`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
` These highlights do not include all the information needed to use
`
`
`
`
`
`
`
` full prescribing
`
`
`
`
`
` STEGLATRO safely and effectively. See
` 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) inhibitor
`
`
` indicated as an adjunct to diet and exercise to improve glycemic
`
`
`
` control in adults with type 2 diabetes mellitus. (1)
`
`Limitations of Use:
`
`
`
`
`
`
`
`
`
`
`
`
`• Not for the treatment of type 1 diabetes mellitus or diabetic
`
`ketoacidosis. (1)
`
`
`
`
`
`----------------------- DOSAGE AND ADMINISTRATION ----------------------
`
`
`
`• Recommended starting dose is 5 mg once daily, taken in the
`
`
`morning, with or without food. (2.1)
`
`
`
`• Increase dose to 15 mg once daily in those tolerating STEGLATRO
`
`
`and needing additional glycemic control. (2.1)
`
`
`
`
`
`• 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------------------------------
`
`
`
`
`• Severe renal impairment, end-stage renal disease, or dialysis. (4,
`
`
`5.3)
`
`• History of serious hypersensitivity reaction to STEGLATRO. (4)
`
`
`
`
`
`----------------------- WARNINGS AND PRECAUTIONS-----------------------
`
`
`
`
`
`• Hypotension: May occur particularly
`in patients with
`renal
`
`
`
`
`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*
`
`
`
`INDICATIONS AND USAGE
`1
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`2.1 Recommended Dosage
`
`
`
`2.2 Patients with Renal Impairment
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`4 CONTRAINDICATIONS
`
`
`
`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
`
`
`6 ADVERSE REACTIONS
`
`
`
`6.1 Clinical Trials Experience
`
`
`
`7 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
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`
`8.2 Lactation
`
`
`
`
`Reference ID: 4197746
`
`• 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)
`
`• 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)
`
`
`• Urosepsis and Pyelonephritis: Evaluate patients for signs and
`
`
`
`
`
`
`symptoms of urinary tract infections and treat promptly, if indicated.
`
`
`(5.4)
`
`• 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
`insulin or
`• Hypoglycemia: Consider a
`lower dose of
`
`
`
`
`
`
`secretagogue to reduce risk of hypoglycemia when used in
`
`combination. (5.6)
`
`• Genital Mycotic Infections: Monitor and treat if indicated. (5.7)
`
`
`
`
`
`• Increased LDL-C: Monitor and treat as appropriate. (5.8)
`
`
`
`
`------------------------------ ADVERSE REACTIONS -----------------------------
`
`
`
`
`• The most common adverse reactions associated with STEGLATRO
`
`
`(incidence ≥ 5%) were female genital mycotic infections. (6.1)
`
`
`
`
`
`
`
`
`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 ----------------------
`
`
`
`
`• Pregnancy: Advise females of the potential risk to a fetus especially
`
`
`
`
`
`
`
`
`
`during the second and third trimesters. (8.1)
`
`• Lactation: Breastfeeding not recommended. (8.2)
`
`
`
`
`• Geriatrics: Higher incidence of adverse reactions related to reduced
`
`
`
`
`
`intravascular volume. (5.1, 8.5)
`
`
`
`• 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.
`
`Novo Nordisk Exhibit 2464
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00001
`
`
`
`
`
`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
`
`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
`
`
`
`
`
`
`
`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)].
`
`
`
`•
`
`
`less
`
`than
`
`
`
`
`2.2 Patients with Renal Impairment
`
`
`• Assess renal function prior to initiation of STEGLATRO and periodically thereafter [see
`
`Warnings and Precautions (5.3)].
`
`
`
`
`in patients with an eGFR
`• Use of STEGLATRO
`is contraindicated
`30 mL/minute/1.73 m2 [see Contraindications (4)].
`
`
`
`
`
`
`
`is not
`Initiation of STEGLATRO
`recommended
`in patients with an eGFR of
`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)].
`
`
`
`
`
`
`• 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
`
`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
`
`Precautions (5.3) and Use in Specific Populations (8.6)].
`
`
`
`• History of a serious hypersensitivity reaction to STEGLATRO.
`
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`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
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`patients (≥65 years), in patients with low systolic blood pressure, and in patients on diuretics. Before
`
`
`initiating STEGLATRO, volume status should be assessed and corrected if indicated. Monitor for signs
`
`
`and symptoms of hypotension after initiating therapy.
`
`
`
`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
`
`
`•
`
`
`3
`
`
`4
`
`Reference ID: 4197746
`
`2
`
`
`Novo Nordisk Exhibit 2464
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00002
`
`
`
`
`
`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
`less
`is not recommended when eGFR
`STEGLATRO
`is persistently between 30 and
`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
`
`
`Novo Nordisk Exhibit 2464
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00003
`
`
`
`
`
`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.
`
`ADVERSE REACTIONS
`6
`
`
`The following important adverse reactions are described elsewhere in the labeling:
`
`
`
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`
`
`•
`
`•
`
`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
`
`
`Novo Nordisk Exhibit 2464
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00004
`
`
`
`
`
`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: Adverse Reactions Reported in ≥2% of Patients with Type 2 Diabetes Mellitus Treated
`
`
`
`
`
`
`
`
`
`
`
`
`with STEGLATRO* and Greater than Placebo in Pooled Placebo-Controlled Clinical Studies of
`
`
`STEGLATRO Monotherapy or Combination Therapy
`
`Number (%) of Patients
`
`
`
`
`Female genital mycotic infections†
`
`
`
`Male genital mycotic infections‡
`
`
`Urinary tract infections§
`
`
`
`Headache
`
`
`Vaginal pruritus¶
`
`
`Increased urination#
`
`
`Nasopharyngitis
`
`
`Back pain
`
`
`Weight decreased
`
`
`
`ThirstÞ
`
`
`
`Placebo
`
`N = 515
`
`
`
`STEGLATRO 5 mg
`
`
`N = 519
`
`
`STEGLATRO 15 mg
`
`
`N = 510
`
`
`
`
` 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%
`
`†
`
`
`‡
`
`
`§
`
`¶
`
`
`#
`Þ
`
`
`
`* 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.
`
`
`
`
`
`
`
`
`
`
`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
`
`Novo Nordisk Exhibit 2464
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`IPR2023-00724
`Page 00005
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`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
`
`
`STEGLATRO 15 mg
`Placebo
`STEGLATRO 5 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)
`
`
`
`
`
`
`
`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)
`
`
`
`
`
` Baseline
`
`Week 6 Change
`
`
`
`Week 26 Change
`
`
`
`
`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 15 mg
`STEGLATRO 5 mg
`
`
`
`
`
`
`N=158
`N=155
`
`
`
`
`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
`
`Novo Nordisk Exhibit 2464
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00006
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`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)
`
`
`
`
`Monotherapy (26 weeks)
`
`
`STEGLATRO
`
`
` 15 mg
` (N = 152)
`
`
`
`
`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
`
`
`
`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)
`
`
`
`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)
`
`
`
`
`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)
`
`
`48 (36.1)
`
`3 (2.3)
`
`
`53 (35.8)
`
`5 (3.4)
`
`
`Overall [N (%)]
`
`Severe [N (%)]
`
`
`
`
`
`
`
`
`
`* 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
`
`Novo Nordisk Exhibit 2464
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00007
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`
`
`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.
`
`
`DRUG INTERACTIONS
`7
`
`
`
`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.
`
`
`
`USE IN SPECIFIC POPULATIONS
`8
`
`
`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 mothe