` CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`209803Orig1s000
`
`
`LABELING
`
`

`

`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`STEGLATRO safely and effectively. See
`full prescribing
`information for STEGLATRO.
`
`STEGLATRO™ (ertugliflozin) tablets, for oral use
`Initial U.S. Approval: 2017
`
`----------------------------INDICATIONS AND USAGE----------------------------
`STEGLATRO is a sodium glucose co-transporter 2 (SGLT2) inh bitor
`indicated as an adjunct to diet and exercise to improve glycemic
`control in adults with type 2 diabetes mellitus. (1)
`
`Limitations of Use:
`(cid:120) Not for the treatment of type 1 diabetes mellitus or diabetic
`ketoacidosis. (1)
`----------------------- DOSAGE AND ADMINISTRATION -----------------------
`(cid:120) Recommended starting dose is 5 mg once daily, taken in the
`morning, with or without food. (2.1)
`(cid:120) Increase dose to 15 mg once daily in those tolerating STEGLATRO
`and needing additional glycemic control. (2.1)
`(cid:120) Assess renal function before initiating STEGLATRO and periodically
`thereafter (2.2):
`o Do not use in patients with an estimated glomerular filtration rate
`(eGFR) below 30 mL/minute/1.73 m2.
`o Initiation is not recommended in patients with an eGFR of 30 to
`less than 60 mL/minute/1.73 m2.
`o Continued use is not recommended in patients with an eGFR
`persistently between 30 and less than 60 mL/min/1.73 m2.
`--------------------- DOSAGE FORMS AND STRENGTHS ---------------------
`Tablets: 5 mg and 15 mg (3)
`-------------------------------CONTRAINDICATIONS-------------------------------
`(cid:120) Severe renal impairment, end-stage renal disease, or dialysis. (4,
`5.3)
`(cid:120) History of serious hypersensitivity reaction to STEGLATRO. (4)
`----------------------- WARNINGS AND PRECAUTIONS------------------------
`in patients with
`renal
`(cid:120) Hypotension: May occur particularly
`impairment, the elderly, or patients on diuretics. Before initiating,
`assess and correct volume status. Monitor for signs and symptoms
`during therapy. (5.1)
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1
`INDICATIONS AND USAGE
`2
`DOSAGE AND ADMINISTRATION
`2.1 Recommended Dosage
`2.2 Patients with Renal Impairment
`DOSAGE FORMS AND STRENGTHS
`3
`CONTRAINDICATIONS
`4
`5 WARNINGS AND PRECAUTIONS
`5.1 Hypotension
`5.2 Ketoacidosis
`5.3 Acute Kidney Injury and Impairment in Renal Function
`5.4 Urosepsis and Pyelonephritis
`5.5
`Lower Limb Amputation
`5.6 Hypoglycemia with Concomitant Use with Insulin and
`Insulin Secretagogues
`5.7 Genital Mycotic Infections
`5.8
`Increases in Low-Density Lipoprotein Cholesterol (LDL-C)
`5.9 Macrovascular Outcomes
`ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`DRUG INTERACTIONS
`7.1 Concomitant Use with Insulin and Insulin Secretagogues
`7.2 Positive Urine Glucose Test
`7.3
`Interference with 1,5-anhydroglucitol (1,5-AG) Assay
`USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.2
`Lactation
`
`6
`
`7
`
`8
`
`Reference ID: 4197746
`
`(cid:120) Ketoacidosis: Assess patients who present with signs and
`symptoms of metabolic acidosis for ketoacidosis, regardless of
`blood glucose level. If suspected, discontinue, evaluate, and treat
`promptly. Before initiating, consider risk factors for ketoacidosis.
`Patients may require monitoring and temporary discontinuation of
`therapy in clinical situations known to predispose to ketoacidosis.
`(5.2)
`(cid:120) Acute Kidney Injury and Impairment in Renal Function: Consider
`temporarily discontinuing in settings of reduced oral intake or fluid
`losses. If acute kidney injury occurs, discontinue and promptly treat.
`Monitor renal function. (5.3)
`(cid:120) Urosepsis and Pyelonephritis: Evaluate patients for signs and
`symptoms of urinary tract infections and treat promptly, if indicated.
`(5.4)
`(cid:120) Lower Limb Amputation: Before initiating, consider factors that may
`increase risk of amputation. Monitor patients for infections or ulcers
`of lower limbs, and discontinue if these occur. (5.5)
`insulin
`lower dose of
`insulin or
`(cid:120) Hypoglycemia: Consider a
`secretagogue to reduce risk of hypoglycemia when used in
`combination. (5.6)
`(cid:120) Genital Mycotic Infections: Monitor and treat if indicated. (5.7)
`(cid:120) Increased LDL-C: Monitor and treat as appropriate. (5.8)
`------------------------------ ADVERSE REACTIONS ------------------------------
`(cid:120) The most common adverse reactions associated with STEGLATRO
`(cid:11)(cid:76)(cid:81)(cid:70)(cid:76)(cid:71)(cid:72)(cid:81)(cid:70)(cid:72) (cid:149) (cid:24)(cid:8)(cid:12) (cid:90)(cid:72)(cid:85)(cid:72) (cid:73)(cid:72)(cid:80)(cid:68)(cid:79)(cid:72) (cid:74)(cid:72)(cid:81)(cid:76)(cid:87)(cid:68)(cid:79) (cid:80)(cid:92)(cid:70)(cid:82)(cid:87)(cid:76)(cid:70) (cid:76)(cid:81)(cid:73)(cid:72)(cid:70)(cid:87)(cid:76)(cid:82)(cid:81)(cid:86)(cid:17) (cid:11)(cid:25)(cid:17)(cid:20)(cid:12)
`To report SUSPECTED ADVERSE REACTIONS, contact Merck
`Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., at 1-877-
`888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`----------------------- USE IN SPECIFIC POPULATIONS -----------------------
`(cid:120) Pregnancy: Advise females of the potential risk to a fetus especially
`during the second and third trimesters. (8.1)
`(cid:120) Lactation: Breastfeeding not recommended. (8.2)
`(cid:120) Geriatrics: Higher incidence of adverse reactions related to reduced
`intravascular volume. (5.1, 8.5)
`(cid:120) Renal Impairment: Higher incidence of adverse reactions related to
`reduced intravascular volume and renal function. (5.1, 5.3, 8.6)
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide.
`
`Revised: 12/2017
`
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Renal Impairment
`8.7 Hepatic Impairment
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`14.1 Overview of Clinical Studies in Patients with Type 2
`Diabetes Mellitus
`14.2 Clinical Study of Monotherapy Use of STEGLATRO in
`Patients with Type 2 Diabetes Mellitus
`14.3 Clinical Studies of Combination Therapy Use of
`STEGLATRO in Patients with Type 2 Diabetes Mellitus
`14.4 Clinical Study of STEGLATRO in Patients with Moderate
`Renal Impairment and Type 2 Diabetes Mellitus
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the full prescribing information
`are not listed.
`
`

`

`FULL PRESCRIBING INFORMATION
`1
`INDICATIONS AND USAGE
`STEGLATRO™ is indicated as an adjunct to diet and exercise to improve glycemic control in adults
`with type 2 diabetes mellitus.
`
`Limitations of Use
`STEGLATRO is not recommended in patients with type 1 diabetes mellitus or for the treatment
`(cid:120)
`of diabetic ketoacidosis.
`DOSAGE AND ADMINISTRATION
`2
`2.1 Recommended Dosage
`The recommended starting dose of STEGLATRO is 5 mg once daily, taken in the morning, with
`(cid:120)
`or without food. In patients tolerating STEGLATRO 5 mg once daily, the dose may be
`increased to a maximum recommended dose of 15 mg once daily if additional glycemic control
`is needed.
`In patients with volume depletion, correct this condition prior to initiation of STEGLATRO [see
`Warnings and Precautions (5.1)].
`
`(cid:120)
`
`less
`
`than
`
`2.2 Patients with Renal Impairment
`Assess renal function prior to initiation of STEGLATRO and periodically thereafter [see
`(cid:120)
`Warnings and Precautions (5.3)].
`in patients with an eGFR
`is contraindicated
`(cid:120) Use of STEGLATRO
`30 mL/minute/1.73 m2 [see Contraindications (4)].
`in patients with an eGFR of
`Initiation of STEGLATRO
`is not
`recommended
`30 mL/minute/1.73 m2 to less than 60 mL/minute/1.73 m2 [see Warnings and Precautions (5.3)
`and Use in Specific Populations (8.6)].
`(cid:120) Continued use of STEGLATRO is not recommended when eGFR is persistently between
`30 and less than 60 mL/minute/1.73 m2.
`No dose adjustment is needed in patients with mild renal impairment.
`DOSAGE FORMS AND STRENGTHS
`Tablets: 5 mg, pink, triangular-shaped debossed with “701” on one side and plain on the other
`(cid:120)
`side.
`Tablets: 15 mg, red, triangular-shaped debossed with “702” on one side and plain on the other
`side.
`CONTRAINDICATIONS
`Severe renal impairment, end-stage renal disease (ESRD), or dialysis [see Warnings and
`(cid:120)
`Precautions (5.3) and Use in Specific Populations (8.6)].
`(cid:120) History of a serious hypersensitivity reaction to STEGLATRO.
`WARNINGS AND PRECAUTIONS
`5
`5.1 Hypotension
`STEGLATRO causes intravascular volume contraction. Therefore, symptomatic hypotension may
`occur after initiating STEGLATRO [see Adverse Reactions (6.1)] particularly in patients with impaired
`renal function (eGFR less than 60 mL/min/1.73 m2) [see Use in Specific Populations (8.6)], elderly
`(cid:83)(cid:68)(cid:87)(cid:76)(cid:72)(cid:81)(cid:87)(cid:86) (cid:11)(cid:149)(cid:25)(cid:24) (cid:92)(cid:72)(cid:68)(cid:85)(cid:86)(cid:12)(cid:15) (cid:76)(cid:81) (cid:83)(cid:68)(cid:87)(cid:76)(cid:72)(cid:81)(cid:87)(cid:86) (cid:90)(cid:76)(cid:87)(cid:75) (cid:79)(cid:82)(cid:90) (cid:86)(cid:92)(cid:86)(cid:87)(cid:82)(cid:79)(cid:76)(cid:70) (cid:69)(cid:79)(cid:82)(cid:82)(cid:71) (cid:83)(cid:85)(cid:72)(cid:86)(cid:86)(cid:88)(cid:85)(cid:72)(cid:15) (cid:68)(cid:81)(cid:71) (cid:76)(cid:81) (cid:83)(cid:68)(cid:87)(cid:76)(cid:72)(cid:81)(cid:87)(cid:86) (cid:82)(cid:81) (cid:71)(cid:76)(cid:88)(cid:85)(cid:72)(cid:87)(cid:76)(cid:70)(cid:86)(cid:17) (cid:37)(cid:72)(cid:73)(cid:82)(cid:85)(cid:72)
`initiating STEGLATRO, volume status should be assessed and corrected if indicated. Monitor for signs
`and symptoms of hypotension after initiating therapy.
`
`(cid:120)
`
`(cid:120)
`
`3
`
`4
`
`5.2 Ketoacidosis
`Reports of ketoacidosis, a serious life-threatening condition requiring urgent hospitalization, have
`been identified in clinical trials and postmarketing surveillance in patients with type 1 and type 2 diabetes
`mellitus receiving sodium glucose co-transporter-2 (SGLT2) inhibitors and cases have been reported in
`
`Reference ID: 4197746
`
`2
`
`

`

`STEGLATRO-treated patients in clinical trials. Across the clinical program, ketoacidosis was identified in
`3 of 3,409 (0.1%) of STEGLATRO-treated patients and 0% of comparator-treated patients. Fatal cases of
`ketoacidosis have been reported in patients taking SGLT2 inhibitors. STEGLATRO is not indicated for the
`treatment of patients with type 1 diabetes mellitus [see Indications and Usage (1)].
`Patients treated with STEGLATRO who present with signs and symptoms consistent with severe
`metabolic acidosis should be assessed for ketoacidosis regardless of presenting blood glucose levels, as
`ketoacidosis associated with STEGLATRO may be present even if blood glucose levels are less than
`250 mg/dL. If ketoacidosis is suspected, STEGLATRO should be discontinued, patient should be
`evaluated, and prompt treatment should be instituted. Treatment of ketoacidosis may require insulin, fluid
`and carbohydrate replacement.
`In many of the reported cases, and particularly in patients with type 1 diabetes, the presence of
`ketoacidosis was not immediately recognized and institution of treatment was delayed because
`presenting blood glucose levels were below those typically expected for diabetic ketoacidosis (often less
`than 250 mg/dL). Signs and symptoms at presentation were consistent with dehydration and severe
`metabolic acidosis and included nausea, vomiting, abdominal pain, generalized malaise, and shortness of
`breath. In some but not all cases, factors predisposing to ketoacidosis such as insulin dose reduction,
`acute febrile illness, reduced caloric intake due to illness or surgery, pancreatic disorders suggesting
`insulin deficiency (e.g., type 1 diabetes, history of pancreatitis or pancreatic surgery), and alcohol abuse
`were identified.
`Before initiating STEGLATRO, consider factors in the patient history that may predispose to
`ketoacidosis, including pancreatic insulin deficiency from any cause, caloric restriction, and alcohol
`abuse. In patients treated with STEGLATRO consider monitoring for ketoacidosis and temporarily
`discontinuing STEGLATRO in clinical situations known to predispose to ketoacidosis (e.g., prolonged
`fasting due to acute illness or surgery).
`
`5.3 Acute Kidney Injury and Impairment in Renal Function
`STEGLATRO causes intravascular volume contraction and can cause renal impairment [see
`Adverse Reactions (6.1)]. There have been postmarketing reports of acute kidney injury some requiring
`hospitalization and dialysis in patients receiving SGLT2 inhibitors.
`Before initiating STEGLATRO, consider factors that may predispose patients to acute kidney injury
`including hypovolemia, chronic renal insufficiency, congestive heart failure and concomitant medications
`(diuretics, ACE inhibitors, ARBs, NSAIDs). Consider temporarily discontinuing STEGLATRO in any
`setting of reduced oral intake (such as acute illness or fasting) or fluid losses (such as gastrointestinal
`illness or excessive heat exposure); monitor patients for signs and symptoms of acute kidney injury. If
`acute kidney injury occurs, discontinue STEGLATRO promptly and institute treatment.
`STEGLATRO increases serum creatinine and decreases eGFR. Patients with moderate renal
`impairment (eGFR 30 to less than 60 mL/min/1.73 m2) may be more susceptible to these changes. Renal
`function abnormalities can occur after initiating STEGLATRO [see Adverse Reactions (6.1)]. Renal
`function should be evaluated prior to initiating STEGLATRO and periodically thereafter. Use of
`STEGLATRO
`is not recommended when eGFR
`is persistently between 30 and
`less
`than
`60 mL/min/1.73 m2 and is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2 [see
`Dosage and Administration (2.2), Contraindications (4), and Use in Specific Populations (8.6)].
`
`5.4 Urosepsis and Pyelonephritis
`There have been postmarketing reports of serious urinary tract infections, including urosepsis and
`pyelonephritis, requiring hospitalization in patients receiving SGLT2 inhibitors. Cases of pyelonephritis
`also have been reported in STEGLATRO-treated patients in clinical trials. Treatment with SGLT2
`inhibitors increases the risk for urinary tract infections. Evaluate patients for signs and symptoms of
`urinary tract infections and treat promptly, if indicated [see Adverse Reactions (6.1)].
`
`5.5
`
`Lower Limb Amputation
`An increased risk for lower limb amputation (primarily of the toe) has been observed in clinical
`studies with another SGLT2 inhibitor. Across seven Phase 3 clinical trials in the STEGLATRO
`development program, non-traumatic lower limb amputations were reported in 1 (0.1%) patient in the
`comparator group, 3 (0.2%) patients in the STEGLATRO 5 mg group, and 8 (0.5%) patients in the
`
`Reference ID: 4197746
`
`3
`
`

`

`STEGLATRO 15 mg group. A causal association between STEGLATRO and lower limb amputation has
`not been definitively established.
`Before initiating STEGLATRO, consider factors in the patient history that may predispose them to
`the need for amputations, such as a history of prior amputation, peripheral vascular disease, neuropathy
`and diabetic foot ulcers. Counsel patients about the importance of routine preventative foot care. Monitor
`patients receiving STEGLATRO for signs and symptoms of infection (including osteomyelitis), new pain or
`tenderness, sores or ulcers involving the lower limbs, and discontinue STEGLATRO if these
`complications occur.
`
`5.6 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues
`Insulin and insulin secretagogues (e.g., sulfonylurea) are known to cause hypoglycemia.
`STEGLATRO may increase the risk of hypoglycemia when used in combination with insulin and/or an
`insulin secretagogue [see Adverse Reactions (6.1)]. Therefore, a lower dose of insulin or insulin
`secretagogue may be required to minimize the risk of hypoglycemia when used in combination with
`STEGLATRO.
`
`5.7 Genital Mycotic Infections
`STEGLATRO increases the risk of genital mycotic infections. Patients who have a history of genital
`mycotic infections or who are uncircumcised are more likely to develop genital mycotic infections [see
`Adverse Reactions (6.1)]. Monitor and treat appropriately.
`
`5.8
`
`Increases in Low-Density Lipoprotein Cholesterol (LDL-C)
`Dose-related increases in LDL-C can occur with STEGLATRO [see Adverse Reactions (6.1)].
`Monitor and treat as appropriate.
`
`5.9 Macrovascular Outcomes
`There have been no clinical studies establishing conclusive evidence of macrovascular risk
`reduction with STEGLATRO.
`6
`ADVERSE REACTIONS
`The following important adverse reactions are described elsewhere in the labeling:
`
`(cid:120)
`(cid:120)
`(cid:120)
`(cid:120)
`(cid:120)
`(cid:120)
`
`(cid:120)
`(cid:120)
`
`Hypotension [see Warnings and Precautions (5.1)]
`Ketoacidosis [see Warnings and Precautions (5.2)]
`Acute Kidney Injury and Impairment in Renal Function [see Warnings and Precautions (5.3)]
`Urosepsis and Pyelonephritis [see Warnings and Precautions (5.4)]
`Lower Limb Amputation [see Warnings and Precautions (5.5)]
`Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues [see Warnings
`and Precautions (5.6)]
`Genital Mycotic Infections [see Warnings and Precautions (5.7)]
`Increases in Low-Density Lipoprotein Cholesterol (LDL-C) [see Warnings and Precautions
`(5.8)]
`
`6.1 Clinical Trials Experience
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates
`observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another
`drug and may not reflect the rates observed in practice.
`
`Pool of Placebo-Controlled Trials Evaluating STEGLATRO 5 and 15 mg
`The data in Table 1 are derived from a pool of three 26-week, placebo-controlled trials.
`STEGLATRO was used as monotherapy in one trial and as add-on therapy in two trials [see Clinical
`Studies (14)]. These data reflect exposure of 1,029 patients to STEGLATRO with a mean exposure
`duration of approximately 25 weeks. Patients received STEGLATRO 5 mg (N=519), STEGLATRO 15 mg
`(N=510), or placebo (N=515) once daily. The mean age of the population was 57 years and 2% were
`older than 75 years of age. Fifty-three percent (53%) of the population was male and 73% were
`
`Reference ID: 4197746
`
`4
`
`

`

`Caucasian, 15% were Asian, and 7% were Black or African American. At baseline the population had
`diabetes for an average of 7.5 years, had a mean HbA1c of 8.1%, and 19.4% had established
`microvascular complications of diabetes. Baseline renal function (mean eGFR 88.9 mL/min/1.73 m2) was
`normal or mildly impaired in 97% of patients and moderately impaired in 3% of patients.
`Table 1 shows common adverse reactions associated with the use of STEGLATRO. These adverse
`reactions were not present at baseline, occurred more commonly on STEGLATRO than on placebo, and
`occurred in at least 2% of patients treated with either STEGLATRO 5 mg or STEGLATRO 15 mg.
`
`Table 1: A(cid:71)(cid:89)(cid:72)(cid:85)(cid:86)(cid:72) (cid:53)(cid:72)(cid:68)(cid:70)(cid:87)(cid:76)(cid:82)(cid:81)(cid:86) (cid:53)(cid:72)(cid:83)(cid:82)(cid:85)(cid:87)(cid:72)(cid:71) (cid:76)(cid:81) (cid:149)(cid:21)(cid:8) (cid:82)(cid:73) (cid:51)(cid:68)(cid:87)(cid:76)(cid:72)(cid:81)(cid:87)(cid:86) (cid:90)(cid:76)(cid:87)(cid:75) (cid:55)(cid:92)(cid:83)(cid:72) (cid:21) (cid:39)(cid:76)(cid:68)(cid:69)(cid:72)(cid:87)(cid:72)(cid:86) (cid:48)(cid:72)(cid:79)(cid:79)(cid:76)(cid:87)(cid:88)(cid:86) (cid:55)(cid:85)(cid:72)(cid:68)(cid:87)(cid:72)(cid:71)
`with STEGLATRO* and Greater than Placebo in Pooled Placebo-Controlled Clinical Studies of
`STEGLATRO Monotherapy or Combination Therapy
`Number (%) of Patients
`
`Placebo
`N = 515
`
`STEGLATRO 5 mg
`N = 519
`
`STEGLATRO 15 mg
`N = 510
`
`Female genital mycotic infections†
`
`Male genital mycotic infections‡
`
`Urinary tract infections§
`
`Headache
`
`Vaginal pruritus¶
`
`Increased urination#
`
`Nasopharyngitis
`
`Back pain
`
`Weight decreased
`
`ThirstÞ
`
`3.0%
`
`0.4%
`
`3.9%
`
`2.3%
`
`0.4%
`
`1.0%
`
`2.3%
`
`2.3%
`
`1.0%
`
`0.6%
`
`9.1%
`
`3.7%
`
`4.0%
`
`3.5%
`
`2.8%
`
`2.7%
`
`2.5%
`
`1.7%
`
`1.2%
`
`2.7%
`
`12.2%
`
`4.2%
`
`4.1%
`
`2.9%
`
`2.4%
`
`2.4%
`
`2.0%
`
`2.5%
`
`2.4%
`
`1.4%
`
`†
`
`* The three placebo controlled studies included one monotherapy trial and two add-on combination trials with metformin or with
`metformin and sitagliptin.
`Includes: genital candidiasis, genital infection fungal, vaginal infection, vulvitis, vulvovaginal candidiasis, vulvovaginal mycotic
`infection, and vulvovaginitis. Percentages calculated with the number of female patients in each group as denominator: placebo
`(N=235), STEGLATRO 5 mg (N=252), STEGLATRO 15 mg (N=245).
`Includes: balanitis candida, balanoposthitis, genital infection, and genital infection fungal. Percentages calculated with the number
`of male patients in each group as denominator: placebo (N=280), STEGLATRO 5 mg (N=267), STEGLATRO 15 mg (N=265).
`Includes: cystitis, dysuria, streptococcal urinary tract infection, urethritis, urinary tract infection.
`Includes: vulvovaginal pruritus and pruritus genital. Percentages calculated with the number of female patients in each group as
`denominator: placebo (N=235), ertugliflozin 5 mg (N=252), ertugliflozin 15 mg (N=245).
`#
`Includes: pollakiuria, micturition urgency, polyuria, urine output increased, and nocturia.
`Þ Includes: thirst, dry mouth, polydipsia, and dry throat.
`
`‡
`
`§
`¶
`
`Volume Depletion
`STEGLATRO causes an osmotic diuresis, which may lead to intravascular volume contraction and
`adverse reactions related to volume depletion, particularly in patients with impaired renal function (eGFR
`less than 60 mL/min/1.73 m2). In patients with moderate renal impairment, adverse reactions related to
`volume depletion (e.g., dehydration, dizziness postural, presyncope, syncope, hypotension, and
`orthostatic hypotension) were reported in 0%, 4.4%, and 1.9% of patients treated with placebo,
`STEGLATRO 5 mg, and STEGLATRO 15 mg, respectively. STEGLATRO may also increase the risk of
`hypotension in other patients at risk for volume contraction [see Use in Specific Populations (8.5, 8.6)].
`
`Ketoacidosis
`
`Reference ID: 4197746
`
`5
`
`

`

`Across the clinical program, ketoacidosis was identified in 3 of 3,409 (0.1%) ertugliflozin-treated patients
`and 0.0% of comparator-treated patients [see Warnings and Precautions (5.2)].
`
`Impairment in Renal Function
`Treatment with STEGLATRO was associated with increases in serum creatinine and decreases in
`eGFR (see Table 2). Patients with moderate renal impairment at baseline had larger mean changes. In a
`study in patients with moderate renal impairment, these abnormal laboratory findings were observed to
`reverse after treatment discontinuation [see Use in Specific Populations (8.5, 8.6)].
`
`Table 2: Changes from Baseline in Serum Creatinine and eGFR in the Pool of Three 26-Week
`Placebo-Controlled Studies, and a 26-Week Moderate Renal Impairment Study in Patients with
`Type 2 Diabetes Mellitus
`Pool of 26-Week Placebo-Controlled Studies
`Placebo
`STEGLATRO 5 mg
`STEGLATRO 15 mg
`N=515
`N=519
`N=510
`
`Creatinine (mg/dL)
`
`Baseline Mean
`
`eGFR (mL/min/1.73 m2)
`
`Creatinine (mg/dL)
`
`Week 6 Change
`
`eGFR (mL/min/1.73 m2)
`
`Creatinine (mg/dL)
`
`Week 26 Change
`
`eGFR (mL/min/1.73 m2)
`
`0.83
`
`89.5
`
`0.00
`
`-0.3
`
`-0.01
`
`0.7
`
`0.82
`
`88.2
`
`0.03
`
`-2.7
`
`0.00
`
`0.5
`
`0.82
`
`89.0
`
`0.03
`
`-3.1
`
`0.01
`
`-0.6
`
`Placebo
`N=154
`
`Moderate Renal Impairment Study
`STEGLATRO 5 mg
`STEGLATRO 15 mg
`N=158
`N=155
`
`Baseline
`
`Week 6 Change
`
`Week 26 Change
`
`Creatinine (mg/dL)
`
`eGFR (mL/min/1.73 m2)
`
`Creatinine (mg/dL)
`
`eGFR (mL/min/1.73 m2)
`
`Creatinine (mg/dL)
`
`eGFR (mL/min/1.73 m2)
`
`1.39
`
`46.0
`
`-0.02
`
`0.6
`
`0.02
`
`0.0
`
`1.38
`
`46.8
`
`0.11
`
`-3.2
`
`0.08
`
`-2.7
`
`1.37
`
`46.9
`
`0.12
`
`-4.1
`
`0.10
`
`-2.6
`
`Renal-related adverse reactions (e.g., acute kidney injury, renal impairment, acute prerenal failure)
`may occur in patients treated with STEGLATRO, particularly in patients with moderate renal impairment
`where the incidence of renal-related adverse reactions was 0.6%, 2.5%, and 1.3% in patients treated with
`placebo, STEGLATRO 5 mg, and STEGLATRO 15 mg, respectively.
`
`Reference ID: 4197746
`
`6
`
`

`

`Lower Limb Amputation
`Across seven Phase 3 clinical trials in which STEGLATRO was studied as monotherapy and in
`combination with other antihyperglycemic agents, non-traumatic lower limb amputations occurred in 1 of
`1,450 (0.1%) in the non-STEGLATRO group, 3 of 1,716 (0.2%) in the STEGLATRO 5 mg group, and 8 of
`1,693 (0.5%) in the STEGLATRO 15 mg group.
`
`Hypoglycemia
`The incidence of hypoglycemia by study is shown in Table 3.
`
`Table 3: Incidence of Overall* and Severe† Hypoglycemia in Placebo-Controlled Clinical Studies in
`Patients with Type 2 Diabetes Mellitus
`Placebo
`STEGLATRO
`(N = 153)
`5 mg
`(N =156)
`
`STEGLATRO
`15 mg
`(N = 152)
`
`Monotherapy (26 weeks)
`
`Overall [N (%)]
`Severe [N (%)]
`Add-on Combination Therapy with
`Metformin (26 weeks)
`
`Overall [N (%)]
`Severe [N (%)]
`Add-on Combination Therapy with
`Metformin and Sitagliptin (26 weeks)
`
`Overall [N (%)]
`Severe [N (%)]
`In Combination with Insulin and/or an
`Insulin Secretagogue in Patients with
`Moderate Renal Impairment
`
`Overall [N (%)]
`Severe [N (%)]
`
`1 (0.7)
`0 (0.0)
`Placebo
`(N = 209)
`
`9 (4.3)
`1 (0.5)
`Placebo
`(N = 153)
`
`5 (3.3)
`1 (0.7)
`Placebo
`(N = 133)
`
`48 (36.1)
`3 (2.3)
`
`4 (2.6)
`0 (0.0)
`STEGLATRO
`5 mg
`(N = 207)
`
`15 (7.2)
`1 (0.5)
`STEGLATRO
`5 mg
`(N = 156)
`
`7 (4.5)
`1 (0.6)
`STEGLATRO
`5 mg
`(N = 148)
`
`53 (35.8)
`5 (3.4)
`
`4 (2.6)
`2 (1.3)
`STEGLATRO
`15 mg
`(N = 205)
`
`16 (7.8)
`0 (0.0)
`STEGLATRO
`15 mg
`(N = 153)
`
`3 (2.0)
`0 (0.0)
`STEGLATRO
`15 mg
`(N = 143)
`
`39 (27.3)
`3 (2.1)
`
`* Overall hypoglycemic events: plasma or capillary glucose of less than or equal to 70 mg/dL.
`† Severe hypoglycemic events: required assistance, lost consciousness, or experienced a seizure regardless of blood glucose.
`
`Genital Mycotic Infections
`In the pool of three placebo-controlled clinical trials, the incidence of female genital mycotic
`infections (e.g., genital candidiasis, genital infection fungal, vaginal infection, vulvitis, vulvovaginal
`candidiasis, vulvovaginal mycotic infection, vulvovaginitis) occurred in 3%, 9.1%, and 12.2% of females
`treated with placebo, STEGLATRO 5 mg, and STEGLATRO 15 mg, respectively (see Table 1). In
`females, discontinuation due to genital mycotic infections occurred in 0% and 0.6% of patients treated
`with placebo and STEGLATRO, respectively.
`In the same pool, male genital mycotic infections (e.g., balanitis candida, balanoposthitis, genital
`infection, genital infection fungal) occurred in 0.4%, 3.7%, and 4.2% of males treated with placebo,
`STEGLATRO 5 mg, and STEGLATRO 15 mg, respectively (see Table 1). Male genital mycotic infections
`occurred more commonly in uncircumcised males. In males, discontinuations due to genital mycotic
`infections occurred in 0% and 0.2% of patients treated with placebo and STEGLATRO, respectively.
`Phimosis was reported in 8 of 1729 (0.5%) male ertugliflozin-treated patients, of which four required
`circumcision.
`
`Laboratory Tests
`Increases in Low-Density Lipoprotein Cholesterol (LDL-C)
`In the pool of three placebo-controlled trials, dose-related increases in LDL-C were observed in
`patients treated with STEGLATRO. Mean percent changes from baseline to Week 26 in LDL-C relative to
`placebo were 2.6% and 5.4% with STEGLATRO 5 mg and STEGLATRO 15 mg, respectively. The range
`of mean baseline LDL-C was 96.6 to 97.7 mg/dL across treatment groups [see Warnings and Precautions
`(5.8)].
`
`Reference ID: 4197746
`
`7
`
`

`

`Increases in Hemoglobin
`In the pool of three placebo-controlled trials, mean changes (percent changes) from baseline to
`Week 26 in hemoglobin were -0.21 g/dL (-1.4%) with placebo, 0.46 g/dL (3.5%) with STEGLATRO 5 mg,
`and 0.48 g/dL (3.5%) with STEGLATRO 15 mg. The range of mean baseline hemoglobin was 13.90 to
`14.00 g/dL across treatment groups. At the end of treatment, 0.0%, 0.2%, and 0.4% of patients treated
`with placebo, STEGLATRO 5 mg, and STEGLATRO 15 mg, respectively, had a hemoglobin increase
`greater than 2 g/dL and above the upper limit of normal.
`Increases in Serum Phosphate
`In the pool of three placebo-controlled trials, mean changes (percent changes) from baseline in
`serum phosphate were 0.04 mg/dL (1.9%) with placebo, 0.21 mg/dL (6.8%) with STEGLATRO 5 mg, and
`0.26 mg/dL (8.5%) with STEGLATRO 15 mg. The range of mean baseline serum phosphate was 3.53 to
`3.54 mg/dL across treatment groups. In a clinical trial of patients with moderate renal impairment, mean
`changes (percent changes) from baseline at Week 26 in serum phosphate were -0.01 mg/dL (0.8%) with
`placebo, 0.29 mg/dL (9.7%) with STEGLATRO 5 mg, and 0.24 mg/dL (7.8%) with STEGLATRO 15 mg.
`7
`DRUG INTERACTIONS
`7.1 Concomitant Use with Insulin and Insulin Secretagogues
`STEGLATRO may increase the risk of hypoglycemia when used in combination with insulin and/or
`an insulin secretagogue [see Adverse Reactions (6.1)]. Therefore, a lower dose of insulin or insulin
`secretagogue may be required to minimize the risk of hypoglycemia when used in combination with
`STEGLATRO [see Warnings and Precautions (5.6)].
`
`7.2 Positive Urine Glucose Test
`Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2
`inhibitors as SGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose
`tests. Use alternative methods to monitor glycemic control.
`
`7.3
`
`Interference with 1,5-anhydroglucitol (1,5-AG) Assay
`Monitoring glycemic control with 1,5-AG assay is not recommended as measurements of 1,5-AG
`are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors. Use alternative methods
`to monitor glycemic control.
`8
`USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`Risk Summary
`Based on animal data showing adverse renal effects, STEGLATRO is not recommended during the
`second and third trimesters of pregnancy.
`
`The limited available data with STEGLATRO in pregnant women are not sufficient to determine a
`drug-associated risk of adverse developmental outcomes. There are risks to the mother and fetus
`associated with poorly controlled diabetes in pregnancy (see Clinical Considerations).
`
`In animal studies, adverse renal changes were observed in rats when ertugliflozin was administered
`during a period of renal development corresponding to the late second and third trimesters of human
`pregnancy. Doses approximately 13 times the maximum clinical dose caused renal pelvic and tubule
`dilatations and renal mineralization that were not fully reversible. There was no evidence of fetal harm in
`rats or rabbits at exposures of ertugliflozin approximately 300 times higher than the maximal clinical dose
`of 15 mg/day when administered during organogenesis (see Data).
`
`The estimated background risk of major birth defects is 6-10% in women with pre-gestational
`diabetes with a HbA1c >7 and has been reported to be as high as 20-25% in women with HbA1c >10.
`The estimated background risk of miscarriage for the indicated population is unknown. 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
`
`Reference ID: 4197746
`
`8
`
`

`

`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, stillbirth, and delivery complications. Poorly
`controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related
`morbidity.
`
`Data
`Animal Data
`When ertugliflozin was orally administered to juvenile rats from PND 21 to PND 90, increased
`kidney weight, renal tubule and renal pelvis dilatation, and renal mineralization occurred at doses greater
`than or equal to 5 mg/kg (13-fold human exposures, based on AUC). These effects occurred with drug
`exposure during periods of renal development in rats that correspond to the late second and third
`trimester of human renal development, and did not fully reverse within a 1-month recovery period.
`
`In embryo-fetal development studies, ertugliflozin (50, 100 and 250 mg/kg/day) was administered
`orally to rats on gestation days 6 to 17 and to rabbits on gestation days 7 to 19. Ertugliflozin did not
`adversely affect developmental outcomes in rats and rabbits at maternal exposures that were
`approximately 300 times the human exposure at the maximum clinical dose of 15 mg/day, based on AUC.
`A maternally toxic dose (250 mg/kg/day) in rats (707 times the clinical dose), was associated with
`reduced fetal viability, and a higher incidence of a visceral