Sotagliflozin

An increase in total exposure and C_max of rosuvastatin of ca 1.2- and 1.4-fold, respectively, was demonstrated when co-administered with sotagliflozin and is not deemed clinically relevant. However, the mechanism behind the limited increase in exposure is not completely elucidated as sotagliflozin and M19 (sotagliflozin 3-O-glucuronide) are characterized as BCRP inhibitors in vitro and M19 also as an inhibitor OATP1B3 and OAT3. Rosuvastatin is a known OATP, BCRP and OAT3 substrate. It cannot be ruled out that sotagliflozin may interact with other sensitive OAT3, OATP- and/or BCRPsubstrates (e.g.: fexofenadine, paclitaxel, bosentan, methotrexate, furosemide, benzylpenicillin) resulting in potentially larger increases of exposure than seen for rosuvastatin. It should be evaluated if additional safety monitoring is needed when using these substrates.

Based on in-vitro data, induction of CYP2C9, CYP2B6 and CYP1A2 cannot be ruled out. Substrates of these enzymes should be monitored for decreases in efficacy.

Sotagliflozin should not be initiated in patients with an eGFR <60 mL/min and should be discontinued at eGFR persistently below 45 mL/min.

Sotagliflozin should not be used in patients with severe renal impairment, end stage renal disease (ESRD) or in patients on dialysis as it has not been studied in these patients.

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 m² relative 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.

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.

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.

There is an increase in AUC_0-inf and C_max of digoxin (27% and 52% respectively) when coadministered with sotagliflozin 400mg, due to inhibition of P-gp by sotagliflozin. Patients taking sotagliflozin with concomitant digoxin should be monitored appropriately.

The coadministration of a multiple dosing regimen of rifampicin, an inducer of various UGT and CYP metabolizing enzymes, with a single dose of 400 mg sotagliflozin resulted in a decrease in the AUC_0-inf (60%) and C_max (40%) of sotagliflozin. This decrease in exposure to sotagliflozin may decrease efficacy. If an enzyme inducer (e.g., rifampicin, phenytoin, phenobarbital, ritonavir) must be co-administered with sotagliflozin, consider frequent monitoring of glucose level.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors should be used with caution in patients with increased risk of DKA. In the clinical trials (pool of two 52-week placebo-controlled trials) of sotagliflozin, the incidence of diabetic ketoacidosis (DKA) was higher in the sotagliflozin treatment group compared with the placebo group.

Before initiating sotagliflozin

Before starting treatment, patients should be evaluated with respect to DKA risk.

Sotagliflozin should not be initiated when patients are at a higher risk of DKA, such as:

• Patients with low insulin needs.
• Patient not on optimal insulin dose or who have recent issues with noncompliance or recurrent errors with insulin dosing and who are unlikely to maintain adequate insulin dosing.
• Patients with recent or recurrent history of DKA (e.g.1 episode in the past 3 months or more than 1 episode in the past 6 months).
• Patients with increased insulin requirements due to acute medical illness or surgery.
• Patients with elevated ketones levels (BHB reading is greater than 0.6 mmol/L or urine ketones one plus (+)). If ketones are elevated (BHB reading is greater than 0.6 mmol/L), treatment with sotagliflozin should not be started until the ketone levels are normal.
• Patients unable or unwilling to monitor ketones.
• Patients who insist on maintaining caloric restriction, carbohydrate restriction or ketogenic diet or who chronically under-dose insulin (e.g. in order to remain in a lipolytic state).
• Patients with excessive alcohol consumption or who use illicit drugs.

Patients using an insulin infusion pump have a higher risk of DKA and should be experienced with pump use, common trouble-shooting strategies when interruptions of insulin delivery via pump occur (issues with insertion site, clogged tubing, empty reservoir, etc.) and use of supplemental insulin injections with pen or syringe as needed in case of pump failure. Patients should consider monitoring ketones levels three to four hours after changing pump materials. Patients using a pump should also check their ketone levels with any suspected insulin interruption, regardless of blood glucose levels. Insulin injections should be given within 2 hours of an unexplained high blood glucose value and sotagliflozin treatment should be interrupted.

Sotagliflozin should only be given to patients:

• with access to ketone testing materials and immediate access to a clinician if blood or urine ketones are elevated.
• who are able to monitor ketone levels and are educated in when it is most appropriate to do so.

During a dedicated counselling session with the patient at the time of first prescription of sotagliflozin the Patient/Carer Guide and Patient Alert card, also available via the QRcode or website, should be presented. The Patient Alert Card is also provided in the product packaging.

The patient should be informed:

• how to recognize the risk factors which can predispose to ketosis and DKA (including, but not limited to, recent or recurrent history of DKA, missed or reduced insulin doses, decreased caloric intake or severe dehydration, vigorous exercise, intercurrent illness, surgery, alcohol abuse, and in patients using an insulin infusion pump, insulin infusion interruption),
• how to recognize DKA signs or symptoms, emphasizing that DKA could occur even when blood glucose levels are below 14 mmol/L (250 mg/dL),
• when to discontinue sotagliflozin therapy,
• what actions to take when ketosis/DKA is suspected.

It is recommended that patients obtain several baseline blood or urine ketone levels over one to two weeks period prior to initiation of sotagliflozin therapy, and patients should become familiar with the behaviours/circumstances associated with elevated ketone levels and how to address them.

Management of DKA risk

The risk of diabetic ketoacidosis must be considered in the event of non-specific symptoms such as nausea, vomiting, anorexia, abdominal pain, excessive thirst, difficulty breathing, confusion, unusual fatigue or sleepiness. It is possible that adverse effects occurring with sotagliflozin may be similar to presenting symptoms of DKA. Patients should be assessed for ketoacidosis immediately if these symptoms occur, by measuring the urine or blood ketones, regardless of blood glucose level. DKA episodes during sotagliflozin use can be atypical, with patients not having blood sugar levels as high as expected. This atypical presentation of DKA (i.e. normal or slightly elevated blood glucose levels) can delay diagnosis and treatment.

During treatment with sotagliflozin

• The patient should remain on optimal insulin dosing.
• When needed to prevent hypoglycaemia, insulin dose reduction should be done cautiously to avoid ketosis and DKA.
• Consider discontinuing sotagliflozin if adequate insulinisation cannot be achieved on treatment.

Treatment with sotagliflozin should be stopped in patients who are hospitalized for major surgical procedures or acute serious medical illnesses.

Ketone monitoring during treatment

After initiating sotagliflozin ketones should be monitored on a regular basis during the initial one to two weeks, then the frequency of ketone level testing should be individualised, according to the patient’s lifestyle and/or risk factors. For all patients, it is recommended that ketones should be measured with changes to the normal routine, including reduced carbohydrate intake, intercurrent illness, reductions in total daily insulin dosing, physical activity and stress. Ketones should be measured repetitively when any signs or symptoms consistent with DKA or euglycaemic DKA are present. Measurement of blood ketone levels is preferred over urine.

Patients must be informed about what actions to take if ketone levels are elevated.

Management of DKA

In patients where DKA is suspected or diagnosed, treatment with sotagliflozin should be discontinued immediately.

With sotagliflozin DKA may be present with low, normal or high blood glucose levels. DKA should be treated as per standard of care. Supplemental carbohydrate may be required based on glucose levels in addition to hydration and additional rapid acting insulin.

Restarting sotagliflozin is not recommended, unless a cause for the ketoacidosis is identified and resolved (e.g., pump malfunction, acute intercurrent illness, excessive reduction of insulin).

Temporary interruption of sotagliflozin should be considered when treating pyelonephritis and urosepsis.

Risk Summary

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 [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.

Risk Summary

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 (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 sotagliflozin.

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.

Carcinogenesis

Carcinogenesis was evaluated in a 6-month study in RasH2 transgenic mice and in a 2-year study in Sprague Dawley rats. Sotagliflozin did not increase the incidence of tumors in RasH2 transgenic mice at doses up to 100 mg/kg/day or in rats at doses up to 15-fold (males) and 45-fold (females) clinical exposure at the MRHD.

Mutagenesis

Sotagliflozin was not mutagenic or clastogenic, with or without metabolic activation, in the in vitro Ames bacterial mutagenicity assay, the in vitro Chinese hamster ovary cell chromosomal aberration study, and an in vivo micronucleus assay in rats.

Impairment of Fertility

Sotagliflozin had no effects on mating, fertility, or early embryonic development in treated male or female rats at doses up to 300 mg/kg/day, which represents an exposure multiple of 55 times the human exposure at the MRHD in both males and females.

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 and SCORED) placebo-controlled trials, 5,896 subjects received sotagliflozin.

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 sotagliflozin 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 sotagliflozin 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 Sotagliflozin and Greater Than Placebo in Either SOLOIST or SCORED:

Changes in Laboratory Test Values During Treatment

Increase in Serum Creatinine and Decrease in eGFR

Initiation of SGLT2 inhibitors, including sotagliflozin, 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 sotagliflozin.