CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`206089Orig1s000
`
`CLINICAL REVIEW(S)
`
`
`
`
`
`
`
`
`

`

`Clinical Review
`Debuene Chang MD
`NDA 206089
`Jatenzo (Oral Testosterone Undecanoate (TU))
`
`CLINICAL REVIEW LABELING ADDENDUM
`
`Application Type
`Application Number(s)
`Priority or Standard
`
`NDA
`206089
`Standard
`
`Submit Date(s)
`Received Date(s)
`PDUFA Goal Date
`Division / Office
`
` September 27, 2018
`September 27, 2018
`March 27, 2019
`DBRUP/ODE3
`
`Debuene Chang MD
`Reviewer Name(s)
`Review Completion Date March 26, 2019
`
`Established Name
`(Proposed) Trade Name
`Therapeutic Class
`
`Applicant
`
`Formulation(s)
`
`Dosing Regimen
`
`Indication(s)
`Intended Population(s)
`
`Testosterone undecanoate-TU
`Jatenzo®
`Testosterone replacement
`therapy (TRT)
`Clarus Therapeutics
`
`158 mg, 198 mg, or 237 mg
`TU oral soft capsule
`237 mg TU twice daily by
`mouth, with titration to 158,
`316 or 396 mg twice daily
`TRT
`Adult hypogonadal men
`
`1
`
`Reference ID: 4409485
`
`

`

`Clinical Review
`Debuene Chang MD
`NDA 206089
`Jatenzo (Oral Testosterone Undecanoate (TU))
`
`Executive Summary
`
`Updated Recommendation on Regulatory Action
`
`Based on successful completion of labeling and postmarketing requirement (PMR)
`discussions, the Clinical review team now recommends an Approval action for this new
`drug application (NDA).
`
`The Clinical review team had previously recommended an Approval action on the
`condition that the Sponsor resolved the remaining Clinical safety deficiencies for this
`new drug application (NDA) through specific labeling revisions. Based on the
`successful completion of labeling and PMR discussions, the remaining Clinical safety
`deficiencies are now considered resolved, as summarized here:
`
`Efficacy: The efficacy data from CLAR-15012 supports the Sponsor’s contention that
`Jatenzo provides testosterone replacement in adult men with hypogonadism.
`
`Safety: The safety profile for Jatenzo is consistent with the known safety profile for TRT,
`as demonstrated by the data submitted in the original NDA, the 1st resubmission, and
`this 2nd resubmission, except for the following clinical safety issue, which is now
`considered resolved:
`
`
`Blood Pressure Increases
`
`Blood pressure (BP) data from CLAR-15012 showed that Jatenzo has the
`potential to raise BP. Based on ambulatory blood pressure monitoring (ABPM)
`conducted in CLAR-15012, Jatenzo was associated with an average increase in
`systolic BP of approximately 5 mm Hg, a clinically meaningful amount.
`
`The Sponsor resolved this safety issue through clear and cautionary product
`labeling, including the following key elements:
` A Boxed Warning for BP Increases
` A new Contraindication that limits use of Jatenzo to men with
`hypogonadism due to structural or genetic conditions
` A comprehensive Medication Guide
`In addition, the Sponsor agreed to conduct a required postmarketing study
`(PMR) to assess patients’ comprehension of the Medication Guide
`
`The Clinical review team considers this deficiency resolved.
`
`Reference ID: 4409485
`
`2
`
`

`

`Clinical Review
`Debuene Chang MD
`NDA 206089
`Jatenzo (Oral Testosterone Undecanoate (TU))
`
`Additionally, there was one Nonclinical issue that required further Clinical assessment
`during this third review cycle, as follows:
`
`Adrenal Findings in Animals
`
`In some dog studies, testosterone undecanoate was associated with findings of
`adrenocortical atrophy and hypocortisolemia. While no human subject in clinical
`studies demonstrated evidence of clinical hypoadrenalism. the Sponsor was
`asked to conduct a Cosyntropin stimulation testing substudy in CLAR-15012.
`Deficiencies in the design and procedures of the Cosyntropin substudy precluded
`conclusions from that data. However, there have been no reports of clinical
`hypoadrenalism in any of the Sponsor’s studies with Jatenzo, and FDA’s Bone,
`Reproductive and Urologic Drug Advisory Committee (BRUDAC) recommended
`that this issue be studied in the postmarketing period. Therefore, the Division
`requested that the Sponsor reassess this issue in a required postmarketing
`Cosyntropin stimulation testing clinical study (a PMR). The Sponsor agreed to
`conduct the requested PMR study. In addition, key information from the dog
`studies is provided in product labeling.
`
`Therefore, this issue is considered resolved.
`
`Risk Benefit Assessment
`
`The Clinical review team concludes that Jatenzo is safe and effective as the Sponsor
`has made labeling revisions which addresses the prior Clinical safety deficiency. The
`risk/ benefit ratio for Jatenzo for TRT in men with hypogonadism is now considered
`acceptable for approval of this NDA.
`
`The Sponsor made substantive labeling revisions, including changes to the Boxed
`Warning, a new Contraindication, and a comprehensive Medication Guide, as well as
`agreed to a PMR study that will assess patients’ comprehension of the Medication
`Guide, and that these changes address the Clinical safety deficiency identified in the
`original submission and 1st resubmission response. Because of these changes and the
`Sponsor’s agreement to conduct the PMR study to assess patient’s comprehension of
`the Medication Guide, the Clinical review team finds that Jatenzo is safe and effective
`as labeled, and that the risk/ benefit ratio for Jatenzo for TRT in men with
`hypogonadism is acceptable for NDA approval.
`
`Recommendations for Postmarket Requirements and Commitments
`
`The Clinical review team recommended and the Sponsor agreed to conduct the
`following two studies as PMRs:
`
`Reference ID: 4409485
`
`3
`
`

`

`Clinical Review
`Debuene Chang MD
`NDA 206089
`Jatenzo (Oral Testosterone Undecanoate (TU))
`
` Medication Guide comprehension study: The Sponsor agreed to conduct this
`required postmarketing study with acceptable milestone dates for protocol
`submission, study completion and study report submission.
`
` Cosyntropin stimulation testing study to re-assess the potential for
`hypoadrenalism: The Sponsor agreed to conduct this required postmarketing
`study with acceptable milestone dates for protocol submission, study
`completion and study report submission.
`
`Reference ID: 4409485
`
`4
`
`

`

`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/
`------------------------------------------------------------
`
`T D CHANG
`03/26/2019 11:29:07 AM
`
`MARK S HIRSCH
`03/26/2019 11:33:10 AM
`I concur.
`
`Reference ID: 4409485
`
`

`

`Clinical Review
`Debuene Chang MD
`NDA 206089
`Jatenzo (Oral Testosterone Undecanoate (TU))
`
`
`CLINICAL REVIEW
`
`NDA
`Application Type
`206089
`Application Number(s)
`Standard
`Priority or Standard
`
`
` September 27, 2018
`Submit Date(s)
`September 27, 2018
`Received Date(s)
`March 27, 2019
`PDUFA Goal Date
`DBRUP/ODE3
`Division / Office
`
`
`Debuene Chang MD
`Reviewer Name(s)
`Review Completion Date March 15, 2019
`
`
`Established Name
`Testosterone undecanoate-TU
`(Proposed) Trade Name
`Jatenzo®
`Therapeutic Class
`Testosterone replacement
`therapy (TRT)
`Clarus Therapeutics
`
`158 mg, 198 mg, or 237 mg
`TU oral soft capsule
`237 mg TU twice daily by
`mouth, with titration to 158,
`316 or 396 mg twice daily
`TRT
`Adult hypogonadal men
`
`Applicant
`
`Formulation(s)
`
`Dosing Regimen
`
`Indication(s)
`Intended Population(s)
`
`Reference ID: 4404777
`
`1
`
`

`

`Clinical Review
`Debuene Chang MD
`NDA 206089
`Jatenzo (Oral Testosterone Undecanoate (TU))
`
`
`
`
`
`Table of Contents
`
`1
`
`2
`
`3
`
` EXECUTIVE SUMMARY ......................................................................................... 4
`Recent Regulatory Overview ....................................................................................... 4
`Recommendation on Regulatory Action ...................................................................... 5
`Risk Benefit Assessment ............................................................................................. 7
`Recommendations for Postmarket Risk Evaluation and Mitigation Strategies (REMS) 7
`Recommendations for Postmarket Requirements and Commitments ......................... 8
` BACKGROUND....................................................................................................... 8
`2.1 Product Information ............................................................................................ 8
`2.2 Availability of Proposed Active Ingredient in the United States .......................... 9
`2.3
`Important Safety Issues with Consideration to Related Drugs ............................ 9
` CLINICAL SAFETY ISSUES ................................................................................. 10
`3.1.1 Blood Pressure (BP) Increases ........................................................................ 10
`3.1.2 Heart Rate Increases ........................................................................................ 13
`3.1.3 Changes in Anti-Hypertensive Medications During the Jatenzo Phase 3 Study
`CLAR-15012 ..................................................................................................... 14
`3.2 Sponsor’s Proposal to Mitigate Increased Blood Pressure Risks ........................ 15
`REMS Oversight Committee (ROC) Meeting ......................................................... 17
`3.3 Cases of Depression and Suicide ........................................................................ 18
`3.4 Erythropoietic AEs, including Increased Hematocrit (HCT) and Polycythemia .... 20
`3.5 Adrenocortical atrophy and Adrenal Insufficiency in Dogs ................................... 21
`4 REVIEW OF EFFICACY ......................................................................................... 23
`
`5
`
` LABELING ............................................................................................................ 27
`
`6 SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW
`DISCIPLINES ......................................................................................................... 30
`6.1 Chemistry Manufacturing and Controls (CMC) ................................................. 30
`6.2 Preclinical Pharmacology/Toxicology ............................................................... 30
`6.3 Clinical Pharmacology ...................................................................................... 31
`6.4 Biometrics ......................................................................................................... 32
`6.5 Divison of Medication Error Prevention and Analysis (DMEPA) ....................... 32
`
`
`
`Reference ID: 4404777
`
`2
`
`

`

`Clinical Review
`Debuene Chang MD
`NDA 206089
`Jatenzo (Oral Testosterone Undecanoate (TU))
`
`
`Table of Tables
`Table 1: Dosage Strengths and Components in Each Oral Capsule ............................... 9
`Table 2: Systolic Blood Pressure Measured by ABPM: Change from Baseline at Visit 6
`(ABPM Population) in Study CLAR-15012 ..................................................... 10
`Table 3: Diastolic Blood Pressure Measured by ABPM: Change from Baseline at Visit 6
`(ABPM Population) in Study CLAR-15012 ..................................................... 11
`Table 4: Heart Rate (HR) Measured by ABPM: Change from Baseline at Visit 6 (ABPM
`Population) in Study CLAR-15012 ................................................................. 13
`Table 5: Patients Who Started on or Increased or Changed Their Anti-HTN Medications
`and Patients in Whom AEs of HTN, HTN Worsened, or Increased BP were
`Reported in CLAR-15012 ............................................................................... 15
`Table 6: Summary of AE Reports of Depression, Suicidal Ideation, Suicidal Behavior,
`Aggression and Anger in All Jatenzo Studies ................................................ 18
`Table 7: Proportion of Subjects with Notable Post-Baseline Hematology Values by
`Treatment Group (Safety Population) in CLAR-15012 ................................... 20
`Table 8: Mean Hematocrit Changes of Subjects on Jatenzo (CLAR-15012) ................. 20
`Table 9: Percentage of Patients Achieving Eugonadal Testosterone Cavg Values at
`Visit 7 for the Primary Analysis (MITT Population) in CLAR-0512 Using
`Success Criteria Range Adjusted for Plasma Testosterone Concentration. .. 24
`Table 10: Percentage of Subjects with Testosterone Cmax Values in the Pre-Specified
`Cmax Outlier Ranges at Visit 7 in CLAR-15012* – Traditional Unadjusted
`Range Criteria ................................................................................................ 25
`Table 11: Observed Testosterone, Dihydrotestosterone, and Dihydrotestosterone/
`Testosterone Ratios in High Testosterone Cmax Samples, and Estimated
`Testosterone Concentrations Assuming High Testosterone Includes
`Contamination from Exogenous Testosterone ............................................... 26
`Table 12: Number (Percentage) of Subjects at Day 105 in CLAR-15012 who Met Cmax
`Outlier Criteria Adjusted for Plasma T Concentrations ................................... 26
`
`
`
`Reference ID: 4404777
`
`3
`
`

`

`Clinical Review
`Debuene Chang MD
`NDA 206089
`Jatenzo (Oral Testosterone Undecanoate (TU))
`
`
`1 Executive Summary
`
`Recent Regulatory Overview
`On January 3, 2014, Clarus Therapeutics (Sponsor) submitted an original NDA 206089
`(testosterone undecanoate [TU]).
`
`On September 18, 2015, a joint meeting of the Bone, Reproductive and Urologic Drugs
`Advisory Committee (BRUDAC) and the DRUG Safety and Risk Management Advisory
`Committee (DSARM) met with most members concluding that efficacy and safety had
`not been adequately established for this product. The questions posed to the members
`with voting results were the following items:
` Is there sufficient evidence to conclude that oral testosterone undecanoate is
`effective as testosterone replacement therapy? Result: 8 Yes, 12 No, and 1
`Abstain.
` Is the overall benefit/risk profile of oral testosterone undecanoate acceptable to
`support approval of this product for testosterone replacement therapy? Result:
`Yes 4, No 17, and Abstain 0.
`
`
`On November 3, 2014, the Division issued a Complete Response Letter informing the
`Sponsor that “additional investigations of efficacy and safety and the effect of food, will
`be necessary, including possible changes to the dose and titration algorithm”. For more
`details, refer to the CRL November 3, 2014.
`
`On April 3, 2015, the Sponsor submitted a formal Dispute Resolution Request, disputing
`the need to conduct additional clinical investigations of efficacy and safety and the effect
`of food, raised in the CRL.
`
`On July 17, 2015, the formal Dispute Resolution Request was denied.
`
`On June 22, 2017, the Sponsor submitted a Complete Response Re-Submission to
`NDA 206089 after completing additional study CLAR 15012. Major amendments during
`the review added 3-month review extension time.
`
`On March 22, 2018, the Division issued a second Complete Response Letter (2nd CRL).
`The Division listed three deficiencies precluding approvability which included clinical,
`clinical pharmacology, and pharmacology/ toxicology deficiencies as follows:
`1) Clinical Deficiency: A clinically meaningful mean increase in blood pressure (BP)
`was observed with use of Jatenzo, with potential for an associated increased risk
`of major adverse cardiovascular events,
`
`Reference ID: 4404777
`
`4
`
`

`

`Clinical Review
`Debuene Chang MD
`NDA 206089
`Jatenzo (Oral Testosterone Undecanoate (TU))
`
`
`2) Clinical Pharmacology Deficiency: Accuracy or reproducibility of patient plasma
`total testosterone (T) concentrations on Jatenzo using sodium fluoride (Na/F)
`ethylenediaminetetraacetic acid (EDTA) tubes was not determined.
`
`3) Pharmacology/Toxicology Deficiency: Unacceptable nonclinical studies for male
`fertility and carcinogenicity were submitted to support NDA approval through the
`505(b)(1) pathway.
`
`
`On June 12, 2018, the Division met with Clarus at a Type A meeting to discuss
`pathways to resolve the deficiencies listed in the 2nd CRL and identify any remaining
`issues. The reader is referred to the final Type A meeting minutes dated July 12, 2018.
`
`On September 27, 2018, the Sponsor submitted a 2nd Complete Response NDA re-
`submission to NDA 206089 (testosterone undecanoate [TU] oral capsule).
`
`No new efficacy and safety clinical data were submitted. To address the clinical
`deficiency of increased blood pressure for patients on Jatenzo, the Sponsor proposed
`revised product labeling.
`
`To address the clinical pharmacology deficiency regarding accurate T concentration
`assessments, the Sponsor submitted data from one clinical study, study CLAR-18019,
`as well as data from 2 bioanalytical studies (Study CLAR-18016 and Study CLAR-
`18021) and 2 assay validation studies (Study CLAR-18018 and Study CLAR-18020). No
`hypogonadal patients were dosed with Jatenzo for the studies submitted in this 2nd NDA
`re-submission.
`
`The 2nd CR submission contains revised labeling and proposals to address the 2nd CRL
`deficiencies. The reader is referred to the Clinical Reviews for NDA 209863, dated
`March 17, 2018 and October 24, 2014 for a review of clinical studies and data in the
`original two submissions.
`
`Recommendation on Regulatory Action
`The Clinical review team recommends an Approval action on the condition that the
`Sponsor fully resolves the outstanding Clinical safety deficiencies for this new drug
`application (NDA) for the following reasons:
`
`Efficacy: The efficacy data from CLAR-15012 supports the Sponsor’s contention that
`Jatenzo provides testosterone replacement in adult men with hypogonadism.
`
`Safety: The safety profile for Jatenzo is consistent with the known safety profile for TRT,
`as demonstrated by the data submitted in the original NDA, the 1st resubmission
`response to the 1st CR Letter, and this 2nd resubmission response to the 2nd CR Letter,
`
`Reference ID: 4404777
`
`5
`
`

`

`Clinical Review
`Debuene Chang MD
`NDA 206089
`Jatenzo (Oral Testosterone Undecanoate (TU))
`
`except for the following two clinical safety issues which need to be fully resolved before
`Approval:
`1. Blood Pressure Increases
`Identification of the potential for Jatenzo to raise average systolic blood pressure
`(SBP) by approximately 5 mm Hg, a clinically meaningful amount.
`
`Specifically, ABPM measurements in Study CLAR-15012 showed that treatment
`with Jatenzo was associated with mean systolic BP increases of 5 mm Hg.
`
`The Sponsor can resolve this deficiency by addressing the Clinical safety
`deficiency through the following:
`a) Substantive labeling revisions, including the following elements:
`• A Boxed Warning
`• A new Contraindications that limits use of Jatenzo to the indicated
`patient population
`• A comprehensive Medication Guide (Med Guide)
`b) A Post marketing requirement (PMR) to assess patients’ comprehension of
`the Med Guide
`
`2. Adrenal Findings in Animals
`In preclinical studies, adrenocortical atrophy and hypocortisolemia were
`observed in animals dosed with testosterone undecanoate. The Sponsor
`submitted inconclusive adrenal-related data from clinical Study CLAR-15012.
`Because there have been no reports of hypoadrenalism in studies with Jatenzo,
`and with the specific recommendation/agreement from the BRUDAC, the
`Sponsor can resolve this safety issue by conducting a required postmarketing
`clinical study (a PMR) involving Cosyntropin stimulation testing to rigorously
`assess for any potential adverse effects of Jatenzo on adrenal function in
`humans.
`
`
`This issue is considered resolved if the Sponsor agrees to the PMR study.
`
`
`Clinical Pharmacology Deficiency:
`Accuracy or reproducibility of patient plasma total testosterone (T) concentrations on
`Jatenzo using sodium fluoride (Na/F) ethylenediaminetetraacetic acid (EDTA) tubes
`was not determined.
`
`The Sponsor has resolved this deficiency by changing to plain tubes for serum
`collection of T concentrations and providing acceptable data and studies to support the
`change from the Clinical Pharmacology perspective, who considered this issue resolved
`and recommended approval.
`
`
`
`
`Reference ID: 4404777
`
`6
`
`

`

`Clinical Review
`Debuene Chang MD
`NDA 206089
`Jatenzo (Oral Testosterone Undecanoate (TU))
`
`Pharmacology/ Toxicology Deficiency:
`Unacceptable nonclinical studies for male fertility and carcinogenicity were submitted to
`support NDA approval through the 505(b)(1) pathway.
`
`The Sponsor has resolved this deficiency by submitting this 2nd resubmission as a
`505(b)(2) and referenced published literature from the original submission and in this
`resubmission. The Pharmacology/ Toxicology determined that the change to a 505(b)(2)
`submission resolved this deficiency and recommended approval.
`
`Risk Benefit Assessment
`The Clinical review team concludes that Jatenzo is safe and effective on the condition
`that the Sponsor makes labeling revisions which addresses the prior Clinical safety
`deficiencies. The risk/ benefit ratio for Jatenzo for TRT in men with hypogonadism will
`then be considered acceptable for approval of this NDA.
`
`In the prior review cycle, the Clinical review team had recommended a Complete
`Response (CR) action based on the blood pressure-related Clinical safety deficiency,
`provided in Section 1 above.
`
`However, the Clinical review team now recommends that the Sponsor make substantive
`labeling revisions, including changes to the Boxed Warning, a new Contraindication,
`and a comprehensive Medication Guide, as well as to a PMR study that will assess
`patients’ comprehension of the Med Guide, and that these changes address the safety
`deficiencies identified in the original submission and 1st resubmission response to 1st
`CR Letter. For more detail, the reader is referred to the Section 5 of this review -
`Labeling. Thus, if the Sponsor address all these changes to fully resolve the Clinical
`safety deficiency, then the Clinical review team finds that Jatenzo is safe and effective
`as labeled, and that the risk/ benefit ratio for Jatenzo for TRT in men with
`hypogonadism is acceptable for NDA approval.
`
`Recommendations for Postmarket Risk Evaluation and Mitigation
`Strategies (REMS)
`The Clinical review team recommends substantive new labeling and that the label
`include the following elements:
`• Boxed warning
`• Contraindication that limits use of Jatenzo to the indicated patient population
`and excludes its use for the treatment of low testosterone concentrations due
`to conditions not associated with a structural or genetic etiology. Examples
`of excluded conditions include “age-related hypogonadism” and obesity-
`related hypogonadism.
`• Medication Guide (Med Guide) - outside of a REMS
`
`
`Reference ID: 4404777
`
`7
`
`

`

`Clinical Review
`Debuene Chang MD
`NOA 206089
`Jatenzo (Oral Testosterone Undecanoate (TU))
`
`In addition, the Clinical review team recommends that the Sponsor conduct a
`postmarketing requirement study that will assess patients' comprehension of key safety
`aspects of the Medication Guide.
`
`Recommendations for Postmarket Requirements and Commitments
`
`The Clinical review team recommended and the Sponsor was requested to conduct the
`following two PMR studies:
`
`a) Medication Guide comprehension study
`The Sponsor committed to conduct the required postmarketing study and the
`Sponsor provided acceptable milestone dates for protocol submission, study
`completion and study report submission.
`b) Cosyntropin stimulation test study to assess the potential for hypoadrenalism
`The Sponsor committed to conduct the required postmarketing study and the
`Sponsor provided acceptable milestone dates for protocol submission, study
`completion and study report submission.
`
`2
`
`Background
`
`2.1
`
`Product Information
`
`Background:
`The natural hormone testosterone and its derivatives have androgenic and anabolic
`properties. The indication for testosterone is replacement therapy in men with deficiency
`or absence of endogenous testosterone and clinical hypogonadism due to certain
`medical conditions that are associated with structural and genetic disorders. For more
`details, refer to the March 17, 2018 and October 24, 2014 prior Clinical Reviews of this
`NOA.
`
`Product:
`The Sponsor submitted a 505(b)(2) NOA for testosterone undecanoate (TU) capsules
`for oral administration. The pro osed soft gelatin TU oral capsules, 158 mg TU, 198 mg
`4
`TU, and 237 mg TU
`CbH
`1
`
`Reviewer's Comment: The Sponsor has revised the application from a 505(b)(1) to
`a 505(b)(2) in this submission to use appropriate published literature references
`to address nonclinical deficiencies for dose selections in preclinical fertility and
`carcinogenicity studies as noted in Deficiency #3 in the 2 nd CR Letter.
`
`Reference ID 4404777
`
`8
`
`

`

`Clinical Review
`Debuene Chang MD
`NOA 206089
`Jatenzo (Oral Testosterone Undecanoate (TU))
`
`The following table identifies each component of the three proposed oral TU
`dosages.
`
`Table 1: Dosage Strengths and Components in Each Oral Capsule
`Ingredient
`
`TU Amount
`TU Amount
`TU Amount
`158 mg capsule 198 mg capsule 237 mg capsule
`
`Function
`
`Formulation
`Testost erone Undecanoat e ~158.30
`
`Oleic Acid NF, EP
`
`197.88
`
`237.46
`
`Active Ingredient
`(b)(4
`
`ltif<'il
`
`Borage Seed Oil
`Butylated Hydroxytoluene
`NF, EP (BHT)
`Peooermint Oil NF FCC
`Polyoxyl 40
`Hydrogenated Castor
`Oil, NF
`I
`I
`l
`Total Fill Weight
`I
`I
`Reviewer Generated Table from Module 2.3, table 2.3.P.1-1 original NDA submission and Module 2.3, table 2.3 P.1-3, page 2 of
`CR submission #1 (June 22, 2017).
`
`(b)(4)
`
`(b)(4l
`
`(b)(4.
`
`Reviewer's Comment: Patients with allergies to TU or other components of the
`capsule (oleic acid, borage seed oil, BHT, peppermint oil, or hydrogenated castor
`oil should be cautioned in the labeling.
`
`2.2 Availability of Proposed Active Ingredient in the United States
`
`One TU product, Aveed injection (Endo Pharmaceuticals) is currently the only approved
`TU product approved for the US market. That product was approved March 5, 2014
`under NOA 22219 for the same TRT indication. However, Aveed is approved with a
`REMS related to acute post-injection reactions; specifically, pulmonary oil
`microembolism (POME) and anaphylaxis.
`
`2.3
`
`Important Safety Issues with Consideration to Related Drugs
`
`The most important, well-known safety issues for the TRT class include, but are not
`limited to, the following:
`
`• Erythropoietic effects: increased hematocrit (Hct) and hemoglobin (Hb),
`polycythemia, with potential for cerebrovascular accident and/or deep venous
`thrombosis as a result
`
`Reference ID 4404777
`
`9
`
`

`

`Clinical Review
`Debuene Chang MD
`NOA 206089
`Jatenzo (Oral Testosterone Undecanoate (TU))
`
`• Prostate effects: increased prostate volume, increased PSA, potential for
`worsening of BPH symptoms
`• Lipid effects: potential for decreased HDL-cholesterol
`• Other effects: exacerbation of sleep apnea, breast tenderness and/or breast
`enlargement, liver toxicity (associated with high doses of orally active 17-alpha(cid:173)
`alkyl androgens, such as methyltestosterone ), decreased
`spermatogenesis/azoospermia (especially at high doses), peripheral edema,
`acne, and mood disorders.
`
`The currently available evidence is not sufficient to establish w hether the use of
`testosterone by older men is associated with an increased risk of serious cardiovascular
`events and/or prostate cancer.
`
`3
`
`Clinical Safety Issues
`
`3.1.1 Blood Pressure (BP) Increases
`
`Jatenzo caused clinically meaningful increases in blood pressure in clinical studies. In
`CLAR-15012, the only phase 3 Jatenzo study that incorporated ambulatory blood
`pressure monitoring (ABPM), a 24-hour average systolic BP (SBP) increase of 4.9
`mmHg was identified, with a larger increase among subjects with hypertension. 24-hour
`average diastolic BP (DBP) by ABPM was increased by 2.5 mmHg. The following two
`tables summarize changes from baseline in SBP and DBP by ABPM for Jatenzo and
`the comparator TRT used in CLAR-15012, topical Axiron. For Jatenzo, the table
`includes subgroup analysis results by patients with no history of HTN and those with
`treated HTN.
`Table 2: Systolic Blood Pressure Measured by ABPM: Change from
`Baseline at Visit 6 (ABPM Population) in Study CLAR-15012
`
`Systolic BP
`(mm Hg)
`Change from
`Baseline (CFB)
`
`Daytime Average Systolic
`Blood Pressure
`
`Nighttime Average
`Systolic Blood Pressure
`
`All ABPM
`Population
`N=135
`95% CI Mean
`Mean
`
`JATENZO
`Subgroup
`Subgroup
`Treated HTN
`No HTN
`N=67
`N=63
`95% CI
`95% CI Mean
`
`Axiron
`All ABPM
`popu lat ion
`N=45
`95% CI
`Mean
`
`5.0
`
`(3.6, 6.5)
`
`4.4
`
`(2.3, 6.4)
`
`5.7
`
`(3.4, 8.0)
`
`-0.1
`
`(-2.7, 2.5)
`
`4.9
`
`(2.9, 6.8)
`
`4.6
`
`(2.0, 7.2)
`
`5.1
`
`(2.3, 8.0)
`
`0.3
`
`(-3.0, 3.6)
`
`Reference ID 4404777
`
`10
`
`

`

`Clinical Review
`Debuene Chang MD
`NOA 206089
`Jatenzo (Oral Testosterone Undecanoate (TU))
`
`24 Hour Average Syst olic
`Blood Pressure
`
`4.9
`
`(3.5, 6.4)
`
`4.4
`
`(2.3, 6.4)
`
`5.4
`
`(3.3, 7.6)
`
`0.1
`
`(-2.4, 2.6)
`
`CLAR-15012 All Jatenzo ABPM patients with acceptable readings N=135; Jatenzo Subgroup without hypertension (HTN) N=63;
`Jatenzo Subgroup Treated HTN N=67;
`All Axiron comparator ABPM with acceptable readings =45;
`95% Cl = 95% Confidence Interval
`Source: Reviewer created table from CLAR-15012 CSR tables 14.3.4.3.5 and 14.3.4.3.6
`
`Table 3: Diastolic Blood Pressure Measured by ABPM: Change from
`Baseline at Visit 6 (ABPM Population) in Study CLAR-15012
`
`AllABPM
`Diast o lic BP
`Poeulation
`(mm Hg)
`N=135
`Changes from Mean
`95%CI
`Baseline (CFB)
`Daytime Average
`Diastolic BP
`
`2.4
`
`(1.3, 3.5)
`
`JATENZO
`Subgroue
`No HTN
`N=63
`95%CI
`
`Mean
`
`AXIRON
`All ABPM
`Subgroue
`Treated HTN
`Poeulation
`N=45
`N=67
`95%CI
`95%CI Mean
`
`Mean
`
`1.5
`
`(-0.1, 3.1)
`
`3.3
`
`(1. 7, 4.9)
`
`0.5
`
`(-1.4, 2.5)
`
`Nighttime Average
`Diastolic BP
`
`24 Hour Average
`Diastolic BP
`
`2.8
`
`(1.5, 4.2)
`
`2.5
`
`(0.4, 4.5)
`
`3.1
`
`(1.1, 5.0)
`
`0.6
`
`(-1.8, 3.0)
`
`2.5
`
`(1.5, 3.6)
`
`1.8
`
`(0.2, 3.3)
`
`3.2
`
`(1.7, 4.7)
`
`0.6
`
`(-1.3, 2.4)
`
`CLAR-15012 All Jatenzo ABPM patients with acceptable readings N=135; Jatenzo Subgroup without hypertension (HTN)
`
`N=63; Jatenzo Subgroup Treated HTN N=67;
`All topical Axiron ABPM patients with acceptable readings N=45;
`95% Cl = 95% Confidence Interval
`Source: Reviewer created table from CLAR-15012 CSR tables 14.3.4.3.5 and 14.3.4.3.6
`
`In the same study, the Sponsor also reported increased SBP by in-office cuff BP
`pressure measurements from baseline to Visit 7/Early Termination in both Jatenzo and
`comparator (Topical Axiron) treatment groups (mean ± SD: Oral TU 2.8 ± 11 .8 mm Hg,
`Topical Axiron 1.8 ± 10.8 mm Hg). Diastolic blood pressures (DBP) were unchanged by
`cuff measurements.
`
`Reference ID 4404777
`
`11
`
`

`

`Clinical Review
`Debuene Chang MD
`NDA 206089
`Jatenzo (Oral Testosterone Undecanoate (TU))
`
`In September 2017, as part of the second cycle (1st resubmission) review, the Division
`of Cardiovascular and Renal products (DCARP) was asked to consult on the blood
`pressure increases with Jatenzo. DCARP was of the opinion that the ABPM data more
`accurately reflected the actual blood pressure changes compared to the cuff BP data. In
`this regard, DCARP made the following statement:
`“The ABPM data more accurately reflects blood pressure changes because of
`the vastly increased amount of data that is being averaged (averaging multiple
`values per hour, then multiple hours per analysis time period).”
`
`
`The DCARP consultant also commented that the final Visit-7/ ET blood pressure data
`from Study CLAR-15012 suggested that blood pressures had not yet stabilized and
`appeared to be still increasing at the end of the study. In this regard, the consultant
`made the following comment:
`“It is somewhat disconcerting that for both of these TU products (both Jatenzo
`and the comparator TRT product, Topical Axiron), the Visit-7/ET blood pressure
`data suggests that SBP increases had not plateaued at the end of the study
`(from the sponsor CRS).”
`
`
`Reviewer’s Comment: Study CLAR-15012 demonstrated that Jatenzo causes
`increased SBP by both ABPM and cuff pressures and increased DBP by ABPM.
`
`Specifically, by ABMP, mean 24-hr BP increases for SBP and DBP were 5 mm Hg
`and 2.5 mm Hg respectively. The BP increases were greater in patients with
`history of hypertension who were treated with anti-hypertensive medications with
`mean 24-hour SBP by ABPM increases of 5.5 mm Hg and DBP increases of