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)].

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)].

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 m2), 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 Urosepsis and Pyelonephritis

Treatment with SGLT2 inhibitors, including INPEFA, increases the risk for urinary tract infections. Serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalization have been reported. Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated [see Adverse Reactions (6.1)].

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 Necrotizing Fasciitis of the Perineum (Fournier's Gangrene)

Reports of necrotizing fasciitis of the perineum (Fournier's Gangrene), a rare but serious and life-threatening necrotizing infection requiring urgent surgical intervention, have been identified in postmarketing surveillance in patients with diabetes mellitus receiving SGLT2 inhibitors. Cases have been reported in both females and males. Serious outcomes have included hospitalization, multiple surgeries, and death.

Patients treated with INPEFA presenting with pain, tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise, should be assessed for necrotizing fasciitis. If suspected, start treatment immediately with broad-spectrum antibiotics and, if necessary, surgical debridement. Discontinue INPEFA, closely monitor blood glucose levels, and provide appropriate alternative therapy for heart failure.

5.6 Genital Mycotic Infections

INPEFA increases the risk of genital mycotic infections. Patients with a history of genital mycotic infections were more likely to develop genital mycotic infections [see Adverse Reactions (6.1)]. Monitor and treat appropriately.

5.7 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.

5.8 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.

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.

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.

8.1 Pregnancy

8.2 Lactation

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 m2) in the SCORED study and in 426 patients with heart failure with eGFR < 60 mL/min/1.73 m2 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 m2 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 m2 or on dialysis. After starting therapy in these studies, patients were discontinued if eGFR fell below 15 mL/min/1.73 m2 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

12.3 Pharmacokinetics

Plasma Cmax 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 Cmax and area under the concentration-time curve from 0 to 24 hours (AUC0-24h) at steady state verses the first day of dosing.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14.1 SOLOIST Study

The SOLOIST (Effects of Sotagliflozin on Clinical Outcomes in Hemodynamically Stable Patients with Type 2 Diabetes Post Worsening Heart Failure) study (NCT03521934) was a randomized, double-blind, placebo-controlled, parallel-group, multicenter study in patients with type 2 diabetes mellitus who had been admitted to the hospital, a heart failure unit, infusion center, or emergency department for worsening heart failure to determine if INPEFA reduces the risk of total occurrence of cardiovascular death, hospitalization for heart failure, and urgent heart failure visit. Patients were randomized to treatment if they met the following criteria for clinical stability: no need for oxygen therapy, a systolic blood pressure of at least 100 mmHg, no need for intravenous inotropic or vasodilator therapy (excluding nitrates) and transitioned from intravenous to oral diuretic therapy.

Of the 1,222 randomized patients, 608 were randomized to INPEFA and 614 to placebo. Assigned treatment was initiated in the hospital or within a median of 2 days following hospital discharge.

The dose of study drug was to be up-titrated from 200 mg to 400 mg sotagliflozin or matching placebo as soon as 2 weeks or up until 8 months after initiation of treatment. The dose was increased to 400 mg once daily for 336 patients (56%) in the sotagliflozin group and 325 patients (53%) in the placebo group. The median time to up-titration was 16 days. Up-titration was to be performed based on the judgment of the investigator, who considered whether the patient's clinical condition was satisfactory, whether the drug was well tolerated, and whether AEs typical of SGLT2 inhibitors had occurred, such as those associated with volume depletion.

At baseline, median age was 70 years, 34% were female, 93% were White and 4% were Black or African American. Median A1C was 7.1%, median body mass index (BMI) was 31 kg/m2, and median eGFR was 50 mL/min/1.73 m2. Median left ventricular ejection fraction (LVEF) was 35% (79% with LVEF < 50%), median N-terminal pro B-type natriuretic peptide (NT-proBNP) was 1806 pg/mL, and the median Kansas City Cardiomyopathy Questionnaire-12 (KCCQ-12) score was 41.

At baseline, 86% were treated with at least one antihyperglycemic medication, including 52% with a biguanide, 36% with insulin, 19% with a sulfonylurea, 16% with a dipeptidyl peptidase-4 (DPP4) inhibitor, and 3% with a glucagon-like peptide 1 (GLP-1) receptor agonist. At baseline, 91% were treated with inhibitors of the renin-angiotensin-aldosterone system, 92% with a beta blocker, 95% with a loop diuretic, and 10% with another diuretic.

INPEFA was superior to placebo in reducing the risk of the primary composite endpoint (Hazard Ratio [HR] 0.67 [95% confidence interval (CI) 0.53, 0.85]; p = 0.001). (Table 2).

Figure 3 displays a cumulative events plot of the primary composite endpoint. The INPEFA and placebo event curves diverged early and remained separated over the study period.

Primary composite endpoint was based on investigator-reported events in all randomized patients, analyzed according to the treatment group allocated by randomization.

Figure 3 Primary Composite Endpoint (Total Occurrences of Cardiovascular Death, Hospitalization for Heart Failure, and Urgent Heart Failure Visit) Over Time in the SOLOIST Study

The results of the primary composite endpoint were generally consistent across prespecified subgroups (Figure 4), including screening LVEF < 50 or ≥ 50% and timing of first dose (post-discharge versus prior to discharge).

HF = heart failure; LVEF = left ventricular ejection fraction; MRA-mineralocorticoid receptor antagonist; NT-proBNP = N-terminal pro B-type natriuretic peptide; PY = patient-years Primary composite endpoint was based on investigator-reported events in all randomized patients, analyzed according to the treatment group allocated by randomization. Discharge may have been from hospital or urgent treatment facility where urgent heart failure visit occurred. Note: The figure above presents effects in various subgroups all of which are baseline characteristics and all of which were pre-specified. The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted.

Figure 4 Treatment Effect for Primary Composite Endpoint (Total Occurrences of Cardiovascular Death, Hospitalization for Heart Failure, and Urgent Heart Failure Visit) Subgroup Analysis (SOLOIST Study)

14.2 SCORED Study

The SCORED (Effects of Sotagliflozin on Cardiovascular and Renal Events in Patients with Type 2 Diabetes Mellitus, Cardiovascular Risk Factors and Moderately Impaired Renal Function) study (NCT03315143) was a randomized, double-blind, placebo-controlled, parallel-group, multicenter study in patients with type 2 diabetes mellitus (A1C > 7%), chronic kidney disease (eGFR 25 to 60 mL/min/1.73 m2), and additional cardiovascular risk factors, such as a history of heart failure, obesity, dyslipidemia, hypertension, or elevated cardiac and inflammatory biomarkers, to determine if INPEFA reduces the risk of total occurrence of cardiovascular death, hospitalization for heart failure, and urgent heart failure visit. Of the 10,584 randomized patients, 5,292 were randomized to INPEFA and 5,292 to placebo.

The dose of study drug was to be up-titrated from 200 mg to 400 mg sotagliflozin or matching placebo as soon as 4 weeks or up until 6 months after initiation of treatment. The dose was increased to 400 mg once daily for 3,934 patients (74%) in the INPEFA group and for 3,987 patients (75%) in the placebo group. The median time to up-titration was 29 days. Up-titration was to be performed based on the judgment of the investigator, who considered whether the patient's clinical condition was satisfactory, whether the drug was well tolerated, and whether AEs typical of SGLT2 inhibitors had occurred, such as those associated with volume depletion.

At baseline, median age was 68 years, 45% were female, 82% were White, 3% Black or African American, 6% Asian, and 4% American Indian or Native Alaskan. Median A1C was 8.3%, median BMI was 32 kg/m2, median eGFR was 45 mL/min/1.73 m2 (8% with eGFR < 30, 44% with eGFR 30 to < 45, and 48% with eGFR ≥ 45 mL/min/1.73 m2), and median urinary albumin-to-creatinine ratio (UACR) was 82 mg/g (32% with UACR ≥ 300 mg/g). A history of heart failure was present in 31%, prior myocardial infarction had occurred in 20%, a prior cerebrovascular event had occurred in 9%, and coronary revascularization had been performed in 22% of patients prior to study entry.

At baseline, 97% were treated with at least one antihyperglycemic medication, including 56% with a biguanide, 64% with insulin, 27% with a sulfonylurea, 20% with a DPP4 inhibitor, and 6% with a GLP-1 receptor agonist. At baseline, 88% were treated with inhibitors of the renin-angiotensin-aldosterone system, 14% with a beta blocker, 42% with a calcium channel blocker, 35% with a loop diuretic, and 30% with another diuretic.

INPEFA was superior to placebo in reducing the risk of the primary composite endpoint (HR 0.75 [95% CI 0.63, 0.88]; p < 0.001) (Table 3).

Figure 5 displays a cumulative events plot of the primary composite endpoint. The INPEFA and placebo event curves separated early and continued to diverge over the study period following randomization.

Primary composite endpoint was based on investigator-reported events in all randomized patients, analyzed according to the treatment group allocated by randomization.

Figure 5 Primary Composite Endpoint (Total Occurrences of Cardiovascular Death, Hospitalization for Heart Failure, and Urgent Heart Failure Visit) Over Time in the SCORED Study

The results of the primary composite endpoint were generally consistent across prespecified subgroups, including history of cardiovascular disease, history of heart failure, and screening LVEF < 50 or ≥ 50% (Figure 6).

CVD = cardiovascular disease; eGFR = estimated glomerular filtration rate; LVEF = left ventricular ejection fraction; HF = heart failure; PY = patient-years Primary composite endpoint was based on investigator-reported events in all randomized patients, analyzed according to the treatment group allocated by randomization. Note: The figure above presents effects in various subgroups all of which are baseline characteristics and all of which were pre-specified. The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted.

Figure 6 Treatment Effect for Primary Composite Endpoint (Total Occurrences of Cardiovascular Death, Hospitalization for Heart Failure, and Urgent Heart Failure Visit) Subgroup Analysis (SCORED Study)

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].

Risk of Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis

In patients with type 1 diabetes mellitus, inform them that using INPEFA can increase their risk of life-threatening diabetic ketoacidosis. For all other patients, inform them that INPEFA can cause potentially fatal ketoacidosis and that type 2 diabetes mellitus is a risk factor.

Educate all patients on precipitating factors (such as infection, reduced caloric intake, ketogenic diet, surgery, insulin dose reduction, dehydration, and alcohol abuse) and symptoms of ketoacidosis (including nausea, vomiting, abdominal pain, tiredness, and labored breathing). Inform patients that blood glucose may be normal even in the presence of ketoacidosis.

Advise patients that they may be asked to monitor ketones. If symptoms of ketoacidosis occur, instruct patients to discontinue INPEFA and seek medical attention immediately [see Warnings and Precautions (5.1)].

Volume Depletion

Inform patients that symptomatic hypotension may occur with INPEFA and advise them to contact their healthcare provider if they experience such symptoms [see Warnings and Precautions (5.2)]. Inform patients that dehydration may increase the risk for hypotension, and to have adequate fluid intake.

Serious Urinary Tract Infections

Inform patients of the potential for urinary tract infections, which may be serious. Provide them with information on the symptoms of urinary tract infections. Advise them to seek medical advice promptly if such symptoms occur [see Warnings and Precautions (5.3)].

Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues

Inform patients that the incidence of hypoglycemia is increased when INPEFA is used in combination with insulin and that a lower dose of insulin may be required to reduce the risk of hypoglycemia [see Warnings and Precautions (5.4)].

Necrotizing Fasciitis of the Perineum (Fournier's Gangrene)

Inform patients that necrotizing infections of the perineum (Fournier's Gangrene) have occurred with INPEFA in patients with diabetes mellitus. Counsel patients to promptly seek medical attention if they develop pain, tenderness, redness, or swelling of the genitals or the area from the genitals back to the rectum, along with a fever above 100.4°F or malaise [see Warnings and Precautions (5.5)].

Genital Mycotic Infections in Females (e.g., Vulvovaginitis)

Inform female patients that vaginal yeast infections may occur and provide them with information on the signs and symptoms of vaginal yeast infections. Advise them of treatment options and when to seek medical advice [see Warnings and Precautions (5.6)].

Genital Mycotic Infections in Males (e.g., Balanitis)

Inform male patients that yeast infections of the penis (e.g., balanitis or balanoposthitis) may occur, especially in patients with prior history. Provide them with information on the signs and symptoms of balanitis and balanoposthitis (rash or redness of the glans or foreskin of the penis). Advise them of treatment options and when to seek medical advice [see Warnings and Precautions (5.6)].

Hypersensitivity Reactions

Inform patients that hypersensitivity reactions (e.g., urticaria, anaphylactic reactions, and angioedema) have been reported with other SGLT2 inhibitors. Advise patients to immediately report any signs or symptoms suggesting allergic reaction or angioedema and to discontinue the drug until they have consulted their prescribing physician.

Pregnancy

Advise pregnant patients of the potential risk to a fetus with treatment with INPEFA.

Instruct patients to immediately inform their healthcare provider if pregnant or planning to become pregnant [see Use in Specific Populations (8.1)].

Lactation

Advise patients that use of INPEFA is not recommended while breastfeeding [see Use in Specific Populations (8.2)].

Laboratory Tests

Due to its mechanism of action, patients taking INPEFA will test positive for glucose in their urine.

Missed Dose

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.

If a dose of INPEFA is missed by more than 6 hours, take the next dose as prescribed the next day. Advise patients not to take two doses of INPEFA at the same time.

Manufactured for:
Lexicon Pharmaceuticals, Inc. (The Woodlands, TX 77381)

INPEFA is a trademark of Lexicon Pharmaceuticals, Inc.