Sotagliflozin

5 WARNINGS AND PRECAUTIONS Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis: Consider ketone monitoring in patients with type 1 diabetes mellitus and consider ketone monitoring in others at risk for ketoacidosis, as indicated. Assess for ketoacidosis regardless of presenting blood glucose levels and discontinue INPEFA if ketoacidosis is suspected. Monitor patients for resolution of ketoacidosis before restarting. ( 5.1 ) Volume Depletion: Before initiating, correct volume status. Monitor for signs and symptoms of hypotension during therapy. ( 5.2 ) Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues: Lower dose of insulin or insulin secretagogue may be required. ( 5.4 ) Genitourinary Infections, including Urosepsis, Pyelonephritis, Necrotizing Fasciitis of the Perineum (Fournier's Gangrene), and Genital Mycotic Infections: Monitor patients for signs and symptoms of genitourinary infections and treat promptly, if indicated. Immediately evaluate patients presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise, for necrotizing fasciitis and if suspected, discontinue INPEFA, and promptly institute appropriate medical and/or surgical intervention. ( 5.3 )

5.1 Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis In patients with type 1 diabetes mellitus, INPEFA significantly increases the risk of diabetic ketoacidosis, a life-threatening event, beyond the background rate. In placebo-controlled trials of patients with type 1 diabetes mellitus, the risk of ketoacidosis was markedly increased in patients who received sodium glucose cotransporter 2 (SGLT2) inhibitors compared to patients who received placebo; this risk may be greater with higher doses of INPEFA. INPEFA is not indicated for glycemic control. Type 2 diabetes mellitus and pancreatic disorders (e.g., history of pancreatitis or pancreatic surgery) are also risk factors for ketoacidosis. There have been postmarketing reports of fatal events of ketoacidosis in patients with type 2 diabetes using SGLT2 inhibitors. Precipitating conditions for diabetic ketoacidosis or other ketoacidosis include acute febrile illness, reduced caloric intake, ketogenic diet, surgery, insulin dose reduction, volume depletion, and alcohol abuse. Signs and symptoms are consistent with dehydration and severe metabolic acidosis and include nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. Blood glucose levels at presentation may be below those typically expected for diabetic ketoacidosis (e.g., less than 250 mg/dL). Ketoacidosis and glucosuria may persist longer than typically expected. Urinary glucose excretion persists for 3 days after discontinuing INPEFA [see Clinical Pharmacology ( 12.3 )]; however, there have been postmarketing reports of ketoacidosis and glucosuria lasting greater than 6 days and some up to 2 weeks after discontinuation of SGLT2 inhibitors. Consider ketone monitoring in patients with type 1 diabetes mellitus and consider ketone monitoring in others at risk for ketoacidosis if indicated by the clinical situation. Assess for ketoacidosis regardless of presenting blood glucose levels in patients who present with signs and symptoms consistent with severe metabolic acidosis. If ketoacidosis is suspected, discontinue INPEFA, promptly evaluate, and treat ketoacidosis, if confirmed. Monitor patients for resolution of ketoacidosis before restarting INPEFA. Withhold INPEFA, if possible, in temporary clinical situations that could predispose patients to ketoacidosis. Resume INPEFA when the patient is clinically stable and has resumed oral intake [see Dosage and Administration ( 2.3 )] . Educate all patients on the signs and symptoms of ketoacidosis and instruct patients to discontinue INPEFA and seek medical attention immediately if signs and symptoms occur.

5.2 Volume Depletion INPEFA can cause intravascular volume depletion which may sometimes manifest as symptomatic hypotension or acute transient changes in creatinine. There have been postmarketing reports of acute kidney injury, some requiring hospitalization and dialysis, in patients with type 2 diabetes mellitus receiving SGLT2 inhibitors. Patients with impaired renal function (eGFR < 60 mL/min/1.73 m 2 ), elderly patients, or patients on loop diuretics may be at increased risk for volume depletion or hypotension [see Adverse Reactions ( 6.1 ) and Use in Specific Populations ( 8.5 , 8.6 ) ]. Before initiating INPEFA in patients with one or more of these characteristics, assess volume status and renal function. Monitor for signs and symptoms of hypotension, and renal function after initiating therapy.

5.3 Genitourinary Infections, including Urosepsis, Pyelonephritis Necrotizing Fasciitis of the Perineum (Fournier's Gangrene), and Genital Mycotic Infections INPEFA increases urinary glucose excretion [see Clinical Pharmacology ( 12.2 )] and increases the risk of genitourinary infections including urinary tract infections and genital mycotic infections in both male and female patients [see Adverse Reactions ( 6.1 )] . Serious genitourinary infections, including urosepsis, pyelonephritis, and necrotizing fasciitis of the perineum (Fournier's gangrene, a rare life-threatening infection requiring urgent surgical intervention), have occurred in patients receiving SGLT2 inhibitors, including INPEFA [see Adverse Reactions ( 6.1 )] . Cases have required hospitalization. In patients with Fournier's gangrene, serious outcomes have included multiple surgeries and death. Patients with a history of chronic or recurrent genitourinary infections are more likely to develop genitourinary infections when using INPEFA. Monitor patients for signs and symptoms of genitourinary infections and treat promptly, if indicated. Immediately evaluate patients presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise, for necrotizing fasciitis. If suspected, discontinue INPEFA and promptly institute appropriate medical and/or surgical intervention.

5.4 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues Insulin and insulin secretagogues are known to cause hypoglycemia. INPEFA may increase the risk of hypoglycemia when combined with insulin 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 these agents are used in combination with INPEFA.

5.5 Positive Urine Glucose Test Monitoring glucose levels with urine glucose tests is not recommended as SGLT2 inhibition increases urinary glucose excretion and will lead to positive urine glucose tests. Use alternative methods to monitor glucose levels.

5.6 Interference with 1,5-anhydroglucitol (1,5-AG) Assay Monitoring glucose levels with 1,5-AG assay is not recommended as measurements of 1,5-AG are unreliable in assessing glucose levels in patients taking SGLT2 inhibitors. Use alternative methods to monitor glucose levels.

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 animal milk, it is likely to be present in human milk. Since human kidney maturation occurs in utero and during the first 2 years of life when lactational exposure may occur, there may be risk to the developing human kidney. Because of the potential for serious adverse reactions in a breastfed infant, advise women that breastfeeding is not recommended while taking INPEFA. Data In rats, after a single oral dose of radiolabeled sotagliflozin to dams on gestation Day 13 or 18, low to moderate levels of radioactivity were present in fetal tissues. In rat milk, the mean milk/plasma concentration ratios ranged from 0.5 to 2. Exposure to radioactivity was approximately 30% greater in milk than in plasma based on AUC 0-inf values.

8.4 Pediatric Use The safety and effectiveness of INPEFA in pediatric patients under 18 years of age have not been established.

8.5 Geriatric Use No INPEFA dosage change is recommended based on age. In the SOLOIST study, a total of 241 (40%) patients treated with INPEFA were between 65 and < 75 years of age, and 174 (29%) were ≥ 75 years of age. In the SCORED study, a total of 2,470 (47%) patients treated with INPEFA were between 65 and < 75 years of age, and 1,240 (23%) were ≥ 75 years of age. No overall differences in efficacy were detected between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Elderly patients may be at increased risk for volume depletion adverse reactions, including hypotension. In patients ≥ 65 years of age, a higher proportion of patients treated with INPEFA had adverse reactions of volume depletion [see Warnings and Precautions ( 5.2 ) and Adverse Reactions ( 6.1 ) ].

8.6 Renal Impairment INPEFA was evaluated in 5,292 patients with chronic kidney disease (eGFR 25 to 60 mL/min/1.73 m 2 ) in the SCORED study and in 426 patients with heart failure with eGFR < 60 mL/min/1.73 m 2 in the SOLOIST study. The safety profile of INPEFA across eGFR subgroups in these studies was consistent with the known safety profile. There was an increase in volume-related adverse events (e.g., hypotension, dizziness) in patients with eGFR < 30 mL/min/1.73 m 2 relative to the overall safety population [see Warnings and Precautions ( 5.2 ) and Adverse Reactions ( 6.1 )]. Efficacy and safety studies with INPEFA did not enroll patients with an eGFR less than 25 mL/min/1.73 m 2 or on dialysis. After starting therapy in these studies, patients were discontinued if eGFR fell below 15 mL/min/1.73 m 2 or were initiated on chronic dialysis.

8.7 Hepatic Impairment In a clinical pharmacology study in patients with hepatic impairment, the exposure in mild hepatic impairment was not increased, but was approximately 3-fold as high in moderate and approximately 6-fold as high in severely hepatic-impaired subjects compared to subjects with normal hepatic function [see Clinical Pharmacology ( 12.3 )] . No dosage adjustment is necessary in patients with mild hepatic impairment. The safety and efficacy of INPEFA have not been established in patients with moderate or severe hepatic impairment [see Clinical Pharmacology ( 12.3 )] . INPEFA is not recommended in patients with moderate or severe hepatic impairment.

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.

12.2 Pharmacodynamics Cardiac Electrophysiology In a randomized, placebo-controlled, active-comparator, crossover study, 58 healthy subjects were administered a single oral dose of sotagliflozin 800 mg or sotagliflozin 2000 mg (5 times the maximum recommended dose), moxifloxacin, and placebo. No increase in QT corrected for heart rate (QTc) was observed with either 800 mg or 2000 mg sotagliflozin.

12.3 Pharmacokinetics Plasma C max and AUC of sotagliflozin increased in a dose-proportional manner in the therapeutic dose range of 200 mg to 400 mg once daily. Accumulation of sotagliflozin was observed with an approximate 50-100% increase in both C max and area under the concentration-time curve from 0 to 24 hours (AUC 0-24h ) at steady state verses the first day of dosing. Absorption The absolute bioavailability of oral sotagliflozin 400 mg dose was approximately 25% (90% confidence interval [CI] 16% to 39%) for area under the concentration-time curve from time 0 to last measurable concentration (AUC 0-last ). The contribution of enterohepatic circulation to the overall exposure is estimated to be approximately 50%. The median time to maximum plasma concentration (T max ) ranged from 1.25 to 3 hours, over a single-dose range of 200 mg to 2000 mg. Following administration of multiple doses (400 mg and 800 mg), the median T max values ranged from 2.5 to 4 hours. Food Effect When sotagliflozin tablets were administered with a high-caloric breakfast compared to fasting conditions, plasma exposure to sotagliflozin as measured by C max and AUC 0-inf increased by 149% and 50%, respectively. Multiple doses of sotagliflozin 400 mg given immediately before breakfast, 30 minutes prior to breakfast, and 1-hour before breakfast in healthy subjects showed a consistent effect of sotagliflozin on urine glucose excretion (UGE), insulin, and postprandial glucose (PPG) across all dose schedules. It is recommended that INPEFA be taken not more than one hour before the first meal of the day. Distribution Both sotagliflozin and its major human metabolite sotagliflozin 3-O-glucuronide exhibited high binding to human plasma proteins in vitro (> 93% bound), which was not dependent on the concentration of sotagliflozin and sotagliflozin 3-O-glucuronide and was not influenced by the degree of renal or hepatic function. Following administration of a single 400 mg dose of [ 14 C]-sotagliflozin, the mean blood/plasma ratios for total radioactivity were 0.5 and 0.4 for C max and AUC 0-last , respectively, and the mean whole blood to plasma concentration ratio of sotagliflozin ranged from 0.5 to 0.6. The mean apparent volume of distribution of sotagliflozin following administration of a single 400 mg oral dose of [ 14 C]-sotagliflozin was 9000 L. Elimination Metabolism Following the administration of a single dose of 400 mg [ 14 C]-sotagliflozin in healthy subjects, sotagliflozin was extensively metabolized predominantly to sotagliflozin 3-O-glucuronide and it represented 94.3% of the radioactivity in plasma. The key enzymes responsible for the metabolism of sotagliflozin were UGT1A9 and, to a lesser extent, CYP3A4. Following incubation of sotagliflozin with UGT1A9, the 3-O-glucuronide metabolite of sotagliflozin was the main conjugate observed. No acyl glucuronides of sotagliflozin were identified. Excretion Following the administration of a single dose of 400 mg [ 14 C]-sotagliflozin, 57% and 37% of the radioactivity was recovered in the urine and feces, respectively. These results indicate that the main route of elimination was renal. The predominant metabolite detected in urine was sotagliflozin 3-O-glucuronide, representing a mean of 33% of the administered radioactive dose. Unchanged [ 14 C]-sotagliflozin was the predominant radioactive peak detected in fecal extracts representing a mean of 23% of the total administered radioactive dose. Sotagliflozin undergoes enterohepatic circulation. Following administration of 200 mg and 400 mg, mean terminal half-life (T 1/2 ) ranged from 21 to 35 hours for sotagliflozin and from 19 to 26 hours for sotagliflozin 3-O-glucuronide. Effective half-life of sotagliflozin ranged from 5 to 10 hours. Steady state was generally achieved after 5 days of once daily dosing with sotagliflozin 200 mg and 400 mg. In healthy volunteers, mean oral clearance (CL/F) of sotagliflozin ranged from 260 to 370 L/hr following administration of 200 mg and 400 mg sotagliflozin. The median population PK model predicted CL/F in type 2 diabetes mellitus patients with normal renal function was about 300 L/hr. Specific Populations Renal Impairment Exposure of sotagliflozin was evaluated in a dedicated PK study in subjects with mild (eGFR 60 to < 90 mL/min/1.73 m 2 ) and moderate (eGFR 30 to < 60 mL/min/1.73 m 2 ) renal impairment and with normal renal function (eGFR ≥ 90 mL/min/1.73 m 2 ). Exposure to sotagliflozin following a single dose of 400 mg was approximately 70% higher in subjects with mild and up to 170% higher in subjects with moderate renal impairment compared to subjects with normal renal function [see Use in Specific Populations ( 8.6 )]. Hepatic Impairment In a study with subjects with reduced hepatic function, AUC of sotagliflozin was not increased in mild (Child Pugh A) hepatic impaired subjects but was increased by approximately 3-fold in moderate (Child Pugh B) and approximately 6-fold in severe (Child Pugh C) hepatic impaired subjects compared to subjects with normal hepatic function [see Use in Specific Populations ( 8.7 )] . Effects of Age, Sex, Race, and Body Weight on Pharmacokinetics Based on population PK analysis, age, body weight, sex and race (non-white versus primarily whites) do not have a clinically meaningful effect on the PK of sotagliflozin. Drug Interactions In Vitro Studies The major human metabolite of sotagliflozin, sotagliflozin 3-O-glucuronide, was shown to have an in vitro potential to inhibit CYP3A4 and CYP2D6 and to induce CYP3A4. Sotagliflozin was shown to have inhibitory effects on P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Sotagliflozin is a substrate of the human uptake transporters organic anion transporter (OAT)3, organic-anion-transporting polypeptides (OATP)1B1, and OATP1B3, but not OAT1 and organic cation transporter 2 (OCT2). Sotagliflozin does not inhibit any of these human uptake transporters at clinically relevant plasma concentrations. In Vivo Studies Figure 1 summarizes the effect on sotagliflozin by concomitantly administered drugs. The observed changes in overall exposure (AUC) of sotagliflozin following coadministration with hydrochlorothiazide, ramipril, metformin, mefenamic acid, and oral contraceptives are not considered to be clinically relevant. Rifampicin (UGT inducer) decreases exposure to sotagliflozin [see Drug Interactions ( 7.2 )] . Figure 1 Effect of Various Medications on the Pharmacokinetics of Sotagliflozin, Displayed as Geometric Mean AUCs and C max Ratios Vertical reference lines indicate 100% (solid) and the 80%-125% range (dashed) a 400 mg sotagliflozin, administered as a single dose b 400 mg sotagliflozin, at steady state AUC 0-last = area under the concentration-time curve from time 0 to last measurable concentration; AUC 0-tau = area under the concentration-time curve from time 0 to end of the dosing period; C max = maximum drug concentration; EE = ethinyl estradiol; NO = norgestimate Figure 2 summarizes the effect on concomitantly administered drugs by sotagliflozin. The increases in exposure (AUC) of metoprolol (CYP2D6 substrate) and rosuvastatin (BCRP substrate), as well as the decrease in exposure to midazolam (CYP3A4 substrate) are not considered to be clinically relevant. The increased exposure (C max and AUC) in ramipril is not considered clinically significant because the exposure of ramiprilat, the primary active metabolite, is minimally increased. The increase in exposure (C max and AUC) of digoxin, a P-gp substrate, when coadministered with sotagliflozin, requires monitoring of patients [see Drug Interactions ( 7.1 )] . Figure 2 Effect of Sotagliflozin on the Pharmacokinetics of Various Medications, Displayed as Geometric Mean AUCs and C max Ratios Vertical reference lines indicate 100% (solid) and the 80%-125% range (dashed) a 400 mg sotagliflozin, administered as a single dose b 400 mg sotagliflozin, at steady state c Norelgestromin is the primary active metabolite of NO d Ramiprilat is the primary active metabolite of ramipril AUC 0-last = area under the concentration-time curve from time 0 to last measurable concentration; AUC 0-tau = area under the concentration-time curve from time 0 to end of the dosing period; C max = maximum drug concentration; EE = ethinyl estradiol; NO = norgestimate Figure 1 Figure 2

Plasma C max and AUC of sotagliflozin increased in a dose-proportional manner in the therapeutic dose range of 200 mg to 400 mg once daily. Accumulation of sotagliflozin was observed with an approximate 50-100% increase in both C max and area under the concentration-time curve from 0 to 24 hours (AUC 0-24h ) at steady state verses the first day of dosing. Absorption The absolute bioavailability of oral sotagliflozin 400 mg dose was approximately 25% (90% confidence interval [CI] 16% to 39%) for area under the concentration-time curve from time 0 to last measurable concentration (AUC 0-last ). The contribution of enterohepatic circulation to the overall exposure is estimated to be approximately 50%. The median time to maximum plasma concentration (T max ) ranged from 1.25 to 3 hours, over a single-dose range of 200 mg to 2000 mg. Following administration of multiple doses (400 mg and 800 mg), the median T max values ranged from 2.5 to 4 hours. Food Effect When sotagliflozin tablets were administered with a high-caloric breakfast compared to fasting conditions, plasma exposure to sotagliflozin as measured by C max and AUC 0-inf increased by 149% and 50%, respectively. Multiple doses of sotagliflozin 400 mg given immediately before breakfast, 30 minutes prior to breakfast, and 1-hour before breakfast in healthy subjects showed a consistent effect of sotagliflozin on urine glucose excretion (UGE), insulin, and postprandial glucose (PPG) across all dose schedules. It is recommended that INPEFA be taken not more than one hour before the first meal of the day. Distribution Both sotagliflozin and its major human metabolite sotagliflozin 3-O-glucuronide exhibited high binding to human plasma proteins in vitro (> 93% bound), which was not dependent on the concentration of sotagliflozin and sotagliflozin 3-O-glucuronide and was not influenced by the degree of renal or hepatic function. Following administration of a single 400 mg dose of [ 14 C]-sotagliflozin, the mean blood/plasma ratios for total radioactivity were 0.5 and 0.4 for C max and AUC 0-last , respectively, and the mean whole blood to plasma concentration ratio of sotagliflozin ranged from 0.5 to 0.6. The mean apparent volume of distribution of sotagliflozin following administration of a single 400 mg oral dose of [ 14 C]-sotagliflozin was 9000 L. Elimination Metabolism Following the administration of a single dose of 400 mg [ 14 C]-sotagliflozin in healthy subjects, sotagliflozin was extensively metabolized predominantly to sotagliflozin 3-O-glucuronide and it represented 94.3% of the radioactivity in plasma. The key enzymes responsible for the metabolism of sotagliflozin were UGT1A9 and, to a lesser extent, CYP3A4. Following incubation of sotagliflozin with UGT1A9, the 3-O-glucuronide metabolite of sotagliflozin was the main conjugate observed. No acyl glucuronides of sotagliflozin were identified. Excretion Following the administration of a single dose of 400 mg [ 14 C]-sotagliflozin, 57% and 37% of the radioactivity was recovered in the urine and feces, respectively. These results indicate that the main route of elimination was renal. The predominant metabolite detected in urine was sotagliflozin 3-O-glucuronide, representing a mean of 33% of the administered radioactive dose. Unchanged [ 14 C]-sotagliflozin was the predominant radioactive peak detected in fecal extracts representing a mean of 23% of the total administered radioactive dose. Sotagliflozin undergoes enterohepatic circulation. Following administration of 200 mg and 400 mg, mean terminal half-life (T 1/2 ) ranged from 21 to 35 hours for sotagliflozin and from 19 to 26 hours for sotagliflozin 3-O-glucuronide. Effective half-life of sotagliflozin ranged from 5 to 10 hours. Steady state was generally achieved after 5 days of once daily dosing with sotagliflozin 200 mg and 400 mg. In healthy volunteers, mean oral clearance (CL/F) of sotagliflozin ranged from 260 to 370 L/hr following administration of 200 mg and 400 mg sotagliflozin. The median population PK model predicted CL/F in type 2 diabetes mellitus patients with normal renal function was about 300 L/hr. Specific Populations Renal Impairment Exposure of sotagliflozin was evaluated in a dedicated PK study in subjects with mild (eGFR 60 to < 90 mL/min/1.73 m 2 ) and moderate (eGFR 30 to < 60 mL/min/1.73 m 2 ) renal impairment and with normal renal function (eGFR ≥ 90 mL/min/1.73 m 2 ). Exposure to sotagliflozin following a single dose of 400 mg was approximately 70% higher in subjects with mild and up to 170% higher in subjects with moderate renal impairment compared to subjects with normal renal function [see Use in Specific Populations ( 8.6 )]. Hepatic Impairment In a study with subjects with reduced hepatic function, AUC of sotagliflozin was not increased in mild (Child Pugh A) hepatic impaired subjects but was increased by approximately 3-fold in moderate (Child Pugh B) and approximately 6-fold in severe (Child Pugh C) hepatic impaired subjects compared to subjects with normal hepatic function [see Use in Specific Populations ( 8.7 )] . Effects of Age, Sex, Race, and Body Weight on Pharmacokinetics Based on population PK analysis, age, body weight, sex and race (non-white versus primarily whites) do not have a clinically meaningful effect on the PK of sotagliflozin. Drug Interactions In Vitro Studies The major human metabolite of sotagliflozin, sotagliflozin 3-O-glucuronide, was shown to have an in vitro potential to inhibit CYP3A4 and CYP2D6 and to induce CYP3A4. Sotagliflozin was shown to have inhibitory effects on P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Sotagliflozin is a substrate of the human uptake transporters organic anion transporter (OAT)3, organic-anion-transporting polypeptides (OATP)1B1, and OATP1B3, but not OAT1 and organic cation transporter 2 (OCT2). Sotagliflozin does not inhibit any of these human uptake transporters at clinically relevant plasma concentrations. In Vivo Studies Figure 1 summarizes the effect on sotagliflozin by concomitantly administered drugs. The observed changes in overall exposure (AUC) of sotagliflozin following coadministration with hydrochlorothiazide, ramipril, metformin, mefenamic acid, and oral contraceptives are not considered to be clinically relevant. Rifampicin (UGT inducer) decreases exposure to sotagliflozin [see Drug Interactions ( 7.2 )] . Figure 1 Effect of Various Medications on the Pharmacokinetics of Sotagliflozin, Displayed as Geometric Mean AUCs and C max Ratios Vertical reference lines indicate 100% (solid) and the 80%-125% range (dashed) a 400 mg sotagliflozin, administered as a single dose b 400 mg sotagliflozin, at steady state AUC 0-last = area under the concentration-time curve from time 0 to last measurable concentration; AUC 0-tau = area under the concentration-time curve from time 0 to end of the dosing period; C max = maximum drug concentration; EE = ethinyl estradiol; NO = norgestimate Figure 2 summarizes the effect on concomitantly administered drugs by sotagliflozin. The increases in exposure (AUC) of metoprolol (CYP2D6 substrate) and rosuvastatin (BCRP substrate), as well as the decrease in exposure to midazolam (CYP3A4 substrate) are not considered to be clinically relevant. The increased exposure (C max and AUC) in ramipril is not considered clinically significant because the exposure of ramiprilat, the primary active metabolite, is minimally increased. The increase in exposure (C max and AUC) of digoxin, a P-gp substrate, when coadministered with sotagliflozin, requires monitoring of patients [see Drug Interactions ( 7.1 )] . Figure 2 Effect of Sotagliflozin on the Pharmacokinetics of Various Medications, Displayed as Geometric Mean AUCs and C max Ratios Vertical reference lines indicate 100% (solid) and the 80%-125% range (dashed) a 400 mg sotagliflozin, administered as a single dose b 400 mg sotagliflozin, at steady state c Norelgestromin is the primary active metabolite of NO d Ramiprilat is the primary active metabolite of ramipril AUC 0-last = area under the concentration-time curve from time 0 to last measurable concentration; AUC 0-tau = area under the concentration-time curve from time 0 to end of the dosing period; C max = maximum drug concentration; EE = ethinyl estradiol; NO = norgestimate Figure 1 Figure 2