-86°F) for 60 days.

10. The storage temperature presented on the container labeling and the storage temperature listed in the prescribing information are inconsistent. The prescribing information states patients may store this product at room temperature and notes an acceptable range of while the prescribing information states that patients may store this product at room temperature (25°C (77°F)) and states excursions permitted to 15°-30° (59°-86°F). Revise the storage temperature to provide accurate and consistent storage temperature requirements between the prescribing information and the container labeling.

11. Remove ancillary dosing information from container label and place in prescribing information as appropriate. Consider removing the following:

a.b.

12. The concentration statement describing methotrexate sodium salt on the container label should be consistent with the concentration statement listed in the prescribing information. The prescribing information states, “2.5 mg of methotrexate per milliliter (equivalent to 2.74 mg of methotrexate sodium/mL” and the container label states “Each mL contains methotrexate sodium equivalent to 2.5 mg of methotrexate.” This is potentially confusing and could be misinterpreted. Consider revising to ensure consistency between container label and prescribing information.



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5

APPENDICES: METHODS & RESULTS FOR EACH MATERIALS REVIEWED

APPENDIX A. PRODUCT INFORMATION/PRESCRIBING INFORMATIONTable 2 presents relevant product information for Xatmep that Silvergate Pharmaceuticals submitted on 31 August 2015 and 4 December 2015.

Table 2. Relevant Product Information for Xatmep

Initial Approval Date N/A

Active Ingredient methotrexate

Indication - Treatement of pediatric patients with acute lymphoblastic leukemia (ALL) as a component of a combination maintenance therapy regimen

- Management of children with active polyarticular juvenile idiopathic arthritis (pJIA) who are intolerant of or had an insufficient therapeutic response to first-line therapy, including full dose nonsteroidal anti-inflammatory agents (NSAIDs).

Route of Administration Oral

Dosage Form solution

Strength 300 mg per 120 mL bottle; 2.5 mg per mL

Dose and Frequency - ALL: mg/m2 given weekly, in multi-agent combination chemotherapy maintenance regimens.

- pJIA: recommended starting dose is 10 mg/m2 once weekly, adjustment dose to optimal response.

How Supplied 120 mL per bottle

Storage (2-8 °C/36-46 °F). Avoid freezing and excessive heat.

Container Closure High-density polyethylene (HPDE) bottle with a child-resistant cap

APPENDIX B. PREVIOUS DMEPA REVIEWSB.1 MethodsOn 19 January 2016, we searched the L:drive and AIMS using the terms, Xatmep to identify reviews previously performed by DMEPA.

B.2 ResultsOur search did not identify any previous DMEPA reviews.


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YELENA L MASLOV02/17/2016


M E M O R A N D U M DEPARTMENT OF HEALTH AND HUMAN SERVICES

PUBLIC HEALTH SERVICE

FOOD AND DRUG ADMINISTRATION


________________________________________________________________

DATE: December 14, 2015

TO: Mitchell Mathis, M.D.,

Director, Division of Psychiatry Products

Ann Farrell, M.D.,

Director, Division of Hematology Products

Dale Conner, Pharm.D.

Director (Acting)

Office of Bioequivalence

Office of Generic Drugs

FROM: Himanshu Gupta, Ph.D.

Division of Generic Drug Bioequivalence Evaluation

(DGDBE)

Office of Study Integrity and Surveillance (OSIS)

Sam H. Haidar, Ph.D., R.Ph.

Acting Director, Division of Generic Drug

Bioequivalence Evaluation


SUBJECT: Review of Establishment Inspection Report (EIR)

covering

NDA 208400, Methotrexate Pediatric Oral Solution,

sponsored by Silvergate Pharmaceuticals Inc.


NON-RESPONSIVE

NON-RESPONSIVE

Page 2 – Review of EIR of

Summary: No Form FDA 483 was issued. The data can be accepted

for further agency review.

The Office of Study Integrity and Surveillance (OSIS) conducted

a surveillance inspection at

The inspection was conducted in support of review of

NDA 208400,

Specifically, the analytical portions of

the following bioequivalence studies were audited during the

inspection:

NDA 208400 Methotrexate Pediatric Oral Solution

Study #: 4002745 (Protocol #SG02-04)

Study Title: “A Randomized, Open-Label, Single-dose, Two-

Period, Two-Treatment, Two-Way Crossover

Relative Bioavailability Study of

Methotrexate Pediatric Oral Solution under

Fasted and Fed Conditions in Healthy Adult

Male Volunteers.”

Sample analysis:


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NON-RESPONSIVENON-RESPONSIVE

NON-RESPONSIVE

NON-RESPONSIVE

NON-RESPONSIVE

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NON-RESPONSIVE


Final Classification:

NAI-

cc:

OTS/OSIS/Taylor/Kadavil/Turner-Rinehardt/Fenty-Stewart/Nkah

OTS/OSIS/DNDBE/Bonapace/Dasgupta/Cho

OTS/OSIS/DGDBE/Haidar/Skelly/Choi/Gupta

Draft: HG 12/11/2015

Edit: SHH 12/14/2015

OSI File #:

NDA 208400- BE#7023

ECMS: Cabinets/CDER_OC/OSI/Division of Bioequivalence & Good

Laboratory Practice Compliance/Inspections/BE Program/Analytical

sites/

FACTS:


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NON-RESPONSIVE

NON-RESPONSIVE


HIMANSHU GUPTA12/14/2015

SAM H HAIDAR12/14/2015


M E M O R A N D U M DEPARTMENT OF HEALTH AND HUMAN SERVICES

PUBLIC HEALTH SERVICE

FOOD AND DRUG ADMINISTRATION


________________________________________________________________

DATE: December 14, 2015

TO: Mitchell Mathis, M.D.,

Director, Division of Psychiatry Products

Ann Farrell, M.D.,

Director, Division of Hematology Products

Dale Conner, Pharm.D.

Director (Acting)

Office of Bioequivalence

Office of Generic Drugs

FROM: Himanshu Gupta, Ph.D.

Division of Generic Drug Bioequivalence Evaluation

(DGDBE)


Sam H. Haidar, Ph.D., R.Ph.

Acting Director, Division of Generic Drug

Bioequivalence Evaluation


SUBJECT: Review of Establishment Inspection Report (EIR)

covering

NDA 208400, Methotrexate Pediatric Oral Solution,

sponsored by Silvergate Pharmaceuticals Inc.


NON-RESPONSIVE

NON-RESPONSIVE



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NON-RESPONSIVE


Final Classification:

NAI-

cc:

OTS/OSIS/Taylor/Kadavil/Turner-Rinehardt/Fenty-Stewart/Nkah

OTS/OSIS/DNDBE/Bonapace/Dasgupta/Cho

OTS/OSIS/DGDBE/Haidar/Skelly/Choi/Gupta

Draft: HG 12/11/2015

Edit: SHH 12/14/2015

OSI File #:

NDA 208400- BE#7023

ECMS: Cabinets/CDER_OC/OSI/Division of Bioequivalence & Good

Laboratory Practice Compliance/Inspections/BE Program/Analytical

sites/

FACTS:


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NON-RESPONSIVE

NON-RESPONSIVE


HIMANSHU GUPTA03/07/2016

SAM H HAIDAR03/08/2016


REGULATORY PROJECT MANAGER PHYSICIAN LABELING RULE (PLR) FORMAT REVIEW

OF THE PRESCRIBING INFORMATION Application: NDA 208400-Original 1; NDA 208400-Original 2 Application Type: New NDA Drug Name(s)/Dosage Form(s): (methotrexate) Oral Solution Applicant: Silvergate Pharmaceuticals, Inc. Receipt Date: August 31, 2015 Goal Date: June 30, 2016

1. Regulatory History and Applicant’s Main Proposals The applicant submitted a new NDA as a 505(b)(2) for the treatment of pediatric patients with acute lymphoblastic leukemia (all), as part of a combination regimen, and the management of children with active polyarticular Juvenile Idiopathic Arthritis (pJIA) who are intolerant of or had an inadequate response to first-line therapy. The NDA is split administratively between DHP and DPARP as Original-1 for acute lymphoblastic leukemia and Original-2 for pJIA indication, respectively. 2. Review of the Prescribing Information This review is based on the applicant’s submitted Word format of the prescribing information (PI). The applicant’s proposed PI was reviewed in accordance with the labeling format requirements listed in the “Selected Requirements of Prescribing Information (SRPI)” checklist (see Section 4 of this review).

3. Conclusions/Recommendations SRPI format deficiencies were identified in the review of this PI. For a list of these deficiencies, see Section 4 of this review. The following labeling issues were identified:

1. A horizontal line must separate:

• TOC from the Full Prescribing Information (FPI).

2. White space should be present before each major heading in the highlights (HL)

section. There must be no white space between the HL Heading and HL Limitation Statement. There must be no white space between the product title and Initial U.S. Approval.

3. The Boxed Warning (BW) must have a title in UPPER CASE, following the word “WARNING” and other words to identify the subject of the warning. Even if there is more than one warning, the term “WARNING” and not “WARNINGS” should be used. For example: “WARNING: SERIOUS INFECTIONS and ACUTE


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Selected Requirements of Prescribing Information

SRPI version 5: October 2015 Page 2 of 10

HEPATIC FAILURE.” If there is more than one warning in the BW title, the word “and” in lower case can separate the warnings. The BW title should be centered.

All SRPI format deficiencies of the PI and other labeling issues identified above will be conveyed to the applicant in the 74-day letter. The applicant will be asked to correct these deficiencies and resubmit the PI in Word format by December 6, 2015. The resubmitted PI will be used for further labeling review.

4. Selected Requirements of Prescribing Information The Selected Requirement of Prescribing Information (SRPI) is a 41-item, drop-down checklist of important format elements of the prescribing information (PI) based on labeling regulations (21 CFR 201.56 and 201.57) and guidances.

Highlights

See Appendix for a sample tool illustrating Highlights format.

HIGHLIGHTS GENERAL FORMAT

1. Highlights (HL) must be in a minimum of 8-point font and should be in two-column format, with ½ inch margins on all sides and between columns.

Comment: 2. The length of HL must be one-half page or less unless a waiver has been granted in a previous

submission. The HL Boxed Warning does not count against the one-half page requirement. Instructions to complete this item: If the length of the HL is one-half page or less, select “YES” in the drop-down menu because this item meets the requirement. However, if HL is longer than one-half page, select “NO” unless a waiver has been granted.

Comment: The HL BW is present. 3. A horizontal line must separate: • HL from the Table of Contents (TOC), and • TOC from the Full Prescribing Information (FPI).

Comment: The line from TOC to FPI is missing. 4. All headings in HL (from Recent Major Changes to Use in Specific Populations) must be bolded

and presented in the center of a horizontal line. (Each horizontal line should extend over the entire width of the column.) The HL headings (from Recent Major Changes to Use in Specific Populations) should be in UPPER CASE letters. See Appendix for HL format.

Comment: 5. White space should be present before each major heading in HL. There must be no white space

between the HL Heading and HL Limitation Statement. There must be no white space between the product title and Initial U.S. Approval. See Appendix for HL format.

Comment: No WS present before each major heading in HL. 6. Each summarized statement or topic in HL must reference the section(s) or subsection(s) of the

Full Prescribing Information (FPI) that contain more detailed information. The preferred format

YES

Yes

NO

YES

NO

YES




Boxed Warning (BW) in Highlights

12. All text in the BW must be bolded.

Comment:

13. The BW must have a title in UPPER CASE, following the word “WARNING” and other words to identify the subject of the warning. Even if there is more than one warning, the term “WARNING” and not “WARNINGS” should be used. For example: “WARNING: SERIOUS INFECTIONS and ACUTE HEPATIC FAILURE”. If there is more than one warning in the BW title, the word “and” in lower case can separate the warnings. The BW title should be centered.

Comment: "And" is in Upper Case

14. The BW must always have the verbatim statement “See full prescribing information for complete boxed warning.” This statement must be placed immediately beneath the BW title, and should be centered and appear in italics.

Comment:

15. The BW must be limited in length to 20 lines. (This includes white space but does not include the BW title and the statement “See full prescribing information for complete boxed warning.”) Comment:

Recent Major Changes (RMC) in Highlights

16. RMC pertains to only five sections of the FPI: BOXED WARNING, INDICATIONS AND USAGE, DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS, and WARNINGS AND PRECAUTIONS. Labeling sections for RMC must be listed in the same order in HL as they appear in the FPI.

Comment:

17. The RMC must include the section heading(s) and, if appropriate, subsection heading(s) affected by the recent major change, together with each section’s identifying number and date (month/year format) on which the change was incorporated in the PI (supplement approval date). For example, “Warnings and Precautions, Acute Liver Failure (5.1) --- 8/2015.”

Comment:

18. A changed section must be listed under the RMC heading for at least one year after the date of the labeling change and must be removed at the first printing subsequent to the one year period. (No listing should be one year older than the revision date.)

Comment:

Dosage Forms and Strengths in Highlights

19. For a product that has more than one dosage form (e.g., capsules, tablets, injection), bulleted headings should be used.

Comment:

YES

NO

YES

YES

N/A

N/A

N/A

N/A




Contraindications in Highlights

20. All contraindications listed in the FPI must also be listed in HL. If there is more than one contraindication, each contraindication should be bulleted. If no contraindications are known, must include the word “None.”

Comment:

Adverse Reactions in Highlights

21. For drug products other than vaccines, the verbatim bolded statement must be present: “To report SUSPECTED ADVERSE REACTIONS, contact (insert name of manufacturer) at (insert manufacturer’s U.S. phone number which should be a toll-free number) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.”

Comment:

Patient Counseling Information Statement in Highlights

22. The Patient Counseling Information statement must include one of the following three bolded verbatim statements that is most applicable:

If a product does not have FDA-approved patient labeling:

• See 17 for PATIENT COUNSELING INFORMATION

If a product has (or will have) FDA-approved patient labeling:

• See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling

• See 17 for PATIENT COUNSELING INFORMATION and Medication Guide

Comment:

Revision Date in Highlights

23. The revision date must be at the end of HL, and should be bolded and right justified (e.g., “Revised: 8/2015 ”). Comment:

YES

YES

YES

YES




Contents: Table of Contents (TOC)

See Appendix for a sample tool illustrating Table of Contents format.

24. The TOC should be in a two-column format.

Comment:

25. The following heading must appear at the beginning of the TOC: “FULL PRESCRIBING INFORMATION: CONTENTS.” This heading should be in all UPPER CASE letters and bolded.

Comment:

26. The same title for the BW that appears in HL and the FPI must also appear at the beginning of the TOC in UPPER CASE letters and bolded.

Comment:

27. In the TOC, all section headings must be bolded and should be in UPPER CASE.

Comment:

28. In the TOC, all subsection headings must be indented and not bolded. The headings should be in title case [first letter of all words are capitalized except first letter of prepositions (for, of, to) and articles (a, an, the), or conjunctions (or, and)].

Comment: 29. The section and subsection headings in the TOC must match the section and subsection headings

in the FPI.

Comment:

30. If a section or subsection required by regulation [21 CFR 201.56(d)(1)] is omitted from the FPI, the numbering in the TOC must not change. The heading “FULL PRESCRIBING INFORMATION: CONTENTS*” must be followed by an asterisk and the following statement must appear at the end of the TOC: “*Sections or subsections omitted from the full prescribing information are not listed.” Comment:

YES

YES

YES

YES

YES

YES

YES




Full Prescribing Information (FPI)

FULL PRESCRIBING INFORMATION: GENERAL FORMAT

31. The bolded section and subsection headings in the FPI must be named and numbered in accordance with 21 CFR 201.56(d)(1) as noted below. (Section and subsection headings should be in UPPER CASE and title case, respectively.) If a section/subsection required by regulation is omitted, the numbering must not change. Additional subsection headings (i.e., those not named by regulation) must also be bolded and numbered.

BOXED WARNING 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 6 ADVERSE REACTIONS 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy 8.2 Lactation (if not required to be in Pregnancy and Lactation Labeling Rule (PLLR) format, use

“Labor and Delivery”) 8.3 Females and Males of Reproductive Potential (if not required to be in PLLR format, use

“Nursing Mothers”) 8.4 Pediatric Use 8.5 Geriatric Use

9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance 9.2 Abuse 9.3 Dependence

10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.4 Microbiology (by guidance) 12.5 Pharmacogenomics (by guidance)

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Toxicology and/or Pharmacology

14 CLINICAL STUDIES 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION

Comment: 32. The preferred presentation for cross-references in the FPI is the section (not subsection)

heading followed by the numerical identifier. The entire cross-reference should be in italics and enclosed within brackets. For example, “[see Warnings and Precautions (5.2)].”

Comment:

YES

YES




33. For each RMC listed in HL, the corresponding new or modified text in the FPI must be marked with a vertical line on the left edge.

Comment:

FULL PRESCRIBING INFORMATION DETAILS

FPI Heading

34. The following heading “FULL PRESCRIBING INFORMATION” must be bolded, must appear at the beginning of the FPI, and should be in UPPER CASE.

Comment:

BOXED WARNING Section in the FPI 35. All text in the BW should be bolded.

Comment:

36. The BW must have a title in UPPER CASE, following the word “WARNING” and other words to identify the subject of the warning. (Even if there is more than one warning, the term, “WARNING” and not “WARNINGS” should be used.) For example: “WARNING: SERIOUS INFECTIONS and ACUTE HEPATIC FAILURE”. If there is more than one warning in the BW title, the word “and” in lower case can separate the warnings.

Comment: "AND" is not in lower case. CONTRAINDICATIONS Section in the FPI

37. If no Contraindications are known, this section must state “None.”

Comment:

ADVERSE REACTIONS Section in the FPI

38. When clinical trials adverse reactions data are included (typically in the “Clinical Trials Experience” subsection), the following verbatim statement (or appropriate modification) should precede the presentation of adverse reactions from clinical trials:

“Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.”

Comment:

39. When postmarketing adverse reaction data are included (typically in the “Postmarketing Experience” subsection), the following verbatim statement (or appropriate modification) should precede the presentation of adverse reactions: “The following adverse reactions have been identified during post-approval use of (insert drug name). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.”

Comment:

N/A

YES

YES

NO

N/A

YES

N/A




PATIENT COUNSELING INFORMATION Section in the FPI

40. Must reference any FDA-approved patient labeling in Section 17 (PATIENT COUNSELING INFORMATION). The reference statement should appear at the beginning of Section 17 and include the type(s) of FDA-approved patient labeling (e.g., Patient Information, Instructions for Use, or Medication Guide). Recommended language for the reference statement should include one of the following five verbatim statements that is most applicable: • Advise the patient to read the FDA-approved patient labeling (Patient Information). • Advise the patient to read the FDA-approved patient labeling (Instructions for Use). • Advise the patient to read the FDA-approved patient labeling (Patient Information and

Instructions for Use). • Advise the patient to read the FDA-approved patient labeling (Medication Guide). • Advise the patient to read the FDA-approved patient labeling (Medication Guide and

Instructions for Use). Comment:

41. FDA-approved patient labeling (e.g., Patient Information, Instructions for Use, or Medication Guide) must not be included as a subsection under Section 17 (PATIENT COUNSELING INFORMATION). All FDA-approved patient labeling must appear at the end of the PI upon approval.

Comment:

N/A

N/A




Appendix: Highlights and Table of Contents Format




LADAN JAFARI11/12/2015


Version: 7/10/2015

RPM FILING REVIEW(Including Memo of Filing Meeting)

To be completed for all new NDAs, BLAs, and Efficacy Supplements [except SE8 (labeling change with clinical data) and SE9 (manufacturing change with clinical data]

Application InformationNDA 208400-Original 1; NDA 208400-Original 2 BLA#

NDA Supplement #: S- BLA Supplement #: S-

Efficacy Supplement Category: New Indication (SE1) New Dosing Regimen (SE2) New Route Of Administration (SE3) Comparative Efficacy Claim (SE4) New Patient Population (SE5) Rx To OTC Switch (SE6) Accelerated Approval Confirmatory Study

(SE7) Labeling Change With Clinical Data (SE8) Manufacturing Change With Clinical Data

(SE9) Animal Rule Confirmatory Study (SE10)

Proprietary Name: (proposed, currently under review)Established/Proper Name: Methotrexate Dosage Form: SolutionStrengths: 2.5 mg/mLApplicant: Silvergate Pharmaceuticals, Inc.Agent for Applicant (if applicable): Date of Application: August 31, 2015Date of Receipt: August 31, 2015Date clock started after UN: PDUFA Goal Date: June 30, 2016 Action Goal Date (if different): Filing Date: October 30, 2015 Date of Filing Meeting: October 7, 2015Chemical Classification (original NDAs only) :

Type 1- New Molecular Entity (NME); NME and New Combination Type 2- New Active Ingredient; New Active Ingredient and New Dosage Form; New Active Ingredient and New

Combination Type 3- New Dosage Form; New Dosage Form and New Combination Type 4- New Combination Type 5- New Formulation or New Manufacturer Type 7- Drug Already Marketed without Approved NDA Type 8- Partial Rx to OTC Switch

Proposed indication(s)/Proposed change(s): treatment of pediatric patients with acute lymphoblastic leukemia (ALL), as part of a combination regimen and the management of children with active polyarticular juvenile idiopathic arthritis (pJIA) who are intolerant of or had an inadequate response to first-line therapy.

505(b)(1) 505(b)(2)

Type of Original NDA: AND (if applicable)

Type of NDA Supplement:

If 505(b)(2): Draft the “505(b)(2) Assessment” review found at: http://inside.fda.gov:9003/CDER/OfficeofNewDrugs/ImmediateOffice/UCM027499.

N/A

1


(b) (4)

Version: 7/10/2015

Type of BLA

If 351(k), notify the OND Therapeutic Biologics and Biosimilars Team

351(a) 351(k)

Review Classification:

The application will be a priority review if: A complete response to a pediatric Written Request (WR) was

included (a partial response to a WR that is sufficient to change the labeling should also be a priority review – check with DPMH)

The product is a Qualified Infectious Disease Product (QIDP) A Tropical Disease Priority Review Voucher was submitted A Pediatric Rare Disease Priority Review Voucher was submitted

Standard Priority

Pediatric WR QIDP Tropical Disease Priority

Review Voucher Pediatric Rare Disease Priority

Review Voucher Resubmission after withdrawal? Resubmission after refuse to file? Part 3 Combination Product?

If yes, contact the Office of Combination Products (OCP) and copy them on all Inter-Center consults

Convenience kit/Co-package Pre-filled drug delivery device/system (syringe, patch, etc.) Pre-filled biologic delivery device/system (syringe, patch, etc.) Device coated/impregnated/combined with drug Device coated/impregnated/combined with biologic Separate products requiring cross-labeling Drug/Biologic Possible combination based on cross-labeling of separate

products Other (drug/device/biological product)

Fast Track Designation Breakthrough Therapy Designation

(set the submission property in DARRTS and notify the CDER Breakthrough Therapy Program Manager)

Rolling Review Orphan Designation

(both indications)

Rx-to-OTC switch, Full Rx-to-OTC switch, Partial Direct-to-OTC

Other:

PMC response PMR response:

FDAAA [505(o)] PREA deferred pediatric studies (FDCA Section

505B) Accelerated approval confirmatory studies (21 CFR

314.510/21 CFR 601.41) Animal rule postmarketing studies to verify clinical

benefit and safety (21 CFR 314.610/21 CFR 601.42)

Collaborative Review Division (if OTC product):

List referenced IND Number(s): 117387Goal Dates/Product Names/Classification Properties YES NO NA CommentPDUFA/BsUFA and Action Goal dates correct in tracking system?

If no, ask the document room staff to correct them immediately. These are the dates used for calculating inspection dates.Are the established/proper and applicant names correct in tracking system?

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If no, ask the document room staff to make the corrections. Also, ask the document room staff to add the established/proper name to the supporting IND(s) if not already entered into tracking system.Is the review priority (S or P) and all appropriate classifications/properties entered into tracking system (e.g., chemical classification, combination product classification, orphan drug)? Check the New Application and New Supplement Notification Checklists for a list of all classifications/properties at:http://inside.fda.gov:9003/CDER/OfficeofBusinessProcessSupport/ucm163969.htm

If no, ask the document room staff to make the appropriate entries.

The request was made

Application Integrity Policy YES NO NA CommentIs the application affected by the Application Integrity Policy (AIP)? Check the AIP list at:http://www.fda.gov/ICECI/EnforcementActions/ApplicationIntegrityPolicy/default.htm

If yes, explain in comment column.

NA

If affected by AIP, has OC been notified of the submission? If yes, date notified:

NA

User Fees YES NO NA CommentIs Form 3397 (User Fee Cover Sheet)/Form 3792 (Biosimilar User Fee Cover Sheet) included with authorized signature?

User Fee Status

If a user fee is required and it has not been paid (and it is not exempted or waived), the application is unacceptable for filing following a 5-day grace period. Review stops. Send Unacceptable for Filing (UN) letter and contact user fee staff.

Payment for this application (check daily email from [email protected]):

Paid Exempt (orphan) Waived (e.g., small business, public health) Not required

If the firm is in arrears for other fees (regardless of whether a user fee has been paid for this application), the application is unacceptable for filing (5-day grace period does not apply). Review stops. Send UN letter and contact the user fee staff.

Payment of other user fees:

Not in arrears In arrears

User Fee Bundling Policy

Refer to the guidance for industry, Submitting Separate Marketing Applications and Clinical Data for Purposes of Assessing User Fees at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM079320.pdf

Has the user fee bundling policy been appropriately applied? If no, or you are not sure, consult the User Fee Staff.

Yes No

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Version: 7/10/2015

505(b)(2) (NDAs/NDA Efficacy Supplements only)

YES NO NA Comment

Is the application a 505(b)(2) NDA? (Check the 356h form, cover letter, and annotated labeling). If yes, answer the bulleted questions below: Is the application for a duplicate of a listed drug and

eligible for approval under section 505(j) as an ANDA?

Is the application for a duplicate of a listed drug whose only difference is that the extent to which the active ingredient(s) is absorbed or otherwise made available to the site of action is less than that of the reference listed drug (RLD)? [see 21 CFR 314.54(b)(1)].

Is the application for a duplicate of a listed drug whose only difference is that the rate at which the proposed product’s active ingredient(s) is absorbed or made available to the site of action is unintentionally less than that of the listed drug [see 21 CFR 314.54(b)(2)]?

If you answered yes to any of the above bulleted questions, the application may be refused for filing under 21 CFR 314.101(d)(9). Contact the 505(b)(2) review staff in the Immediate Office of New Drugs for advice.

Is there unexpired exclusivity on another listed drug product containing the same active moiety (e.g., 5-year, 3-year, orphan, or pediatric exclusivity)?

Check the Electronic Orange Book at: http://www.accessdata.fda.gov/scripts/cder/ob/default.cfm

If yes, please list below:

Application No. Drug Name Exclusivity Code Exclusivity Expiration

If there is unexpired, 5-year exclusivity remaining on another listed drug product containing the same active moiety, a 505(b)(2) application cannot be submitted until the period of exclusivity expires (unless the applicant provides paragraph IV patent certification; then an application can be submitted four years after the date of approval.) Pediatric exclusivity will extend both of the timeframes in this provision by 6 months. 21 CFR 314.108(b)(2). Unexpired, 3-year exclusivity may block the approval but not the submission of a 505(b)(2) application.Exclusivity YES NO NA CommentDoes another product (same active moiety) have orphan exclusivity for the same indication? Check the Orphan Drug Designations and Approvals list at: http://www.accessdata.fda.gov/scripts/opdlisting/oopd/index.cfm

If another product has orphan exclusivity, is the product considered to be the same product according to the orphan drug definition of sameness [see 21 CFR 316.3(b)(13)]?

If yes, consult the Director, Division of Regulatory Policy II, Office of Regulatory Policy

NDAs/NDA efficacy supplements only: Has the applicant requested 5-year or 3-year Waxman-Hatch exclusivity?

They are requesting 7 years orphan drug exclusivity for both

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Version: 7/10/2015

If yes, # years requested:

Note: An applicant can receive exclusivity without requesting it; therefore, requesting exclusivity is not required.

proposed indications.

NDAs only: Is the proposed product a single enantiomer of a racemic drug previously approved for a different therapeutic use?

If yes, did the applicant: (a) elect to have the single enantiomer (contained as an active ingredient) not be considered the same active ingredient as that contained in an already approved racemic drug, and/or (b): request exclusivity pursuant to section 505(u) of the Act (per FDAAA Section 1113)?

If yes, contact the Orange Book Staff (CDER-Orange Book Staff).

BLAs only: Has the applicant requested 12-year exclusivity under section 351(k)(7) of the PHS Act?

If yes, notify Marlene Schultz-DePalo, CDER Purple Book Manager

Note: Exclusivity requests may be made for an original BLA submitted under Section 351(a) of the PHS Act (i.e., a biological reference product). A request may be located in Module 1.3.5.3 and/or other sections of the BLA and may be included in a supplement (or other correspondence) if exclusivity has not been previously requested in the original 351(a) BLA. An applicant can receive exclusivity without requesting it; therefore, requesting exclusivity is not required.

Format and Content

Do not check mixed submission if the only electronic component is the content of labeling (COL).

All paper (except for COL) All electronic Mixed (paper/electronic)

CTD Non-CTD Mixed (CTD/non-CTD)

If mixed (paper/electronic) submission, which parts of the application are submitted in electronic format? Overall Format/Content YES NO NA CommentIf electronic submission, does it follow the eCTD guidance?1

If not, explain (e.g., waiver granted).

Index: Does the submission contain an accurate comprehensive index?

Is the submission complete as required under 21 CFR 314.50

1 http://www fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072349.pdf

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Version: 7/10/2015

(NDAs/NDA efficacy supplements) or under 21 CFR 601.2 (BLAs/BLA efficacy supplements) including:

legible English (or translated into English) pagination navigable hyperlinks (electronic submissions only)

If no, explain.BLAs only: Companion application received if a shared or divided manufacturing arrangement?

If yes, BLA #

Forms and CertificationsElectronic forms and certifications with electronic signatures (scanned, digital, or electronic – similar to DARRTS, e.g., /s/) are acceptable. Otherwise, paper forms and certifications with hand-written signatures must be included. Forms include: user fee cover sheet (3397/3792), application form (356h), patent information (3542a), financial disclosure (3454/3455), and clinical trials (3674); Certifications include: debarment certification, patent certification(s), field copy certification, and pediatric certification. Application Form YES NO NA CommentIs form FDA 356h included with authorized signature per 21 CFR 314.50(a)?

If foreign applicant, a U.S. agent must sign the form [see 21 CFR 314.50(a)(5)].

Are all establishments and their registration numbers listed on the form/attached to the form?

Patent Information (NDAs/NDA efficacy supplements only)

YES NO NA Comment

Is patent information submitted on form FDA 3542a per 21 CFR 314.53(c)?

Financial Disclosure YES NO NA CommentAre financial disclosure forms FDA 3454 and/or 3455 included with authorized signature per 21 CFR 54.4(a)(1) and (3)?

Forms must be signed by the APPLICANT, not an Agent [see 21 CFR 54.2(g)].

Note: Financial disclosure is required for bioequivalence studies that are the basis for approval.

Clinical Trials Database YES NO NA CommentIs form FDA 3674 included with authorized signature?

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Version: 7/10/2015

If yes, ensure that the application is also coded with the supporting document category, “Form 3674.”

If no, ensure that language requesting submission of the form is included in the acknowledgement letter sent to the applicantDebarment Certification YES NO NA CommentIs a correctly worded Debarment Certification included with authorized signature?

Certification is not required for supplements if submitted in the original application; If foreign applicant, both the applicant and the U.S. Agent must sign the certification [per Guidance for Industry: Submitting Debarment Certifications].

Note: Debarment Certification should use wording in FD&C Act Section 306(k)(1) i.e.,“[Name of applicant] hereby certifies that it did not and will not use in any capacity the services of any person debarred under section 306 of the Federal Food, Drug, and Cosmetic Act in connection with this application.” Applicant may not use wording such as, “To the best of my knowledge…”

Field Copy Certification (NDAs/NDA efficacy supplements only)

YES NO NA Comment

For paper submissions only: Is a Field Copy Certification (that it is a true copy of the CMC technical section) included?

Field Copy Certification is not needed if there is no CMC technical section or if this is an electronic submission (the Field Office has access to the EDR)

If maroon field copy jackets from foreign applicants are received, return them to CDR for delivery to the appropriate field office.

Controlled Substance/Product with Abuse Potential YES NO NA CommentFor NMEs:Is an Abuse Liability Assessment, including a proposal for scheduling, submitted per 21 CFR 314.50(d)(5)(vii)?

If yes, date consult sent to the Controlled Substance Staff:

For non-NMEs:Date of consult sent to Controlled Substance Staff :

Pediatrics YES NO NA CommentPREA

Does the application trigger PREA?

If yes, notify [email protected] to schedule required PeRC meeting2

PREA does not apply due to orphan drug designation

2 http://inside fda.gov:9003/CDER/OfficeofNewDrugs/ImmediateOffice/PediatricandMaternalHealthStaff/ucm027829 htm

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Version: 7/10/2015

Note: NDAs/BLAs/efficacy supplements for new active ingredients (including new fixed combinations), new indications, new dosage forms, new dosing regimens, or new routes of administration trigger PREA. All waiver & deferral requests, pediatric plans, and pediatric assessment studies must be reviewed by PeRC prior to approval of the application/supplement.If the application triggers PREA, is there an agreed Initial Pediatric Study Plan (iPSP)?

If no, may be an RTF issue - contact DPMH for advice.

If required by the agreed iPSP, are the pediatric studies outlined in the agreed iPSP completed and included in the application?

If no, may be an RTF issue - contact DPMH for advice.

BPCA:

Is this submission a complete response to a pediatric Written Request?

If yes, notify Pediatric Exclusivity Board RPM (pediatric exclusivity determination is required)3

Proprietary Name YES NO NA CommentIs a proposed proprietary name submitted?

If yes, ensure that the application is also coded with the supporting document category, “Proprietary Name/Request for Review.”

REMS YES NO NA CommentIs a REMS submitted?

If yes, send consult to OSE/DRISK and notify OC/ OSI/DSC/PMSB via the CDER OSI RMP mailbox

Prescription Labeling Not applicableCheck all types of labeling submitted. Package Insert (PI)

Patient Package Insert (PPI) Instructions for Use (IFU) Medication Guide (MedGuide) Carton labels Immediate container labels Diluent Other (specify)

YES NO NA CommentIs Electronic Content of Labeling (COL) submitted in SPL format?

If no, request applicant to submit SPL before the filing date.

Is the PI submitted in PLR format?4

3 http://inside fda.gov:9003/CDER/OfficeofNewDrugs/ImmediateOffice/PediatricandMaternalHealthStaff/ucm027837 htm 4

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If PI not submitted in PLR format, was a waiver or deferral requested before the application was received or in the submission? If requested before application was submitted, what is the status of the request?

If no waiver or deferral, request applicant to submit labeling in PLR format before the filing date.

For applications submitted on or after June 30, 2015:Is the PI submitted in PLLR format?5

Has a review of the available pregnancy and lactation data been included?

No new pregnancy and lactation data was included in the application. The Applicant relies on the information contained in the RLD PI.

For applications submitted on or after June 30, 2015: If PI not submitted in PLLR format, was a waiver or deferral requested before the application was received or in the submission? If requested before application was submitted, what is the status of the request?

If no waiver or deferral, request applicant to submit labeling in PLR/PLLR format before the filing date.

All labeling (PI, PPI, MedGuide, IFU, carton and immediate container labels) consulted to OPDP?

Consult to OPDP is in process

MedGuide, PPI, IFU (plus PI) consulted to OSE/DRISK? (send WORD version if available)

Carton and immediate container labels, PI, PPI sent to OSE/DMEPA and appropriate CMC review office in OPQ (OBP or ONDP)?

OTC Labeling Not ApplicableCheck all types of labeling submitted. Outer carton label

Immediate container label Blister card Blister backing label Consumer Information Leaflet (CIL) Physician sample Consumer sample Other (specify)

YES NO NA Comment

http://inside fda.gov:9003/CDER/OfficeofNewDrugs/ImmediateOffice/StudyEndpointsandLabelingDevelopmentTeam/ucm025576 htm 5 http://inside fda.gov:9003/CDER/OfficeofNewDrugs/ImmediateOffice/StudyEndpointsandLabelingDevelopmentTeam/ucm025576 htm

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Is electronic content of labeling (COL) submitted?

If no, request in 74-day letter.

Are annotated specifications submitted for all stock keeping units (SKUs)?


If representative labeling is submitted, are all represented SKUs defined?


All labeling/packaging sent to OSE/DMEPA?

Other Consults YES NO NA CommentAre additional consults needed? (e.g., IFU to CDRH; QT study report to QT Interdisciplinary Review Team)

If yes, specify consult(s) and date(s) sent:Maternal Health consult is in process

Maternal Health

Meeting Minutes/SPAs YES NO NA CommentEnd-of Phase 2 meeting(s)? Date(s):

If yes, distribute minutes before filing meeting

Pre-NDA/Pre-BLA/Pre-Supplement meeting(s)? Date(s):

If yes, distribute minutes before filing meeting

Any Special Protocol Assessments (SPAs)?Date(s):

If yes, distribute letter and/or relevant minutes before filing meeting

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ATTACHMENT

MEMO OF FILING MEETING

DATE: October 7, 2015

BACKGROUND: Silvergate Pharmaceuticals has submitted a 505(b)(2) NDA for Methotrexate Oral Solution for the following indications: (1) treatment of pediatric patients with acute lymphoblastic leukemia (ALL), as part of a combination regimen, and (2) the management of children with active polyarticular juvenile idiopathic arthritis (pJIA) 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). They have received orphan drug designation for both indications. The reference listed drug is DAVA’s Methotrexate Sodium Tablets, NDA 008085.

REVIEW TEAM:

Discipline/Organization Names Present at filing meeting? (Y or N)

RPM: Jessica Boehmer, DHPSadaf Nabavian, DPARP

YY

Regulatory Project Management

CPMS/TL: Theresa Carioti, DHP Y

Cross-Discipline Team Leader (CDTL) Albert Deisseroth, DHP Y

Division Director/Deputy Ann Farrell, DHP Y

Office Director/Deputy Richard Pazdur, OHOP N

Reviewer: Patricia Dinndorf, DHPPeter Starke/DPARP

YClinical

TL: Albert Deisseroth, DHPJanet Maynard/DPARP

Y

Reviewer: Social Scientist Review (for OTC products)

TL:

Reviewer: OTC Labeling Review (for OTC products)

TL:

Reviewer: Clinical Microbiology (for antimicrobial products) TL:

Clinical Pharmacology Reviewer: Salaheldin Hamed, for DHP

Y

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TL: Bahru Habtemariam, for DHP

Y

Genomics Reviewer: Pharmacometrics Reviewer:

Reviewer: Biostatistics

TL:

Reviewer: Pedro Del Valle, DHOT YNonclinical (Pharmacology/Toxicology)

TL: Christopher Sheth, DHOT Y

Reviewer: Statistics (carcinogenicity)

TL:

ATL: Janice Brown YProduct Quality (CMC) Review Team:

RBPM: Rabiya Laiq Y

Drug Substance Reviewer: Drug Product Reviewer: Process Reviewer: Sam Bain

Donna Christner, TLYY

Microbiology Reviewer: Facility Reviewer: Biopharmaceutics Reviewer: Immunogenicity Reviewer: Labeling (BLAs only) Reviewer: Other (e.g., Branch Chiefs, EA

Reviewer)

Reviewer: OMP/OMPI/DMPP (Patient labeling: MG, PPI, IFU)

TL:

Reviewer: TBD OMP/OPDP (PI, PPI, MedGuide, IFU, carton and immediate container labels)

TL:

Reviewer: Rhiannon Leutner NOSE/DMEPA (proprietary name, carton/container labels)

TL: Yelena Maslov N

Reviewer: OSE/DRISK (REMS)

TL:

OC/OSI/DSC/PMSB (REMS) Reviewer:

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TL:

Reviewer: Bioresearch Monitoring (OSI)

TL:

Reviewer: Controlled Substance Staff (CSS)

TL:

Other reviewers/disciplines

FILING MEETING DISCUSSION:

GENERAL 505 b)(2) filing issues:

o Is the application for a duplicate of a listed drug and eligible for approval under section 505(j) as an ANDA?

o Did the applicant provide a scientific “bridge” demonstrating the relationship between the proposed product and the referenced product(s)/published literature?

Describe the scientific bridge (e.g., information to demonstrate sufficient similarity between the proposed product and the listed drug(s) such as BA/BE studies or to justify reliance on information described in published literature):

Not Applicable

YES NO

YES NO

The applicant is relying on FDA’s previous findings of safety and effectiveness for the RLD, MTX tablets, under NDA 008085. The applicant is relying on the nonclinical section of Dava and 2 pivotal BE studies.

Per reviewers, are all parts in English or English translation?

If no, explain:

YES NO

Electronic Submission comments

List comments:

Not Applicable No comments

CLINICAL

Comments:

Not Applicable FILE REFUSE TO FILE

Review issues for 74-day letter

Clinical study site(s) inspections(s) needed? YES

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If no, explain:

NO

Advisory Committee Meeting needed?

Comments:

If no, for an NME NDA or original BLA, include the reason. For example:

o this drug/biologic is not the first in its classo the clinical study design was acceptableo the application did not raise significant safety

or efficacy issueso the application did not raise significant public

health questions on the role of the drug/biologic in the diagnosis, cure, mitigation, treatment or prevention of a disease

YESDate if known:

NO To be determined

Reason:

If the application is affected by the AIP, has the division made a recommendation regarding whether or not an exception to the AIP should be granted to permit review based on medical necessity or public health significance?

Comments:

Not Applicable YES NO

CONTROLLED SUBSTANCE STAFF Abuse Liability/Potential

Comments:



CLINICAL MICROBIOLOGY

Comments:



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Version: 7/10/2015

CLINICAL PHARMACOLOGY

Comments:


Review issues for 74-day letter Clinical pharmacology study site(s) inspections(s)

needed? YES NO

BIOSTATISTICS

Comments:



NONCLINICAL (PHARMACOLOGY/TOXICOLOGY)

Comments:



PRODUCT QUALITY (CMC)

Comments:



New Molecular Entity (NDAs only)

Is the product an NME? YES NO

Environmental Assessment

Categorical exclusion for environmental assessment (EA) requested?

If no, was a complete EA submitted?

Comments:

YES NO

NA

Facility Inspection

Establishment(s) ready for inspection?

Comments:

Not Applicable

YES NO

15


Version: 7/10/2015

Facility/Microbiology Review (BLAs only)

Comments:



CMC Labeling Review (BLAs only)

Comments: NA

APPLICATIONS IN THE PROGRAM (PDUFA V) (NME NDAs/Original BLAs)

Were there agreements made at the application’s pre-submission meeting (and documented in the minutes) regarding certain late submission components that could be submitted within 30 days after receipt of the original application?

If so, were the late submission components all submitted within 30 days?

N/A

YES NO

YES NO

What late submission components, if any, arrived after 30 days?

Was the application otherwise complete upon submission, including those applications where there were no agreements regarding late submission components?

YES NO

Is a comprehensive and readily located list of all clinical sites included or referenced in the application?

YES NO

Is a comprehensive and readily located list of all manufacturing facilities included or referenced in the application?

YES NO

16


Version: 7/10/2015

REGULATORY PROJECT MANAGEMENT

Signatory Authority: Ann Farrell, DHP; Sarah Yim, DPARP

Date of Mid-Cycle Meeting (for NME NDAs/BLAs in “the Program” PDUFA V): NA

21st Century Review Milestones (listing review milestones in this document is optional):

Comments:

REGULATORY CONCLUSIONS/DEFICIENCIES

The application is unsuitable for filing. Explain why:

The application, on its face, appears to be suitable for filing.

Review Issues:

No review issues have been identified for the 74-day letter. Review issues have been identified for the 74-day letter.

Review Classification:

Standard Review for both Orig-1 and Orig-2 Priority Review

ACTION ITEMS

Ensure that any updates to the review priority (S or P) and classifications/properties are entered into the electronic archive (e.g., chemical classification, combination product classification, orphan drug). If RTF, notify everyone who already received a consult request, OSE PM, and RBPM

If filed, and the application is under AIP, prepare a letter either granting (for signature by Center Director) or denying (for signature by ODE Director) an exception for review.

If priority review, notify applicant in writing by day 60 (see CST for choices)

Send review issues/no review issues by day 74

Conduct a PLR format labeling review and include labeling issues in the 74-day letter

Update the PDUFA V DARRTS page (for applications in the Program)

Other

Annual review of template by OND ADRAs completed: September 2014

17



JESSICA L BOEHMER10/30/2015

PATRICIA N GARVEY10/30/2015


LADAN JAFARI10/30/2015


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