Clinically meaningful increase in blood pressure and cardiovascular risk
Severity: criticalStudies QST13-003 and QST15-005 showed mean increases in systolic and diastolic blood pressure (approx 4 mmHg and 2 mmHg respectively) in normotensive patients. Approximately 60% of patients had increased systolic BP, with increases up to 20 mmHg, and 9.5% required antihypertensive medication. The agency is concerned these findings may underestimate effects in real-world hypertensive populations, increasing cardiovascular risk.
Recommended response: Conduct a new ABPM study in a population more consistent with real-world testosterone replacement users to further characterize blood pressure effects and cardiovascular risk. Collect data on other cardiovascular parameters (e.g., hematocrit, hemoglobin, cholesterol).
Suicidality signal (suicide attempts and depression)
Severity: criticalTwo cases of suicide attempt (including one completed suicide) and two cases of depression were observed in the development program. The agency is unable to exclude drug causality.
Recommended response: Propose a plan to address the suicidality signal, potentially by including prespecified, periodic, validated psychiatric evaluations to monitor for depression and suicidality in the new ABPM study.
Proposed labeling not adequate; reserve comment until application is otherwise adequate
Severity: majorThe agency reserves comment on the proposed labeling until the clinical deficiencies are resolved. The sponsor is encouraged to review PLR Requirements, Pregnancy and Lactation Labeling Final Rule websites, regulations, guidance documents, and the SRPI checklist to ensure compliance.
Recommended response: Review PLR requirements, Pregnancy and Lactation Labeling Final Rule, and SRPI checklist. Update content of labeling in SPL format, ensuring conformance with regulations and guidances. Provide highlighted/marked-up and clean Microsoft Word versions.
Cited: 21 CFR: 314.50(l)(1)(i)
Use errors with critical task of uncapping device in Instructions for Use (IFU)
Severity: minorPatient/caregiver and healthcare provider validation studies showed use errors with uncapping the device before ready to inject, posing risk of infection and unintended exposure. The statement 'Do not remove cap until ready to inject' is not in close proximity to the corresponding use task in the IFU.
Recommended response: Add the statement 'Do not remove cap until ready to inject' to the 'Inspect Autoinjector' section of the IFU to emphasize not removing the cap until ready to inject, based on human factors validation study findings.
Submit draft carton and container labeling based on proposed revisions
Severity: minorSubmit draft carton and container labeling based on the agency's proposed revisions dated May 18, 2017.
Recommended response: Submit updated draft carton and container labeling incorporating the agency's proposed revisions.
Resubmit proposed proprietary name
Severity: infoThe proposed proprietary name, Xyosted, was found acceptable pending approval of the application. It needs to be resubmitted when responding to the application deficiencies.
Recommended response: Resubmit the proposed proprietary name, Xyosted, with the complete response.
Include a comprehensive safety update with resubmission
Severity: majorA safety update is required as described in 21 CFR 314.50(d)(5)(vi)(b), including data from all nonclinical and clinical studies, significant changes in safety profile, updated tabulations of adverse events, comparison of frequencies, case report forms for deaths/serious AEs, updated exposure information, and worldwide experience.
Recommended response: Prepare a comprehensive safety update according to 21 CFR 314.50(d)(5)(vi)(b), incorporating all new nonclinical and clinical safety data, updated adverse event tabulations, and worldwide experience.
Cited: 21 CFR 314.50(d)(5)(vi)(b)
