CENTER FOR DRUG EVALUATION AND
`
`
`
` RESEARCH
`
`
`
`
`APPLICATION NUMBER:
`
`
` 209863Orig1s000
`
`
`
`
` OTHER REVIEW(S)
`
`
`
`
`

`

`MEMORANDUM
`
`REVIEW OF REVISED LABEL AND LABELING
`
`
`Division of Medication Error Prevention and Analysis (DMEPA)
`
`Office of Medication Error Prevention and Risk Management (OMEPRM)
`
`Office of Surveillance and Epidemiology (OSE)
`
`Center for Drug Evaluation and Research (CDER)
`
`
` Date of This Memorandum:
`
`Requesting Office or Division:
`
`Application Type and Number:
`Product Name and Strength:
`
`Applicant/Sponsor Name:
`FDA Received Date:
`
`OSE RCM #:
`DMEPA Safety Evaluator:
`DMEPA Team Leader:
`
`September 21, 2018
`Division of Bone, Reproductive and Urologic Products
`(DBRUP)
`NDA 209863
`Xyosted (testosterone) injection, USP
`50 mg, 75 mg, 100 mg
`Antares Pharma Inc.
`April 16, 2018, August 20, 2018, August 29, 2018,
`September 6, 2018, September 19 2018
`2017-432-2
` Denise V. Baugh, PharmD, BCPS
`
`Lolita G. White, PharmD
`
`PURPOSE OF MEMORANDUM
`1
`The Division of Bone, Reproductive and Urologic Products (DBRUP) requested that we review
`the revisions to the container label, carton labeling, Instructions for Use (IFU), and prescribing
`
`information (PI) for Xyosted (Appendix A) to determine if it is acceptable from a medication
`error perspective. The revisions are in response to recommendations that we made in previous
`
`label and labeling reviews, container label and carton labeling negotiations via email, as well as
`Instructions for Use (IFU) recommendations based on our previous review of a human factors
`
`validation results.abc
`
`a Fava W. Human Factors Validation Results Review for XYOSTED (NDA 209863). Silver Spring (MD): Food and Drug
`Administration, Center for Drug Evaluation and Research, Office of Surveillance and Epidemiology, Division of
`Medication Error Prevention and Analysis (US); 2017 Oct 18. RCM No.: 2016-2905 and 2017-432.
` b Baugh, D. Label, Labeling, and Packaging Review for XYOSTED (NDA 209863). Silver Spring (MD): Food and Drug
`
`Administration, Center for Drug Evaluation and Research, Office of Surveillance and Epidemiology, Division of
`Medication Error Prevention and Analysis (US); 2017 May 12. RCM No.: 2017-432.
`
`c Baugh, D. Label, Labeling, and Packaging Review Memo for XYOSTED (NDA 209863). Silver Spring (MD): Food and
`
`Drug Administration, Center for Drug Evaluation and Research, Office of Surveillance and Epidemiology, Division of
`Medication Error Prevention and Analysis (US); 2018 Aug 14. RCM No.: 2017-432-1.
`1
`
`
`Reference ID: 4324626
`
`

`

` CONCLUSION
`2
`
`
`The revised container label and carton labeling for Xyosted is acceptable from a medication
`
`error perspective. We have no further recommendations at this time.
`
`
`Additionally, we find the revised Instructions for Use (IFU) is acceptable from a medication error
`
`perspective and we have determined that no further human factors validation study of the IFU
`
`
`labeling is required at this time.
`
`Reference ID: 4324626
`
`2
`
`
`9 Pages of Draft Labeling have been Withheld in Full as B4 (CCI/TS) immediately
`following this page
`
`

`

`Signature Page 1 of 1
`--------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
`electronic signatures for this electronic record.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`DENISE V BAUGH
`09/21/2018
`
`LOLITA G WHITE
`09/22/2018
`
`Reference ID: 4324626
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Date:
`
` To:
`
`
`
`
` Through:
`
`
`
`
` From:
`
`
`
`
`
` Subject:
`
`
`
` Department of Health and Human Services
`
`
` Public Health Service
`
` Food and Drug Administration
`
`
` Center for Drug Evaluation and Research
`
`
`
` Office of Medical Policy
`
`
`
`PATIENT LABELING REVIEW
`
`
` September 21, 2018
`
` Hylton Joffe, MD
`
` Director
`
`
`Division of Bone, Reproductive and Urologic Products
`
` (DBRUP)
`
`
` LaShawn Griffiths, MSHS-PH, BSN, RN
`
`
` Associate Director for Patient Labeling
` Division of Medical Policy Programs (DMPP)
`
`
` Marcia Williams, PhD
`
`
`
` Team Leader, Patient Labeling
` Division of Medical Policy Programs (DMPP)
`
`
`
` Kelly Jackson, PharmD
`
` Patient Labeling Reviewer
`
` Division of Medical Policy Programs (DMPP)
`
` Lynn Panholzer, PharmD
`
`Regulatory Review Officer
` Office of Prescription Drug Promotion (OPDP)
`
`
`
` Review of Patient Labeling: (Medication Guide (MG) and
` Instructions for Use (IFU)
`
`
`
` Drug Name (established XYOSTED (testosterone enanthate)
`
`
` name):
`
` Dosage Form and
` injection, for subcutaneous use
`
` Route:
`Application
`Type/Number:
`
` Applicant:
`
`
`
`
`
`
`
`
`
` NDA 209863
`
`
`
`
`
` Antares Pharma, Inc.
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4324331
`
`

`

`
`
` 1
`
` INTRODUCTION
`
`
`
` On December 20, 2016, Antares Pharma, Inc. submitted for the Agency’s review an
` original New Drug Application (NDA) 209863 for QuickShot Testosterone
`
`
`
`
` (testosterone enanthate). The Agency responded with a Complete Response Letter
`
`
`
` (CRL) filed on March 29, 2018. On April 16, 2018, the Applicant resubmitted the
` application for the Agency’s review in response to the CRL. The proposed indication
`
` is testosterone replacement therapy in adult males for conditions associated with a
`
`
`
` deficiency or absence of endogenous testosterone.
`
`
` This collaborative review is written by the Division of Medical Policy Programs
`
` (DMPP) and the Office of Prescription Drug Promotion (OPDP) in response to a
` request by the Division of Bone, Reproductive and Urologic Products (DBRUP) on
`
` April 2, 2018 for DMPP and OPDP to review the Applicant’s proposed Medication
`
` Guide (MG) and Instructions for Use (IFU) for XYOSTED (testosterone enanthate)
`
`
`
`injection, for subcutaneous use.
`
`
`2 MATERIAL REVIEWED
`
`
`
`• Draft XYOSTED (testosterone enanthate) MG and IFU received on April 16,
`
`
`
`
`
`2018, revised by the Review Division throughout the review cycle, and received
`
`
`by DMPP and OPDP on September 17, 2018 and September 20, 2018,
`
`
`respectively.
`
`• Draft XYOSTED (testosterone enanthate) Prescribing Information (PI) received
`
`
`
`on April 16, 2018, revised by the Review Division throughout the review cycle,
`
`and received by DMPP and OPDP on September 17, 2018 and September 14,
`
`
`
`2018, respectively.
`
`
`
`3 REVIEW METHODS
`
`
`
`To enhance patient comprehension, materials should be written at a 6th to 8th grade
`
`
`
`
`
`
`reading level, and have a reading ease score of at least 60%. A reading ease score of
`60% corresponds to an 8th grade reading level. In our review of the MG and IFU the
`
`
`
`
`
`target reading level is at or below an 8th grade level.
`
`
`
`
`Additionally, in 2008 the American Society of Consultant Pharmacists Foundation
`(ASCP) in collaboration with the American Foundation for the Blind (AFB)
`
`published Guidelines for Prescription Labeling and Consumer Medication
`Information for People with Vision Loss. The ASCP and AFB recommended using
`
`
`fonts such as Verdana, Arial or APHont to make medical information more
`
`
`
`
`accessible for patients with vision loss. We reformatted the MG and IFU document
`
`
`using the Arial font, size 10 where applicable.
`
`
`In our collaborative review of the MG and IFU we:
`
`
`
`simplified wording and clarified concepts where possible
`
`
`•
`ensured that the MG and IFU is consistent with the Prescribing Information (PI)
`
`
`
`
`•
`removed unnecessary or redundant information
`
`
`
`•
`
`
`
`
`
`
`
`
`
`Reference ID: 4324331
`
`

`

`
`•
`
`
`•
`
`•
`
`
`•
`
` ensured that the MG and IFU is free of promotional language or suggested
`
`
` revisions to ensure that it is free of promotional language
` ensured that the MG meets the Regulations as specified in 21 CFR 208.20.
`
`
`
`
` ensured that the MG and IFU meets the criteria as specified in FDA’s Guidance
` for Useful Written Consumer Medication Information (published July 2006)
`
`
`
`
`
` ensured that the MG and IFU is consistent with the approved comparator
` labeling where applicable.
`
`
`
`
`
`
`4 CONCLUSIONS
`
`
`The MG and IFU are acceptable with our recommended changes.
`
`
`
`
`5 RECOMMENDATIONS
`
`
`
`
`
`• Please send these comments to the Applicant and copy DMPP and OPDP on the
`
`correspondence.
`
`
`• Our collaborative review of the MG and IFU is appended to this memorandum.
`
`
`
`Consult DMPP and OPDP regarding any additional revisions made to the PI to
`
`determine if corresponding revisions need to be made to the MG and IFU.
`
` Please let us know if you have any questions.
`
`
`
`
`
`
`
`
`Reference ID: 4324331
`
`24 Pages of Draft Labeling have been Withheld in Full as B4 (CCI/TS) immediately
`following this page
`
`

`

`Signature Page 1 of 1
`--------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
`electronic signatures for this electronic record.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`KELLY D JACKSON
`09/21/2018
`
`LYNN M PANHOLZER
`09/21/2018
`
`MARCIA B WILLIAMS
`09/21/2018
`
`LASHAWN M GRIFFITHS
`09/21/2018
`
`Reference ID: 4324331
`
`

`

`
` FOOD AND DRUG ADMINISTRATION
`
` Center for Drug Evaluation and Research
`
` Office of Prescription Drug Promotion
`
`
`****Pre-decisional Agency Information****
`
`
`
`
`Memorandum
`
`
` Date:
`
` September 19, 2018
`
`
` To:
`
`
`
`
`
`
`
` Jeannie Roule, Regulatory Project Manager
`
`
` Division of Bone, Reproductive, and Urologic Products (DBRUP)
`
`
`Lynn Panholzer, PharmD, Regulatory Review Officer
`
`Office of Prescription Drug Promotion (OPDP)
`
`
`
`
`
`Matthew Falter, Team Leader, OPDP
`
`From:
`
`
`
`
`
`CC:
`
`
`Subject:
`
`
`OPDP Labeling Comments for XYOSTED (testosterone enanthate)
`
`
`injection (Xyosted)
`
`
`
`
`209863
`
`
`NDA:
`
`
`
` In response to DBRUP’s consult request dated April 2, 2018, OPDP has reviewed the
`
`
`
`
`
` proposed product labeling (PI), Medication Guide, Instructions for Use (IFU), and carton and
` container labeling for the original NDA submission for Xyosted.
`
`
`
`
`
` PI and Medication Guide/IFU: OPDP’s comments on the proposed PI are based on the draft
`
`
`
`
`
`
`
`
`PI received by electronic mail from DBRUP on September 14, 2018, and are provided below.
`
`
`
`
`A combined OPDP and Division of Medical Policy Programs (DMPP) review will be completed
`
`
`for the Medication Guide and IFU, and comments on the proposed Medication Guide/IFU will
`
`be sent under separate cover.
`
`Carton and Container Labeling: OPDP has reviewed the attached proposed carton and
`
`
`
`container labeling submitted by the Sponsor to the electronic document room on September 6,
`
`2018, and we do not have any comments.
`
`
`
`
`Thank you for your consult. If you have any questions, please contact Lynn Panholzer at (301)
`
`
`796-0616 or lynn.panholzer@fda.hhs.gov.
`
`
`
`
`Reference ID: 4323149
`
`
`
` 1
`
`
`31 Pages of Draft Labeling have been Withheld in Full as B4 (CCI/TS) immediately following this
`page
`
`

`

`Signature Page 1 of 1
`--------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
`electronic signatures for this electronic record.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`LYNN M PANHOLZER
`09/19/2018
`
`Reference ID: 4323149
`
`

`

`M E M O R A N D U M
`
`Department of Health and Human Services
`
`Food and Drug Administration
`
`Center for Drug Evaluation and Research
`
`
`
`Date:
`
`To:
`
`Through:
`
`From:
`
`Subject:
`
`Aug 16, 2018
`
`Hylton V. Joffe, M.D., Director
`Division of Bone, Reproductive, and Urologic Products
`
`Dominic Chiapperino, Ph.D., Director
`Martin Rusinowitz, M.D., Senior Medical Officer
`Controlled Substance Staff
`
`Alicja Lerner, M.D., Ph.D., Medical Officer
`Controlled Substance Staff
`
`NDA 209863/IND 116022
`Name: XYOSTED, Testosterone Enanthate Injection, QuickShot™ USP, QST
`Indication: For the treatment of adult males with hypogonadism.
`Dosage: 100 mg/ mL, 150 mg/mL, and 200 mg/mL at injection volume of 0.5
`
`mL administered subcutaneously delivering 50, 75, or 100 mg of testosterone
`enanthate once weekly
`Sponsor: Antares Pharma, Inc.
`Filing meeting May 9, 2018
`PDUFA September 29, 2018
`
` Complete Response, in DARRTS April 2, 2018
` CSS Review by Dr. A. Lerner, in DARRTS Oct 5, 2017 and March 6, 2018
` Meeting Minutes, March 22, 2018
` CSS review, Testosterone TSI # 1351, by Dr. A. Lerner, March 9, 2015
` OSE/DPV reviews by Dr. R. Kapoor, Aug 30, 2017 and June 12, 2018
`
`Materials Reviewed:
`
`A.
`
`SUMMARY
`
`I. BACKGROUND
`
`
`This memorandum responds to a consult from the Division of Bone, Reproductive, and Urologic
`Products (DBRUP) requesting Controlled Substance Staff (CSS) to review the Sponsor’s proposed
`pharmacovigilance plan and labeling changes related to Suicide and Depression, as requested by FDA
`
`during the meeting with the Sponsor on Feb 21, 2018.
`
`Reference ID: 4308235
`
`

`

`CSS Consult:
`
`
`
`NDA 209863 Testosterone Enanthate Injection, QuickShot - Post CR
`
`The Sponsor is developing Testosterone Enanthate Injection for SC administration, QuickShot™ (QST),
`under NDA
`, indicated for the treatment of adult men with hypogonadism. The QST is designed
`as a single-use, pressure-assisted autoinjector prefilled with testosterone solution for SC self-
`administration.
`
`
` was submitted as a 505(b)(2) NDA using Delatestryl® Injection as the approved listed
`NDA
`drug (LD). However, NDA
` received a CR action on October 20, 2017, due to clinically
`meaningful increases in blood pressure, and cases of suicidality (2) and depression (2).
`
`During the meeting with the Sponsor on February 21, 2018, FDA requested enhanced
`pharmacovigilance in the postmarketing period and potential label changes.
`
`The Sponsor submitted the following responses concerning the depression and suicidality issue
`described in the CR letter:
`
`Enhanced pharmacovigilance in the Postmarketing Period
`
`FDA’s Request:
`
`
`We agree that product labeling and enhanced pharmacovigilance (EPV) in the
`
`
`
`
`
`
`
`
`postmarketing period could address the issue of depression and
`
`
`
`
`
`
`
`suicidality.
`
`It is premature to provide agreement on specific labeling for this issue.
`
`
`
`
`
`
`
`
`In regard to EPV, you should include specific AE terms in your
`
`
`
`
`
`
`
`surveillance plan (e.g., for suicidal ideation, suicidal behavior and
`
`
`
`
`
`
`
`depression).
`
`
`The Sponsor agrees to establish enhanced pharmacovigilance for these types of events
`reported in men receiving XYOSTED during the post-marketing period. EPV is designed to
`ensure there is targeted and complete follow up for spontaneously reported events that are
`considered to be of special interest. By handling such events using periodic review and
`signal detection based on Standardized MedDRA Queries (SMQ) specific for depression and
`
`suicide events and increased attempts at getting more information, EPV can provide greater
`
`insights into these events when they occur outside of a clinical trial setting. When coupled
`with expedited reporting, both the manufacturer and the FDA are able to have a more
`current view of any changes in the reports as they evolve.
`
`Following the commercial launch of XYOSTED, Antares will conduct the following
`activities:
`1) All completed suicide based on MedDRA preferred terms will be handled as expedited
`reports and submitted to the FDA within 15 days of receipt regardless of expectedness.
`2) All post-marketing reports of depression and suicidality-type events based on MedDRA
`preferred terms will be subject to enhanced follow up.
`3) Antares’ pharmacovigilance staff will provide initial case review via phone at the time of
`initial case or subsequently by mail or telephone follow up to capture sufficient
`information to completely categorize reported events.
`Page 2 of 5
`
`Reference ID: 4308235
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`CSS Consult:
`
`NDA 209863 Testosterone Enanthate Injection, QuickShot - Post CR
`
`4) Ifinitial case intake is insufficient to ful~y describe these events, a minimum of3 written
`attempts to contact the reporter will be carried out by Antares in order to have complete
`f ollow-up information. Ifthese are unsuccessful, a 4th attempt byphone will be
`conducted. This is one more attempt than is standard f or reported serious adverse events.
`5) Antares will provide periodic and cumulative summaries and analysis ofall reports of
`depression and suicidality-type events since approval ofXYOSTED as part of the
`quarter~y Periodic Adverse Drug Event Report (P ADER) for the first 3 years of
`marketing of XYOSTED.
`6) Antares will discuss the effectiveness of its labeling regarding this safety issue in each
`P ADER and will make recommendations for any changes in labeling, ifneeded, based on
`such reports.
`
`Proposed label changes related to suicidality and depression.
`
`Proposed Labeling Changes:
`
`WARNINGS AND PRECAUTIONS
`Suicidal ideation and behavior, including completed suicide, have occmTed during
`clinical trials in patients treated with XYOSTED (5.16).
`
`And...
`
`5.16
`
`(b) (41
`
`Advise patients and caregivers to seek medical
`attention for manifestations of suicidafideation or behavior, new onset or worsening
`depression, anxiety, or other mood changes.
`
`II. CSS has following Recommendations:
`
`1. The Sponsor's proposed Pharmacovigilance plan for suicidality and depression is appropriate.
`In addition to expedited reporting of "completed suicides", CSS recommends expedited reporting
`also for "attempted suicide" and "suicidal ideation." Providing the suicidality AE data in
`quaiierly PAD ER submissions is acceptable, too (consistent with the approach proposed by
`DPV/OSE, review by Dr. R. Kapoor, June 12 2018). However, expedited reporting of
`suicidality-related cases, as the Sponsor proposed, would be prefe1Ted in case there is indeed an
`unusual effect of this testosterone fo1mulation on suicidality, which could be captured in eai·ly
`stages if expedited repo1iing would be available.
`
`2. Of note is that the Sponsor ah-eady included a waining language on suicidality in section 5.16.
`CSS proposes consideration of a Boxed Warning for suicidality and the addition of suicidality
`as an AE in 9 .3 Dependence section, as shown below in Discussion section.
`
`Page 3 of5
`
`Reference ID 4308235
`
`

`

`CSS Consult:
`
`
`
`NDA 209863 Testosterone Enanthate Injection, QuickShot - Post CR
`
`III. DISCUSSION
`
`Labeling Considerations
`
`To address suicidality in product labeling for XYOSTED, the Sponsor has included Warnings
`and Precautions section 5.16, and CSS further recommends consideration of a Boxed Warning
`and mention of suicidality AEs in section 9.3. These proposed changes are supported by the
`FAERS cases cited in OSE/DPV review by Dr. R. Kapoor, Aug 30, 2017. In this review,
`
`OSE/DPV identified 74 of suicidality cases which included 15 cases of completed suicides, 13
`cases of suicidal attempt, and 46 cases of suicidal ideation reported with testosterone use and
`after exclusion of: duplicates, body builders, women, Nebido cases, overdoses, and cross-sex
`
`hormonal therapy. Although the OSE/DPV reviewer states that “However, a vast majority of the
`cases did not provide necessary information regarding concomitant medications, past medical
`history, duration of therapy, time-to-onset of suicidal symptoms, and previous history of suicidal
`attempts to ascertain a drug-event association,” in some cases the only drug taken by the
`
`patients was testosterone, and in fact some patients describe their suicidality as emerging
`coincident with their treatment with testosterone therapy (or due to testosterone withdrawal)
`(CSS review by Dr. A. Lerner, October 5, 2017).
`
`A potential Boxed Warning is further supported by the evidence of suicidality cases during
`previous testosterone NDAs (Androgel NDA 21015, Testim NDA 21454, Aveed NDA 22219;
`
`Nebido-PSUR Nov 2009 – Nov 2010); and literature cases of suicidality related to testosterone
`and anabolic androgenic steroids abuse (Brower, 1989; Corrigan, 1996; Porcerelli et al., 1998;
`Thilblin et al., 1999, 2000; Petersson et al., 2006; Darke et al., 2014). It is notable that
`the supplemental doses of testosterone administered in these hypogonadal men, which are trying
`to establish normal levels (~1100 ng/dL) from the very low initial levels of testosterone (less
`than 300 ng/dL) represent an up-to-10-fold increase from their pre-treatment testosterone level.
`It is plausible that these extreme testosterone level increases for these individuals are producing
`
`similar AEs as those observed from overdoses in testosterone abusers.
`
`In addition, while the currently proposed Warning section 5.16 is a valuable addition to labeling,
`it may not be prominent enough for such a serious adverse event, and might be overlooked. It is
`important to emphasize that testosterone treatment, especially in older men, is intended mainly to
`treat uncomfortable effects of aging. Thus, the discrepancy between the risk of the testosterone
`
`treatment, such as suicidality, versus benefits of the treatment is significant. Also, suicidality
`meets the regulatory requirements for the Boxed Warning1:
`
` “There is an adverse reaction so serious in proportion to the potential benefit from the
`drug (e.g., a fatal, life-threatening or permanently disabling adverse reaction) that it is
`essential that it be considered in assessing the risks and benefits of using the drug”.
`
`Suggested language for the Boxed Warning:
`
`1 Guidance for Industry - Warnings and Precautions, Contraindications, and Boxed Warning Sections of Labeling for Human
`Prescription Drugs and Biological Products, 2011.
`
`Page 4 of 5
`
`Reference ID: 4308235
`
`

`

`CSS Consult:
`
`
`
`NDA 209863 Testosterone Enanthate Injection, QuickShot - Post CR
`
`Occasional cases of suicidality occurred during clinical trials with XYOSTED, during
`treatment or following discontinuation of treatment.t.
`
`In the section 9.3 Dependence, add “suicidality” as a possible adverse event following TRT
`discontinuation, as shown below:
`
`After the discontinuation of Testosterone Replacement Therapy in hypogonadal men
`
`
`occasional emergence of suicidality was observed.
`
`*These labeling changes may be appropriate for all testosterone products.
`
`IV. REFERENCES
`
`
`1. Brower KJ, Blow FC, Eliopulos GA, Beresford P. Anabolic androgenic steroids and suicide. Am
`J Psychiatry 1989; 146: 1075.
`
`2. Corrigan B Anabolic steroids and the mind. Med J Aust. 1996 Aug 19;165(4):222-6. Review.
`
`3. Darke S, Torok M, Duflou J. Sudden or unnatural deaths involving anabolic-androgenic steroids.
`J Forensic Sci. 2014 Jul;59(4):1025-8.
`
`4. Petersson A, Garle M, Granath F, Thiblin I. Morbidity and mortality in patients testing positively
`for the presence of anabolic androgenic steroids in connection with receiving medical care. A
`controlled retrospective cohort study. Drug Alcohol Depend. 2006 Feb 28;81(3):215-20.
`
`5. Porcerelli JH, Sandler BA. Psychiatr Clin North Am. 1998 Dec;21(4):829-33. Review. Anabolic-
`androgenic steroid abuse and psychopathology.
`
`6. Thiblin I, Runeson B, Rajs J. Anabolic androgenic steroids and suicide. Ann Clin Psychiatry.
`1999 Dec;11(4):223-31.
`
`7. Thiblin I, Lindquist O, Rajs J. Cause and manner of death among users of anabolic androgenic
`steroids. J Forensic Sci. 2000 Jan;45(1):16-23.
`
`Page 5 of 5
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`Reference ID: 4308235
`
`

`

`Signature Page 1 of 1
`--------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
`electronic signatures for this electronic record.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`ALICJA LERNER
`08/16/2018
`
`MARTIN S RUSINOWITZ
`08/16/2018
`
`DOMINIC CHIAPPERINO
`08/16/2018
`
`Reference ID: 4308235
`
`

`

`MEMORANDUM
`
`REVIEW OF REVISED LABEL AND LABELING
`
`
`Division of Medication Error Prevention and Analysis (DMEPA)
`
`Office of Medication Error Prevention and Risk Management (OMEPRM)
`
`Office of Surveillance and Epidemiology (OSE)
`
`Center for Drug Evaluation and Research (CDER)
`
`
` Date of This Memorandum:
`
`Requesting Office or Division:
`
`
`
` August 14, 2018
`
` Division of Bone, Reproductive, and Urologic Products
`(DBRUP)
`Application Type and Number: NDA 209863
`Product Name and Strength:
`Xyosted (testosterone) injection, USP
`50 mg, 75 mg, 100 mg
`Antares Pharma, Inc.
`March 29, 2018
`2017-432-1
` Denise V. Baugh, PharmD, BCPS
`
`Lolita G. White, PharmD
`
`Applicant/Sponsor Name:
`FDA Received Date:
`OSE RCM #:
`DMEPA Safety Evaluator:
`DMEPA Team Leader:
`
`PURPOSE OF MEMORANDUM
`1
`The Division of Bone, Reproductive, and Urologic Products (DBRUP) requested that we review
`the revised container label and carton labeling for Xyosted (testosterone injection [Appendix
`
`A]) to determine if it is acceptable from a medication error perspective. The revisions are in
`
`response to recommendations that we made during a previous label and labeling review.a
`
` CONCLUSION
`2
`The revised container label and carton labeling for Xyosted (testosterone injection) is
`
`unacceptable from a medication error perspective. The autoinjector label does not include a
`
`linear barcode in accordance with 21 CFR 201.25(c)(2) and the NDC number proposed on the
`carton labeling for the 100 mg product do not align with NDC numbers presented in Section
`
`16.1 (How Supplied) of the full prescribing information.
`
`
` a Baugh D. Label and Labeling Review for Xyosted (NDA 209863). Silver Spring (MD): Food and Drug Administration,
`
`
` Center for Drug Evaluation and Research, Office of Surveillance and Epidemiology, Division of Medication Error
`Prevention and Analysis (US); 2017 May 12. RCM No.: 2017-432.
`1
`
`
`Reference ID: 4306583
`
`

`

`
`
`3 RECOMMENDATIONS FOR ANTARES
` We recommend the following be implemented prior to approval of this NDA:
`
`A. We note that your trade autoinjector label does not include a linear bar code in
`
`
`accordance with 21 CFR 201.25(c)(2). We recommend that you include a linear bar code
`to assist with the correct product selection during the dispensing and administration
`
`process. The barcode should be horizontally placed and surrounded by enough white
`space to allow scanners to read the bar code properly. The print density should be
`consistent to allow for an accurate scan and it should be placed in a conspicuous
`
`location where it will not be difficult to read due to distorted text.
`
`
`B. We note that the package code of the NDC number on the 100 mg Xyosted carton
`
`labeling differs from what is presented in the full prescribing information Section 16.1
`
`
`How Supplied. Revise the NDC number for the ‘100 mg’ carton labeling from “54436-
`” to read “54436-200-04” to minimize the potential for dispensing errors.
`200-
`
`Reference ID: 4306583
`
`2
`
`
`(b) (4)
`
`9 Pages of Draft Labeling have been Withheld in Full as B4 (CCI/TS) immediately following
`this page
`
`

`

`Signature Page 1 of 1
`--------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
`electronic signatures for this electronic record.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`DENISE V BAUGH
`08/14/2018
`
`LOLITA G WHITE
`08/14/2018
`
`Reference ID: 4306583
`
`

`

`
`
`
`
`
`
`
`
` Inter-Center Consult
`
`
` ICCR Consult Number:
` ICCR2018-02873
`
`
`
` Document Number: NDA 209863
`
`
`
` Applicant: Antares Pharma, Inc.
`
`
`
`
` Trade Name: XYOSTED - Testosterone enanthate injection
`
`
`
`
`
` Consult Type: Analytical consult – Cross-reactivity studies
`
`
`
`
` Requestor: Jeannie Roule
`
`
`
` Requestor Home: CDER/OND/ODEIII/DBRUP
`
`
`
`
` Gatekeeper / Consultant: Marianela Perez-Torres, Chemistry Branch Chief
`
`
`
` Consultants Home: CDRH/OIR/DCTD/CHTB
`
`
`
` Date Requested: May 9, 2018
`
`
`
`
` Due Date: August 1, 2018
`
`
`
`
`
`
`
` I. CONSULT SCOPE:
`
`
`
`
`
`CDER/OND/ODEIII/DBRUP requested CDRH to evaluate information provided on cross-
`
`
`
`
`
`
`reactivity studies of TE with an immunoassay that measure testosterone levels. Specifically,
`
`
`Clinical Pharmacology reviewers formulated the following questions:
`
`At the Type A meeting on 2/21/2018 for NDA 209863 the applicant claimed that cross-
`
`
`
`
`reactivity of testosterone proprionate (TP) ranges from 0 to <7.48%.
`
`
`1. Do you agree that cross-reactivity of TP to testosterone (T) immunoassays is expected to
`
`be <10%?
`
`
`
`2. Based on the observed data for TP, what range of cross-reactivity may be expected for T
`
`enanthate?
`
`
`
`
`Please reference the applicant’s CR submission and the meeting minutes to the Type A
`
`meeting.
`
`
`
`
`II. DOCUMENTS REVIEWED:
`
`
`
` CR submitted by Antares on March 2018 - Section 7.2. Immunoassay cross reactivity of
`
`testosterone enanthate
`
` Minutes from the meeting held on February 21, 2018
`
`
`
`
` Data on Correlation of trough Total Testosterone between ECLIA and LC-MS/MS for the
`
`same subjects from studies QST-13-003 and QST-15-005
`
`
`
`
`
`Reference ID: 4302430
`
`

`

`
`
`
`
`
`
` ICCR2018-02873 for NDA 209863
`
`
`
`
` III. CDRH ASSESSMENT AND COMMENTS TO CDER:
`
`
`The company provided a comparison of the testosterone results using an LC-MS validated assay
`
`
`(which is not susceptible to interference due to cross-reactivity) and compared to the results of
`
`
`the Roche ECLIA Testosterone assay on the Roche E-170 Modular analyzer.
`
`
`
`
`In study QST-13-003, samples from 139 subjects in the safety population at week 12 were
`
`analyzed using both methods. The pretreatment baseline samples from eight of those subjects
`
`
`were also analyzed by both methods. The trough TT correlation between the two methods for
`
`
`samples collected at pretreatment baseline (week 1) and week 12 for each subject from study
`
`
`
`QST-13-003 was presented.
`Data for trough TT analyzed by ECLIA and LC-MS/MS for the same subjects from study QST­
`
`
`
`15-005 were available at baseline, week 6, and week 12 (Table 2). The trough TT correlation
`
`
`
`
`between the two methods for samples collected at pretreatment baseline (week 1), week 6, and
`
`
`week 12 for each subject from safety population in study QST-15-005.
`
`
`
`
`While there is an acceptable correlation between the results obtained by the 2 methods, which
`would suggest that the antibodies used to capture testosterone in the Roche ECLIA assay may
`
`
`
`
`
`not cross-react with TE, the data is not adequate to characterize if commonly used testosterone
`
`
`
`immunoassays would significantly cross-react with TE. The limitations of the data are the
`
`
`
`following:
`
`
`1. The study was conducted using only one immunoassay. Because each T assay includes
`
`
`
`different antibodies for the detection of T, one assay is insufficient to represent all other
`
`
`test systems that are currently available in the market. We believe that typical cross-
`
`reactivity testing should be conducted using a minimum of 5 different testosterone
`
`immunoassays. This number would provide a better representation and coverage of the
`
`current testosterone market share (which according to information in the CDRH
`
`Registration and Listing Database is approximately ~25 assays). [We note that this
`
`
`information on the minimum number of assays that we would expect was also
`
`
`
`
`
` on a meeting held on July 19, 2018.]
`communicated
`
`
`
`
`
`
`2. It is unclear the concentration of TE in each sample, or if any of the samples is
`
`
`representative of the highest level that is possible in patients injected with TE.
`
`
`Typically, cross-reactivity studies are conducted by