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CENTER FOR DRUG EVALUATION AND RESEARCH

APPLICATION NUMBER:

209296Orig1s000

CLINICAL REVIEW(S)

CLINICAL REVIEW

Application Type NDA Application Number(s) 209,296/ IND 125,926

Priority or Standard Standard

Submit Date(s) 12 January 2017 Received Date(s) 12 January 2017

PDUFA Goal Date 12 November 2017 Division / Office Division of Gastroenterology and Inborn Errors

Products Office of Drug Evaluation (ODE) III

Reviewer Name(s) Aisha P. Johnson, MD, MPH, MBA Review Completion Date 2 October 2017

Established Name Aprepitant Injectable Emulsion

(Proposed) Trade Name Cinvanti™ Therapeutic Class NK-1 inhibitor

Applicant Heron Therapeutics, Inc

Formulation(s) Emulsion for intravenous use available in single-dose glass vial, 130 mg/18 mL (7.2 mg/mL)

Dosing Regimen • HEC (Single Dose Regimen): The recommended dosage in adults is 130 mg on Day 1 as an intravenous infusion over 30 minutes approximately 30 minutes prior to chemotherapy.

• MEC (3-Day Regimen): The recommended dosage in adults is 100 mg administered on Day 1 as an intravenous infusion over 30 minutes approximately 30 minutes prior to chemotherapy. Aprepitant capsules (80 mg) are given orally on Days 2 and 3.

Indication(s) 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. The prevention of nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC).

Intended Population(s) Adult Patients Template Version: March 6, 2009

Reference ID: 4161506

Clinical Review NDA 209,296 Aisha Peterson Johnson, MD, MPH, MBA aprepitant injectable emulsion

Table of Contents

1 RECOMMENDATIONS/RISK BENEFIT ASSESSMENT ......................................... 6

1.1 Recommendation on Regulatory Action ............................................................. 6 1.2 Risk Benefit Assessment .................................................................................... 7 1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies ... 8 1.4 Recommendations for Postmarket Requirements and Commitments ................ 8

2 INTRODUCTION AND REGULATORY BACKGROUND ........................................ 8

2.1 Product Information ............................................................................................ 8 2.2 Tables of Currently Available Treatments for Proposed Indications ................... 9 2.3 Availability of Proposed Active Ingredient in the United States ........................ 11 2.4 Important Safety Issues With Consideration to Related Drugs ......................... 11 2.5 Summary of Presubmission Regulatory Activity Related to Submission .......... 14 2.6 Other Relevant Background Information .......................................................... 15

3 ETHICS AND GOOD CLINICAL PRACTICES ....................................................... 16

3.1 Submission Quality and Integrity ...................................................................... 16 3.2 Compliance with Good Clinical Practices ......................................................... 16 3.3 Financial Disclosures ........................................................................................ 16

4 SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW DISCIPLINES ......................................................................................................... 17

4.1 Chemistry Manufacturing and Controls ............................................................ 17 4.2 Clinical Microbiology ......................................................................................... 17 4.3 Preclinical Pharmacology/Toxicology ............................................................... 17 4.4 Clinical Pharmacology ...................................................................................... 18

4.4.2 Pharmacodynamics.................................................................................... 19 4.4.3 Pharmacokinetics ....................................................................................... 19

5 SOURCES OF CLINICAL DATA............................................................................ 19

5.1 Tables of Studies/Clinical Trials ....................................................................... 19 5.2 Review Strategy ............................................................................................... 19 5.3 Discussion of Individual Studies/Clinical Trials ................................................. 19

Study Summaries ................................................................................................... 19 Key Inclusion Criteria ............................................................................................. 21 Study Visits and Procedures .................................................................................. 22

6 REVIEW OF EFFICACY ......................................................................................... 22

Efficacy Summary ...................................................................................................... 22 6.1 Indication .......................................................................................................... 22

6.1.2 Demographics ............................................................................................ 23 6.1.3 Patient Disposition ..................................................................................... 23 6.1.4 Analysis of Primary Endpoint(s) ................................................................. 23 6.1.5 Analysis of Secondary Endpoints(s)........................................................... 23 6.1.6 Other Endpoints ......................................................................................... 23

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6.1.7 Subpopulations .......................................................................................... 23 6.1.8 Analysis of Clinical Information Relevant to Dosing Recommendations .... 23 6.1.9 Discussion of Persistence of Efficacy and/or Tolerance Effects ................. 23 6.1.10 Additional Efficacy Issues/Analyses ........................................................... 23

7 REVIEW OF SAFETY ............................................................................................. 24

Safety Summary ........................................................................................................ 24 7.1 Methods ............................................................................................................ 24

7.1.1 Studies/Clinical Trials Used to Evaluate Safety ......................................... 24 7.1.3 Pooling of Data Across Studies/Clinical Trials to Estimate and Compare

Incidence .................................................................................................... 24 7.2 Adequacy of Safety Assessments .................................................................... 24

7.2.1 Overall Exposure at Appropriate Doses/Durations and Demographics of Target Populations ..................................................................................... 25

7.2.3 Special Animal and/or In Vitro Testing ....................................................... 31 7.2.4 Routine Clinical Testing ............................................................................. 31 7.2.5 Metabolic, Clearance, and Interaction Workup .......................................... 31 7.2.6 Evaluation for Potential Adverse Events for Similar Drugs in Drug Class .. 31

7.3 Major Safety Results ........................................................................................ 32 7.3.1 Deaths ........................................................................................................ 32 7.3.2 Nonfatal Serious Adverse Events .............................................................. 32 7.3.3 Dropouts and/or Discontinuations .............................................................. 32 7.3.5 Submission Specific Primary Safety Concerns .......................................... 35

7.4 Supportive Safety Results ................................................................................ 41 7.4.1 Common Adverse Events .......................................................................... 41 7.4.2 Laboratory Findings ................................................................................... 44 7.4.3 Vital Signs .................................................................................................. 44 7.4.4 Electrocardiograms (ECGs) ....................................................................... 44 7.4.5 Special Safety Studies/Clinical Trials ......................................................... 44 7.4.6 Immunogenicity .......................................................................................... 44

7.5 Other Safety Explorations ................................................................................. 44 7.5.1 Dose Dependency for Adverse Events ...................................................... 44 7.5.2 Time Dependency for Adverse Events ....................................................... 44 7.5.3 Drug-Demographic Interactions ................................................................. 47 7.5.4 Drug-Disease Interactions .......................................................................... 47 7.5.5 Drug-Drug Interactions ............................................................................... 47 7.6.1 Human Carcinogenicity .............................................................................. 49 7.6.2 Human Reproduction and Pregnancy Data ................................................ 49 7.6.4 Overdose, Drug Abuse Potential, Withdrawal and Rebound ...................... 49

7.7 Additional Submissions / Safety Issues ............................................................ 49

8 POSTMARKET EXPERIENCE ............................................................................... 49

9 APPENDICES ........................................................................................................ 50

9.1 Literature Review/References .......................................................................... 50 9.2 Labeling Recommendations ............................................................................. 51

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9.3 Advisory Committee Meeting ............................................................................ 51

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Table of Tables

Table 1. Currently Available Drugs for Prevention of CINV .......................................... 10 Table 2. Clinical Pharmacology Studies Submitted in Support of NDA 209,296 .......... 18 Table 3. Summary of Key Plasma Pharmacokinetic Parameters of Aprepitant after IV

Administration of HTX-019 and EMEND for Injection (Study 104 &Study 106) ....................................................................................................................... 21

Table 4. Schedule of Events, Study 104 ...................................................................... 22 Table 5. Extent of Exposure, Studies 104 and 106 (Part B) ......................................... 25 Table 6. Extent of Exposure, Study 106, Part A ........................................................... 26 Table 7. Subject Disposition, Study 104 and Study 106, Part B .................................... 27 Table 8. Study Discontinuations, Study 104 and Study 106, part B ............................. 27 Table 9. Demographics and Baseline Characteristics, Study 104 and Study 106, Part B

....................................................................................................................... 29 Table 10. Demographics and Baseline Characteristics, Study 106, Part A ................. 30 Table 11. Overview of Subjects With TEAEs of Dyspnea, Study 104 & Study 106 (Part

B) ................................................................................................................... 37 Table 12. Infusion Site Reactions, Study 104 ............................................................... 39 Table 13. Infusion Site Reaction TEAEs, Study 106 (Part B) ....................................... 39 Table 14. Summary of Treatment Emergent Adverse Events, Study 104 and Study 106

(Part B) .......................................................................................................... 41 Table 15. Summary of Treatment Emergent Adverse Events Study 106 (Part A) ........ 42 Table 16. Most Common Adverse Events: Incidence ≥2% With Any Treatment (Study

104 and Study 106, Part B) ............................................................................ 43 Table 17. Treatment-Emergent Adverse Events in the First 60 Minutes Following the

Start of the Infusion, Study 104 and Study 106 (Part B) ................................ 46 Table 18. Effects of Aprepitant on the Pharmacokinetics of Other Drugs ..................... 48

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1 Recommendations/Risk Benefit Assessment

1.1 Recommendation on Regulatory Action

In the opinion of this reviewer, the current 505(b)(2) Application for aprepitant emulsion for injection (HTX-019, CINVANTI) should receive an approval action. Heron Therapeutics is pursuing the 505(b)(2) regulatory pathway with the FDA-approved listed drug EMEND (fosaprepitant dimeglumine) for Injection (NDA 22-023). The current Application relies on the FDA’s previous findings of safety and efficacy for EMEND for injection, the results of two phase 1 relative bioavailability studies conducted by the Applicant, and literature documenting the safety of higher plasma levels of aprepitant. The Applicant is relying on the discontinued 115 mg strength of EMEND for Injection. Therefore, the Applicant can rely on the version of the EMEND for Injection label which contains CINV regimens using this strength. The Applicant has chosen to adopt the language of the EMEND for injection (NDA 22023) label from supplement S-011 (August 2014) that contains the following indications:

• Prevention of nausea and vomiting in patients receiving HEC o single dose 150 mg EMEND for Injection dose

• Prevention of nausea and vomiting in patients receiving HEC and MEC (3 Day IV/oral/oral regimen)

o Single dose 115 mg EMEND for Injection dose (Day 1) o Single dose 80 mg EMEND oral (Day 2) o Single dose 80 mg EMEND oral (Day 3)

The 3-day (IV/oral/oral) regimen using EMEND for Injection and EMEND oral was discontinued by Merck & Co., Inc. in 2016 with the approval of a single dose 150 mg EMEND for Injection dose for patients receiving MEC (NDA 22-023/S-006). This regimen was not discontinued for reasons of safety or efficacy. The acceptability of reliance on this discontinued version of the EMEND for Injection label was confirmed by the Office of Regulatory Policy during the process of the current review. The proprietary name CINVANTI has been approved for product. The Applicant’s approved indication statement should read as follows: CINVANTI is a substance P/neurokinin-1 (NK1) receptor antagonist, in combination with other antiemetic agents, is indicated in adults 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

• nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC)

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Clinical Review NDA 209,296 Aisha Peterson Johnson, MD, MPH, MBA aprepitant injectable emulsion See Section 2.3 for a more detailed regulatory history of EMEND for Injection. MO Comment: Two key specifics regarding the approved indications included in CINVANTI labeling should be noted:

1) In contrast to the current EMEND for Injection labeling, the CINVANTI label does not include . From a regulatory perspective, the indication(s) should be granted as presented in the label upon which the Applicant is relying. Not including this qualifying term gives CINVANTI a broader indication than the RLD, EMEND for Injection. However, this reviewer understands that this is the correct approach from a regulatory perspective.

2) The Applicant has chosen not to include the 3-day regimen for HEC patients in the CINVANTI label. However, the 3-day regimen is included as an option for patients receiving HEC in the EMEND for Injection version of the label upon which the Applicant is relying. Applicants are not required to pursue each indication presented in a referenced label.

1.2 Risk Benefit Assessment

Given the totality of the information submitted in support of this Application, the known benefits associated with the use of CINVANTI (aprepitant injectable emulsion, HTX-019) currently outweigh the known risks associated with use of the therapy for the proposed indications. The current NDA relies on the FDA’s findings of safety and efficacy for NDA 22,023 (EMEND for Injection). In addition, the Applicant conducted two phase 1 relative bioavailability/bioequivalence (BA/BE) studies—Study 104 and Study 106. Study 104 was designed as a phase 1, open-label, randomized, cross-over study to determine the bioequivalence of a single 130 mg IV dose of aprepitant emulsion (HTX-019) with commercially available fosaprepitant (150 mg). Study 106 was a 2-part study. Part A was a randomized study to characterize the Cmax of aprepitant (EMEND for injection and HTX-019). Part B was a BE study comparing HTX-019 mg infused over 30 minutes (test) with Emend for Injection 150 mg infused over 20 minutes (reference). The results in Part B demonstrated that the test and reference treatments met BE criteria for AUC0-t, AUC0-inf, and C12hr and also supported the Applicant’s proposal to infuse their product over 20 minutes compared with the labeled 20 to 30 minute infusion time of Emend for Injection. These studies demonstrated that 130 mg HTX-019 (test product) met BE criteria for AUC relative to 150 mg EMEND for Injection (reference product). However, the Cmax for 130 mg HTX-019 was 28% higher than the Cmax for 150 mg EMEND for Injection (both infused over 30 minutes). Therefore, the clinical pharmacology reviewers concluded that additional safety information would be needed to support the higher

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(b) (4)

Clinical Review NDA 209,296 Aisha Peterson Johnson, MD, MPH, MBA aprepitant injectable emulsion Cmax of HTX-019 in order to establish an adequate bridge between 130 mg HTX-019 and 150 mg EMEND for Injection. This additional safety information was obtained from healthy subjects in Studies 104 and 106 (270 subjects total) and published safety data of patients receiving relevant aprepitant concentrations. After reviewing the aforementioned safety data, this reviewer has concluded that the 28% higher Cmax for HTX-019 130 mg (infused over 30 minutes) was not shown to be associated with any new safety concerns when compared with 150 mg EMEND for Injection (infused over 20 to 30 minutes). For the proposed lower dose (100 mg) of HTX-019, the clinical pharmacology reviewers concluded that the relative BA/BE study results support the proposed dose. Similarly, the safety of the HTX-019 100 mg dose is supported by the safety of the 130 mg dose.

1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies

None.

1.4 Recommendations for Postmarket Requirements and Commitments

The Applicant submitted plans for a pediatric program for HTX-019. The Division issued correspondence confirming agreement with sponsor’s initial Pediatric Study Program (iPSP). The Applicant requested a deferral for studies in patient’s 0 to <18 years of age in accordance with the provisions of Section 505B (a)(3)(A)(i) of the Federal Food, Drug and Cosmetic Act (FDCA), “The drug or biological product is ready for approval for use in adults before pediatric studies are complete”.

2 Introduction and Regulatory Background

2.1 Product Information

The reference product, EMEND for Injection, has fosaprepitant dimeglumine as the active ingredient. Fosaprepitant is a prodrug of aprepitant. Fosaprepitant is converted to aprepitant (within 30 minutes) after intravenous administration via the action of ubiquitous phosphatases, and the pharmacological effect of fosaprepitant is attributed to aprepitant. The EMEND for Injection formulation contains polysorbate 80

. The product of the current application contains aprepitant formulated as a lipid emulsion to allow administration as an intravenous injection and does not contain polysorbate 80. From Current Emend for Injection label (02/2016) and the Applicant’s proposed label

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(b) (4)


Aprepitant is a selective high-affinity antagonist of human substance P/neurokinin 1 (NK1) receptors. Aprepitant has little or no affinity for serotonin (5-HT3), dopamine, and corticosteroid receptors, the targets of existing therapies for chemotherapy-induced nausea and vomiting (CINV). Aprepitant has been shown in animal models to inhibit emesis induced by cytotoxic chemotherapeutic agents, such as cisplatin, via central actions. Animal and human Positron Emission Tomography (PET) studies with aprepitant have shown that it crosses the blood brain barrier and occupies brain NK1 receptors. Animal and human studies show that aprepitant augments the antiemetic activity of the 5-HT3-receptor antagonist ondansetron and 9 the corticosteroid dexamethasone and inhibits both the acute and delayed phases of cisplatin-induced emesis.

2.2 Tables of Currently Available Treatments for Proposed Indications

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Clinical Review NDA 209,296 Aisha Peterson Johnson, MD, MPH, MBA aprepitant injectable emulsion 2.3 Availability of Proposed Active Ingredient in the United States

Fosaprepitant’s active metabolite, aprepitant, to which its efficacy is attributed, has been available in the U.S. since 2003 as EMEND oral. Brief Regulatory History of fosaprepitant in the US

o Fosaprepitant dimeglumine was first approved in 2008 for use as part of the 3-day dosing regimen with aprepitant (Day 1: fosapripitant 115 mg; Days 2 and 3: aprepitant 80 mg). This approval of fosaprepitant 115mg was based upon its bioequivalence to aprepitant 125mg.

o In 2010, fosaprepitant dimeglumine was approved as a single dose regimen for

the prevention of acute and delayed CINV in patients receiving HEC. For details, see the clinical review in DARRTS by Dr. Tamara Johnson (10/15/2015).

o In 2016, fosaprepitant dimglumine was approved as a single dose regimen for

the prevention of delayed CINV in patients receiving MEC. MO Comment: Single dose (150 mg) EMEND for Injection for the HEC indication was approved in 2010, prior to the American Society of Clinical Oncology (ASCO) publishing new entiemetic guidelines changing the emetogenicity category (from MEC to HEC) for anthracyclines (including doxorubicin, epirubicin, idarubicin and daunorubicin) administered in combination with cyclophosphamide (AC).1 The single dose EMEND for Injection (150 mg) indication for MEC (delayed) was approved in 2015. The pre-specified study population was patients receiving MEC as categorized prior to ASCO 2011 guidelines. As part of the review, FDA requested the Applicant conduct a post-hoc analysis dividing patients by HEC and MEC according to the ASCO 2011 guidelines. These results showed a significant treatment difference for those patients receiving AC regimens (HEC, ASCO, 2011).

2.4 Important Safety Issues With Consideration to Related Drugs

There are currently three NK-1 products on the market in the U.S.— VARUBI (oral form only), EMEND (intravenous and oral forms) and AKYNZEO (oral form only). Rolapitant (Varubi®) was approved in 2015 and is currently only marketed as an oral formulation. The rolapitant label (09/2015) contains the following contraindications and warnings:

1 Basch E, Prestrud A, Hesketh P, et al. Antiemetics; American Society of Clinical Oncology Clinical Practice Guideline Update. JCO. 2011. Vol 29:4189-4198.

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4 CONTRAINDICATIONS VARUBI is contraindicated in patients receiving thioridazine, a CYP2D6 substrate. A significant increase in plasma concentrations of thioridazine may result in QT prolongation and Torsades de Pointes. 5 WARNINGS AND PRECAUTIONS 5.1 Interaction with CYP2D6 Substrates with a Narrow Therapeutic Index: The inhibitory effect of a single dose of VARUBI on CYP2D6 lasts at least 7 days and may last longer. Avoid use of pimozide; monitor for adverse reactions if concomitant use with other CYP2D6 substrates with a narrow therapeutic index cannot be avoided. (4, 5.1, 7.1)

EMEND is available in oral forms (suspension and capsules) and as a solution for intravenous injection. Netupitant/palonosetron (Akynzeo) is a fixed combination of netupitant, a substance P/neurokinin1 receptor antagonist, and palonosetron, a 5-HT3 receptor antagonist. The EMEND label (05/2017) contains the following contraindications and warnings:

4 CONTRAINDICATIONS EMEND is contraindicated in patients:

• who are hypersensitive to any component of the product. Hypersensitivity reactions including anaphylactic reactions have been reported [see Adverse Reactions (6.2)].

• taking pimozide. Inhibition of CYP3A4 by aprepitant 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 Aprepitant is a substrate, a weak-to-moderate (dose-dependent) inhibitor, and an 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.

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FDA requested that the Sponsor clarify whether the aprepitant measured in Study 104 from HTX-019 130 mg was aprepitant released from the emulsion or emulsion encapsulated aprepitant.

03 August 2016

Written Responses Only Sponsor’s background document stated that finding of safety and/or effectiveness for

Emend (aprepitant) Capsules (NDA 021549) and Emend (fosaprepitant) for Injection (NDA 022023) will be relied upon for the planned HTX-019 NDA. FDA asked the Sponsor to identify which sections of these NDAs would be relied upon and also asked for a description of the “bridge” to support the scientific appropriateness of such reliance.

FDA acknowledged that the 90% confidence interval for geometric mean ratio for C12hr, AUCt, and AUCinf are within the range of 80% – 125%. However, FDA recommended a secondary analysis of the carryover effect. FDA stated that if the null hypothesis of no carryover effect is rejected, then the data from the 2nd period cannot be used for analysis and only the first period data can be used. In this case, the study would have to be treated as a study with two parallel groups.

FDA stated that therapeutic equivalence evaluations are made after approval of an application. However, therapeutic equivalents must be pharmaceutical equivalents and pharmaceutical equivalents must contain the same active ingredient. Aprepitant and fosaprepitant are considered different active ingredients.

Sponsor should address the potential safety issues associated with the higher Cmax from the proposed product including the even higher Cmax associated with infusing the proposed product over 20 minutes instead of the 30 minute infusion time of Emend IV.

While the Emend 115 mg I.V. application relied upon the 375 mg oral exposure data to support safety, in referencing the findings of safety and efficacy for that I.V. product, the Sponsor can only rely upon the safety associated with the I.V. product. Therefore, comparisons are limited to Emend I.V. and the Sponsor cannot rely upon information in the review regarding exposure associated with 375 mg oral Emend.

For the 100 mg HTX-019 strength that was not used in the BE study, the Sponsor must provide a biowaiver request including justification that the proposed lower and higher strength I.V. products are compositionally the same.

15 June 2016

Written Responses Only A “bridge” is necessary to support the scientific appropriateness of relying on the drug(s)

which the Sponsor intends to rely upon for the 505(b)(2) Application, Emend capsules (oral) vs Emend for Injection

FDA agreed that the 23-day repeat dose toxicity study conducted by the Sponsor is adequate to support the 505(b)(2) and no further repeat dose toxicity studies are required.

FDA agreed that the excipients in HTX-019 are adequately qualified an nonclinical studies of these excipients is not required.

13 May 2015

Type B Meeting, Pre-IND Teleconference (IND 125,926) Based on your proposed development plan bridging to the

fosaprepitant 150 mg I.V. dose, the only indication that could be supported would be the single dose HEC indication.

2.6 Other Relevant Background Information

None known except as described in other portions of this review.

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Clinical Review NDA 209,296 Aisha Peterson Johnson, MD, MPH, MBA aprepitant injectable emulsion Number of investigators with disclosable financial interests/arrangements (Form FDA 3455): 0

If there are investigators with disclosable financial interests/arrangements, identify the number of investigators with interests/arrangements in each category (as defined in 21 CFR 54.2(a), (b), (c) and (f)): n/a

Compensation to the investigator for conducting the study where the value could be influenced by the outcome of the study: Significant payments of other sorts: Proprietary interest in the product tested held by investigator: Significant equity interest held by investigator in sponsor of covered study:

Is an attachment provided with details of the disclosable financial interests/arrangements:

Yes n/a

No (Request details from applicant)

Is a description of the steps taken to minimize potential bias provided:

Yes n/a

No (Request information from applicant)

Number of investigators with certification of due diligence (Form FDA 3454, box 3) 0

Is an attachment provided with the reason:

Yes n/a

No (Request explanation from applicant)

4 Significant Efficacy/Safety Issues Related to Other Review Disciplines

4.1 Chemistry Manufacturing and Controls

See the complete CMC review in DARRTS.

4.2 Clinical Microbiology

See the complete microbiology review in DARRTS.

4.3 Preclinical Pharmacology/Toxicology

For the HTX-019 nonclinical program, the Applicant conducted eight studies to evaluate the PK and general and local toxicity of HTX-019 in comparison to EMEND for injection

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Clinical Review NDA 209,296 Aisha Peterson Johnson, MD, MPH, MBA aprepitant injectable emulsion following single or repeat dosing. These studies were considered adequate by the nonclinical team for submission of a 505(b)(2) (see 15 June 2016 WRO responses summary above or complete WRO responses in DARRTS). Heron is also relying on the nonclinical studies (i.e., pharmacology, metabolism, excretion, genotoxicity, carcinogenicity, and developmental and reproductive toxicology) for EMEND for injection (NDA 22-023). None of these nonclinical studies for EMEND for injection were conducted by or for Heron and Heron has not obtained a right of reference. For further discussion of these studies and their results, see the pharmacology/toxicology review in DARRTS.

4.4 Clinical Pharmacology

Table 2. Clinical Pharmacology Studies Submitted in Support of NDA 209,296

Reviewer’s table adapted from ISS Table 5.3.5.3.2-1 The safety results of Studies 104 and 106 are discussed in this review. In addition, brief summary results for these studies are presented in Section 5.3. For further details, see the final clinical pharmacology review in DARRTS. 4.4.1 Mechanism of Action Aprepitant is a neurokinin-1 (NK-1) receptor antagonist. These receptors are broadly distributed in the central and peripheral nervous systems. Studies have shown that aprepitant binds to the NK-1 receptor with high affinity and has little or no activity for the other NK receptors. The endogenous activator of the NK-1 receptor is the neuropeptide Substance P.

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Clinical Review NDA 209,296 Aisha Peterson Johnson, MD, MPH, MBA aprepitant injectable emulsion 4.4.2 Pharmacodynamics

No significant efficacy or safety issues related to pharmacodynamics were identified.

4.4.3 Pharmacokinetics

For clinical pharmacology details of aprepitant, see the final label and the clinical pharmacology review in DARRTS by Susie Zhang.

5 Sources of Clinical Data

5.1 Tables of Studies/Clinical Trials

See Table 2 above for a summary of the clinical studies submitted in support of the current Application.

5.2 Review Strategy

For this clinical review, the safety results for the four phase 1 studies submitted in support of the current Application will be presented. See the full clinical pharmacology review for other details regarding these studies.

5.3 Discussion of Individual Studies/Clinical Trials

Study Summaries

Study 104 This study was a phase 1, open-label, randomized, cross-over study of the bioequivalence of HTX-019 and EMEND for Injection administered as a single intravenous dose in healthy subjects. The primary objective of the study was to determine the bioequivalence of a single 130 mg IV dose of aprepitant emulsion (HTX-019) with commercially available fosaprepitant (150 mg). There was a seven day washout period between treatments. Subjects were confined to the clinic from Day –1 through 72 hours (Day 4) after dosing of one the following treatments:

• 30-minute IV infusion of 130 mg dose of HTX-019 • 30-minute IV infusion of 150 mg dose of EMEND for Injection

During Study 104, HTX-019 130 mg (test) was considered to have met BE criteria relative to EMEND for Injection 150 mg (reference) based on AUC0-t, AUC0-inf, and C12hr as the 90% confidence intervals (CIs) were within the typical BE standards of 80 to

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Clinical Review NDA 209,296 Aisha Peterson Johnson, MD, MPH, MBA aprepitant injectable emulsion 125%. As expected, the observed mean Cmax of the of total aprepitant equivalents was higher following administration of HTX-019 130 mg compared with Emend for Injection 150 mg (6265 ng/mL vs 4303 ng/mL). See the full clinical pharmacology review for a more detailed discussion of the BE results. MO Comment: To address the safety of the higher Cmax seen with HTX-019, the safety data of healthy subjects in Studies 104 and 106 were reviewed along with published literature documenting adverse event data of patients who received doses of aprepitant which resulted in exposure levels similar to those seen with HTX-019 150 mg. See Section 6 for a detailed safety evaluation. Study 106 This study was a 2-part study of the relative bioavailability (BA) of aprepitant following IV administration of EMEND for injection and HTX-019 that consisted of two parts. Part A was a randomized, pilot PK study during which patients were randomized to one of 5 cohorts: Cohort 1: 30-minute IV infusion of 130 mg HTX-019 Cohort 2: 30-minute IV infusion of 150 mg EMEND for injection Cohort 3: 20-minute IV infusion of 150 mg EMEND for injection Cohort 4: 30-minute IV infusion of 100 mg HTX-019 Cohort 5: 115 mg EMEND, 15 min IV The results of Part A provided a characterization of the Cmax for aprepitant (EMEND for injection and HTX-019) and fosaprepitant (EMEND for injection).

Part B was a BE study comparing HTX-019 mg infused over 30 minutes (test) with Emend for injection 150 mg infused over 20 minutes (reference). The study used a cross-over design similar to Study 104. There was a seven day washout period between treatments. The results in Part B demonstrated that the test and reference treatments met BE criteria for AUC0-t, AUC0-inf, and C12hr. These results support the Applicant’s proposal to infuse their product over 20 minutes instead of the labeled 20 to 30 minute infusion time for Emend for injection. MO Comment: A 7-day washout period was appropriate given that it is longer than 5-times the terminal elimination half-life (t1/2) of aprepitant which ranged from approximately 9 to 13 hours.

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Clinical Review NDA 209,296 Aisha Peterson Johnson, MD, MPH, MBA aprepitant injectable emulsion Table 3. Summary of Key Plasma Pharmacokinetic Parameters of Aprepitant after IV Administration of HTX-019 and EMEND for Injection (Study 104 &Study 106)

Electronically copied and reproduced from the Summary of Clinical pharmacology Table 2.7.2-3 Figure 1. Study Design, Study 104

Electronically copied and reproduced from Study 104, CSR p 23/293

Key Inclusion Criteria

In each of the Phase 1 BA/BE studies, subjects eligible to participate were healthy, non-smoking, male or female subjects aged 18 to 55 years with body mass index between 18.5 and 32 kg/m2 and a weight of ≥ 50 kg. Female subjects of childbrearing potential must have had a negative serum pregnancy test at screening and on Day -1 and be using acceptable method(s) of contraception. Subjects had to be in good health as determined by a physician and have laboratory evaluation within the reference range unless results were deemed not clinically significant by the investigator.

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Clinical Review NDA 209,296 Aisha Peterson Johnson, MD, MPH, MBA aprepitant injectable emulsion Study Visits and Procedures

The Study Visits and procedures are summarized in the Table below. Table 4. Schedule of Events, Study 104

Electronically copied and reproduced, Complete Study Report Table 9-3, p 36/293

6 Review of Efficacy Efficacy Summary No efficacy evaluation was conducted in support of the current Application

6.1 Indication

The Sponsor has proposed the following indication statement for aprepitant injectable emulsion:

• 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.

• The prevention of nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC).

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Clinical Review NDA 209,296 Aisha Peterson Johnson, MD, MPH, MBA aprepitant injectable emulsion 6.1.1 Methods N/A

6.1.2 Demographics

See Safety section for demographic summary of the safety population.

6.1.3 Patient Disposition

See Safety section for patient disposition summary of the safety population.

6.1.4 Analysis of Primary Endpoint(s)

N/A

6.1.5 Analysis of Secondary Endpoints(s)

N/A

6.1.6 Other Endpoints

N/A

6.1.7 Subpopulations

N/A

6.1.8 Analysis of Clinical Information Relevant to Dosing Recommendations

N/A

6.1.9 Discussion of Persistence of Efficacy and/or Tolerance Effects

N/A

6.1.10 Additional Efficacy Issues/Analyses

N/A

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Clinical Review NDA 209,296 Aisha Peterson Johnson, MD, MPH, MBA aprepitant injectable emulsion 7 Review of Safety Safety Summary In general, the use of aprepitant injectable emulsion for the proposed indication appears to represent an acceptable risk. See the Risk Benefit Assessment Section 1.2.

7.1 Methods

Adverse events and medical histories in Studies 104 and 106 were coded using the Medical Dictionary for Regulatory Activities (MedDRA) Version 18.1.

7.1.1 Studies/Clinical Trials Used to Evaluate Safety

Overall, aprepitant injectable emulsion was evaluated in 270 healthy subjects in two phase 1 studies—104 and 106. 7.1.2 Categorization of Adverse Events Adverse events were categorized using the Common Terminology Criteria for Adverse Events (CTCAE) grading system.

7.1.3 Pooling of Data Across Studies/Clinical Trials to Estimate and Compare Incidence

To evaluate the safety of HTX-019 compared with EMEND for injection, the safety data of the 100 healthy subjects in Study 104 and the 100 healthy subjects in part B of Study 106 were pooled. Study 104 and Study 106, Part B used a cross-over design during which subjects received both HTX-019 130 mg and EMEND for injection 150 mg allowing for a direct comparison of safety results between the two drugs. Study 106, Part A did not include a cross-over design and included five cohorts of patients with only two cohorts receiving the drug/dose combinations of interest (21 subjects in Cohort 1 received HTX-019 130 mg; 12 subjects in Cohort 2 received EMEND for injection 150 mg). Therefore, the results of Study 106, Part A are presented separately.

7.2 Adequacy of Safety Assessments

The safety assessments performed were adequate. Safety variables included adverse events (AEs), clinical laboratory evaluations (hematology, clinical chemistry, and urinalysis), vital signs, and physical examination parameters. Patients who were given at least one dose of the study medication were included in the safety analysis populations described in Section 7.1.

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Clinical Review NDA 209,296 Aisha Peterson Johnson, MD, MPH, MBA aprepitant injectable emulsion 7.2.1 Overall Exposure at Appropriate Doses/Durations and Demographics of

Target Populations

During Study 104, a total of 99 subjects were infused with HTX-019 130 mg over 28 to 33 minutes. In addition, 98 subjects were infused with EMEND for injection 150 mg over 28 to 34 minutes. Subjects 1068 and 1098 discontinued the study at the beginning of the infusion.

In Part B of Study 106, 96 subjects were infused with HTX-019 130 mg over 28 to 33 minutes. In addition, 99 subjects were infused with EMEND for injection 150 mg (one subject discontinued study drug at the beginning of the infusion) over 18 to 30 minutes.

See Table 5 below.

Table 5. Extent of Exposure, Studies 104 and 106 (Part B)

Electronically copied and reproduced from Applicant’s Summary of Clinical Safety Table 2.7.4-5 During Study 106, part A, 22 subjects were infused with HTX-019 130 mg over 28 to 38 minutes (Cohort 1). In addition, 12 subjects in cohort 4 were infused with HTX-019 100 mg form 28 to 30 minutes. See Table 6 below.

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Clinical Review NDA 209,296 Aisha Peterson Johnson, MD, MPH, MBA aprepitant injectable emulsion Table 6. Extent of Exposure, Study 106, Part A

Electronically copied and reproduced form Applicant’s Summary of clinical Safety Table 2.7.4-7 During Study 104 and Study 106, Part B, the majority of subjects completed the study (97.0% and 95.0% of patients, respectively). For a summary of subject disposition, see Table 7 below. In addition, narratives of adverse discontinuations are presented in Section 7.3.3 below.

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Clinical Review NDA 209,296 Aisha Peterson Johnson, MD, MPH, MBA aprepitant injectable emulsion Safety Population Demographics The baseline demographic characteristics were similar between sequence groups (AB vs BA) for Study 104 and Study 106, Part B. Subjects were relatively young with mean ages of 34.0 years and 31.0 years, respectively. See Table 9 below.

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Clinical Review NDA 209,296 Aisha Peterson Johnson, MD, MPH, MBA aprepitant injectable emulsion Table 9. Demographics and Baseline Characteristics, Study 104 and Study 106, Part B

Electronically copied and reproduced from Applicant’s Summary of Clinical Safety, Table 2.7.4-9

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Clinical Review NDA 209,296 Aisha Peterson Johnson, MD, MPH, MBA aprepitant injectable emulsion Table 10. Demographics and Baseline Characteristics, Study 106, Part A

Electronically copied and reproduced from Applicant’s Summary of Clinical Safety, Table 2.7.4-10 MO Comment: Of note, the majority of subjects in Study 106, Parts A and B were African American. And nearly 40% of subjects in Study 104 were African American. Both studies were conducted at Spaulding Clinical Research in West Bend, WI. As of the 2010 census, the racial makeup of West Bend, WI was 94.8% White, 1.0% African American, 0.4% 0.4% Native American, 0.8% Asian, 1.4% from other races. However, Study 106, Part B was 61% African American. The recruitment practices of the center are likely

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Clinical Review NDA 209,296 Aisha Peterson Johnson, MD, MPH, MBA aprepitant injectable emulsion responsible for this racial make-up given that these numbers do not reflect the surrounding population. 7.2.2 Explorations for Dose Response No evaluation of dose response in the number of reported TEAEs was done. Most patients in Studies 104 and 106 received the 130 mg dose of HTX-019. Only 12 subjects across both studies received HTX-019 100 mg.

7.2.3 Special Animal and/or In Vitro Testing

N/A

7.2.4 Routine Clinical Testing

Routine clinical testing as described in Section 7.2 was included as part of the safety assessments in the three submitted studies. See Section 5.3.5 for detailed information on study visits and procedures.

7.2.5 Metabolic, Clearance, and Interaction Workup

For more information, see the Clinical Pharmacology Review in DARRTS by Susie (Xinyuan) Zhang, PhD.

7.2.6 Evaluation for Potential Adverse Events for Similar Drugs in Drug Class

Use of drugs in the NK-1 antagonist class is not known to be associated with any specific adverse events. None of the drugs in this class has a boxed warning. The Warnings and Precautions section of labels for drugs in this class include the following: Aprepitant Capsules/Emend (label revised 8/2014)

• Coadministration of aprepitant with warfarin (a CYP2C9 substrate) may result in a clinically significant decrease in International Normalized Ratio (INR) of prothrombin time. (5.2)

• The efficacy of hormonal contraceptives during and for 28 days following the last dose of EMEND may be reduced. Alternative or back-up methods of contraception should be used. (5.3, 7.1)

• EMEND is a dose-dependent inhibitor of CYP3A4, and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4. (5.1)

• Caution should be exercised when administered in patients with severe hepatic impairment. (2.5, 5.4, 12.3)

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Clinical Review NDA 209,296 Aisha Peterson Johnson, MD, MPH, MBA aprepitant injectable emulsion Netupitant and palonosetron/Akynzeo (label revised 10/2014) There are no warnings and precautions related to the netupitant part of the fixed dose combination product.

7.3 Major Safety Results

There were no serious adverse events or deaths reported in any of the studies submitted in support of the current Application.

7.3.1 Deaths

None reported.

7.3.2 Nonfatal Serious Adverse Events

No serious AEs were reported by subjects in Study 104 or 106.

7.3.3 Dropouts and/or Discontinuations

See Table 8 for a summary of subjects who discontinued study drug during Studies 104 and 106. Brief narratives of the HTX-019 patients who discontinued study drug are provided below: Subject 1098 in Study 104 was a 42-year-old black or African American female

who was assigned to the AB treatment sequence. The patient reported taking no medication at the time of enrollment. On 20 December 2015, the subject received an infusion of HTX-019 130 mg. On 29 December, the subject received EMEND for injection. Within one minute of the infusion, the subject reported abdominal pain, dizziness, and dyspnea. The infusion was stopped within two minutes. The subject reported resolution of symptoms within 10 minutes. The subject received 2 L of IV normal saline to treat the symptoms. The investigator considered the TEAE to be probably related to the study drug. All TEAEs resolved without sequelae.

Subject 1031 in Study 104 was a 23-year old black or African American female assigned to the BA treatment sequence. The patient reported no medical history at enrollment. Patient received EMEND for injection 150 mg without even on 19December 2015. On 27 December 2015 the subject received HTX-019 mg infusion. Five days after receiving HTX-019, the subject reported TEAEs of chest pain, dyspnea, and respiratory congestion. These AEs were reported as mild in severity. All TEAEs resolved without sequelae.

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Clinical Review NDA 209,296 Aisha Peterson Johnson, MD, MPH, MBA aprepitant injectable emulsion Subject 1067 in Study 104 was a 34-year old white female assigned to treatment

sequence BA. The subject was healthy at the time of enrollment on no medications. The subject received EMEND for injection 150 mg on 20 December 2015. Eighteen minutes into the infusion, the subject reported TEAE of dyspnea (mild in severity). The investigator assessed that the patient was in no distress and decided to continue the infusion. No concomitant treatment was given. The subject reported resolution dyspnea within two hours of the event starting. The investigator considered the TEA to be probably related to the study drug. The subject went on to receive HTX-019 130 mg without event.

Subject 2010 in Study 106 was a 26-year-old black female randomly assigned on 18SEP2016 to Treatment Sequence BA. Subject 2010 was healthy at the time of enrollment in the study. The subject did not report taking medications during the 28 days before Check-in (Day –1). The subject received a 150 mg IV infusion of EMEND for injection (Treatment B) on 19SEP2016 beginning at 0708. On 19SEP2016 at 0710, the subject reported TEAEs of dyspnea and tachycardia and the infusion was stopped per the investigator’s instruction; the dose received was 16.6 mg. The investigator considered the TEAE of dyspnea mild in severity and definitively related to study drug and the TEAE of tachycardia mild in severity and probably related to study drug. On 19SEP2016, the subject reported resolution of the TEAEs of dyspnea and tachycardia at 0720 and 0722, respectively. The TEAEs resolved without sequelae. No concomitant medication or nondrug therapy was administered for the TEAEs of dyspnea and tachycardia. The subject completed all procedures thereafter, including Period 2 dosing with HTX-019 130 mg (Treatment A), with no further TEAEs.

Subject 2056 was a 22-year-old black female in Study 106 randomly assigned on 19SEP2016 to Treatment Sequence BA. Subject 2056 was healthy at the time of enrollment. The subject did not report taking medications during the 28 days before Check-in (Day –1). The subject received a 150 mg IV infusion of EMEND for injection (Treatment B) on 20SEP2016 beginning at 0704 and ending at 0725. On 20SEP2016, the subject reported a TEAE of fatigue at 0800. The investigator considered the TEAE of fatigue mild in severity and possibly related to study drug. On 22SEP2016, the subject reported resolution of the TEAE of fatigue at 0800. No concomitant medication or nondrug therapy was administered for the TEAE of fatigue. The TEAE of fatigue resolved without sequelae. The subject subsequently received a 130 mg IV infusion of HTX-019 (Treatment A) on 04OCT2016, beginning at 0704. On 04OCT2016, the subject reported TEAEs of dyspnea and hyperhidrosis at 0706, nausea at 0720, and fatigue at 0942. The study drug was stopped at approximately 0708 per the investigator’s instruction due to the TEAEs of dyspnea and hyperhidrosis; the dose received was 13.7 mg. The investigator considered all TEAEs mild in severity and possibly related to study drug, with the exception of dyspnea which considered moderate in severity. The subject was discontinued from the study on 05OCT2016 due to the TEAEs of dyspnea and hyperhidrosis. The 4 TEAEs resolved without sequelae. The subject had 2 clinically notable elevated serum creatinine values during the study

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prior to dosing on Period 1, Day –1 (2.66 mg/dL) and on Period 2, Day –1 (2.23 mg/dL). Note that this subject’s serum creatinine was also elevated at Screening (1.82 mg/dL) and at unscheduled laboratory assessments taken later on Day –1 prior to dosing (1.53 and 1.63 mg/dL); although these values were lower than the initial Day –1 values. The serum creatinine value (0.83 mg/dL) for Subject 2056 was within normal limits after study treatment on Period 2, Day 4.

Subject 2031 was a 45-year-old black female in Study 106 randomly assigned on 18SEP2016 to Treatment Sequence BA. Subject 2031 was healthy at the time of enrollment in the study. The subject did not report taking medications during the 28 days before Check-in (Day –1). The subject received a 150 mg IV infusion of EMEND for injection (Treatment B) on 19SEP2016 beginning at 0730 and ending at 0750 (full infusion). On 19SEP2016, the subject reported a TEAE of peripheral nerve injury at 0745 and a TEAE of infusion site bruising at 1945. On 22SEP2016, the subject reported a TEAE of infusion site swelling at 1328. The investigator considered the TEAEs of peripheral nerve injury and infusion site swelling mild in severity and probably related to study drug and the TEAE of infusion site bruising mild in severity and not related to study drug. The TEAEs of infusion site swelling and infusion site bruising were treated with nondrug therapy (ie, ice pack). No concomitant medication was administered for the TEAE of peripheral nerve injury. The subject reported resolution of the TEAE of infusion site bruising on 03OCT2016 at 0100, the TEAE of infusion site swelling on 11OCT2016 at 1509, and the TEAE of peripheral nerve injury on 22OCT2016 at 0800. The subject was discontinued from the study on 11OCT2016 due to the TEAE of peripheral nerve injury and did not receive HTX-019 130 mg for 30 minutes (Treatment A) during Period 2. The 3 TEAEs resolved without sequelae.

Subject 2012 was a 29-year-old Asian male in Study 106 randomly assigned on 18SEP2016 to Treatment Sequence AB. Subject 2012 was healthy at the time of enrollment in the study. The subject did not report taking medications during the 28 days before Check-in (Day –1). The subject received a 130 mg IV infusion of HTX-019 (Treatment A) on 19SEP2016 beginning at 0856 and ending at 0925. The subject received a 150 mg IV infusion of EMEND for injection (Treatment B) on 03OCT2016 beginning at 0856 and ending at approximately 0916. On 03OCT2016, the subject reported TEAEs of dyspnea, abdominal pain, paraesthesia, and visual impairment at 0858. The investigator considered the TEAEs mild in severity and possibly related to study drug. On 03OCT2016, the subject reported resolution of the TEAEs of dyspnea, abdominal pain, paraesthesia, and visual impairment at 0859. No concomitant medication or nondrug therapy was administered for the TEAEs of dyspnea, abdominal pain, paraesthesia, and visual impairment. The TEAEs resolved without sequelae.

Subject 2037 was a 23-year-old black male in Study 106 randomly assigned on 18SEP2016 to Treatment Sequence AB. Subject 2037 was healthy at the time of enrollment in the study. The subject did not report taking medications during the 28 days before Check-in (Day –1). The subject received a 130 mg IV infusion of

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HTX-019 (Treatment A) on 19SEP2016 beginning at 1020 and ending at 1049. The subject received a 150 mg IV infusion of EMEND for injection (Treatment B) on 03OCT2016 beginning at 1020 and ending at 1039. On 03OCT2016, the subject reported TEAEs of dyspnea and cough at 1020. The investigator considered the TEAEs mild in severity and definitively related to study drug. On 03OCT2016, the subject reported resolution of the TEAEs of dyspnea and cough at 1021 and 1025, respectively. No concomitant medication or nondrug therapy was administered for the TEAEs of dyspnea and cough. The TEAEs resolved without sequelae.

7.3.4 Significant Adverse Events No new or unlabeled adverse events were seen in subjects receiving EMEND for injection. Similarly, no safety signal was seen with HTX-019.

7.3.5 Submission Specific Primary Safety Concerns

28% higher Cmax of HTX-019 130 mg compared with EMEND for Injection 150 mg A primary safety concern for the current Application is the possibility of an increased rate or severity of adverse events related to the increased exposure (Cmax) of aprepitant seen with HTX-019 130 mg when compared with EMEND for injection 150 mg. To address this risk, this reviewer analyzed the safety data from the phase 1 BA/BE studies (104 and 106) along with published literature of patients who received doses of aprepitant resulting in similar exposures to those seen with HTX-019 130 mg. The results of this review revealed that the higher exposure of HTX-019 is not associated with a clinically significant increased rate or increased severity of adverse events. Additionally, the safety review provides evidence that HTX-019 may be associated with a lower overall risk of injection site reactions. The imbalance in injection site reactions seen between EMEND for injection and HTX-019 may be due to the presence of polysorbate-80 in the EMEND for injection formulation which is not present in HTX-019. Although a 28% higher Cmax was observed for HTX-019 130 mg (infused over 30 minutes) as compared to EMEND for injection 150 mg (infused over 30 minutes), the potential for drug-drug interaction with CYP3A4 substrates is expected to be similar based on the safety data from the phase 1 BA/BE studies and the published literature. Therefore, Heron proposes the same recommendations for the coadministration of HTX-019 with CYP3A4 substrates as in the EMEND for injection USPI. Hypersensitivity Reactions including Injection Site Reactions A second primary safety concern for the current Application is the occurrence of hypersensitivity and infusion site reactions. Hypersensitive reactions are currently a labeled warning of EMEND for injection.

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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)]. Monitor patients during and after infusion. If hypersensitivity reactions occur, discontinue the infusion and administer appropriate medical therapy. Do not reinitiate EMEND in patients who experience these symptoms with first-time use [see Contraindications (4)].

A total of eight events of dyspnea were reported in Study 104 and Part B of Study 106. Of these, six occurred following treatment with EMEND for injection 150 mg and two events occurred in subjects following infusion of HTX-019 130 mg. Additional details about each of these events is presented in the Table below. Associated TEAEs included tachycardia, nausea, flushing, hyperhidrosis, dizziness, and abdominal pain. The temporal proximity of the dyspnea events to the start of drug infusion led the investigator to deem each of these events as at least “possibly related” with the exception of the event of dyspnea in a subject with respiratory tract congestion. MO Comment: Dyspnea along with the associated symptoms of tachycardia, nausea, flushing, hyperhidrosis, dizziness, and abdominal pain provides support for the diagnosis of hypersensitivity reaction in these subjects. Given that this AE is currently included in EMEND for Injection labeling and is planned to be included in Cinvanti labeling, no additional action is required at this time.

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Clinical Review NDA 209,296 Aisha Peterson Johnson, MD, MPH, MBA aprepitant injectable emulsion Table 11. Overview of Subjects With TEAEs of Dyspnea, Study 104 & Study 106 (Part B)

Electronically copied and reproduced from Applicant’s Summary of Clinical Safety, Table 2.7.4-20

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Clinical Review NDA 209,296 Aisha Peterson Johnson, MD, MPH, MBA aprepitant injectable emulsion Table 12. Infusion Site Reactions, Study 104

Electronically copied and reproduced from Applicant’s CSR, Study 104, Table 12-2 (portion of table) Table 13. Infusion Site Reaction TEAEs, Study 106 (Part B)

Electronically copied and reproduced from Applicant’s CSR, Study 106, Table 12-4 (portion of table)

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Clinical Review NDA 209,296 Aisha Peterson Johnson, MD, MPH, MBA aprepitant injectable emulsion MO Comment: The difference in the rate of HSRs including ISRs seen between HTX-019 and EMEND for Injection is seen in both Study 104 and 106 and the trend is consistent (with the exception of vessel site pain, Study 104) between all HSRs including ISRs and therefore likely represents a real phenomenon. However, because the Applicant has chosen the 505(b)(2) pathway relying on the FDAs finding for safety and efficacy for EMEND for Injection, HTX-019 labeling should at this time contain the information on ISRs contained in the EMEND for Injection label and should not describe the observed difference in rate of HSRs including ISRs in favor of HTX-019. A powered safety study to more fully understand the difference in the rate of HSRs including ISRs between these products would be required before HTX-019 labeling could be updated to claim this. At this time, it would be premature to allow the Applicant to market their product as having a safety advantage over EMEND for Injection based on the results of two BA/BE studies in healthy subjects.

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7.4 Supportive Safety Results

7.4.1 Common Adverse Events

During Study 104 and Study 106 (Part B), more adverse events were reported by patients during the EMEND for Injection treatment portions of each study than during the HTX-019 treatment portions. The difference in TEAE rates was 6.8% and 16.6%, respectively in Study 104 and Study 106 (Part B). There were no serious TEAEs or deaths reported in either study. In Study 104, two subjects withdrew due to adverse events. Both of these subjects withdrew during the EMEND for Injection treatment period. During Study 106 (Part B), two subjects withdrew due to TEAE(s) during the THTX-019 treatment portion while one subject withdrew during the EMEND for Injection treatment portion. Table 14. Summary of Treatment Emergent Adverse Events, Study 104 and Study 106 (Part B)

Electronically copied and reproduced from the Summary of Clinical Safety, Table 2.7.4-11

During Part A of Study 106, 16 of 70 subjects (22.9%) reported a TEAE. Of these, none were considered severe. There were no deaths, SAEs or adverse discontinuations. Similar to what was seen in Study 104 and Part B of Study 106, a higher percentage of subjects reported TEAEs during the EMEND for Injection treatment cohorts than in the HTX-019 treatment cohorts. See Table 12 below.

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Table 15. Summary of Treatment Emergent Adverse Events Study 106 (Part A)

Electronically copied and reproduced form Study 106 CSR, Table 12-1

The most common preferred terms (PTs) reported as TEAEs during Study 104 and Part B of Study 106, respectively, during the HTX-019 130 mg treatment portions were headache (5.1%, 1.0%), fatigue (2.0%, 2.1%), lethargy (0%, 2.0%), and vessel puncture site pain (5.1%, 1.0%). During the EMEND for injection 150 mg treatment portions, the most commonly reported TEAEs in Study 104 and Part B of Study 106, respectively, were abdominal pain (2.0%, 3.0%), dizziness (4.0%, 0%), headache (8,0%, 5.0%), infusion site pain (9.0%, 9.0%), and nausea (5.0%, 0%). Overall, for each of the common (>2% incidence) preferred terms, with the exception of vessel puncture site pain, the incidence of TEAEs was higher in the EMEND for Injection 150 mg treatment portion than the HTX-019 treatment portion of Studies 104 and part B of Study 106. See Table 13 below. MO Comment: Each of the common TEAEs reported is currently listed in the EMEND for Injection labeling.

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Clinical Review NDA 209,296 Aisha Peterson Johnson, MD, MPH, MBA aprepitant injectable emulsion Table 16. Most Common Adverse Events: Incidence ≥2% With Any Treatment (Study 104 and Study 106, Part B)

Electronically copied and reproduced from summary of Clinical Safety Table 12.7.4-12

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7.4.2 Laboratory Findings

In general, the mean baseline values and mean changes from baseline over time observed in the hematology and chemistry parameters were similar between the treatment groups in Studies 104 and 106. In addition, none of the changes was considered to be clinically significant by the Investigator.

7.4.3 Vital Signs

In Studies104 and 106, there were no clinically meaningful changes or shifts in vital signs.

7.4.4 Electrocardiograms (ECGs)

Mean and median changes from Baseline to end of treatment (Day 4/early termination) in ECG parameters were similar between HTX-019 130 mg and EMEND for injection 150 mg for Studies 104 and 106.

7.4.5 Special Safety Studies/Clinical Trials

No special clinical safety studies were submitted.

7.4.6 Immunogenicity

N/A

7.5 Other Safety Explorations

7.5.1 Dose Dependency for Adverse Events

There was no clear trend of increasing AEs with increasing HTX-019 dose.

7.5.2 Time Dependency for Adverse Events

Given the initial higher peak plasma concentration of aprepitant following infusion of HTX-019 130 mg compared with EMEND for injection150 mg, an exploration for adverse events occurring within the first 60 minutes following the start of infusion was undertaken. It should be noted that the initially high peak plasma aprepitant concentration seen with HTX-019 130 mg became similar to that seen with EMEND for

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Clinical Review NDA 209,296 Aisha Peterson Johnson, MD, MPH, MBA aprepitant injectable emulsion injection 150 mg approximately 45 minutes after the start of infusion. The data from Studies 104 and Part B of Study 106 show that during the first 60 minutes after the start of infusion, the trend continued that subjects being treated with EMEND for injection 150 mg had a higher incidence of TEAEs than did patients receiving an infusion of HTX-019 130 mg. During the first 60 minutes after the start of infusion, 1.0% and 5.2% (Studies 104 and 106 (Part B), respectively) of HTX-019 130 mg subjects reported at least one TEAE. This is compared with 20.0% and 15.0% of subjects receiving an infusion of EMEND for injection 150 mg during Study 104 and Part B of Study 106, respectively. See Table 14 below.

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Clinical Review NDA 209,296 Aisha Peterson Johnson, MD, MPH, MBA aprepitant injectable emulsion Table 17. Treatment-Emergent Adverse Events in the First 60 Minutes Following the Start of the Infusion, Study 104 and Study 106 (Part B)

Electronically copied and reproduced from Summary of clinical Safety, Table 2.7.4-15

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Clinical Review NDA 209,296 Aisha Peterson Johnson, MD, MPH, MBA aprepitant injectable emulsion 7.5.3 Drug-Demographic Interactions

No particular explorations for drug-demographic interactions related to adverse events were conducted.

7.5.4 Drug-Disease Interactions

No particular explorations for drug-disease interactions were conducted.

7.5.5 Drug-Drug Interactions

According to the current EMEND for injection label, aprepitant undergoes extensive metabolism primarily by CYP3A4 with minor metabolism by CYP1A2 and CYP2C19. Current EMEND for injection labeling also includes the following Warning in Section 5:

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.

See Table 5 and Table 6 for a listing of potentially significant drug interactions [see Drug Interactions (7.1, 7.2)

Despite the 28% higher Cmax, the potential for drug-drug interaction is expected to be similar to that of EMEND for injection given that HTX-019 130 mg has been found to be bioequivalent to EMEND for injection 150 mg. Current EMEND for injection labeling contains extensive information regarding drug-drug interactions along with the clinical impact and interventions to mitigate these impacts. The following table is a part of EMEND for injection labeling and is proposed for inclusion in CINVANTI labeling.

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Clinical Review NDA 209,296 Aisha Peterson Johnson, MD, MPH, MBA aprepitant injectable emulsion 9 Appendices

9.1 Literature Review/References

To support the higher Cmax associated with the use of CINVANTI compared to the listed drug EMEND for Injection, the Applicant provided literature references. Three representative references are summarized below. Navari RM, Reinhardt RR, Gralla RJ, Kris MG, Hesketh PJ, Khojasteh A, Kindler H, Grote TH, Pendergrass K, Grunberg SM, Carides AD, Gertz BJ (1999). Reduction of cisplatin-induced emesis by a selective neurokinin-1-receptor antagonist. L-754,030 Antiemetic Trials Group, N Engl J Med 1999;340(3): 190-195. Safety Summary During this study, 108 patients were treated with oral aprepitant split evenly between two dose groups—400 before cisplatin and 300 mg on days 2 to 5 (group 1) or 400 mg before cisplatin and placebo on days 2 to 5 (group 2). While the peak plasma concentration of aprepitant was not reported in this paper, the oral aprepitant dose is significantly higher than the 80 mg once daily (on days 2 and 3) that is a part of the MEC regimen in the current application. There were no significant differences in adverse events between active and placebo groups. Tebas, P, Spitsin S, Barrett JS, Tuluc F, Elci O, Korelitz JJ, Wagner W, Winters A, Kim D, Catalano R, Evans DL, Douglas SD. Reduction of soluble CD163, substance P, programmed death 1 and inflammatory markers: phase 1B trial of aprepitant in HIV-1-infected adults." AIDS 2015; 29(8): 931-939. Safety Summary During this study, nine patients were treated with oral aprepitant 375 mg once daily for two weeks. This dose resulted in mean peak aprepitant plasma concentrations as high as 7600±3100ng/mL which was higher than the peak aprepitant plasma concentrations of HTX-019 (mean values of 6056 ng/mL and 6265 ng/mL in Study 106 Part B and Study 104, respectively). There were no serious adverse events reported and the adverse events were reported as mild and self-limited in nature with equal frequency in both active treatment and placebo arms. Marbury TC, Jin B, Panebianco D, Murphy MG, Sun H, Evans JK, Han TH, Constanzer ML, Dru J, Shadle CR. Lack of effect of aprepitant or its prodrug fosaprepitant on QTc intervals in healthy subjects. Anesth Analg 2009;109(2): 418-425.

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Clinical Review NDA 209,296 Aisha Peterson Johnson, MD, MPH, MBA aprepitant injectable emulsion Safety Summary During this double-blind, active-controlled, randomized, three-treatment, three-period, crossover study in 33 healthy, young subjects, one arm received 200 mg fosaprepitant. The maximum aprepitant concentration measured was 6300 ng/mL. This value was higher which was higher than the peak aprepitant plasma concentrations of HTX-019 (mean values of 6056 ng/mL and 6265 ng/mL in Study 106 Part B and Study 104, respectively). During this study, the fosaprepitant arm was associated with higher incidence of infusion site pain, thrombosis, and superficial thrombophlebitis compared with placebo. There were no deaths, serious clinical adverse events, or laboratory adverse events. MO Comment: The literature reviewed supports the relative safety of CINVANTI 130 mg with a 28% higher Cmax than EMEND for Injection 150 mg for the proposed indications in the proposed populations.

9.2 Labeling Recommendations

See the final approved label for final labeling recommendations.

9.3 Advisory Committee Meeting

N/A

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AISHA P JOHNSON10/02/2017

ANIL K RAJPAL10/02/2017


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