`
` CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`Approval Package for:
`
`
`APPLICATION NUMBER:
`
`
`
` 022023Orig1s017
`
`
` EMEND
`
`
` fosaprepitant
`
`
`
`
`
`
`
`
`
` Trade Name:
`
`
`
` Generic or Proper
`
` Name:
`
` Sponsor:
`
`
`
`
`
`
`
` Merck Sharp & Dohme
`
` April 3, 2018
`
` EMEND for injection is a substance P/neurokinin-1 (NK1)
`
` receptor
`
` antagonist, indicated in adults and pediatric patients 6 months of
`
` age
`
`
` and older, in combination with other antiemetic agents, for the
` prevention of :
`
`
`
`
`
`• acute and delayed nausea and vomiting associated with initial
`
`and
`repeat courses of highly emetogenic cancer chemotherapy
`
`(HEC)
`
`including high-dose cisplatin.
`
`
`
`
`
`• delayed nausea and vomiting associated with initial and repeat
`
`
`
`courses of moderately emetogenic cancer chemotherapy (MEC).
`
`Limitations of Use
` • EMEND has not been studied for treatment of established
`
` nausea
`
`and vomiting.
`
`
`
`
` Approval Date:
`
`
`
`
`
`
` Indication:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`

`

`
`
`
`
`
`
` CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
` 022023Orig1s017
`
`
`
` 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)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` X
`
`
` X
`
`
` X
`
` X
`
`
` X
`
` X
`
`
`
` X
`
` X
`
`
` X
`
` X
`
`
`
`
`

`

`
`
`
`
`
`
`
`
` CENTER FOR DRUG EVALUATION AND
`
`
`
` RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`
`
` 022023Orig1s017
`
`
`
`APPROVAL LETTER
`
`
`

`

`
`
`
`
` DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`
`
`
`
`
`
`
` NDA 022023/S-017
`
`
`
`
`
`
`
`
`
`
`
`
`
` Food and Drug Administration
`
`
`
` Silver Spring MD 20993
`
`
`
`
`SUPPLEMENT APPROVAL
`
`
`
`
`Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
`
`
`
`Attention: Nicholas W. Andrew
`
`
`Director, Global Regulatory Affairs
`
`
`
`126 E. Lincoln Avenue
`
`
`P.O. Box 2000, RY34-B293
`
`
`Rahway, NJ 07065
`
`
`
` Dear Mr. Andrew:
`
`Please refer to your Supplemental New Drug Application (sNDA) dated October 3, 2017,
`
`
` received October 3, 2017, and your amendments, submitted under section 505(b) of the Federal
` Food, Drug, and Cosmetic Act (FDCA) for Emend (fosaprepitant) injection, for intravenous use.
`
`
` This Prior Approval supplemental new drug application provides for the use of Emend
`
`
`
` (fosaprepitant) injection for prevention of chemotherapy-induced nausea and vomiting in patients
`
` ages 6 months of age and older.
`
`
` APPROVAL & LABELING
`
` We have completed our review of this supplemental application, as amended. It is approved,
`
` effective on the date of this letter, for use as recommended in the enclosed, agreed-upon labeling
`
` text.
`
` 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), with the addition of any labeling changes in pending “Changes Being
`Effected” (CBE) supplements, as well as annual reportable changes not included in the enclosed
`
`labeling.
`
` Information on submitting SPL files using eList may be found in the guidance for industry titled
`
`
`
` “SPL Standard for Content of Labeling Technical Qs and As” at
`http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/U
`
`CM072392.pdf.
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4243652
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` NDA 022023/S-017
` Page 2
`
`
`
` The SPL will be accessible from publicly available labeling repositories.
`
` Also within 14 days, amend all pending supplemental applications that include labeling changes
`
`
` for this NDA, including CBE supplements for which FDA has not yet issued an action letter,
` with the content of labeling [21 CFR 314.50(l)(1)(i)] in MS Word format, that includes the
`
`
`
`
`
`changes approved in this supplemental application, as well as annual reportable changes and
`
` annotate each change. To facilitate review of your submission, provide a highlighted or marked-
` up copy that shows all changes, as well as a clean Microsoft Word version. The marked-up copy
`
`
`
`
`
`
` should provide appropriate annotations, including supplement number(s) and annual report
`date(s).
`
`
` 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 note that you have fulfilled the pediatric study requirement under this legislation for all
`
`
` relevant pediatric age groups for this application.
`
` FULFILLMENT OF POSTMARKETING REQUIREMENT(S)/COMMITMENT(S)
`
`We have received your submission dated October 3, 2017, containing the final report(s) for the
`
`
`
`
` following postmarketing requirement listed in the October 13, 2016 postapproval postmarketing
` requirement letter.
`
`
`
`
`
`
`
`
`
`
`1663-3 A PK/PD study to characterize aprepitant PK parameters following administration
`
`
`
` of a single dose of intravenous fosaprepitant, in combination with a 5HT3
`
`
`
`
` antagonist and dexamethasone, in pediatric cancer patients ages 0 to 17 years
`
`
` undergoing treatment with highly emetogenic chemotherapy. You must conduct
`
`
`
` this study with an age appropriate formulation.
`
`
`
` Use modeling and simulation including the results of the above study to identify
`
`
`
`
` 1-Day and 3-Day intravenous fosaprepitant doses in pediatric patients 0 to 17
`
` years of age that provide similar aprepitant PK exposures to pediatric aprepitant
`
`
`
`
` doses and exposures which have demonstrated acceptable safety and efficacy
`
`
`
`
` profiles in patients receiving single and multi-day chemotherapy regimens,
`
`
` respectively.
`
`
`
`
`
`
` We have reviewed your submission and conclude that the above requirement was fulfilled.
`
` This completes your postmarketing requirement acknowledged in our October 13, 2016, letter.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4243652
`
`

`

`
`
`
`
`NDA 022023/S-017
`
`
`
`Page 3
`
`
`
`
` POSTMARKETING REQUIREMENTS UNDER 505(o)
`
` Section 505(o)(3) of the Federal Food, Drug, and Cosmetic Act (FDCA) authorizes FDA to
`
` require holders of approved drug and biological product applications to conduct postmarketing
`studies and clinical trials for certain purposes, if FDA makes certain findings required by the
`
` statute.
`
` Since Emend (fosaprepitant) was approved on January 25, 2008, we have become aware of
`
`
`
`
`
`
` reports of hypersensitivity reactions including anaphylaxis and anaphylactic shock in pediatric
` patients. We consider this information to be “new safety information” as defined in section 505-
`
` 1(b)(3) of the FDCA.
`
`
`We have determined that an analysis of spontaneous postmarketing adverse events reported
`under subsection 505(k)(1) of the FDCA will not be sufficient to identify the unexpected serious
`
`
`
`
`
` risk of hypersensitivity reactions including anaphylaxis and anaphylactic shock in pediatric
` patients.
`
`
`Furthermore, the new pharmacovigilance system that FDA is required to establish under section
`
` 505(k)(3) of the FDCA will not be sufficient to assess this serious risk.
`
` Finally, we have determined that only a clinical trial (rather than a nonclinical or observational
`
`study) will be sufficient to identify an unexpected serious risk of hypersensitivity reactions
`
` including anaphylaxis and anaphylactic shock.
`
`Therefore, based on appropriate scientific data, FDA has determined that you are required to
`
` conduct the following:
`
`
`3361-1
`
`
`Conduct a trial to evaluate the safety of multiple cycles of intravenous
`
` administration of fosaprepitant daily for three consecutive days for the prevention
`of chemotherapy-induced nausea and vomiting in pediatric patients 6 months to
`
`
` 17 years of age.
`
`
`
`
`
`
`
`
` The timetable you submitted on March 28, 2018 states that you will conduct this study according
`
` to the following schedule:
`
`
`
`
`
` Draft Protocol Submission: 10/2018
`
`
` Final Protocol Submission: 04/2019
`
` 03/2021
`
`
` Trial Completion:
` Final Report Submission:
`
` 09/2021
`
` Submit the protocol(s) to your IND 048924, with a cross-reference letter to this NDA. Submit
`
`
`nonclinical and chemistry, manufacturing, and controls protocols and all postmarketing final
`report(s) to your NDA. Prominently identify the submission with the following wording in bold
`
` capital letters at the top of the first page of the submission, as appropriate: “Required
` Postmarketing Protocol Under 505(o)”, “Required Postmarketing Final Report Under
`
` 505(o)”, “Required Postmarketing Correspondence Under 505(o)”.
`
`
`
`
`
`
`Reference ID: 4243652
`
`

`

`
`
`
`
`
`
`
` NDA 022023/S-017
` Page 4
`
`
`
`
` Section 505(o)(3)(E)(ii) of the FDCA requires you to report periodically on the status of any
`
`
` study or clinical trial required under this section. This section also requires you to periodically
` report to FDA on the status of any study or clinical trial otherwise undertaken to investigate a
`
`
`
`
` safety issue. Section 506B of the FDCA, as well as 21 CFR 314.81(b)(2)(vii) requires you to
` report annually on the status of any postmarketing commitments or required studies or clinical
`
`
` trials.
`
` FDA will consider the submission of your annual report under section 506B and
`
`
`
` 21 CFR 314.81(b)(2)(vii) to satisfy the periodic reporting requirement under section
`505(o)(3)(E)(ii) provided that you include the elements listed in 505(o) and
`
`
` 21 CFR 314.81(b)(2)(vii). We remind you that to comply with 505(o), your annual report must
`also include a report on the status of any study or clinical trial otherwise undertaken to
` investigate a safety issue. Failure to submit an annual report for studies or clinical trials required
`
` under 505(o) on the date required will be considered a violation of FDCA section
` 505(o)(3)(E)(ii) and could result in enforcement action.
`
`
` PROMOTIONAL MATERIALS
`
` You may request advisory comments on proposed introductory advertising and promotional
`
`
`
`
`
`
` labeling. To do so, submit the following, in triplicate, (1) a cover letter requesting advisory
` comments, (2) the proposed materials in draft or mock-up form with annotated references, and
`
`
`
` (3) the package insert(s) to:
`
`
`
`
`
`
`
`
`OPDP Regulatory Project Manager
`
`
`Food and Drug Administration
`
`
`Center for Drug Evaluation and Research
`
`
`Office of Prescription Drug Promotion (OPDP)
`
`
`5901-B Ammendale Road
`
`
`Beltsville, MD 20705-1266
`
`
`
`
` Alternatively, you may submit a request for advisory comments electronically in eCTD format.
`
`
`For more information about submitting promotional materials in eCTD format, see the draft
`
` Guidance for Industry (available at:
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`
`
` CM443702.pdf ).
`
`
` You must submit final promotional materials and package insert(s), accompanied by a Form
` FDA 2253, at the time of initial dissemination or publication [21 CFR 314.81(b)(3)(i)]. 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.
`
`
`
`
`
`Reference ID: 4243652
`
`

`

`
`
`
`
`
` NDA 022023/S-017
` Page 5
`
`
`
` 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 Mary Chung, Regulatory Project Manager, at (301) 796-0260.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Sincerely,
`
` {See appended electronic signature page}
`
` Lisa M. Soule, M.D.
`
` Associate Director
`Division of Gastroenterology and Inborn Errors
`
` Products
` Office of Drug Evaluation III
`
` Center for Drug Evaluation and Research
`
`
`
`
` ENCLOSURE(S):
`
`
` Content of Labeling
`
`
`
`
`Reference ID: 4243652
`
`

`

`
`
`
`CENTER FOR DRUG EVALUATION AND
`
`
` RESEARCH
`
`
`
`
`APPLICATION NUMBER:
`
`
` 022023Orig1s017
`
`
`
` LABELING
`
`
`
`
`
`
`

`

`
`
`
`
`
`
`
`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
`
`
`
`
`
`
` These highlights do not include all the information needed to use
`EMEND FOR
`INJECTION safely and effectively. See
`
` full
`
`
` prescribing information for EMEND FOR INJECTION.
`
` EMEND (fosaprepitant) for injection, for intravenous use
`
`
` Initial U.S. Approval: 2008
`
`
` ---------------------------RECENT MAJOR CHANGES ---------------------------
`
`
` 04/2018
`
` Indications and Usage (1)
`
`
` 04/2018
`
` Dosage and Administration (2.2, 2.3)
`
` 08/2017
`
` Warnings and Precautions (5.2)
`
`
` 03/2018
`
` Warnings and Precautions (5.3)
`
`
`
` ----------------------------INDICATIONS AND USAGE ----------------------------
`
`
`EMEND for injection is a substance P/neurokinin-1 (NK1) receptor
`
`
`
`
`
`antagonist, indicated in adults and pediatric patients 6 months of age
`
`
`and older, in combination with other antiemetic agents, for the
`
`
`
`
`
`prevention of (1):
`
`• acute and delayed nausea and vomiting associated with initial and
`
`repeat courses of highly emetogenic cancer chemotherapy (HEC)
`
`
`
`
`including high-dose cisplatin.
`
`• delayed nausea and vomiting associated with initial and repeat
`
`
`courses of moderately emetogenic cancer chemotherapy (MEC).
`
`
`Limitations of Use (1)
`
`
`
`• EMEND has not been studied for treatment of established nausea
`
`and vomiting.
`
`
`
`----------------------- DOSAGE AND ADMINISTRATION------------------------
`
`
`
`• Recommended Dosage (2.1, 2.2)
`
`
`
`• Adults: 150 mg on Day 1.
`
`
`
`
`
`• Pediatrics (6 months to 17 years): a single-day of EMEND for
`injection on Day 1 (for single dose chemotherapy regimens) or a 3­
`
`
`
`
`
`
`
`day EMEND regimen of EMEND for injection on Day 1 and EMEND
`
`
`
`
`
`capsules or oral suspension on Days 2 and 3 (for single or multi-day
`
`chemotherapy regimens).
`
`
`
`
`
`
`• Administer EMEND for injection on Day 1 as an intravenous infusion
`
`
`
`
`
`
`
`over 20 to 30 minutes (adults), 30 minutes (12 years to 17 years) or
`
`
`
`
`60 minutes (6 months to less than 12 years) completing the infusion
`
`approximately 30 minutes prior to chemotherapy.
`
`
`
`
`
`• In pediatrics, administer EMEND through a central venous catheter.
`
`
`
`• See Full Prescr bing Information for dosages of concomitant
`
`
`
`
`
`antiemetic(s) and pediatric dosages of EMEND. (2.1, 2.2)
`
`
`
`
`
`--------------------- DOSAGE FORMS AND STRENGTHS ---------------------
`
`
`EMEND for injection: 150 mg fosaprepitant, lyophilized powder in
`
`
`single-dose vial for reconstitution. (3)
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`INDICATIONS AND USAGE
`1
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`
`2.1 Prevention of Nausea and Vomiting Associated with HEC
`
`
`
`and MEC in Adult Patients
`
`
`2.2 Prevention of Nausea and Vomiting Associated with HEC
`
`
`
`and MEC in Pediatric Patients
`
`
`2.3 Preparation of EMEND for Injection
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`
`4 CONTRAINDICATIONS
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`5.1 Clinically Significant CYP3A4 Drug Interactions
`
`
`5.2 Hypersensitivity Reactions
`
`
`5.3
`Infusion Site Reactions
`
`
`5.4 Decrease in INR with Concomitant Warfarin
`
`
`5.5 Risk of Reduced Efficacy of Hormonal Contraceptives
`
`
`6 ADVERSE REACTIONS
`
`
`6.1 Clinical Trials Experience
`
`
`6.2 Postmarketing Experience
`
`
`7 DRUG INTERACTIONS
`
`
`
`7.1 Effect of Fosaprepitant/Aprepitant on the Pharmacokinetics
`
`
`
`of Other Drugs
`
`
`7.2 Effect of Other Drugs on
`
`
`
`Fosaprepitant/Aprepitant
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`
`
`the Pharmacokinetics of
`
`
`
`
` 1
`
`Reference ID: 4243652
`
`
`
`
`
`-------------------------------CONTRAINDICATIONS-------------------------------
`
`
`
`
`
`• Known hypersensitivity to any component of this drug. (4, 5.2)
`
`
`
`
`
`• Concurrent use with pimozide. (4)
`
`
`
`------------------------WARNINGS AND PRECAUTIONS------------------------
`
`
`
`
`
`• CYP3A4 Interactions: Fosaprepitant is a weak inhibitor of CYP3A4,
`
`and aprepitant, the active moiety, is a substrate, inhibitor, and
`
`
`
`inducer of CYP3A4; see Full Prescribing
`Information
`for
`recommendations regarding contraindications, risk of adverse
`
`
`reactions, and dosage adjustment of EMEND and concomitant
`
`
`drugs. (4, 5.1, 7.1, 7.2)
`
`
`
`
`• Hypersensitivity Reactions (including anaphylaxis and anaphylactic
`
`
`
`
`
`
`
`
`
`shock): May occur during or soon after infusion. If symptoms occur,
`
`
`
`discontinue the drug. Do not reinitiate EMEND if symptoms occur
`
`
`
`
`
`with previous use. (4, 5.2)
`
`
`
`
`• Infusion Site Reactions (including thrombophlebitis, necrosis, and
`vasculitis): Majority of reactions reported in patients receiving
`
`
`vesicant chemotherapy. Avoid infusion into small veins. Discontinue
`
`
`
`
`infusion and administer treatment if a severe reaction develops.
`
`(5.3)
`
`INR of
`• Warfarin (a CYP2C9 substrate): Risk of decreased
`
`
`
`
`
`prothrombin time; monitor INR in 2–week period, particularly at 7 to
`
`
`
`
`
`
`10 days, following initiation of EMEND. (5.4, 7.1)
`
`
`• Hormonal Contraceptives: Efficacy of contraceptives may be
`
`
`reduced during and for 28 days following administration of EMEND.
`
`
`
`
`
`Use effective alternative or back-up methods of contraception. (5.5,
`
`
`
`
`
`
`7.1, 8.3)
`
`------------------------------ ADVERSE REACTIONS ------------------------------
`
`
`
`
`• Most common adverse reactions in adults (≥2%) are: fatigue,
`
`
`
`diarrhea, neutropenia, asthenia, anemia, peripheral neuropathy,
`
`
`leukopenia, dyspepsia, urinary tract infection, pain in extremity. (6.1)
`
`
`
`
`• Adverse reactions in pediatrics are similar to adults.
`
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Merck
`
`Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., at 1-
`
`at
`or
`877-888-4231
`or
`FDA
`1-800-FDA-1088
`
`
`www.fda.gov/medwatch.
`
`-------------------------------DRUG INTERACTIONS -------------------------------
`
`
`
`
`
`See Full Prescribing Information for a list of clinically significant drug
`
`
`
`
`interactions. (4, 5.1, 5.4, 5.5, 7.1, 7.2)
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`
`
`
`approved patient labeling.
`
`
`
`
`
`Revised: 04/2018
`
`
`
`8.1 Pregnancy
`
`
`8.2
`Lactation
`
`
`8.3 Females and Males of Reproductive Potential
`
`
`8.4 Pediatric Use
`
`
`8.5 Geriatric Use
`
`
`8.6 Patients with Hepatic Impairment
`
`
`10 OVERDOSAGE
`
`
`11 DESCRIPTION
`
`
`12 CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`
`12.2 Pharmacodynamics
`
`
`12.3 Pharmacokinetics
`
`
`13 NONCLINICAL TOXICOLOGY
`
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`14 CLINICAL STUDIES
`
`
`14.1 Prevention of Nausea and Vomiting Associated with HEC in
`
`
`Adults
`
`14.2 Prevention of Nausea and Vomiting Associated with MEC in
`
`
`Adults
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`17 PATIENT COUNSELING INFORMATION
`
`
`
`*Sections or subsections omitted from the full prescribing information
`
`are not listed.
`
`
`
`

`

`
` EMEND for injection
`
`
`
`
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`
`
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`
`
`
`
`FULL PRESCRIBING INFORMATION
`
`
`1
`
`
`INDICATIONS AND USAGE
`EMEND for injection, in combination with other antiemetic agents, is indicated in adults and
`
`
`
`
`
`pediatric patients 6 months of age and older for the prevention of:
`
`
`• acute and delayed nausea and vomiting associated with initial and repeat courses of highly
`
`emetogenic cancer chemotherapy (HEC) including high-dose cisplatin.
`
`
`
`• delayed nausea and vomiting associated with initial and repeat courses of moderately
`
`emetogenic cancer chemotherapy (MEC).
`
`
`
`Limitations of Use
`
`
`
`• EMEND has not been studied for the treatment of established nausea and vomiting.
`
`
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`DOSAGE AND ADMINISTRATION
`2
`
`
`
`2.1 Prevention of Nausea and Vomiting Associated with HEC and MEC in Adult Patients
`
`
`
`The recommended dosage of EMEND for injection, dexamethasone, and a 5-HT3 antagonist for the
`
`
`
`
`
`
`prevention of nausea and vomiting associated with administration of HEC or MEC in adults is shown in
`
`
`
`
`
`
`Table 1 or Table 2, respectively. Administer EMEND for injection as an intravenous infusion on Day 1 over
`
`
`
`20 to 30 minutes, completing the infusion approximately 30 minutes prior to chemotherapy.
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`
` Table 1
`
`
`
` Recommended Adult Dosing for the Prevention of Nausea and Vomiting Associated with HEC
`
`
` Day 2
` Day 4
`
`
`
` Day 3
` Day 1
`
` none
`
`
` 150 mg intravenously
`
` none
`
` none
`
`
` over 20 to 30 minutes
`approximately 30
`minutes prior to
`
` chemotherapy
`
` 12 mg orally
`
`
`
` Dexamethasone*
`
`
`
` 8 mg orally
`
`
`
` 5-HT3 antagonist
`
`
`
`
`
` none
`
`
`
` 8 mg orally twice
`
` daily
`
` none
`
`8 mg orally twice
`
` daily
`
` none
`
` See selected 5-HT3
`
`
` antagonist prescribing
`information for the
`
`
` recommended dosage
` *Administer dexamethasone 30 minutes prior to chemotherapy treatment on Day 1 and in the morning on Days 2
`
`
`
` through 4. Also administer dexamethasone in the evenings on Days 3 and 4. A 50% dosage reduction of
` dexamethasone on Days 1 and 2 is recommended to account for a drug interaction with EMEND [see Clinical
`
`
`
` Pharmacology (12.3)].
`
`
`
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` Table 2
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`
` Recommended Adult Dosing for the Prevention of Nausea and Vomiting Associated with
`
`
`MEC
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`
`
` EMEND for injection
`
`
`
`
`
`
`
` Day 1
`
` 150 mg intravenously over 20 to 30 minutes approximately 30
`
`
`
` minutes prior to chemotherapy
` 12 mg orally
`
`
`
` See selected 5-HT3 antagonist prescr bing information for the
` recommended dosage
`
`*Administer dexamethasone 30 minutes prior to chemotherapy treatment on Day 1. A 50%
`
`
`
`
`
` dosage reduction of dexamethasone is recommended to account for a drug interaction with
`
`
`
`
` EMEND [see Clinical Pharmacology (12.3)].
`
`2.2 Prevention of Nausea and Vomiting Associated with HEC and MEC in Pediatric Patients
`
`
`
` The recommended pediatric dose regimens of EMEND, to be administered with a 5-HT3 antagonist,
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`
`
`
`
`
`
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`with or without a corticosteroid, for the prevention of nausea and vomiting associated with administration
`
`
`
`
`
`
`
`
`
`
`
`
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`of single or multi-day chemotherapy regimens of HEC or MEC, are shown in Tables 3 and 4. Single-day
`
`
`
`
`chemotherapy regimens include those regimens in which HEC or MEC is administered for a single day
`
`
` Dexamethasone*
`
` 5-HT3 antagonist
`
`
`
`
`Reference ID: 4243652
`
`
`2
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
` only. Multi-day chemotherapy regimens include chemotherapy regimens in which HEC or MEC is
`
`administered for 2 or more days.
`
`EMEND Dosage Regimens for Use with Single-Day Chemotherapy Regimens
`
`
`
`For pediatric patients weighing at least 6 kg receiving single-day HEC or MEC, EMEND may be
`
`administered as:
`
`
`
`
`• a single dose regimen of EMEND for injection infused through a central venous catheter on Day 1,
`
`as shown in Table 3; or
`
`• as a 3-day EMEND regimen consisting of EMEND for injection as an intravenous infusion through
`
`a central venous catheter on Day 1 and EMEND capsules or EMEND for oral suspension on Days
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`2 and 3, as shown in Table 4.
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`
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`Administer EMEND for injection on Day 1 over 30 minutes (12 years to 17 years) or 60 minutes (6
`
`months to less than 12 years), completing the infusion approximately 30 minutes prior to chemotherapy.
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`
`
`Table 3
`
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`
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`Single Dose Regimen of EMEND for injection for Pediatric Patients 6 Months* to 17 Years for the Prevention of
`
`
`Nausea and Vomiting Associated with Single-Day Regimens of HEC or MEC
`
` Regimen
`
`
` Age
` 12 Years to 17 Years
`
`
` 150 mg
` intravenously over 30 minutes
`
`
` 4 mg/kg
` (maximum dose 150 mg)
`
` intravenously over 60 minutes
`
` 5 mg/kg
`
`
` (maximum dose 150 mg)
`
` intravenously over 60 minutes
`
` If a corticosteroid, such as dexamethasone, is
`co-administered, administer 50% of the
`recommended corticosteroid dose on Days 1
` and 2.
`
`
`
` See selected 5-HT3 antagonist prescribing
` information for the recommended dosage
`
`
`
` Drug
`
` EMEND for injection
`
`
`
`
`
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`
` 2 Years to less than 12 Years
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`
`
` 6 Months to less than 2 Years
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`
`
` Dexamethasone†
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`
`
` 6 Months to 17 Years
`
`
`
`
`
` 5-HT3 antagonist
`
`
`
`
`
` 6 Months to 17 Years
`
` * Dosing in pediatric patients less than 6 kg is not recommended
`
`
`
`†Administer dexamethasone 30 minutes prior to chemotherapy treatment on Day 1
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`
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` EMEND Dosage Regimen for Use with Multi-Day Chemotherapy Regimens
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`
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`
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`For pediatric patients weighing at least 6 kg receiving multi-day regimens of HEC or MEC,
`
`
`
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`administer EMEND on Days 1, 2, and 3. Administer EMEND for injection as an intravenous infusion
`
`
`through a central venous catheter on Day 1 and EMEND capsules or EMEND for oral suspension on Days
`
`2 and 3, as shown in Table 4.
`
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`
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`Administer EMEND for injection on Day 1 over 30 minutes (12 years to 17 years) or 60 minutes (6
`
`months to less than 12 years), completing the infusion approximately 30 minutes prior to chemotherapy.
`
`
`Reference ID: 4243652
`
`
`
` 3
`
`

`

`
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` Age Group
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`
` 12 Years to 17
`
` Years
`
` Table 4
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`
` Pediatric Patients 6 Months* to 17 Years Recommended 3-Day EMEND Dosage Regimen for Prevention of Nausea and
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`
`
`
`
` Vomiting Associated with Single or Multi-day Regimens of HEC or MEC
`
` Day 1
`
`
`
` Drug
` Day 2
`
`
` EMEND for injection
` 115 mg
`
`
`-­
` intravenously over 30 minutes
`
`
`
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`
`
` Day 3
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`
`-­
`
`
`
` EMEND capsules†
`
` EMEND for injection
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`
`
`6 Months to
`Less than 12
`Years
`
`
`-­
`
`
`
` 3 mg/kg
`
`
` (maximum dose 115 mg)
`
` intravenously over 60 minutes
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`
`
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`
` 80 mg orally
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` 80 mg orally
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`
`-­
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`
`-­
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`
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` EMEND for oral suspension
`
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`
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`
`-­
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` 2 mg/kg orally
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` (maximum 80 mg)
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` 2 mg/kg orally
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` (maximum 80 mg)
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`
`
`6 Months to 17
`Years
`
`
`Dexamethasone‡
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`
`If a corticosteroid, such as dexamethasone, is co-administered, administer 50% of the
`recommended corticosteroid dose on Days 1 through 4
`
`
`
`5-HT3 antagonist
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`
`
`6 Months to 17
`
`Years
`Dosing in pediatric patients less than 6 kg is not recommended
`
`
`† For patients 12 years to 17 years who cannot swallow oral capsules, EMEND for oral suspension can be used instead.
`
`
`‡ Administer dexamethasone 30 minutes prior to chemotherapy treatment on Day 1
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`
`
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`See selected 5-HT3 antagonist prescr bing information for the recommended dosage
`
`
`
`Reference ID: 4243652
`
`
`
` 4
`
`

`

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`
` 2.3
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`
` Preparation of EMEND for injection
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` Table 5
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` Preparation Instructions for EMEND for injection (150 mg)
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`Step 1 Aseptically inject 5 mL 0.9% Sodium Chloride Injection, USP into the vial. Assure that 0.9%
`
`Sodium Chloride Injection, USP is added to the vial along the vial wall in order to prevent
`
`foaming. Swirl the vial gently. Avoid shaking and jetting 0.9% Sodium Chloride Injection,
`
`USP into the vial.
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`
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`Step 2 Aseptically prepare an infusion bag filled with 145 mL of 0.9% Sodium Chloride Injection,
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`USP.
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`Step 3 Aseptically withdraw the entire volume from the vial and transfer it into the infusion bag
`containing 145 mL of 0.9% Sodium Chloride Injection, USP to yield a total volume of
`
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`
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`150 mL and a final concentration of 1 mg/mL.
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`Step 4 Gently invert the bag 2 to 3 times.
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`Step 5 Determine the volume to be administered from this prepared infusion bag, based on the
`
`
`recommended dose [see Dosage and Administration (2.1, 2.2)].
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`
`Adults
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`The entire volume of the prepared infusion bag (150 mL) should be administered.
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`Pediatrics
`In patients 12 years and older, the volume to be administered is calculated as follows:
`
`• Volume to administer (mL) equals the recommended dose (mg)
`
`
`
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`In patients 6 months to less than 12 years, the volume to be administered is calculated as
`
`follows:
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`• Volume to administer (mL) = recommended dose (mg/kg) x weight (kg)
`
`
`o Note: Do not exceed the maximum dose [see Dosage and Administration
`
`
`
`
`(2.2)]
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`In pediatric patients, the entire volume in the infusion bag may not be required.
`
`
`If necessary, for volumes less than 150 mL, the calculated volume can be transferred to an
`
` appropriate size bag or syringe prior to administration by infusion.
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`
`
` Step 6
`
`Step 7 Before administration, inspect the bag for particulate matter and discoloration. Discard the
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`bag if particulate and/or discoloration are observed.
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` The recommended dose of EMEND for injection is based on the patient’s age and weight.
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`Caution: Do not mix or reconstitute EMEND for injection with solutions for which physical and
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`
`
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`chemical compatibility have not been established. EMEND for injection is incompatible with any solutions
`
`
`
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`
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`
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`containing divalent cations (e.g., Ca2+ , Mg2+), including Lactated Ringer’s Solution and Hartmann's
`
`
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`
`
`
`
`Solution.
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`
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`Reference ID: 4243652
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`
`
` 5
`
`

`

`
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` Storage
`
`
`
`
`The reconstituted final drug solution is stable for 24 hours at ambient room temperature [at or below
`
`
`25°C (77°F)].
`
`
`3
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`DOSAGE FORMS AND STRENGTHS
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`EMEND for injection: 150 mg fosaprepitant, white to off-white lyophilized powder in single-dose
`
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`glass vial for reconstitution
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`CONTRAINDICATIONS
`4
`
`
`EMEND is contraindicated in patients:
`
`
`• who are hypersensitive to any component of the product. Hypersensitivity reactions including
`
`
`
`anaphylactic reactions, flushing, erythema, and dyspnea have been reported [see Warnings and
`
`Precautions (5.2), Adverse Reactions (6.2)].
`
`
`
`taking pimozide. Inhibition of CYP3A4 by aprepitant, the active moiety, could result in elevated plasma
`
`
`
`
`
`
`
`concentrations of this drug, which is a CYP3A4 substrate, potentially causing serious or life-
`
`threatening reactions, such as QT prolongation, a known adverse reaction of pimozide [see Warnings
`
`
`
`and Precautions (5.1)].
`
`
`•
`
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`5.1 Clinically Significant CYP3A4 Drug Interactions
`
`
`Fosaprepitant, a prodrug of aprepitant, is a weak inhibitor of CYP3A4, and aprepitant is a substrate,
`
`inhibitor, and inducer of CYP3A4.
`
`• Use of EMEND with other drugs that are CYP3A4 substrates, may result in increased plasma
`
`concentration of the concomitant drug.
`o Use of pimozide with EMEND is contraindicated due to the risk of significantly increased
`
`
`
`
`
`
`
`plasma concentrations of pimozide, potentially resulting in prolongation of the QT interval, a
`
`known adverse reaction of pimozide [see Contraindications (4)].
`
`
`
`
`
`
`
`
`
`• Use of EMEND with strong or moderate CYP3A4 inhibitors (e.g., ketoconazole, diltiazem) may
`
`
`
`
`increase plasma concentrations of aprepitant and result in an increased risk of adverse reactions
`
`related to EMEND.
`
`
`
`
`
`
`
`
`• Use of EMEND with strong CYP3A4 inducers (e.g., rifampin) may result in a reduction in aprepitant
`
`plasma concentrations and decreased efficacy of EMEND.
`
`
`
`
`
`
`
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`
`
`See Table 7 and Table 8 for a listing of potentially significant drug interactions [see Drug Interactions
`
`
`(7.1, 7.2)].
`
`
`
`
`5.2 Hypersensitivity Reactions
`
`Serious hypersensitivity reactions, including anaphylaxis and anaphylactic shock, during or soon
`
`
`
`after infusion of fosaprepitant have occurred. Symptoms including flushing, erythema, dyspnea,
`
`
`
`hypotension and syncope have been reported [see Adverse Reactions (6.2)].
`
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`
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`Monitor pat