Sotagliflozin (Monograph)

Brand name: Inpefa
Drug class: Sodium-glucose (SGLT) Cotransporter Inhibitors

Introduction

Sotagliflozin is sodium-glucose cotransporter 2 (SGLT2) inhibitor.

Uses for Sotagliflozin

Sotagliflozin has the following uses:

Sotagliflozin is indicated to reduce the risk of cardiovascular death, hospitalization for heart failure, and urgent heart failure visit in adults with heart failure, or adults with type 2 diabetes mellitus, chronic kidney disease, and other cardiovascular risk factors.

Sotagliflozin Dosage and Administration

General

Sotagliflozin is available in the following dosage form(s) and strength(s):

Tablets: 200 mg and 400 mg

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration

Correct volume status before starting sotagliflozin. The recommended starting dosage is 200 mg orally once daily, not more than 1 hour before the first meal of the day. Dosage should be up-titrated after at least 2 weeks to 400 mg orally once daily as tolerated. Down-titrate to 200 mg as necessary. In patients with decompensated heart failure, begin dosing when patients are hemodynamically stable.

Withhold sotagliflozin at least 3 days, if possible, prior to major surgery or procedures associated with prolonged fasting.

Cautions for Sotagliflozin

Contraindications

History of serious hypersensitivity reaction to sotagliflozin.

Warnings/Precautions

Diabetic Ketoacidosis in Patients With Type 1 Diabetes Mellitus and other Ketoacidosis

In patients with type 1 diabetes mellitus, sotagliflozin 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 sotagliflozin. Sotagliflozin 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 sotagliflozin; 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 sotagliflozin, promptly evaluate, and treat ketoacidosis, if confirmed. Monitor patients for resolution of ketoacidosis before restarting sotagliflozin.

Withhold sotagliflozin, if possible, in temporary clinical situations that could predispose patients to ketoacidosis. Resume sotagliflozin when the patient is clinically stable and has resumed oral intake.

Educate all patients on the signs and symptoms of ketoacidosis and instruct patients to discontinue sotagliflozin and seek medical attention immediately if signs and symptoms occur.

Volume Depletion

Sotagliflozin 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. Before initiating sotagliflozin 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.

Urosepsis and Pyelonephritis

Treatment with SGLT2 inhibitors, including sotagliflozin, 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.

Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues

Insulin and insulin secretagogues are known to cause hypoglycemia. Sotagliflozin may increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue. 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 sotagliflozin.

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 sotagliflozin 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 sotagliflozin, closely monitor blood glucose levels, and provide appropriate alternative therapy for heart failure.

Genital Mycotic Infections

Sotagliflozin increases the risk of genital mycotic infections. Patients with a history of genital mycotic infections were more likely to develop such infections. Monitor and treat appropriately.

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.

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.

Specific Populations

Pregnancy

Based on animal data showing renal effects, sotagliflozin is not recommended during the second and third trimesters of pregnancy.

Available data with sotagliflozin 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.

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.

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.

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.

Lactation

There are no data on the presence of sotagliflozin in human milk, the effects on the breastfed infant, or the effects on milk production. Sotagliflozin is present in rat milk. 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 sotagliflozin.

Pediatric Use

The safety and effectiveness of sotagliflozin in pediatric patients under 18 years of age have not been established.

Geriatric Use

No sotagliflozin dosage change is recommended based on age.

In the SOLOIST study, a total of 241 (40%) patients treated with sotagliflozin 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 sotagliflozin 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 sotagliflozin had adverse reactions of volume depletion.

Renal Impairment

Sotagliflozin 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 sotagliflozin 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 m²relative to the overall safety population.

Efficacy and safety studies with sotagliflozin 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.

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.

No dosage adjustment is necessary in patients with mild hepatic impairment.

The safety and efficacy of sotagliflozin have not been established in patients with moderate or severe hepatic impairment. Sotagliflozin is not recommended in patients with moderate or severe hepatic impairment.

Common Adverse Effects

Most common adverse reactions (incidence ≥ 5%) are urinary tract infection, volume depletion, diarrhea, and hypoglycemia.

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Digoxin: Monitor digoxin levels.

Uridine 5'-diphospho-glucuronosyltransferase (UGT) Inducers (e.g., rifampin): Sotagliflozin exposure is reduced. Consider monitoring of clinical status.

Lithium: Monitor serum lithium concentrations.

Actions

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.

Advice to Patients

Inform patients with type 1 diabetes mellitus that using sotagliflozin can increase their risk of life-threatening diabetic ketoacidosis. For all other patients, inform them that sotagliflozin 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 sotagliflozin and seek medical attention immediately.
Inform patients that symptomatic hypotension may occur with sotagliflozin and advise them to contact their healthcare provider if they experience such symptoms. Inform patients that dehydration may increase the risk for hypotension, and to have adequate fluid intake.
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.
Inform patients that the incidence of hypoglycemia is increased when sotagliflozin is used in combination with insulin and that a lower dose of insulin may be required to reduce the risk of hypoglycemia.
Inform patients that necrotizing infections of the perineum (Fournier's Gangrene) have occurred with sotagliflozin 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.
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.
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.
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.
Advise pregnant patients of the potential risk to a fetus with treatment with sotagliflozin. Instruct patients to immediately inform their healthcare provider if pregnant or planning to become pregnant.
Advise patients that use of sotagliflozin is not recommended while breastfeeding.
If a dose of sotagliflozin is missed by more than 6 hours, take the next dose as prescribed the next day. Advise patients not to take two doses of sotagliflozin at the same time.

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.