`
`
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`208026Orig1s000
`
`
`OTHER REVIEW(S)
`
`

`

`
`Date:
`
`To:
`
`
`Through:
`
`
`From:
`
`Subject:
`
`Department of Health and Human Services
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Medical Policy
`
`PATIENT LABELING REVIEW
`
`May 5, 2016
`
`Jean-Marc Guettier, MD
`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)
`Shawna Hutchins, MPH, BSN, RN
`Team Leader, Patient Labeling
`Division of Medical Policy Programs (DMPP)
`
`Sharon W. Williams, MSN, BSN, RN
`Patient Labeling Reviewer
`Division of Medical Policy Programs (DMPP)
`
`Charuni Shah, PharmD
`Regulatory Review Officer
`Office of Prescription Drug Promotion (OPDP)
`Review of Patient Labeling: Medication Guide (MG)
`
`JENTADUETO XR (linagliptin and metformin
`hydrochloride)
`
`extended-release tablets, for oral use
`
`
`NDA 208026
`
`
`
`Boehringer Ingelheim Pharmaceuticals, Inc.
`
`
`
`
`
`Drug Name (established
`name):
`
`Dosage Form and Route:
`
`Application
`Type/Number:
`
`
`Applicant:
`
`
`
`
`
`
`
`
`Reference ID: 3927045
`
`

`

` 1
`
`
`
`INTRODUCTION
`On July 27, 2015, Boehringer Ingelheim Pharmaceuticals, Inc. submitted for the
`Agency’s review a New Drug Application for JENTADUETO XR (linagliptin and
`metformin hydrochloride) extended-release tablets. The purpose of the submission is
`to seek approval for the extended release form for JENTADUETO (linagliptin and
`metformin hydrochloride) tablets which are currently approved.
`JENTADUETO XR (linagliptin and metformin hydrochloride) extended-release
`tablets are used as an adjunct to diet and exercise to improve glycemic control in
`adults with type 2 diabetes mellitus when treatment with both linagliptin and
`metformin is appropriate.
` 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 July
`31, 2015, for DMPP and OPDP to review the Applicant’s proposed Medication
`Guide (MG) for JENTADUETO XR (linagliptin and metformin hydrochloride)
`extended-release tablets.
`
`2 MATERIAL REVIEWED
`• Draft JENTADUETO XR (linagliptin and metformin hydrochloride) extended-
`release tablets MG received on July 27, 2015, revised by the Review Division
`throughout the review cycle and received by DMPP and OPDP on April 29, 2016.
`• Draft, JENTADUETO XR (linagliptin and metformin hydrochloride) extended-
`release tablets Prescribing Information (PI) received on July 27, 2015, revised by
`the Review Division throughout the review cycle, and received by DMPP and
`OPDP on April 29, 2016.
`• Approved JENTADUETO (linagliptin and metformin hydrochloride) tablet
`labeling dated April 28, 2015.
`
` 3
`
` REVIEW METHODS
`In 2008 the American Society of Consultant Pharmacists Foundation (ASCP) in
`collaboration with the American Foundation for the Blind (AFB) published
`Guidelines for Prescription Labeling and Consumer Medication Information for
`People with Vision Loss. The ASCP and AFB recommended using fonts such as
`Verdana, Arial or APHont to make medical information more accessible for patients
`with vision loss. We reformatted the MG document using the Arial font, size 10.
`In our collaborative review of the MG we:
`simplified wording and clarified concepts where possible
`•
`ensured that the MG is consistent with the Prescribing Information (PI)
`•
`ensured that the MG is free of promotional language or suggested revisions to
`•
`ensure that it is free of promotional language
`
`
`
`
`
`Reference ID: 3927045
`
`
`
`

`

`•
`
`•
`
`ensured that the MG meets the criteria as specified in FDA’s Guidance for
`Useful Written Consumer Medication Information (published July 2006)
`ensured that the MG is consistent with the approved comparator labeling where
`applicable
`
` CONCLUSIONS
`The MG is 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 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.
` Please let us know if you have any questions.
`
` 4
`
` 5
`
`
`
`
`
`Reference ID: 3927045
`
`
`
`7 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`SHARON W WILLIAMS
`05/05/2016
`
`CHARUNI P SHAH
`05/05/2016
`
`SHAWNA L HUTCHINS
`05/05/2016
`
`Reference ID: 3927045
`
`

`

`suVlCu.
`
`”‘9
`
`9“
`3°
`
`3&0 C
`(”Mum
`
`DEPARTNIENT OF HEALTH & HUMAN SERVICES
`
`Public Health Service
`
`Division ofPediatric and Maternal Health
`Office ofNew 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 Memorandum
`
`Date:
`
`April 28, 2016
`
`Date consulted: July 31, 2015
`
`From:
`
`Miriam Dinatale, DO, Medical Officer, Maternal Health
`Division of Pediatric and Maternal Health
`
`Through:
`
`Tamara Johnson, MD, MS, Acting Team Leader, Maternal Health
`Division of Pediatric and Maternal Health
`
`Lynne P. Yao, MD, 0ND, Division Director
`Division of Pediatric and Maternal Health
`
`To:
`
`Division of Metabolic and Endocrine Products (DMEP)
`
`Drug/NDA:
`
`Jentadueto XR (linagliptin and metformin hydrochloride extended-release),
`NDA 208026
`
`Applicant:
`
`Boehringer Ingelheirn Pharmaceuticals, Inc.
`
`Subject:
`
`Pregnancy and Lactation Labeling
`
`Indication:
`
`Treatment of adults with Type 2 Diabetes Mellitus
`
`Materials
`
`Reviewed:
`
`0 DPMH consult request dated July 31, 2015, DARRTS Reference ID 3800707.
`
`Sponsor’s submitted background package for NDA 208026, Linagliptin/Metformin XR
`0
`o DPMH review of pioglitazone products. March 9, 2016. Miriam Dinatale, DO. and
`Christos Mastroyannis, M.D. DARRTS Reference ID 3898973.
`
`0 DPMH addendum of pioglitazone products. April 28, 2016. Miriam Dinatale, DO. and
`Christos Mastroyannis, M.D. DARRTS Reference ID 3921521.
`
`Reference ID: 3924141
`
`

`

`Consult Question:
`DMEP requests DPMH to review the applicant’s proposed labeling and confirm that the PLLR
`format is acceptable.
`
`INTRODUCTION
`The Division of Metabolic and Endocrine Products (DMEP) consulted the Division of Pediatric
`and Maternal Health (DPMH) to provide input for appropriate labeling of the pregnancy and
`lactation subsections of Jentadueto XR labeling to comply with the Pregnancy and Lactation
`Labeling Rule format.
`
`REGULATORY HISTORY
`On July 27, 2015, Boehringer Ingelheim Pharmaceuticals, Inc.(BIPI), submitted a 505 (b)(1)
`New Drug Application (NDA 208026) for Jentadueto XR (linagliptin/metformin extended-
`release) for the proposed indication of treatment of adults with type 2 diabetes mellitus. The
`reference listed drugs include: Tradjenta (linagliptin), NDA 201280, approved May 2, 2011;
`Glumetza (metformin hydrochloride), NDA 021748, approved June 3, 2005, and Jentadueto
`(linagliptin/metformin), NDA 201281, approved January 30, 2012.
`
`BACKGROUND
`Diabetes and Pregnancy1,2,3,4,5,6,7
`Diabetes mellitus (DM) complicates approximately 4% of all pregnancies in the Unites States.
`Poorly controlled DM during pregnancy increases the risk for maternal complications,
`including diabetic ketoacidosis, preeclampsia, spontaneous abortions (SAB), preterm delivery,
`stillbirth and cesarean section (due to fetal macrosomia).
`
`Poorly controlled DM during pregnancy increases the risk for fetal malformations, including
`neural tube defects (anencephaly, open spina bifida, and holoprosencephaly), cardiovascular
`anomalies (ventricular septal defects and transposition of the great vessels), oral clefts,
`genitourinary abnormalities (absent kidneys, polycystic kidney, and double ureter), and sacral
`agenesis or caudal regression. The estimated background risk of major birth defects is 6-10%
`in women with pre-gestational diabetes with a HemoglobinA1c>7 and has been reported to be
`as high as 20-25% in women with a Hemoglobin A1c>10. In addition, poorly controlled DM
`may result in fetal complications, including macrosomia-related injuries (brachial plexus
`injury, hypoxia), fetal hypoglycemia, and respiratory distress. However, achieving and
`maintaining maternal euglycemia prior to conception and throughout pregnancy decreases the
`risk of adverse outcomes for both the mother and the infant.
`
`
`
`1 Mills JL. Malformations in infants of diabetic mothers. Teratology.1982:25;385-94
`2 Persson, M. and Fadi, H. Perinatal outcome in relation to fetal sex in offspring to mothers with pre-gestational and
`gestational diabetes- a population-based study. Diabetes Med. 2014; 31(9): 1047-54.
`3 www.cdc.gov. Problems of Diabetes in Pregnancy. Accessed 12/30/2015.
`4 ACOG Practice Bulletin: Clinical Management Guidelines for Obstetrician-Gynecologists. 2005; 60:675-685.
`5 Organization of Teratology Information Specialists (OTIS) Fact Sheet. MotherToBaby.org. Accessed 3/9/2016.
`6 Allen, Victoria, et al. Teratology Associated with Pre-Existing and Gestational Diabetes. SOGC Practice
`Guidelines. 2007; 200: 927-934.
`7 E. Albert Reece, John C. Hobbins. Handbook of Clinical Obstetrics: The Fetus & Mother, Third Edition. 2007.
`Blackwell Publishing Ltd.
`
`Reference ID: 3924141
`
`

`

`Linagliptin and Drug Characteristics8
`Linagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor. DPP-4 is an enzyme that degrades the
`incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic
`polypeptide (GIP). Linagliptin increases the concentrations of active incretin hormones,
`stimulates the release of insulin and decreases the levels of glucagon. Linagliptin has a
`molecular weight of 472 Daltons, is 70-80% protein bound and has a half-life of 12 hours.9
`
`Metformin and Drug Characteristics10
`Metformin is a biguanide that improves glucose tolerance in patients with type 2 diabetes by
`lowering basal and postprandial plasma glucose. Metformin decreases hepatic glucose
`production, decreases intestinal absorption of glucose and improves insulin sensitivity by
`increasing peripheral glucose uptake and utilization. Metformin has a molecular weight of
`165.65 Daltons, a plasma elimination half-life of six hours, and does not bind to proteins. Serious
`adverse events that have occurred with use of metformin include: lactic acidosis and impairment
`of renal function.
`
`Pregnancy and Lactation Labeling
`On June 30, 2015, the “Content and Format of Labeling for Human Prescription Drug and
`Biological Products; Requirements for Pregnancy and Lactation Labeling,”11 also known as the
`Pregnancy and Lactation Labeling Rule (PLLR) went into effect. The PLLR requirements
`include a change to the structure and content of labeling for human prescription drug and
`biologic products with regard to pregnancy and lactation and create a new subsection for
`information with regard to females and males of reproductive potential. Specifically, the
`pregnancy categories (A, B, C, D and X) are removed from all prescription drug and biological
`product labeling and a new format is required for all products that are subject to the 2006
`Physicians Labeling Rule12 format to include information about the risks and benefits of using
`these products during pregnancy and lactation.
`
`LITERATURE REVIEW
`Nonclinical Experience
`In animal reproduction studies performed with linagliptin/metformin administered to pregnant
`rats during the period of organogenesis at doses similar to clinical exposure, there was no
`evidence of adverse developmental effects. There was no evidence of adverse developmental
`effects with administration of linagliptin to pregnant rats and rabbits during the period of
`organogenesis at doses 943 and 1943-times, respectively, the clinical dose. In addition, there
`was no evidence of adverse developmental effects with administration of metformin to pregnant
`rats and rabbits during the period of organogenesis at doses 3 and 6- times the maximum
`recommended human dose, respectively. The reader is referred to the full
`Pharmacology/Toxicology review by David Carlson, Ph.D.
`
`
`8 Tradjenta (linagliptin) Labeling. Section 12: Clinical Pharmacology. Drugs @FDA. Accessed 10/29/2015
`9 http://www.drugbank.ca/drugs/db00422. Accessed 2/16/2015
`10 Glumetza (metformin hydrochloride XR) Labeling. Section 12: Clinical Pharmacology. Drugs @FDA. Accessed
`10/29/2015
`11 Content and Format of Labeling for Human Prescription Drug and Biological Products, Requirements for
`Pregnancy and Lactation Labeling (79 FR 72063, December 4, 2014).
`12 Requirements on Content and Format of Labeling for Human Prescription Drug and Biological Products,
`published in the Federal Register (71 FR 3922; January 24, 2006).
`
`Reference ID: 3924141
`
`

`

`Linagliptin and Pregnancy
`The applicant performed a literature search in Medline and Embase covering the period between
`1995 and August 24, 2015 to identify published literature on pregnancy-related publications for
`linagliptin/metformin or linagliptin. However, there was no relevant information that discussed
`the use of linagliptin during pregnancy.
`
`In clinical trials, there were four cases of exposure to linagliptin/metformin during pregnancy.
`The pregnancy outcomes were known in three out of the four cases and included three elective
`abortions (one due to holoprosencephaly, one due to the absence of a fetal heartbeat, no reason
`identified for the third abortion).
`
`In addition, there were two reports of pregnancy during linagliptin or linagliptin/metformin use
`in the Boehringer Ingelheim global safety database. In one case the father was exposed to
`linagliptin/metformin during conception, but the outcome of the pregnancy was not known. In
`the second case, a female patient was exposed to linagliptin/metformin and was switched to
`insulin half-way through her pregnancy. She had a normal fetal ultrasound, and the outcome of
`the pregnancy was not reported.13
`
`In addition to the search of published literature and pharmacovigilance databases performed by
`the applicant, DPMH also conducted a literature search in PubMed and Embase and the TERIS
`and ReproTox databases14 for linagliptin and use in pregnancy. No adequate and well-controlled
`studies of linagliptin have been conducted in pregnant women, and there were no additional
`human data that discussed the use of linagliptin during pregnancy.
`
`Linagliptin and Lactation
`Nonclinical studies demonstrated that linagliptin is present in the milk of lactating rats in a 4:1
`ratio to plasma.
`
`No exposure to infants during breastfeeding was reported during the clinical trials for linagliptin.
`In addition to the search of published literature and pharmacovigilance databases performed by
`the applicant, DPMH also performed a search of the Drugs and Lactation Database (LactMed)15
`and PubMed. There is no information in published literature about the use of linagliptin (or
`other drugs in the same class) during breastfeeding. LactMed states the following:
`
`
`Because no information is available on the use of linagliptin during breastfeeding, an
`alternate drug may be preferred, especially while nursing a newborn or preterm infant.
`
`
`Summary
`Linagliptin is present in rat milk at up to four-fold higher concentration in maternal milk than
`plasma. Drug presence and accumulation in breast milk is species specific; therefore, no direct
`
`
`13 Boehringer Ingelheim. Periodic Benefit-Risk Evaluation Report. May 3, 2014 to May 2, 2015.
`14 TERIS and ReproTox databases, Truven Health Analytics, Micromedex Solutions, 2016.
`15 http://toxnet nlm nih.gov/cgi-bin/sis/htmlgen?LACT. The LactMed database is a National Library of Medicine
`(NLM) database with information on drugs and lactation geared toward healthcare practitioners and nursing women.
`The LactMed database provides information when available on maternal levels in breast milk, infant blood levels,
`any potential effects in the breastfed infants if known, alternative drugs that can be considered and the American
`Academy of Pediatrics category indicating the level of compatibility of the drug with breastfeeding.
`
`Reference ID: 3924141
`
`

`

`relationship can be made in humans. However, the rat data appear to support active transport of
`drug into milk because the levels are higher in milk compared to plasma. Linagliptin has a low
`molecular weight (472 Daltons), a long half-life (12 hours), and low protein-binding (70-80%),
`characteristics that all may increase the likelihood that the drug is transferred into breast milk.16
`Current Tradjenta (linagliptin) labeling17 notes that “caution should be exercised when Tradjenta
`is administered to a nursing woman.”
`
`Based on recent DPMH recommendations for another DDP4 (alogliptin)18 and given the lack of
`lactation information for linagliptin, DPMH recommends that the following statement appear in
`the “Risk Summary” section of Jentadueto XR labeling:
`The developmental and health benefits of breastfeeding should be considered along with the
`mother’s clinical need for JENTADUETO XR and any potential adverse effects on the
`breastfed
` from JENTADUETO XR or from the underlying maternal condition.
`
`
`Linagliptin and Females and Males of Reproductive Potential
`In animal fertility studies in rats given linagliptin at doses 943-times the clinical dose based on
`the Area under the Curve (AUC) exposure, there was no evidence of impaired fertility.19 The
`applicant performed a literature review of Medline, Embase and PubMed to identify reports of
`reproductive toxicity with linagliptin and linagliptin/metformin use in humans, and no reports of
`reproductive toxicity were found.
`
`In addition to the search of published literature performed by the applicant, DPMH also
`conducted a review of published literature in PubMed and Embase to evaluate the use of
`linagliptin and its effects on fertility. No additional data were found.
`
`Summary
`There are no human data on the effects of linagliptin on fertility and no evidence of infertility
`in animal studies to inform a potential clinical risk.
`
`Metformin and Pregnancy
`Metformin is primarily used in women with pre-gestational diabetes and off-label in women with
`polycystic ovary syndrome (PCOS) for infertility. For treatment of pre-gestational diabetes,
`metformin is often continued during pregnancy and insulin is added as appropriate to the therapy
`regimen. In women with PCOS, metformin is often continued until the end of the first trimester,
`with only limited evidence to suggest that such use decreases the risks of adverse pregnancy
`outcomes, including first-trimester loss.20 Metformin use in women with gestational diabetes and
`PCOS has not been approved by the U.S. Food and Drug Administration.
`
`
`16 Nice, F and Luo, Amy. Medications and breast-feeding: Current Concepts. Journal of the American Pharmacists
`Association. 2012; 51 (1): 86-94.
`17 Drugs@FDA. Tradjenta (linagliptin) Labeling. Section 8.3, Nursing Mothers. Accessed 3/25/2016.
`18 DPMH addendum of pioglitazone products. April 28, 2016. Miriam Dinatale, D.O. and Christos Mastroyannis,
`M.D. DARRTS Reference ID 3921521.
`19 Boehringer Ingelheim Pharmaceuticals, Inc proposed Jentadueto XR Labeling: Section 13, Nonclinical
`Toxicology.
`20 De Leo, et al. The administration of metformin during pregnancy reduces polycystic ovary syndrome related
`gestational complications. Eur J Obstet Gynecol Reprod Biol 2011; 157:63–6.
`
`Reference ID: 3924141
`
`(b) (4)
`
`

`

`The applicant performed a literature search in Medline and Embase covering the period between
`1995 and August 24, 2015 to identify published literature on pregnancy-related publications for
`the linagliptin and metformin combination or metformin alone. The search retrieved a total of
`483 publications related to metformin monotherapy in pregnancy and reviewed 34 relevant
`articles. In addition to the applicant’s search of published literature for information about
`metformin use during pregnancy, DPMH also conducted a literature search in PubMed, Embase,
`ReproTox, and TERIS. The results of the literature search are described below.
`
`Metformin use in Gestational Diabetes
`Overall, published literature that has evaluated metformin use for gestational diabetes has shown
`no clear association between metformin use in pregnancy and adverse maternal or fetal
`outcomes. 21,22,23 The Metformin in Gestational Diabetes (MiG) trial was a large (n=751)
`randomized, open label trial comparing the use of metformin versus insulin in the treatment of
`gestational diabetes. The primary focus of the study was on neonatal outcomes. There was no
`significant difference in the primary composite outcome (neonatal hypoglycemia, respiratory
`distress, phototherapy need, birth trauma, 5 minute APGAR score <7 and prematurity) between
`the two arms (32% metformin vs 32.2% insulin [p=0.95], RR=0.99, 95% CI 0.8-1.23). There
`were more incidences of neonatal severe hypoglycemia (BG levels <28.8mg/dL) with insulin
`compared to metformin (8.1% vs 3.3%, p=0.008). There was a significant increase in the
`number of preterm births (<37 weeks gestation) with metformin compared to insulin (12.1% vs
`7.6%, p=0.04). However, there was minimal clinical difference in mean gestational age between
`the two agents (38.3 weeks with metformin versus 38.5 weeks with insulin).24
`
`Since the MiG trial, nine other metformin studies (randomized control trials, case-control trials
`and observational studies) in women with gestational diabetes have been published. Six trials
`compared metformin to insulin25,26,27,28,29,30and three trials compared metformin to
`glyburide.31,32,33 For all but one of the studies that compared insulin to metformin [24, 25, 26,
`
`
`21 Langer, et al. There is no association between oral hypoglycemic use and fetal anomalies. Am J Obstet Gynecol
`1999;180:S38
`22 Nicholson W, Bolen S, Witkop CT, Neale D, Wilson L, Bass E. Benefits and risks of oral diabetes agents
`compared with insulin in women with gestational diabetes: a systematic review. Obstet Gynecol 2009; 113:193–205.
`23 Carrol, D., Kelley, K.: Review of metformin and glyburide in the management of gestational diabetes. Pharm
`Pract (Granada). 2014 Oct-Dec; 12(4): 528
`24 Rowan, J. et al. Metformin versus Insulin for the Treatment of Gestational Diabetes. The New England Journal of
`Medicine. 2008; 358: 2003-2015.
`25 Tertti, et al. Comparison of metformin and insulin in the treatment of gestational diabetes: a retrospective case-
`control study. Rev Diabet Stu. 2008; 5 (2): 95-101.
`26 Balani, et al. Pregnancy outcomes in women with gestational diabetes treated with metformin or insulin: a case-
`control study. Diabet Med. 2009; 26 (8):798–802.
`27 Ijäs, et al. Metformin should be considered in the treatment of gestational diabetes: a prospective
`randomised study. BJOG. 2011; 118(7):880–885.
`28 Niromanesh, et al. Metformin compared with insulin in the management of gestational diabetes: a randomized
`clinical trial. Diabetes Res Clin Pract. 2012;98(3):422–9.
`29 Tertti K, et al. Metformin vs insulin in gestational diabetes. A randomized study characterizing metformin
`patients needing additional insulin. Diabetes Obes Metab. 2013;15(3):246–251.
`30 Spaulonci, et al. Randomized trial of metformin vs insulin in the management of gestational diabetes. Am J
`Obstet Gynecol. 2013; 209(1):34.e1–7.
`31 Silva, et al. Metformin compared to glyburide for the management of gestational diabetes. Int J Gynaecol
`Obstet. 2010;111(1):37–40.
`
`Reference ID: 3924141
`
`

`

`27, 29], there were no differences in birth weight, gestational age, mode of delivery, prematurity
`or perinatal deaths. One trial [28] reported more infants with birth weights >90th percentile (35%
`versus 17.5%, p=0.012) and higher birth weights (3.4 kg versus 3.3kg, p-value= 0.005) in the
`insulin group compared to the metformin group. For trials that compared metformin to
`glyburide, there was no difference in maternal blood glucose, neonatal hypoglycemia,
`macrosomia or gestational age of delivery.
`
`The American College of Obstetrics and Gynecology (ACOG) recently updated its position
`statement regarding the use of oral medications in the treatment of gestational diabetes and noted
`that both glyburide and metformin have favorable safety profiles.34
`
`Metformin Use in PCOS and Type 2 Diabetes Mellitus
`Data from PCOS and Type 2 Diabetes Mellitus (i.e., DM that was present prior to pregnancy)
`studies provide information on the effects of metformin use in the first trimester of pregnancy.
`Published observational studies do not report a clear association with metformin use in the first
`trimester of pregnancy and major birth defects, miscarriage or adverse perinatal outcomes
`(decreased fetal growth, neonatal hypoglycemia).35,36,37,38,39,40
`
`There are two studies that have demonstrated an increase in complications with metformin use
`during pregnancy.
`
`In a retrospective cohort study (Hellmuth, et al), the authors found that the prevalence of
`pre-eclampsia was increased in the metformin group compared to the sulfonylurea and
`insulin groups (32% versus 7% versus 10%, p-value <0.001). There was also an increase
`in perinatal mortality in the metformin group versus women not treated with metformin
`(11.6% versus 1.3%, p-value <0.02).41
`In a multicenter, observational prospective cohort study (Panchaud, et al.), major
`congenital anomalies were more frequent among the infants of 323 women who had used
`metformin during pregnancy than among control infants (7.6% vs. 2.5% respectively;
`odds ratio=3.2, 95% confidence interval 1.3-9.2, p=0.005). However, the authors noted
`that there is a potential for confounding effects of the underlying metabolic disease and
`
`32 Moore, et al. Metformin compared with glyburide in gestational diabetes. Obstet Gynecol. 2010;115(1):55–59.
`33 Silva JC, Fachin DR, Coral ML, Bertini AM. Perinatal impact of the use of metformin and glyburide for the
`treatment of gestational diabetes mellitus. J Perinat Med. 2012;40(3):225–228.
`34 Practice Bulletin No. 137: Gestational diabetes mellitus. Committee on Practice Bulletins--Obstetrics. Obstet
`Gynecol. 2013 Aug;122(2 Pt 1):406-16
`35 Bolton, et al. Continuation of metformin in the first trimester of women with polycystic ovarian syndrome is not
`associated with increased perinatal morbidity. Eur J Pediatr.2009;168(2):203–206
`36 Gilbert C, Valois M, Koren G. Pregnancy outcomes after first trimester exposure to metformin: a meta-
`analysis. Fertil Steril. 2006 Sep;86(3):658–663
`37 Briggs GG, editor. 9th edition. Philadelphia, PA: Lippincott Williams & Wilkins; 2011. Metformin. Drugs in
`Pregnancy and Lactation; pp. 912–915
`38 Diav-Citrin, O.; Steinmetz-Shoob, S.; Shechtman, S. and Ornoy, A.: Pregnancy outcome following in utero
`exposure to metformin: A prospective comparative observational study. Birth Defects Res. A Clin. Mol. Teratol.
`100(7):520, 2014
`39 Glueck CJ, et al. Pregnancy outcomes among women with polycystic ovary syndrome treated with metformin.
`Hum Reprod. 2002 Nov;17(11):2858-64.
`40 Coetzee, E.J. and Jackson, W.P.U.: Oral hypoglycemics in the first trimester and fetal outcome. S. Afr. Med. J.
`65:635-637, 1984
`41 Hellmuth, et al. Oral hypoglycaemic agents in 118 diabetic pregnancies. Diabetic Medicine. 2000; 17: 507-511.
`
`
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`Reference ID: 3924141
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`that further data collection and analysis of potential bias was being undertaken at the time
`the results of the study were published. 42
`
`
`Reviewer comments:
`In the study by Hellmuth, et al. the women in the metformin group were more likely to be obese
`(pre-pregnancy BMI was 31.2 compared to 22.8 and 24.8 in the sulfonylurea and insulin groups,
`respectively). An obese or overweight patient with type 2 diabetes is at an increased risk of
`preeclampsia, cesarean delivery, shoulder dystocia, preterm delivery, large-for-gestational age
`infant, fetal malformations and admission of the infant into the neonatal intensive care unit.
`Therefore, it is difficult to determine whether the increased prevalence of pre-eclampsia was due
`to metformin use or due to obesity.43,44
`
`In the study by Panchaud, et al., the metformin-exposed population was made up of patients with
`pre-gestational diabetes, but the control population was made up of non-diabetic patients.
`Having a diabetes diagnosis increases the risk of congenital malformations, and it is likely that
`increased rate of congenital malformations seen in the metformin-exposed pregnancies was due
`to the underlying diabetes and not necessarily due to metformin use during pregnancy.
`
`See the previous DPMH reviews45,46 by Miriam Dinatale, D.O. and Christos Mastroyannis, M.D.
`for a complete review of published studies that evaluated the use of metformin during pregnancy.
`
`Summary
`Overall, published safety data from controlled trials and post-marketing observational studies do
`not report a clear association with major birth defects, miscarriage, or adverse maternal or fetal
`outcomes when metformin is used during pregnancy. However, these studies cannot definitely
`establish the absence of any risk because of methodological limitations, including small sample
`size and inconsistent comparator groups.
`
`Metformin and Lactation
`The applicant performed a literature search in Medline and Embase covering the period between
`1995 and August 24, 2015 to identify published literature on lactation-related publications for
`metformin and retrieved two publications. In addition to the applicant’s search of published
`literature for information about metformin use during lactation, DPMH also performed a search
`of the Drugs and Lactation Database (LactMed)47 and PubMed and Embase.
`
`
`42 Panchaud, A et al. Pregnancy outcome following maternal exposure to metformin: Preliminary results of a
`collaborative ENTIS and Motherisk study. Birth Defects Res. A Clin. Mol. Teratol. 100(7):521, 2014
`43 www.cdc.gov. Reproductive Health: Maternal and Infant Health and Pregnancy Complications. Accessed
`12/18/2015.
`44 Racusin, et al. Obesity and the Risk and Detection of Fetal Malformations. Seminars in Perinatology. 2012; 36(3):
`213-221.
`45 DPMH review of pioglitazone products. March 9, 2016. Miriam Dinatale, D.O. and Christos Mastroyannis, M.D.
`DARRTS Reference ID 3898973.
`46 DPMH addendum of pioglitazone products. April 28, 2016. Miriam Dinatale, D.O. and Christos Mastroyannis,
`M.D. DARRTS Reference ID 3921521.
`47 http://toxnet nlm nih.gov/cgi-bin/sis/htmlgen?LACT. The LactMed database is a National Library of Medicine
`(NLM) database with information on drugs and lactation geared toward healthcare practitioners and nursing women.
`The LactMed database provides information when available on maternal levels in breast milk, infant blood levels,
`
`Reference ID: 3924141
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`

`

`LactMed notes that data from clinical lactation studies demonstrate that metformin levels in
`breast milk are low and that “metformin should be used with caution when women are
`breastfeeding neonates and premature infants, especially those with renal impairment.”
`
`In a lactation study (Eyal, et al.), breast milk samples were collected from four women with
`either PCOS or diabetes (Type 2 diabetes mellitus or gestational diabetes) who were treated with
`metformin (1500 mg/day in one patient; 2000 mg/day in three patients) in the post-partum
`period. The amounts of me