CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`213051Orig1s000
`
`
`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:
`
`September 3, 2019
`Division of Metabolism and Endocrinology Products
`(DMEP)
`Application Type and Number: NDA 213051
`Product Name and Strength:
`Rybelsus (semaglutide) tablet, 3 mg, 7 mg, and 14 mg
`Applicant/Sponsor Name:
`Novo Nordisk Inc. (Novo)
`FDA Received Date:
`August 30, 2019
`OSE RCM #:
`2019-643-1
`DMEPA Safety Evaluator:
`Ariane O. Conrad, PharmD, BCACP, CDE
`DMEPA Team Leader:
`Hina Mehta, PharmD
`
`PURPOSE OF MEMORANDUM
`1
`Novo Nordisk submitted revised labels and labeling for Rybelsus on August 30, 2019. We
`reviewed the revised labels and labeling for Rybelsus (Appendix A) to determine if they are
`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 Applicant implemented all of our recommendations and we have no additional
`recommendations at this time.
`
`a Conrad A. Label and Labeling Review for Rybelsus (NDA 213051). Silver Spring (MD): FDA, CDER, OSE, DMEPA
`(US); 2019 Aug 2 MON DD. RCM No.: 2019-643.
`
`1
`
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`Reference ID: 4486067Reference ID: 4497378
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`8 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following
`this page
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`

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`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/
`------------------------------------------------------------
`
`ARIANE O CONRAD
`09/03/2019 03:18:47 PM
`
`HINA S MEHTA
`09/04/2019 09:57:17 AM
`
`Reference ID: 4486067
`Reference ID: 4497378
`
`

`

`DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service
`
`
`Division of Pediatric and Maternal Health
`Office of New Drugs
`Center for Drug Evaluation and Research
`Food and Drug Administration
`Silver Spring, MD 20993
`Tel 301-796-2200
`FAX 301-796-9744
`
`
`Division of Pediatric and Maternal Health
`PLLR Labeling Memorandum
`
`August 29, 2019 Date consulted: April 8, 2019
`
`
`
`
`
`
`Date:
`
`From:
`
`
`Through:
`
`Jane Liedtka, M.D. Medical Officer, Maternal Health
`Division of Pediatric and Maternal Health (DPMH)
`
`Lynne P. Yao, MD, OND, Director
`Division of Pediatric and Maternal Health
`
`
`To: Peter Franks, Regulatory Health Project Manager (RPM)
`Division of Metabolic and Endocrine Products (DMEP)
`
`
`Drug/NDA: Rybelsus (semaglutide tablet), NDA 213051
`
`Applicant: Novo Nordisk Inc.
`
`Subject:
`
`Pregnancy and Lactation Labeling [New drug application (NDA), priority review,
`contains excipient not previously approved)
`
`
`Indications:
`
`• an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes
`mellitus (T2DM)
`• an adjunct to standard treatment of cardiovascular risk factors to reduce the risk of
`myocardial infarction or stroke in adults with T2DM and high cardiovascular risk
`
`
`Materials Reviewed:
`
`• DPMH review of Ozempic (semaglutide) injection, NDA 209637. Jane Liedtka, MD,
`September 6, 2017. DARRTS Reference ID 4148940.
`• Pharmacology/Toxicology review for semaglutide oral tablet, NDA 213051. Elena
`Braithwaite, PhD, August 23, 2019. DARRTS Reference ID 4482035.
`
`
`Consult Question:
`Please confirm PLLR format is acceptable.
`
`
`
`
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`Reference ID: 4484773Reference ID: 4497378
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`INTRODUCTION
`DMEP consulted DPMH on April 8, 2019, to provide input for appropriate labeling of the
`pregnancy and lactation subsections of NDA 213051 for Rybelsus, [semaglutide oral tablets
`formulated with an absorption enhancer, salcaprozate sodium (SNAC).] to comply with the
`Pregnancy and Lactation Labeling Rule (PLLR) format.
`
`REGULATORY HISTORY AND BACKGROUND
`• Ozempic [semaglutide, a human glucagon-like peptide-1 (GLP-1) receptor agonist], for
`injection was approved on December 5, 2017.
`• On March 20, 2019, Novo Nordisk, Inc. submitted a NDA for Rybelsus, a semaglutide oral
`tablet via the 505 (b) 2 pathway, which contains a novel absorption enhancer, SNAC. This
`product is indicated as an adjunct to diet and exercise to improve glycemic control in adults
`with T2DM and as an adjunct to standard treatment of cardiovascular risk factors to reduce
`the risk of myocardial infarction or stroke in adults with T2DM and high cardiovascular risk.
`• The Applicant proposes dosing as a once daily oral tablet.
`• The original submission included a review of the literature and a summary of the
`pharmacoviglance database regarding pregnancy, lactaion and effects on fertility for
`semaglutide.
`• At the time of the original consultation, DPMH proposed to attend the labeling meeting and
`provide recommendations for PLLR language but did not plan to provide a written review. A
`previous written DPMH review for Ozempic (semaglutide for injection), NDA 209637 was
`to be the basis for the labeling recommendations. Labeling recommendations similar to those
`proposed for the previous semaglutide injection product were provided prior to the first
`labeling meeting. The language for labeling that was approved are reproduced below from
`the 2019 Ozempic label1. Minor modifications in the language for the first sentence of
`section 8.1 Risk Summary are proposed by DPMH to update the language as follows:
`
`
`Available data with TRADENAME use in pregnant women are insufficient to
`evaluate for a drug-associated risk of major birth defects, miscarriage or other
`adverse maternal or fetal outcomes.
`
`
`
`OZEMPIC LABEL1
`Highlights of Prescribing Information (HPI)
`
` ∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙USE IN SPECIFIC POPULATIONS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
`Females and Males of Reproductive Potential: Discontinue OZEMPIC in women
`at least 2 months before a planned pregnancy due to the long washout period for
`semaglutide (8.3).
`
`
`
`
`
`
`
`
`
`1 Approved label for Ozempic, dated 4/9/2019
`
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`Reference ID: 4484773Reference ID: 4497378
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`Full Prescribing Information
`
` 8
`
` Use in Specific Populations
`8.1 Pregnancy
`Risk Summary
`There are limited data with semaglutide use in pregnant women to inform a drug-
`associated risk for adverse developmental outcomes. There are clinical
`considerations regarding the risks of poorly controlled diabetes in pregnancy (see
`Clinical Considerations). Based on animal reproduction studies, there may be
`potential risks to the fetus from exposure to semaglutide during pregnancy.
`OZEMPIC should be used during pregnancy only if the potential benefit justifies
`the potential risk to the fetus.
`
`In pregnant rats administered semaglutide during organogenesis, embryofetal
`mortality, structural abnormalities and alterations to growth occurred at maternal
`exposures below the maximum recommended human dose (MRHD) based on AUC.
`In rabbits and cynomolgus monkeys administered semaglutide during organogenesis,
`early pregnancy losses and structural abnormalities were observed at below the
`MRHD (rabbit) and ≥5-fold the MRHD (monkey). These findings coincided with a
`marked maternal body weight loss in both animal species (see Data).
`
`The estimated background risk of major birth defects is 6–10% in women with pre-
`gestational diabetes with an HbA1c >7 and has been reported to be as high as 20–25%
`in women with a HbA1c >10. In the U.S. general population, the estimated
`background risk of major birth defects and miscarriage in clinically recognized
`pregnancies is 2-4% and 15-20%, respectively.
`
`Clinical Considerations
`Disease associated maternal and fetal risk
`Poorly controlled diabetes during pregnancy increases the maternal risk for diabetic
`ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, stillbirth and
`delivery complications. Poorly controlled diabetes increases the fetal risk for major
`birth defects, stillbirth, and macrosomia related morbidity.
`
`Data
`Animal Data
`In a combined fertility and embryofetal development study in rats, subcutaneous
`doses of 0.01, 0.03 and 0.09 mg/kg/day (0.1-, 0.4-, and 1.1-fold the MRHD) were
`administered to males for 4 weeks prior to and throughout mating and to females for
`2 weeks prior to mating, and throughout organogenesis to Gestation Day 17. In
`parental animals, pharmacologically mediated reductions in body weight gain and
`food consumption were observed at all dose levels. In the offspring, reduced growth
`and fetuses with visceral (heart blood vessels) and skeletal (cranial bones, vertebra,
`ribs) abnormalities were observed at the human exposure.
`
`
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`In an embryofetal development study in pregnant rabbits, subcutaneous doses of
`0.0010, 0.0025 or 0.0075 mg/kg/day (0.03-, 0.3-, and 2.3-fold the MRHD) were
`administered throughout organogenesis from Gestation Day 6 to 19.
`Pharmacologically mediated reductions in maternal body weight gain and food
`consumption were observed at all dose levels. Early pregnancy losses and increased
`incidences of minor visceral (kidney, liver) and skeletal (sternebra) fetal
`abnormalities were observed at ≥0.0025 mg/kg/day, at clinically relevant exposures.
`
`In an embryofetal development study in pregnant cynomolgus monkeys,
`subcutaneous doses of 0.015, 0.075, and 0.15 mg/kg twice weekly (1.0-, 5.2-, and
`14.9-fold the MRHD) were administered throughout organogenesis, from Gestation
`Day 16 to 50. Pharmacologically mediated, marked initial maternal body weight loss
`and reductions in body weight gain and food consumption coincided with the
`occurrence of sporadic abnormalities (vertebra, sternebra, ribs) at ≥0.075 mg/kg twice
`weekly (>5X human exposure).
`
`In a pre-and postnatal development study in pregnant cynomolgus monkeys,
`subcutaneous doses of 0.015, 0.075, and 0.15 mg/kg twice weekly (0.7-, 3.3-, and
`7.2-fold the MRHD) were administered from Gestation Day 16 to 140.
`Pharmacologically mediated marked initial maternal body weight loss and reductions
`in body weight gain and food consumption coincided with an increase in early
`pregnancy losses and led to delivery of slightly smaller offspring at ≥0.075 mg/kg
`twice weekly (>3X human exposure).
`
`8.2 Lactation
`Risk Summary
`There are no data on the presence of semaglutide in human milk, the effects on the
`breastfed infant, or the effects on milk production. Semaglutide was present in the
`milk of lactating rats, however, due to species-specific differences in lactation
`physiology, the clinical relevance of these data are not clear (see Data). The
`developmental and health benefits of breastfeeding should be considered along with
`the mother’s clinical need for OZEMPIC and any potential adverse effects on the
`breastfed infant from OZEMPIC or from the underlying maternal condition.
`
`Data
`In lactating rats, semaglutide was detected in milk at levels 3-12 fold lower than in
`maternal plasma.
`
`8.3 Females and Males of Reproductive Potential
`Discontinue OZEMPIC in women at least 2 months before a planned pregnancy due
`to the long washout period for semaglutide [see Use in Specific Populations (8.1)].
`
`
`On August 13, 2019, the DPMH reviewer was advised by the Pharmacology-Toxicology (PT)
`team, of the Division’s concerns regarding the high concentration of the novel excipient SNAC,
`in the milk of lactating rats. More details were provided at a telecon with this reviewer and the
`PT team later that day. On August 14, 2019, the DPMH team (team leader Tamara Johson, MD
`and reviewer Jane Liedtka, MD) met with the division (including PT, clinical pharmacology and
`
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`clinical) and changes to the proposed lactation language were discussed. The need for a possible
`PMR for a lactation study was also discussed. DPMH advised DMEP that following
`consulatation with upper management on August 19, 2019, final labeling recommendations and a
`decision as to whether a lactation study was needed as a PMR would be provided.
`
`REVIEW
`
`Nonclinical Experience
`See above for nonclinical data for semaglutide. The division PT team proposed to add the
`following information about SNAC to the animal data for section 8.1 for NDA 213051.
`
`In a pre- and postnatal development study in pregnant Sprague Dawley rats, salcaprozate sodium
`(SNAC), an excipient in TRADENAME, was administered orally at 1,000 mg/kg/day (32-fold a
`clinical 300 mg dose based on BSA) on gestation days 7 through 24 or lactation day 20.
`Statistically significant increases in gestation length and the number of stillbirths, and decreases
`in pup viability were observed in the F1 generation descended from SNAC-treated rats when
`compared to F1 generation rats descended from controls.
`
`See nonclinical review by Federica Basso, PhD for further details.
`
`DPMH had previously reviewed Ozempic2, a semaglutide for injection at the time of the original
`submission for approval in 2017. See that review for the previous human experience with regard
`to the active moiety semaglutide.
`
`DMEP also provided the following information regarding SNAC:
`• The rat lacteal study showed that SNAC can accumulate in the breast milk after a single
`maternal administration on lactation day 10. Mean SNAC concentrations in rat breast milk
`could reach levels 12-fold higher than maternal plasma but ratios ranged between 0.982 –
`18.1-fold (please see table below).
`
`
`2 DPMH review of Ozempic(semaglutide) injection, NDA 209637. Jane Liedtka, MD, September 6, 2017. DARRTS
`Reference ID 4148940.
`
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`• SNAC plasma concentrations were not measured in the pups in the lacteal study. In a
`pre- and post-natal study, pups born to SNAC-treated mothers had an increased incidence
`of stillbirths and decreases in pup viability that exceeded ranges observed in historical
`controls. Discussion with the PT reviewer revealed that milk was not present in the
`stomachs of the rat pups that died, so mortality was not due to SNAC exposure via milk.
`We understand that it is difficult to determine how much pup exposure will occur through
`maternal milk; however, we are concerned because:
`o General toxicology studies show that SNAC causes mortality at Cmax values greater
`than 1,000,000 ng/mL. Since SNAC accumulates in the milk of lactating rats,
`neonates may achieve higher SNAC plasma concentrations than the mother.
`o The main enzyme responsible for detoxifying SNAC (UGT2B7) is not fully
`developed in neonates and their capacity to detoxify this compound may be reduced.
`o Maternal exposure to SNAC can vary greatly. While toxicokinetic parameters were
`not measured for the pre- and post-natal study, other mechanistic toxicology studies
`in rats show that Cmax values can vary 23-fold within a dosing group after repeated
`administration. So, it is unclear how much SNAC would be found in the milk of
`nursing mothers clinically. Therefore, the 32-fold safety margin we calculated using
`body surface area may not be very meaningful.
`o SNAC concentrations found in milk continued to accumulate up to 24 hours after a
`single exposure. We are not sure if SNAC would accumulate further after repeated
`administration. SNAC does not accumulate in humans after oral administration.
`
`
`The division proposed adding the following to the language for section 8.2
`
`
`SNAC and/or its metabolites were excreted in milk of lactating rats following
`administration at 1,000 mg/kg on lactation day 10. Levels of SNAC in milk were
`approximately 12-fold higher than those found in maternal blood based on Cmax.
`
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`Higher SNAC plasma levels may occur in neonates and infants, given that activity
`of UGT2B7, the major enzyme involved in SNAC clearance, is lower in infants
`compared to adults. SNAC caused inhibition of cellular respiration in adult rats at
`>30-times the clinical Cmax.
`
`The division proposed adding the following to the language for section 13.2
`
`
`SNAC caused inhibition of cellular respiration leading to mortality in rats at >30-
`and 96-times the clinical Cmax, respectively. In mechanistic studies, a single
`dose of SNAC resulted in adverse clinical signs (lethargy, abnormal respiration,
`ataxia, abnormal body posture and reduced activity, body tone and reflexes),
`marked increases in lactate levels and decreases in glucose levels in the plasma
`and cerebrospinal fluid, and reduced heart and liver ATP levels. In a 13-week
`mechanistic study, slight increases in lactate levels in the cerebrospinal fluid
`were observed at >8x the clinical Cmax. These findings are consistent with
`inhibition of cellular respiration.
`
`
`
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`
`
`Further information regarding SNAC includes
`• SNAC is currently available in a marketed ‘medical food’ in the US where 1,000 mcg
`vitamin B12 is formulated with 100 mg SNAC as EligenB123. The amount of SNAC
`present at the maximum recommended dose for EligenB12 is 200 mg, which is less
`than the 300 mg/day dose proposed in Rybelsus®; therefore, SNAC has not been used
`in a marketed product at the proposed level. EligenB12 has been on the market since at
`least 2016. Medical foods do not have to undergo premarket review or approval,
`making them similar to dietary supplements. SNAC has “generally regarded as safe”
`(GRAS) status.4
`• The FDA designation of EligenB12 as a medical food was based on 2 limited drug trials,
`including a pharmacokinetics study of oral formulations in 20 healthy men, and an efficacy
`and tolerability comparison of EligenB12with the current FDA-approved IM formulation in
`48 patients for 3 months.5 Adverse events associated with the product in the two small
`studies performed prior to marketing included constipation, diarrhea, nausea, fatigue,
`headache, back pain, and upper respiratory tract infection.
`• Pediatric patients may especially be at risk for decreased detoxification of SNAC. At birth, it
`is estimated that UGT2B7 operates at approximately 3-10% of its maximal activity in adults
`and its maturation profile can vary significantly (Badee, Fowler6 et al. 2019). Therefore,
`pediatric patients might be at a greater risk of adverse events due to immature detoxifying
`enzymes.
`
`3 EligenB12 Fact Sheet https://www.emisphere.com/wp-content/uploads/2017/01/Eligen-B12-Fact-Sheet-FINAL-
`12.3.14.pdf
`4 Twarog C et al. Intestinal Permeation Enhancers for Oral Delivery of Macromolecules: A Comparison between
`Salcaprozate Sodium (SNAC) and Sodium Caprate (C10). Pharmaceutics. 2019; 11(2) 78.
`5Smith L et al. Cyanocobalamin/Salcaprozate Sodium: A Novel Way to Treat Vitamin B12 Deficiency and Anemia.
`Hematol Oncol Pharm. 2016;6(2):42-45.
`6 Badee, J. et al. The Ontogeny of UDP-glucuronosyltransferase Enzymes, Recommendations for Future Profiling
`Studies and Application Through Physiologically Based Pharmacokinetic Modelling. Clin Pharmacokinet. 2019;
`58(2): 189-211.
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`Discussion of the Need for a PMR for a Lactation Study
`There are no published data on Rybelsus or SNAC levels in human milk or of exposure in
`breastfed infants. Animal studies indicate that SNAC and/or its metabolites was detected in the
`milk of lactating rats up to 12-fold the maternal blood concentration based on Cmax. When a
`drug is present in animal milk, it is likely that the drug will also be present in human milk.
`Higher SNAC plasma levels may occur in neonates and infants, given that activity of UGT2B7,
`the major enzyme involved in SNAC clearance, is lower in infants compared to adults. Based on
`findings in animals, it is possible that SNAC will be present in human milk and that an infant
`may be at risk for harm. DPMH recommends including information about possible exposure to
`SNAC in the risk summary for subsection 8.2. See DPMH Proposed Rybelsus (semaglutide)
`Oral Tablet Labeling for details.
`
`Rybelsus is indicated for a condition that would be expected to be seen commonly in females of
`reproductive potential and increased use may be expected with a new oral route of
`administration. Since there are concerns based on animal studies, that the drug may accumulate
`in human milk, DPMH recommends a PMR for the applicant to conduct a milk only lactation
`study.
`
`RECOMMENDATIONS
`1. DPMH recommends a PMR for a milk only lactation study in women receiving Rybelsus
`using a validated assay to assess concentrations of semaglutide and salcaprozate sodium
`(SNAC) in breast milk.
`
`2. DPMH proposes the following language for Rybelsus (semaglutide) oral tablet PLLR
`labeling. DPMH met again with the DMEP team to discuss labeling and the PMR for a
`lactation study on August 28, 2019. DPMH refers to the final NDA action for final
`labeling.
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`8
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`DPMH Proposed Rybelsus (semaglutide) oral tablet Pregnancy and Lactation Labeling
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`
` -----------------------USE IN SPECIFIC POPULATIONS------------------------
`• Pregnancy: May cause fetal harm (8.1).
`• Lactation: Breastfeeding not recommended (8.2).
`• Females and Males of Reproductive Potential: Discontinue TRADENAME in women at
`least 2 months before a planned pregnancy due to the long washout period for
`semaglutide (8.3).
`
`
`FULL PRESCRIBING INFORMATION
`
` 8
`
` USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`Risk Summary
`Available data with TRADENAME use in pregnant women are insufficient to evaluate for a
`drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal
`outcomes. There are clinical considerations regarding the risks of poorly controlled diabetes in
`pregnancy (see Clinical Considerations). Based on animal reproduction studies, there may be
`potential risks to the fetus from exposure to TRADENAME during pregnancy. TRADENAME
`should be used during pregnancy only if the potential benefit justifies the potential risk to the
`fetus.
`
`In pregnant rats administered semaglutide during organogenesis, embryofetal mortality,
`structural abnormalities and alterations to growth occurred at maternal exposures below the
`maximum recommended human dose (MRHD) based on AUC. In rabbits and cynomolgus
`monkeys, early pregnancy losses and structural abnormalities, which did not resemble the
`abnormalities in rats, were observed at exposures ≥ 0.3-fold the MRHD (rabbit) and ≥ 10-fold
`the MRHD (monkey). These findings coincided with a marked maternal body weight loss in both
`animal species (see Data).
`
`The estimated background risk of major birth defects from women with uncontrolled pre-
`gestational diabetes (Hemoglobin A1C >7) is 6 to 10%. The major birth defect rate has been
`reported to be as high as 20 to 25% in women with a Hemoglobin A1C >10. In the U.S. general
`population, the estimated background risk of major birth defects and miscarriage in clinically
`recognized pregnancies is 2-4% and 15-20%, respectively.
`
`Clinical Considerations
`Disease-associated maternal and/or embryo/fetal risk
`Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-
`eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly
`controlled diabetes increases the fetal risk for major birth defects, still birth, and macrosomia
`related morbidity.
`
`
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`Data
`Animal Data
`In a combined fertility and embryofetal development study in rats, subcutaneous doses of 0.01,
`0.03 and 0.09 mg/kg/day (0.2-, 0.7-, and 2.1-fold the MRHD) were administered to males for 4
`weeks prior to and throughout mating and to females for 2 weeks prior to mating, and throughout
`organogenesis to Gestation Day 17. In parental animals, pharmacologically mediated reductions
`in body weight gain and food consumption were observed at all dose levels. In the offspring,
`reduced growth and fetuses with visceral (heart blood vessels) and skeletal (cranial bones,
`vertebra, ribs) abnormalities were observed at the human exposure.
`
`In an embryofetal development study in pregnant rabbits, subcutaneous doses of 0.0010, 0.0025
`or 0.0075 mg/kg/day (0.06-, 0.6-, and 4.4-fold the MRHD) were administered from Gestation
`Day 6 throughout organogenesis to Gestation Day 19. Pharmacologically mediated reductions in
`maternal body weight gain and food consumption were observed at all dose levels. Early
`pregnancy losses and increased incidences of minor visceral (kidney, liver) and skeletal
`(sternebra) fetal abnormalities were observed at ≥0.0025 mg/kg/day, at clinically relevant
`exposures.
`
`In an embryofetal development study in pregnant cynomolgus monkeys, subcutaneous doses of
`0.015, 0.075, and 0.15 mg/kg twice weekly (1.9-, 9.9-, and 29-fold the MRHD) were
`administered from gestation day 16 to 50. Pharmacologically mediated, marked initial maternal
`body weight loss and reductions in body weight gain and food consumption coincided with the
`occurrence of sporadic abnormalities (vertebra, sternebra, ribs) at ≥0.075 mg/kg twice weekly
`(>9X human exposure).
`
`In a pre- and postnatal development study in pregnant cynomolgus monkeys, subcutaneous doses
`of 0.015, 0.075, and 0.15 mg/kg twice weekly (1.3-, 6.4-, and 14-fold the MRHD) were
`administered from Gestation Day 16 to 140. Pharmacologically mediated marked initial maternal
`body weight loss and reductions in body weight gain and food consumption coincided with an
`increase in early pregnancy losses and led to delivery of slightly smaller offspring at ≥0.075
`mg/kg twice weekly (>6X human exposure).
`
`Salcaprozate sodium (SNAC), an absorption enhancer in TRADENAME, crosses the placenta
`and reaches fetal tissues in rats. In a pre- and postnatal development study in pregnant Sprague
`Dawley rats, SNAC was administered orally at 1,000 mg/kg/day ((approximately 39-fold the
`MRHD based on mg/body surface area) on gestation day 7 through lactation day 20. An increase
`in gestation length, an increase in the number of stillbirths and a decrease in pup viability were
`observed.
`
`
`Lactation
`8.2
`Risk Summary
`There are no data on the presence of semaglutide in human milk, the effects on the breastfed
`infant, or the effects on milk production. Semaglutide was present in the milk of lactating rats.
`SNAC and/or its metabolites concentrated in the milk of lactating rats. When a substance is
`present in animal milk, it is likely that the substance will be present in human milk (see Data).
`There are no data on the presence of SNAC in human milk. Since the activity of UGT2B7, an
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`enzyme involved in SNAC clearance, is lower in infants compared to adults, higher SNAC
`plasma levels may occur in neonates and infants. Because of the potential for serious adverse
`reactions in the breastfed infant due to possible accumulation of SNAC from breastfeeding and
`because there are alternative formulations of semaglutide that can be used during lactation,
`advise patients that breastfeeding is not recommended during treatment with TRADENAME.
`
`Data
`In lactating rats, semaglutide was detected in milk at levels 3-12 fold lower than in maternal
`plasma. SNAC and/or its metabolites were detected in milk of lactating rats following a single
`maternal administration on lactation day 10. Levels of and its metabolites in milk were
`approximately 2-12 fold higher than those found in maternal plasma.
`
`8.3 Females and Males of Reproductive Potential
`Discontinue TRADENAME at least 2 months before a planned pregnancy due to the long
`washout period for semaglutide [see Use in Specific Populations (8.1)].
`
`17 PATIENT COUNSELING INFORMATION
`Pregnancy
`Advise a pregnant woman of the potential risk to a fetus. Advise women to inform their
`healthcare provider if they are pregnant or intend to become pregnant [see Use in Specific
`Populations (8.1)].
`
`Lactation
`Advise females not to breastfeed during treatment with TRADENAME [see Use in Specific
`Populations (8.2)].
`
`Females and Males of Reproductive Potential
`Discontinue TRADENAME at least 2 months before a planned pregnancy due to the long
`washout period for semaglutide [see Use in Specific Populations (8.3)].
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`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/
`------------------------------------------------------------
`
`JANE E LIEDTKA
`08/29/2019 04:11:00 PM
`
`MIRIAM C DINATALE
`08/29/2019 04:15:40 PM
`
`LYNNE P YAO
`09/03/2019 10:07:29 AM
`
`Reference ID: 4484773
`Reference ID: 4497378
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`

`

`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
`
`August 28, 2019
`
`Lisa Yanoff, MD
`Acting Director
`Division of Metabolism and Endocrinology Products
`(DMEP)
`
`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)
`
`Maria Nguyen, MSHS, BSN, RN
`Patient Labeling Reviewer
`Division of Medical Policy Programs (DMPP)
`Samantha Bryant, PharmD, BCPS
`Regulatory Review Officer
`Office of Prescription Drug Promotion (OPDP)
`Review of Patient Labeling: Medication Guide (MG)
`
`TRADENAME (semaglutide)
`
`tablets, for oral use
`
`
`Date:
`
`To:
`
`
`Through:
`
`
`From:
`
`Subject:
`
`Drug Name (established
`name):
`Dosage Form and
`Route:
`Application
`Type/Number:
`Applicant:
`
`NDA 213051
`
`Novo Nordisk, Inc.
`
`
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`Reference ID: 4483815Reference ID: 4497378
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` 1
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` 2
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`INTRODUCTION
`On March 20, 2019, Novo Nordisk, Inc., submitted for the Agency’s review a New
`Drug Application (NDA) 213051 TRADENAME (semaglutide) tablets, for oral use.
`The proposed indication is for treatment as an adjunct to diet and exercise to improve
`glycemic control in adults with type 2 diabetes mellitus.
`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 Metabolism and Endocrinology Products (DMEP) on
`April 8, 2019, for DMPP and OPDP to review the Applicant’s proposed Medication
`Guide (MG) for TRADENAME (semaglutide) tablets, for oral use.
`
` MATERIAL REVIEWED
`• Draft TRADENAME (semaglutide) tablets MG received on March 20, 2019,
`revised by the Review Division throughout the review cycle, and received by
`DMPP and OPDP on August 26, 2019.
`• Draft TRADENAME (semaglutide) Prescribing Information (PI) received on
`March 20, 2019, revised by the Review Division throughout the review cycle, and
`received by DMPP on August 26, 2019.
`• Approved OZEMPIC (semaglutide) injection, for subcutaneous use, labeling
`dated December 5, 2017.
`
`
`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%.
`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.
`In our collaborative review