CENTER FOR DRUG EVALUATION AND RESEARCH
Approval Package for:

APPLICATION NUMBER:

205596Orig1s000
Trade Name:

Noxafil

Generic Name: Posaconazole injection, 18 mg/mL
Sponsor:

Merck Sharp Dohme

Approval Date: March 16, 2014
Indications:

For prophylaxis of invasive Aspergillus and Candida
infections in patients, 18 years of age and older, who
are at high risk of developing these infections due to
being severely immunocompromised, such as
hematopoietic stem cell transplant (HSCT) recipients
with graft versus host disease (GVHD) or those with
hematologic malignancies with prolonged neutropenia
from chemotherapy.

 CENTER FOR DRUG EVALUATION AND
RESEARCH

205596Orig1s000
CONTENTS

Reviews / Information Included in this NDA Review.
Approval Letter
Other Action Letters
Labeling
REMS
Summary Review
Officer/Employee List
Office Director Memo
Cross Discipline Team Leader Review
Medical Review(s)
Chemistry Review(s)
Environmental Assessment
Pharmacology Review(s)
Statistical Review(s)
Microbiology / Virology Review(s)
Clinical Pharmacology/Biopharmaceutics Review(s)
Other Reviews
Risk Assessment and Risk Mitigation Review(s)
Proprietary Name Review(s)
Administrative/Correspondence Document(s)

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 CENTER FOR DRUG EVALUATION AND
RESEARCH

APPLICATION NUMBER:

2055960rig15000

APPROVAL LETTER

 

DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
Silver Spring MD 20993

NDA 205596
NDA APPROVAL

Merck Sharp & Dohme Corp.
Attention: Laurie J. MacDonald, MD
Executive Director, Global Regulatory Affairs
351 North Sumneytown Pike, P.O. Box 1000
MAILSTOP UG2D68
North Wales, PA 19454-2505

Dear Dr. MacDonald:
Please refer to your New Drug Application (NDA) dated September 13, 2013, received
September 13, 2013, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic
Act (FDCA) for Noxafil (posaconazole) injection, 18 mg/mL.
We acknowledge receipt of your amendments dated October 14, and 24, and December 12 (2),
2013, and January 3, and 8, and February 13, 25, 27 (2), and 28, and March 13 (2), 2014.
This new drug application provides for the use of Noxafil (posaconazole) injection, 18 mg/mL
for prophylaxis of invasive Aspergillus and Candida infections in patients, 18 years of age and
older, who are at high risk of developing these infections due to being severely
immunocompromised, such as hematopoietic stem cell transplant (HSCT) recipients with graft
versus host disease (GVHD) or those with hematologic malignancies with prolonged neutropenia
from chemotherapy.
We have completed our review of this application, as amended. It is approved, effective on the
date of this letter, for use as recommended in the enclosed agreed-upon labeling text.
WAIVER OF HIGHLIGHTS SECTION
We are waiving the requirements of 21 CFR 201.57(d)(8) regarding the length of Highlights of
prescribing information. This waiver applies to all future supplements containing revised
labeling unless we notify you otherwise.

Reference ID: 3470974

 NDA 205596
Page 2

CONTENT OF LABELING
As soon as possible, but no later than 14 days from the date of this letter, submit the content of
labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using the FDA
automated drug registration and listing system (eLIST), as described at
http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Content
of labeling must be identical to the enclosed labeling (text for the package insert, text for the
patient package insert). Information on submitting SPL files using eLIST may be found in the
guidance for industry SPL Standard for Content of Labeling Technical Qs and As, available at
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
CM072392.pdf.
The SPL will be accessible via publicly available labeling repositories.
CARTON AND IMMEDIATE CONTAINER LABELS
Submit final printed carton and immediate container labels that are identical to the enclosed
carton and immediate container labels as soon as they are available, but no more than 30 days
after they are printed. Please submit these labels electronically according to the guidance for
industry Providing Regulatory Submissions in Electronic Format – Human Pharmaceutical
Product Applications and Related Submissions Using the eCTD Specifications (June 2008).
Alternatively, you may submit 12 paper copies, with 6 of the copies individually mounted on
heavy-weight paper or similar material. For administrative purposes, designate this submission
“Final Printed Carton and Container Labels for approved NDA 205596.” Approval of this
submission by FDA is not required before the labeling is used.
Marketing the product(s) with FPL that is not identical to the approved labeling text may render
the product misbranded and an unapproved new drug.
REQUIRED PEDIATRIC ASSESSMENTS
Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new
active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of
administration are required to contain an assessment of the safety and effectiveness of the
product for the claimed indication(s) in pediatric patients unless this requirement is waived,
deferred, or inapplicable.
We are waiving the pediatric study requirement for ages birth to less than 2 years because
necessary studies are impossible or highly impracticable. This is because antifungal prophylaxis
is rarely used in immunocompromised patients with hematologic malignancies in the age group
less than 2 years of age.
We are deferring submission of your pediatric studies for ages 2 to less than 18 years for this
application because this product is ready for approval for use in adults and the pediatric studies
have not been completed.

Reference ID: 3470974

 NDA 205596
Page 3

Your deferred pediatric studies required by section 505B(a) of the Federal Food, Drug, and
Cosmetic Act/FDCA are required postmarketing studies. The status of these postmarketing
studies must be reported annually according to 21 CFR 314.81 and section 505B(a)(3)(B) of the
Federal Food, Drug, and Cosmetic Act/FDCA. These required studies are listed below.

(
(

2132-1: Conduct a trial in patients, ages 2 to < 18 years, to evaluate the pharmacokinetic (PK),
safety, and tolerability of two new formulations of posaconazole (IV solution and/or new
age-appropriate oral formulation) in immunocompromised pediatric patients with known
or expected neutropenia.
Final Protocol Submission: 09/30/14
Trial Completion:
06/30/17
Final Report Submission: 09/30/17
If the trial for PMR 2132-1 fails to find a pediatric dosing regimen that provides pediatric
patients with exposures similar to those in adult patients, then the following efficacy trial (PMR
2132-2) will be required, provided a safe and tolerable dosage regimen can still be identified. If
the trial for PMR 2132-1 is successful in determining a pediatric dosing regimen, you may
request release from PMR 2132-2.
2132-2: Conduct a comparative, double-blind, randomized, multi-center trial, in patients ages 2
to < 18 years, to evaluate the safety, efficacy, and tolerability of posaconazole for the
prophylaxis of invasive fungal infections (IFI) in pediatric patients with known or
expected neutropenia.
Final Protocol Submission: 09/30/17
Trial Completion:
11/30/20
Final Report Submission: 03/31/21
Submit the protocol(s) to your IND 75061, with a cross-reference letter to this NDA.
Reports of these required pediatric postmarketing studies must be submitted as a new drug
application (NDA) or as a supplement to your approved NDA with the proposed labeling
changes you believe are warranted based on the data derived from these studies. When
submitting the reports, please clearly mark your submission "SUBMISSION OF REQUIRED
PEDIATRIC ASSESSMENTS" in large font, bolded type at the beginning of the cover letter of
the submission.
POSTMARKETING COMMITMENTS NOT SUBJECT TO THE REPORTING
REQUIREMENTS UNDER SECTION 506B
We remind you of your postmarketing commitments:
2132-3: Provide USP <788> test results using both Method 1 and Method 2 for the diluted

Reference ID: 3470974

 NDA 205596
Page 4

infusion solutions of posaconazole injection in D5W and normal saline at drug product
release and at annual stability test time points for 10 commercial batches of the drug
product, Noxafil Injection, 300 mg.
The timetable you submitted on March 13, 2014, states that you will conduct this study
according to the following schedule:
Final Protocol Submission: June 2014
Interim Report Submission: June 2015
Interim Report Submission: June 2016
Interim Report Submission: June 2017
Study Completion:
June 2018
Final Report Submission: September 2018*
*Final report will include 3 year stability test time-point for 10 batches

2132-4: Conduct and provide the results of a detailed root-cause analysis of the particulate
formation reported in Section 3.2.P.2.6 of the NDA for infusion solutions of
posaconazole in 5% Dextrose and normal saline. This analysis should include evaluation
of conditions under which particulates can be formed, the potential causes for the
observed precipitation, an evaluation of whether particulate matter is more likely to
appear in infusion solutions of newly manufactured batches of posaconazole injection,
and if “batch aging” is likely to reduce particulates. Use both USP<788> Method 1 and
Method 2 in your analysis. For particulates observed, identify the particulate matter.
The timetable you submitted on March 13, 2014, states that you will conduct this study
according to the following schedule:
Final Protocol Submission: 6/30/14
Study Completion:
12/31/14
Final Report Submission: 3/31/15
Submit clinical protocols to your IND 75061, for this product. Submit nonclinical and
chemistry, manufacturing, and controls protocols and all postmarketing final reports to this
NDA. In addition, under 21 CFR 314.81(b)(2)(vii) and 314.81(b)(2)(viii) you should include a
status summary of each commitment in your annual report to this NDA. The status summary
should include expected summary completion and final report submission dates, any changes in
plans since the last annual report, and, for clinical studies/trials, number of patients entered into
each study/trial. All submissions, including supplements, relating to these postmarketing
commitments should be prominently labeled “Postmarketing Commitment Protocol,”
“Postmarketing Commitment Final Report,” or “Postmarketing Commitment
Correspondence.”

Reference ID: 3470974

 NDA 205596
Page 5

PROMOTIONAL MATERIALS
You may request advisory comments on proposed introductory advertising and promotional
labeling. To do so, submit, in triplicate, a cover letter requesting advisory comments, the
proposed materials in draft or mock-up form with annotated references, and the package insert
to:
Food and Drug Administration
Center for Drug Evaluation and Research
Office of Prescription Drug Promotion
5901-B Ammendale Road
Beltsville, MD 20705-1266
As required under 21 CFR 314.81(b)(3)(i), you must submit final promotional materials, and the
package insert, at the time of initial dissemination or publication, accompanied by a Form FDA
2253. Form FDA 2253 is available at
http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083570.pdf.
Information and Instructions for completing the form can be found at
http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM375154.pdf. For
more information about submission of promotional materials to the Office of Prescription Drug
Promotion (OPDP), see http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm.
REPORTING REQUIREMENTS
We remind you that you must comply with reporting requirements for an approved NDA
(21 CFR 314.80 and 314.81).
If you have any questions, call Alison Rodgers, Regulatory Project Manager, at (301) 796-0797.
Sincerely,
{See appended electronic signature page}

Katherine A. Laessig, MD
Deputy Director
Division of Anti-Infective Products
Office of Antimicrobial Products
Center for Drug Evaluation and Research
Enclosures:
Content of Labeling
Carton and Container Labeling

Reference ID: 3470974

 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic
signature.
--------------------------------------------------------------------------------------------------------/s/
---------------------------------------------------KATHERINE A LAESSIG
03/13/2014

Reference ID: 3470974