CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`215256Orig1s000
`
`
`
`OTHER REVIEW(S)
`
`

`

`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
`
`May 25, 2021
`
`Martin White, M.S.
`Regulatory Project Manager
`Division of Diabetes, Lipid Disorders, and Obesity
`(DDLO)
`
`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)
`Meena Savani, PharmD
`Regulatory Reviewer
`Office of Prescription Drug Promotion (OPDP)
`Review of Patient Labeling: Medication Guide (MG) and
`Instructions for Use (IFU)
`
`WEGOVY (semaglutide)
`
`injection, for subcutaneous use
`
`
`Date:
`
`To:
`
`
`Through:
`
`
`From:
`
`Subject:
`
`Drug Name (established
`name):
`Dosage Form and
`Route:
`Application
`Type/Number:
`Applicant:
`
`
`
`NDA 215256
`
`Novo Nordisk Inc.
`
`
`
`
`
`
`
`Reference ID: 4801116
`
`

`

`
`1
`
`INTRODUCTION
`On December 4, 2020, Novo Nordisk Inc. submitted for the Agency’s review an
`original New Drug Application (NDA) 215256 for WEGOVY (semaglutide)
`injection, for subcutaneous use. This NDA is proposing an indication of weight
`management.
`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 Diabetes, Lipid Disorders, and Obesity (DDLO) on
`January 7, 2021, for DMPP and OPDP to review the Applicant’s proposed
`Medication Guide (MG) and Instructions for Use (IFU) for WEGOVY (semaglutide)
`injection, for subcutaneous use.
`
` 2
`
` MATERIAL REVIEWED
`• Draft WEGOVY (semaglutide) MG and IFU received on December 4, 2020, and
`received by DMPP and OPDP on May 14, 2021.
`• Draft WEGOVY (semaglutide) Prescribing Information (PI) received on
`December 4, 2020, revised by the Review Division throughout the review cycle,
`and received by DMPP and OPDP on May 14, 2021.
`
`
`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.
`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 IFU document using the
`Arial font, size 10.
`In our collaborative review of the MG and IFU we:
`simplified wording and clarified concepts where possible
`•
`•
`ensured that the MG and IFU are consistent with the Prescribing Information
`(PI)
`removed unnecessary or redundant information
`ensured that the MG and IFU are 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
`
`•
`•
`
`•
`
`
`
`
`
`
`
`Reference ID: 4801116
`
`

`

`•
`
`•
`
`ensured that the MG and IFU meet the criteria as specified in FDA’s Guidance
`for Useful Written Consumer Medication Information (published July 2006)
`ensured that the MG and IFU are consistent with the approved comparator
`labeling where applicable.
`
` CONCLUSIONS
`The MG and IFU are acceptable with our recommended changes.
`
` 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.
`
` 4
`
` 5
`
`
`
`
`
`
`
`Reference ID: 4801116
`
`18 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
`05/25/2021 12:46:21 PM
`
`MEENA R SAVANI
`05/25/2021 01:01:45 PM
`
`MARCIA B WILLIAMS
`05/25/2021 01:06:17 PM
`
`LASHAWN M GRIFFITHS
`05/25/2021 01:28:11 PM
`
`Reference ID: 4801116
`
`

`

`FOOD AND DRUG ADMINISTRATION
`Center for Drug Evaluation and Research
`Office of Prescription Drug Promotion
`****Pre-decisional Agency Information****
`
`
`
`
`Memorandum
`
`Date:
`May 25, 2021
`
`
`To:
`
`Martin White, Regulatory Project Manager, Division of Diabetes, Lipid
`Disorders, and Obesity (DDLO)
`
`Monika Houston, Associate Director for Labeling, (DDLO)
`
`Meena Savani, Regulatory Review Officer
`Office of Prescription Drug Promotion (OPDP)
`
`Melinda McLawhorn, Team Leader, OPDP
`
`
`
`
`From:
`
`
`
`CC:
`
`Subject:
`
`OPDP Labeling Comments for WEGOVYTM (semaglutide) injection, for
`subcutaneous use
`
`215256
`
`
`NDA:
`
`
`
`In response to DDLO’s consult request dated January 7, 2021, 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 WEGOVY.
`
`
`Labeling: OPDP’s comments on the proposed labeling are based on the draft labeling
`downloaded from SharePoint on May 24, 2021, and are provided below.
`
` A
`
` combined OPDP and Division of Medical Policy Programs (DMPP) review will be completed,
`and comments on the proposed Medication Guide and 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 April 23,
`2021, and we do not have any comments.
`
`Thank you for your consult. If you have any questions, please contact Meena Savani at (240)
`402-1348 or Meena.Savani@fda.hhs.gov.
`
`
`
`
`Reference ID: 4801004
`
`1
`
`38 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/
`------------------------------------------------------------
`
`MEENA R SAVANI
`05/25/2021 10:44:02 AM
`
`Reference ID: 4801004
`
`

`

` DEPARTMENT OF HEALTH AND HUMAN SERVICES
` PUBLIC HEALTH SERVICE
` FOOD AND DRUG ADMINISTRATION
` CENTER FOR DRUG EVALUATION AND RESEARCH
` DIVISION OF CARDIOLOGY AND NEPHROLOGY
`
`Date:
`May 21, 2021
`
`From:
`
`Interdisciplinary Review Team for Cardiac Safety Studies
`
`Through:
`
`Christine Garnett, PharmD
`Clinical Analyst, DCN
`
`To:
`
`Martin White, RPM
`DDLO
`
`Subject:
`
`IRT Consult to NDA-215256 (SDN001)
`
`Note: Any text in the review with a light background should be inferred as copied from the
`sponsor’s document.
`
`This memo responds to your consult to us dated 5/13/2021 regarding the Division’s QT related
`question. We reviewed the following materials:
` Previous IRT review for IND-126360 dated 10/05/2017 in DARRTS (link);
` Previous IRT review for NDA-209637 dated 05/03/2017 in DARRTS (link); and
` Sponsor’s proposed product label (SN0001; link).
`
`IRT Responses
`1
`Previously, the IRT agreed with the sponsor’s proposal to characterize QT effects using the data
`from Phase-3 study to support the weight management indication (Dt: 10/05/2017). The expected
`steady-state peak concentrations (~116 nmol/L vs ~73 nmol/L) with the proposed therapeutic dose
`are higher (~58%) than those observed with 1.5 mg dose in the thorough QT study (Study NN9535-
`3652). However, considering - 1) a shallow exposure-response relationship between ΔΔQTcI and
`plasma concentrations of semaglutide observed in the thorough QT study; 2) peptide nature of
`semaglutide; and 3) no considerable impact of intrinsic and extrinsic factors of the exposures of
`semaglutide, the sponsor’s approach of extending the findings of previous thorough QT study
`appears reasonable. In addition, relatively lower exposures of semaglutide were observed in the
`target population (obese) compared to the healthy subjects.
`Below are proposed edits to the label submitted to SDN001(link) from the IRT. Our changes are
`highlighted (addition, deletion). Please note, that this is a suggestion only and that we defer final
`labeling decisions to the Division.
`
`Reference ID: 4799532
`
`

`

`12.2 Pharmacodynamics
`Cardiac Electrophysiology
`
`The effect of semaglutide on cardiac repolarization was tested in a thorough QTc trial.
`Semaglutide did not prolong QTc intervals at doses up to 1.5 mg at steady state.
`
`
`We propose to use labeling language for this product consistent with the “Clinical
`Pharmacology Section of Labeling for Human Prescription Drug and Biological Products –
`Content and Format” guidance.
`
`Internal Comments to the Division
`2
` None.
`
`3 Background
`
`3.1 Product Information
`Novo Nordisk is developing semaglutide as an adjunct to a reduced calorie meal plan and increased
`physical activity for chronic weight management
` in adult
`patients. Semaglutide (MW: 4113.58 g/mol; the peptide backbone is produced by yeast
`fermentation) is glucagon-like peptide-1 (GLP-1) receptor agonist. Previously, semaglutide is
`approved for the treatment of diabetes (type 2) as once-weekly subcutaneous administration
`(Ozempic solution; NDA-209637) or once-daily oral administration (Rybelsus; NDA-213051 &
`NDA-213182).
`The product is formulated as sterile solution containing 0.25, 0.5, or 1 mg semaglutide (in 0.5 mL
`single dose pen) for subcutaneous administration. The maximum proposed therapeutic dose for the
`present indication is 2.4 mg once weekly (the starting dose is 0.25 mg qW. After 4 weeks, the dose
`is increased to 0.5 mg qW, followed by 1.0 mg qW, 1.7 mg qW and finally the maintenance dose
`of 2.4 mg qW. All escalation steps are given for 4 weeks). The peak concentrations of ~119 nmol/L
`(Tmax: 1-3 days; half-life: ~1 week) were observed at steady state with the anticipated therapeutic
`dose (Study # 4590 and POP-PK). The product exhibit dose-proportional increase in exposures up
`to 2.4 mg once weekly.
`Since semaglutide is primarily metabolized by proteolytic degradation (cleavage of the peptide
`backbone and sequential beta-oxidation of the fatty acid sidechain; no major metabolites were
`identified), it has no significant drug interaction liability. Semaglutide is excreted in the urine (~3%
`as unchanged drug) and feces. The sponsor states that renal (mild, moderate, severe, or ESRD) or
`hepatic (mild, moderate, severe) impairment did not have any impact on the exposure of
`semaglutide (single dose of 0.5 mg semaglutide). The sponsor proposed no dose adjustment based
`on age, gender, race, ethnicity, body weight, renal function, injection site or glycemic status.
`Previously, the IRT agreed with the sponsor’s proposal to characterize QT effects using the data
`from Phase-3 study to support the weight management indication (Dt: 10/05/2017).
`
`Reference ID: 4799532
`
`2
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Sponsor’s Position related to the Question
`3.2
`The sponsor states that the risk of QT prolongation of semaglutide was adequately characterized
`in the previous thorough QT study in healthy subjects conducted under NDA-209637 (Dt:
`05/03/2017). Refer to the sponsor’s summary of clinical pharmacology studies (m2.7.2)
`The potential effect of semaglutide on cardiac repolarization by QTc has previously been studied
`for Ozempic®. No prolongation of the QTc interval was observed with semaglutide in doses up to
`1.5 mg and no semaglutide exposure-QTc relation was observed in the QTc trial for Ozempic®.
`In addition, as expected, body weight was the most important covariate resulting in lower exposure
`with higher body weight and vice versa, while other investigated covariates had a minor or no
`influence on semaglutide exposure. Further, semaglutide elimination is not organ specific, thus,
`conditions such as renal or hepatic impairment are not associated with higher semaglutide
`exposure.
`As evident from Figure 4-1, comparable exposures were observed between the semaglutide 2.4
`mg weight management program (STEP 1 and STEP 2) and trial NN9535-3652. Therefore, the
`QTc trial (NN9535-3652) is considered adequate to support the weight management indication
`with semaglutide 2.4 mg.
`Figure 4-1 Exposure of semaglutide – Semaglutide 2.4 mg vs. semaglutide QTc assessment -
`modelling
`
`N: Number of subjects contributing with PK data (STEP 1 and 2) or completing the trial (NN9535-
`3652). Data are individual Cavg values (open symbols) and geometric means with 90% ranges
`(closed symbols with error bars) obtained with semaglutide 2.4 mg (STEP 1 and STEP 2) or
`semaglutide 1.5 mg (trial NN9535-3652). Cavg values in STEP 1 and 2 were derived as described
`for estimation of steady-state exposure in Section 1.3.3.2. Cavg values in trial NN9535-3652 were
`derived from noncompartmental analyses.
`Based on the population PK analysis, an estimated expected highest exposure scenario in the
`clinical setting based on the covariates included in the final model (including only significant
`covariate factors) was evaluated to be the exposure of a normo-glycaemic Black female with
`moderate renal impairment and with a body weight of 74 kg (5th percentile in the PK population).
`
`Reference ID: 4799532
`
`3
`
`

`

`The estimated average concentration at steady state for this subject profile was 116 nmol/L (90%
`prediction interval 87−155 nmol/L). Based on the full profiles from previous clinical
`pharmacology trials, the influence of covariates on Cavg and Cmax is close to identical. Cmax is
`approximately 25% above the Cavg. Adding 25% to the Cavg from the expected highest clinical
`exposure scenario above, gives an approximate expected Cmax of 145 nmol/L.
`Reviewer’s comment: Based on population pharmacokinetics, body weight is a significant
`covariate and higher exposures are expected in subjects with lower body weight (e.g., 74 kg: 1.4-
`fold and 143 kg: 0.8-fold, compared to exposure relative to body weight 110 kg). Relatively, lower
`exposures of semaglutide were observed in the target population (obese) compared to the healthy
`subjects.
`
`3.3 Nonclinical Cardiac Safety
`Refer to the sponsor’s highlights of clinical pharmacology and clinical safety (m2.7.2; Appendix
`5.1), the sponsor’s non-clinical overview (m2.4), and the previous IRT review for NDA-209637
`dated 05/03/2017 in DARRTS (link).
`In vitro cardiovascular studies were also performed to evaluate potential effects on the cardiac
`action potential. In addition, cardiac electrophysiology was monitored by ECG in the repeat dose
`toxicity studies in cynomolgus monkeys.
`Semaglutide was well tolerated in the monkey, and no adverse effects were observed in the
`cardiovascular telemetry study, evaluating single doses of up to 0.5 mg/kg corresponding to 6-fold
`the exposure at the MRHD based on Cavg. GLP-1R agonists have been reported to decrease the
`arterial blood pressure in humans and to cause an increase in heart rate of 2-3 beats per minute
`(88). These effects were not detected in the acute, single dose study in monkeys.
`Semaglutide had no effect in the hERG study or Purkinje fiber study investigating cardiac ion
`channels when tested up to 8.2 μM (109-fold the expected human Cavg at a clinical dose of 2.4
`mg qW).
`
`3.4 Clinical Cardiac Safety
`Refer to the sponsor’s highlights of clinical pharmacology and clinical safety, integrated summary
`of safety (link), and the sponsor’s clinical overview (m2.5)
`Clinical cardiac safety was evaluated based on the phase 3a pool (phase 3a trials: STEP 1, STEP
`2, STEP 3 and STEP 4), the number of exposed subjects to semaglutide 2.4 mg was 2650 and
`patient years of exposure was 3309.5.
`There was no apparent treatment difference in the reporting of AEs within the HLGT Cardiac
`arrhythmias (semaglutide 2.4 mg: 2.3%, 2.1◦events per 100 PYE, placebo: 2.0%, 1.9 events per
`100 PYE) in the phase 3a pool. The most frequently reported events were atrial fibrillation and
`tachycardia. One event of atrial fibrillation led to premature treatment discontinuation. Also, AEs
`of increased heart rate (grouped preferred terms) were reported in a small proportion of subjects
`with no apparent imbalance between the treatment groups (semaglutide 2.4 mg: 0.8%, placebo:
`0.6%).
`In all the phase 3a trials, a 12-lead ECG was performed at the randomization visit, the week 20
`visit and the end-of-treatment visit. The ECGs were to be interpreted by the investigator and
`
`Reference ID: 4799532
`
`4
`
`

`

`categorized as normal or abnormal, and, if abnormal, furthermore indicated whether or not the
`finding was clinically significant.
`Overall, the proportion of subjects with ECG abnormalities did not differ between the treatment
`groups for any of the abnormality categories. The effects of semaglutide s.c. 2.4 mg once weekly
`on cardiovascular outcomes are currently being investigated in a dedicated cardiovascular outcome
`trial, SELECT (trial NN9536-4388), in subjects with established cardiovascular disease and
`obesity or overweight and without T2D. Reporting of results from SELECT is expected during
`2024.
`
`Summary Results of Prior QTc Assessments
`3.5
`The sponsor conducted a thorough QT study under NDA-209637. In our previously assessment,
`no significant QTc prolongation effect of semaglutide (0.5 mg, 1.0 mg, and 1.5 mg) was detected
`(TQT study # NN9535-3652; Dt: 05/03/2017). It was a randomized, blinded, 3-arm parallel study
`with a nested crossover design (n=168). Healthy subjects were randomized to receive semaglutide
`(dose escalation regimen of 0.25 mg, 0.5 mg, 1.0 mg, and 1.5 mg), semaglutide placebo,
`moxifloxacin placebo, and a single dose of moxifloxacin 400 mg. Within the studied exposure
`range (up to 1.5 mg), no exposure-response relationship was seen between baseline- and placebo-
`adjusted QTcF and QTcI intervals and semaglutide concentrations.
`Study Design:
`
`The exposure-response relationship was assessed by baseline- and placebo-adjusted QTcI at steady
`state of semaglutide 0.5, 1.0 and 1.5 mg versus corresponding semaglutide plasma concentrations.
`No significant exposure-response relationship was identified between ΔΔQTcI and semaglutide
`concentrations.
`The mean (90% CI) ΔΔQTcF and ΔΔQTcI at mean steady-state Cmax of 74.19 nmol/L following
`supratherapeutic dosing regimen 1.5 mg once weekly is estimated to be -0.22 (-3.07, 2.63) and -
`5.11 (-7.77, -2.46) ms, respectively.
`Figure: The relationships between ΔΔQTcF and ΔΔQTcI and semaglutide concentrations.
`
`Reference ID: 4799532
`
`5
`
`

`

`Reviewer’s comment: Based on the previous assessment, the mean (90% CI) ΔΔQTcF and ΔΔQTcI
`at mean steady-state Cmax of 74.19 nmol/L following supratherapeutic dosing regimen 1.5 mg
`once weekly is estimated to be -0.22 (-3.07, 2.63) and -5.11 (-7.77, -2.46) ms, respectively. The
`expected steady state peak concentrations (~116 nmol/L vs 72.6 nmol/L) with the proposed
`therapeutic dose are higher (~60%) than those observed with 1.5 mg dose in the thorough QT
`study (Study NN9535-3652). However, a shallow exposure-response relationship between ΔΔQTcI
`and plasma concentrations of semaglutide was observed in the thorough QT study.
`
`3.6 Relevant Details of Planned Phase 3 Study
`Not applicable.
`
`Thank you for requesting our input into the development of this product. We welcome more
`discussion with you now and in the future. Please feel free to contact us via email at
`cderdcrpqt@fda.hhs.gov.
`
`Reference ID: 4799532
`
`6
`
`

`

`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/
`------------------------------------------------------------
`
`GIRISH K BENDE
`05/21/2021 02:19:31 PM
`
`CHRISTINE E GARNETT
`05/21/2021 02:43:06 PM
`
`Reference ID: 4799532
`
`

`

`Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research | Office of Surveillance and Epidemiology (OSE)
`Epidemiology: ARIA Sufficiency
`
`Date:
`
`Reviewer:
`
`May 21, 2021
`
`Christian Hampp, PhD
`Division of Epidemiology I
`
`Team Leader:
`
`Division Director:
`
`Yandong Qiang, MD, PhD, MPH, MHS
`Division of Epidemiology I
`Simone P. Pinheiro, ScD, MSc, ALM
`Division of Epidemiology I
`ARIA Sufficiency Assessment for pregnancy safety of semaglutide
`in the treatment of obesity
`Wegovy® (semaglutide)
`Drug Name:
`Application Type/Number: NDA 215256
`Applicant/sponsor:
`Novo Nordisk
`OSE RCM #:
`2020-2565
`
`Subject:
`
`Reference ID: 4799277
`
`Page 1 of 9
`
`

`

`EXECUTIVE SUMMARY
`Memo type
`
`Source of safety concern
`
`-Initial
`-Interim
`-Final
`-Peri-approval
`-Post-approval
`-Yes
`-No
`-Surveillance or Study Population
`-Exposure
`-Outcome(s) of Interest
`-Covariate(s) of Interest
`-Surveillance Design/Analytic Tools
`
`Is ARIA sufficient to help characterize the safety concern?
`
`If “No”, please identify the area(s) of concern.
`
`X
`X
`X
`X
`X
`
`Reference ID: 4799277
`
`Page 2 of 9
`
`

`

`1. BACKGROUND INFORMATION
`1.1. Medical Product
`
`On December 4, 2020, Novo Nordisk submitted a New Drug Application (NDA 215256) for
`semaglutide, a long-acting glucagon-like peptide-1 (GLP-1) receptor agonist, for the proposed
`indication of weight management. NDA 215256 is a 505(b)(2) application referencing IND
`126360 and NDA 209637 for Ozempic (semaglutide) injection prefilled pen, which is indicated
`for use in adult patients with type 2 diabetes mellitus. Ozempic is a subcutaneous injection
`administered at a starting dose of 0.25 mg once weekly, and can be increased to 0.5 mg once
`weekly after 4 weeks, up to a maximum of 1 mg once weekly.1
`
`The proposed indication for NDA 215456 is as an adjunct to a reduced calorie diet and increased
`physical activity for chronic weight management in adults with an initial body mass index (BMI)
`of:
`
`
`
`
`30 kg/m2 or greater (obese) or
`27 kg/m2 or greater (overweight) in the presence of at least one weight-related comorbid
`condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia)
`
`The starting dose of semaglutide is 0.25 mg injected subcutaneously once-weekly, which can be
`escalated to 2.4 mg once-weekly according to the following schedule to minimize
`gastrointestinal adverse reactions:
`
`Dose Escalation Schedule
`Weeks
`1 through 4
`5 through 8
`9 through 12
`13 through 16
`Week 17 and onward
`
`Weekly Dose
`0.25 mg
`0.5 mg
`1 mg
`1.7 mg
`2.4 mg
`
`1.2. Describe the Safety Concern
`
`Preclinical data
`The pharmacology/toxicology review by Dr. Elena Braithwaite, Division of Pharm/Tox for
`Cardiology, Hematology, Endocrinology and Nephrology (DPT-OCHEN), includes an
`evaluation of embryofetal development and pre- and postnatal development studies that were
`conducted in rats, rabbits, and cynomolgus monkeys.(1) In rats, findings included decreased
`placental and fetal weights, and major malformations, including cardiovascular abnormalities
`
`1 Semaglutide is also available in tablet form (Rybelsus, NDA 213051) for the treatment of type 2 diabetes mellitus,
`with a starting dose of 3 mg once daily, which can be increased in a stepwise fashion to 14 mg once daily if
`additional glycemic control is needed.
`
`Page 3 of 9
`
`Reference ID: 4799277
`
`

`

`(retro-esophageal aortic arch, double aortic arch, and membranous ventricular septal defect) and
`short tibia at doses below the maximum recommended human dose (MRHD). In rabbits, there
`were minor skeletal abnormalities (additional sternebral centers, bridge of ossification/partially
`fused/fused sternebra, unossified/incompletely ossified metacarpals/phalanges) and minor
`visceral abnormalities (dilated renal pelvis, additional liver lobe, and forepaw flexure) observed
`at 0.9-fold the MRHD.
`
`Cynomolgus monkey experienced decreased maternal body weight that was associated with
`reduced food consumption during the semaglutide dosing phase at all doses examined. A few
`sporadic abnormalities (focal reddening of the skin, kinked and stiff wrist, blood accumulation
`under the skull causing misshapen right brain hemisphere, fused kidneys, liver cysts and shift in
`alignment of the vertebrae, ribs, and first sternebra, at the cervico-thoracic border) were observed
`in fetuses (at ≥2-fold the MRHD). Pregnant monkeys also experienced an increased incidence
`of early pregnancy loss (at 3-fold the MRHD). Reduced infant body weights at birth were also
`observed; but, by Day 91, body weights were similar across all groups. Semaglutide treatment
`did not result in neurobehavioral impairment during a neurobehavioral test battery conducted on
`post-partum day 1 and 7.
`
`Because these findings in animals are potentially due to the weight loss that occurred in the
`animals, and it is not clear if the findings are clinically relevant.
`
`Clinical experience
`According to a review by the Dr. Carrie Ceresa, Division of Pediatric and Maternal Health
`(DPMH), 29 pregnancies were reported in females treated with semaglutide across 4 clinical
`trials within the clinical development program for semaglutide 2.4 mg.(2) These and other
`exposed pregnancies are included in the Novo Nordisk safety database, which contains a total of
`98 pregnancies exposed to semaglutide (including Ozempic and Rybelsus), with known fetal
`outcomes in 47 pregnancies. They include 26 live births without congenital anomalies, 1 live
`birth with congenital anomaly,2 9 fetal losses (spontaneous abortion), and 11 terminations
`without known fetal defects.
`
`Dr. Ceresa summarized the sponsor’s review of the literature and conducted her own literature
`review. None of the retrieved publications contain pregnancy exposure cases to semaglutide.
`
`The reviewer concluded that the data are insufficient to determine if there is a drug associated
`risk of maternal or fetal adverse reactions.
`
`Weight management and pregnancy
`
`According to the DPMH review, women with a BMI ≥ 30kg/m2 are at risk for gestational
`diabetes, pre-eclampsia, and cesarean delivery. Also, women with excessive pregnancy weight
`gain are at risk for postpartum weight retention, obesity and type 2 diabetes. Yet, fetal/neonatal
`
`2 One case of “small left ear fold/anomaly of external ear congenital” involved exposure to semaglutide during
`pregnancy at unknown gestational timing. The mother was HIV positive and the pregnancy was conceived while
`mother had an IUD in place. The infant was born at 38 weeks and 4 days gestation and had a small left ear fold that
`resolved itself 4 weeks after birth. This event was categorized as “unlikely” related to study drug.
`
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`adverse outcomes, such as fetal growth restriction, can occur in obese women who try to lose
`weight during pregnancy.
`
`Consequently, the draft labeling of semaglutide (below) states that
`
`
`
`Nevertheless, because women of childbearing age represent a large proportion of antiobesity
`drug users, (3) a substantial number of pregnancies could be affected by early exposure to
`semaglutide.
`
`Draft Labeling
`
`As of the date of this memo, Section 8.1 of the draft labeling states:
`
`Reference ID: 4799277
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`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`1.3. FDAAA Purpose (per Section 505(o)(3)(B))
`
`Purpose
`Assess a known serious risk
`Assess signals of serious risk
`Identify unexpected serious risk when available data indicate potential for
`serious risk
`
`X
`
`Reference ID: 4799277
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`(b) (4)
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`

`2. REVIEW QUESTIONS
`2.1. Why is pregnancy safety a safety concern for this product? Check all that apply.
`☐ Specific FDA-approved indication in pregnant women exists and exposure is expected
`☐ No approved indication, but practitioners may use product off-label in pregnant women
`☒ No approved indication, but there is the potential for inadvertent exposure before a
`pregnancy is recognized
`☒ No approved indication, but use in women of childbearing age is a general concern
`
`2.2. Regulatory Goal
`
`☒ Signal detection – Nonspecific safety concern with no prerequisite level of statistical
`precision and certainty
`☐ Signal refinement of specific outcome(s) – Important safety concern needing moderate level
`of statistical precision and certainty.
`☐ Signal evaluation of specific outcome(s) – Important safety concern needing highest level of
`statistical precision and certainty (e.g., chart review).
`
`2.3. What type of analysis or study design is being considered or requested along with
`ARIA? Check all that apply.
`
`☒ Pregnancy registry with internal comparison group
`☐ Pregnancy registry with external comparison group
`☐ Enhanced pharmacovigilance (i.e., passive surveillance enhanced by with additional actions)
`☒ Electronic database study with chart review
`☒ Electronic database study without chart review
`☐ Other, please specify:
`
`2.4. Which are the major areas where ARIA not sufficient, and what would be needed to
`make ARIA sufficient?
`☐ Study Population
`☐ Exposures
`☐ Outcomes
`☒ Covariates
`☒ Analytical Tools
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`For any checked boxes above, please describe briefly:
`
`Covariates
`BMI is not comprehensively and reliably available in Sentinel claims data. Because it is an
`important predictor of treatment initiation, and is associated with various pregnancy
`complications, the ability to ascertain BMI is critical.
`
`Analytical Tools
`The requested PMR targets more than one outcome, including major congenital
`malformations (MCM), spontaneous abortions, stillbirths, small for gestational age, and
`preterm birth. Moreover, the MCM outcome covers several subclasses of potential interest
`(e.g., congenital malformation of the circulatory system, congenital malformation of the
`nervous system, or cleft lip and cleft palate). ARIA might address the complexity presented
`by multiple discrete outcomes by means of an appropriate data mining approach. However, a
`suitable data mining approach (e.g., TreeScan) is not yet available for signal detection of
`birth defects and other pregnancy outcomes in ARIA.
`
`2.5. Please include the proposed PMR language in the approval letter.
`
`As of the date of this memo, the FDA drafted the PMR language below:
`
`1. Conduct a prospective, registry based observational exposure cohort study that compares
`the maternal, fetal, and infant outcomes of women exposed to semaglutide during
`pregnancy to an unexposed reference population. The registry will detect and record
`major and minor congenital malformations, spontaneous abortions, stillbirths, elective
`terminations, small for gestational age, preterm birth, and any other adverse pregnancy
`outcomes. These outcomes will be assessed throughout pregnancy. Infant outcomes,
`including effects on postnatal growth and development, will be assessed through at least
`the first year of life.
`
`2. Conduct an additional pregnancy study that uses a different observational design from the
`Pregnancy Exposure Registry, using claims or electronic medical record data, to assess
`the associations between semaglutide exposure during pregnancy with pregnancy
`outcomes and infant outcomes including but not limited to major congenital
`malformations, spontaneous abortions, stillbirths, and small for gestational age, preterm
`birth, and postnatal growth and development.
`
`Reference ID: 4799277
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`3. REFERENCES
`
`Elena Braithwaite. Pharmacology/toxicology NDA review and evaluation, semaglutide
`1.
`injection. 5/13, 2021, RefID: 47