INPEFA

1 INDICATIONS AND USAGE INPEFA is indicated to reduce the risk of cardiovascular death, hospitalization for heart failure, and urgent heart failure visit in adults with: heart failure or type 2 diabetes mellitus, chronic kidney disease, and other cardiovascular risk factors INPEFA is a sodium-glucose cotransporter 2 (SGLT2) inhibitor indicated to reduce the risk of cardiovascular death, hospitalization for heart failure, and urgent heart failure visit in adults with: heart failure ( 1 ) or type 2 diabetes mellitus, chronic kidney disease, and other cardiovascular risk factors ( 1 )

2 DOSAGE AND ADMINISTRATION Correct volume status before starting INPEFA at 200 mg daily and titrate to 400 mg as tolerated. (2.2) In patients with decompensated heart failure, begin dosing when patients are hemodynamically stable. ( 2.1 ) Withhold INPEFA at least 3 days, if possible, prior to major surgery or procedures associated with prolonged fasting. ( 2.3 ) 2.1 Prior to Initiation of INPEFA Assess volume status and, if necessary, correct volume depletion prior to initiation of INPEFA [see Warnings and Precautions ( 5.2 ) and Use in Specific Populations ( 8.5 , 8.6 )] . Assess renal function prior to initiation of INPEFA and then as clinically indicated [see Warnings and Precautions ( 5.2 )] . For patients with decompensated heart failure, dosing may begin as soon as the patient is hemodynamically stable, including during hospitalization or urgent outpatient treatment or immediately upon discharge. 2.2 Recommended Dosage The recommended starting dose of INPEFA is 200 mg orally once daily not more than one hour before the first meal of the day. Up-titrate after at least 2 weeks to 400 mg orally once daily as tolerated [see Clinical Studies ( 14 )] . Down-titrate to 200 mg as necessary [see Adverse Reactions ( 6.1 ), Warnings and Precautions ( 5 ) and Use in Specific Populations ( 8.6 )]. Swallow tablets whole. Do not cut, crush, or chew tablets. If a dose of INPEFA is missed by more than 6 hours, take the next dose as prescribed the next day. 2.3 Temporary Interruption for Surgery Withhold INPEFA at least 3 days, if possible, prior to major surgery or procedures associated with prolonged fasting. Resume INPEFA when the patient is clinically stable and has resumed oral intake [see Warnings and Precautions ( 5.1 ) and Clinical Pharmacology ( 12.3 )] .

3 DOSAGE FORMS AND STRENGTHS INPEFA 200 mg tablet is an oval, blue, film-coated tablet debossed with “LEX” on one side and “200” on the other side. INPEFA 400 mg tablet is an oval, yellow, film-coated tablet debossed with “LEX” on one side and “400” on the other side. Tablets: 200 mg and 400 mg ( 3 )

4 CONTRAINDICATIONS INPEFA is contraindicated in patients with a history of serious hypersensitivity reaction to INPEFA. History of serious hypersensitivity reaction to INPEFA. ( 4 )

6 ADVERSE REACTIONS The following important adverse reactions are described elsewhere in the labeling: Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis [see Warnings and Precautions ( 5.1 )] Volume Depletion [see Warnings and Precautions ( 5.2 )] Genitourinary Infections, including Urosepsis, Pyelonephritis, Necrotizing Fasciitis of the Perineum (Fournier's Gangrene), and Genital Mycotic Infections [see Warnings and Precautions ( 5.3 )] Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues [see Warnings and Precautions ( 5.4 )] Most common adverse reactions (incidence ≥ 5%) are urinary tract infection, volume depletion, diarrhea, and hypoglycemia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Lexicon at 1-855-330-2573 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 clinical practice. In the phase 3 (SOLOIST [see Clinical Studies ( 14.1 )] and SCORED [see Clinical Studies ( 14.2 )] ) placebo-controlled trials, 5,896 subjects received INPEFA. In the SOLOIST study, 336 patients (56%) reached the 400 mg dose. In the SCORED study, 3,934 patients (74%) reached the 400 mg dose. In the SOLOIST study, 5.6% of patients in the INPEFA group and 5.4% of patients in the placebo group discontinued therapy due to adverse events (AEs). In the SCORED study, 5.0% of patients in the INPEFA group and 4.5% of patients in the placebo group discontinued therapy due to AEs. Table 1 Adverse Reactions Reported in ≥ 2% of Patients Treated with INPEFA and Greater Than Placebo in Either SOLOIST or SCORED Adverse Reaction SOLOIST N = 1,216 SCORED N = 10,577 Placebo (%) N = 611 INPEFA (%) N = 605 Placebo (%) N = 5,286 INPEFA (%) N = 5,291 Urinary tract infection 7.2 8.6 11.0 11.5 Volume depletion 8.8 9.3 4.0 5.2 Diarrhea 4.1 6.9 6.0 8.4 Hypoglycemia 2.8 4.3 7.9 7.7 Dizziness 2.5 2.6 2.8 3.3 Genital mycotic infection 0.2 0.8 0.9 2.4 Changes in Laboratory Test Values During Treatment Increase in Serum Creatinine and Decrease in eGFR Initiation of SGLT2 inhibitors, including INPEFA, causes a small increase in serum creatinine and decrease in eGFR. These changes in serum creatinine and eGFR generally occur within 4 weeks of starting therapy and then stabilize regardless of baseline kidney function. Changes that do not fit this pattern should prompt further evaluation to exclude the possibility of acute kidney injury. In studies that included patients with type 2 diabetes mellitus with moderate renal impairment, the acute effect on eGFR reversed after treatment discontinuation, suggesting acute hemodynamic changes may play a role in the renal function changes observed with INPEFA [see Warnings and Precautions ( 5.2 ) and Use in Specific Populations ( 8.6 )] .

7 DRUG INTERACTIONS Digoxin : Monitor digoxin levels. ( 7.1 ) Uridine 5'-diphospho-glucuronosyltransferase Inducers (e.g., rifampin): Sotagliflozin exposure is reduced. Consider monitoring of clinical status. ( 7.2 ) Lithium: Monitor serum lithium concentrations. ( 7.3 ) 7.1 Digoxin There is an increase in the exposure of digoxin when coadministered with INPEFA 400 mg. Patients taking INPEFA with concomitant digoxin should be monitored appropriately [see Clinical Pharmacology ( 12.3 )] . 7.2 Uridine 5'-diphospho-glucuronosyltransferase (UGT) Inducer Glucuronidation by UGT1A9, to form the 3-O-glucuronide, was identified as a major metabolic pathway for sotagliflozin. The coadministration of rifampicin, an inducer of UGTs, with a single dose of 400 mg sotagliflozin resulted in a decrease in the exposure to sotagliflozin. This decrease in exposure to sotagliflozin may decrease efficacy [see Clinical Pharmacology ( 12.3 )] . 7.3 Lithium Concomitant use of an SGLT2 inhibitor with lithium may decrease serum lithium concentrations. Monitor serum lithium concentration more frequently during INPEFA initiation and dosage changes.

8 USE IN SPECIFIC POPULATIONS Pregnancy : Advise females of the potential risk to a fetus especially during the second and third trimesters. ( 8.1 ) Lactation : INPEFA is not recommended when breastfeeding. ( 8.2 ) Geriatrics : Higher incidence of adverse reactions related to volume depletion. ( 5.2 , 8.5 ) Renal Impairment : Higher incidence of adverse reactions related to volume depletion. ( 5.2 , 8.6 ) 8.1 Pregnancy Risk Summary Based on animal data showing renal effects, INPEFA is not recommended during the second and third trimesters of pregnancy. Available data with INPEFA in pregnant women are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. There are risks to the mother and fetus associated with untreated heart failure in pregnancy [see Clinical Considerations ] . In rats, renal changes were observed when sotagliflozin was administered during a period of renal development corresponding to the late second and third trimesters of human pregnancy. Exposure approximately 5 times the clinical exposure at the maximum recommended human dose (MRHD) of 400 mg once daily caused increased kidney weights and renal pelvis and tubule dilatations that were partially reversible [see Data ] . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-associated Maternal and/or Embryo-fetal Risk Pregnant women with congestive heart failure are at increased risk for preterm birth. Clinical classification of heart disease may worsen with pregnancy and lead to maternal death. Data Animal Data In embryo-fetal development studies in rats and rabbits, sotagliflozin was administered for intervals coinciding with the first trimester period of organogenesis in humans. Sotagliflozin was not teratogenic when administered at doses up to 100 mg/kg/day in pregnant rats during embryonic organogenesis (40 times the human exposure at the MRHD). Higher exposures (350 mg/kg or 161 times the human exposure at the MRHD) resulted in embryo-lethality, effects on fetal growth, and cardiovascular and skeletal fetal abnormalities commensurate with maternal toxicity. Sotagliflozin was not teratogenic when administered at doses up to 200 mg/kg/day in pregnant rabbits (9 times the human exposure at the MRHD). In a prenatal and postnatal development study in pregnant and lactating rats, sotagliflozin was administered at oral doses up to 100 mg/kg/day from gestation Day 6 through to lactation Day 20 (weaning). An increased incidence of dilated kidneys with discoloration and dilated ureters was observed at doses ≥ 30 mg/kg (≥ 4 times the human exposure at the MRHD). Sotagliflozin did not adversely affect developmental landmarks, sexual maturation, or reproductive performance of the offspring at doses up to 40 times the human exposure at the MRHD. Sotagliflozin dosed directly to juvenile rats from postnatal Day (PND) 21 until PND 90 at doses of 3, 10, 30, and 75 mg/kg/day caused dose-related increased kidney weights for males given ≥ 10 mg/kg/day and females given ≥ 30 mg/kg/day and was correlated with renal tubular and pelvis dilation for animals given ≥ 30 mg/kg/day. These findings were fully or partially reversed after a 29-day recovery period. These outcomes occurred with drug exposure during periods of renal development in rats that correspond to the late second and third trimesters of human development. 8.2 Lactation Risk Summary There are no data on the presence of INPEFA in human milk, the effects on the breastfed infant, or the effects on milk production. Sotagliflozin is present in rat milk (see Data ). When a drug is present in an …

12.1 Mechanism of Action Sotagliflozin is an inhibitor of SGLT2 and SGLT1. Inhibiting SGLT2 reduces renal reabsorption of glucose and sodium which may influence several physiological functions such as lowering both pre-and afterload of the heart and downregulating sympathetic activity. Inhibiting SGLT1 reduces intestinal absorption of glucose and sodium which likely contributes to diarrhea. The mechanism for sotagliflozin's cardiovascular benefits has not been established.

11 DESCRIPTION INPEFA tablets for oral administration contain sotagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor. The chemical name of sotagliflozin is (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol. Its molecular formula is C 21 H 25 ClO 5 S and the molecular weight is 424.94. The structural formula is: Sotagliflozin is a white to off-white solid. It is practically insoluble in water. Each film-coated tablet of INPEFA contains 200 mg or 400 mg of sotagliflozin and the following inactive ingredients. The core of the tablet contains colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, and talc. The film coating for the 200 mg tablet contains: indigo carmine aluminum lake, polyethylene glycol, polyvinyl alcohol (partly hydrolyzed), talc, and titanium dioxide. The film coating for the 400 mg tablet contains: hypromellose, lactose monohydrate, titanium dioxide, triacetin, and yellow iron oxide. Structural Formula

10 OVERDOSAGE There were no confirmed reports of symptomatic overdose with sotagliflozin during the clinical development program of INPEFA. In the event of an overdose with INPEFA, contact the Poison Control Center. Employ the usual supportive measures as dictated by the patient's clinical status. The removal of sotagliflozin by hemodialysis has not been studied.

16 HOW SUPPLIED/STORAGE AND HANDLING INPEFA tablets are oval and film-coated. Debossed Tablets Strength (mg) Color Deboss Bottle/30 Blister/30 (3 x 10) 200 Blue LEX on one side, 200 on other side NDC 70183-221-30 NDC 70183-221-31 400 Yellow LEX on one side, 400 on other side NDC 70183-241-30 -- Storage Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature].