Source: FDA, National Drug Code (US) Revision Year: 2023
INPEFA is contraindicated in patients with a history of serious hypersensitivity reaction to INPEFA.
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.
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.
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)].
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.
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.
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.
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.
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.
The following important adverse reactions are described elsewhere in the labeling:
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
In the phase 3 (SOLOIST [see Clinical Studies (14.1)] and SCORED [see Clinical Studies (14.2)]) placebo-controlled trials, 5,896 subjects received INPEFA.
In the SOLOIST study, 336 patients (56%) reached the 400 mg dose. In the SCORED study, 3,934 patients (74%) reached the 400 mg dose.
In the SOLOIST study, 5.6% of patients in the INPEFA group and 5.4% of patients in the placebo group discontinued therapy due to adverse events (AEs). In the SCORED study, 5.0% of patients in the INPEFA group and 4.5% of patients in the placebo group discontinued therapy due to AEs.
Table 1. Adverse Reactions Reported in ≥2% of Patients Treated with INPEFA and Greater Than Placebo in Either SOLOIST or SCORED:
| Adverse Reaction | SOLOIST N=1,216 | SCORED N=10,577 | ||
| Placebo (%) N=611 | INPEFA (%) N=605 | Placebo (%) N=5,286 | INPEFA (%) N=5,291 | |
| Urinary tract infection | 7.2 | 8.6 | 11.0 | 11.5 |
| Volume depletion | 8.8 | 9.3 | 4.0 | 5.2 |
| Diarrhea | 4.1 | 6.9 | 6.0 | 8.4 |
| Hypoglycemia | 2.8 | 4.3 | 7.9 | 7.7 |
| Dizziness | 2.5 | 2.6 | 2.8 | 3.3 |
| Genital mycotic infection | 0.2 | 0.8 | 0.9 | 2.4 |
Initiation of SGLT2 inhibitors, including INPEFA, causes a small increase in serum creatinine and decrease in eGFR. These changes in serum creatinine and eGFR generally occur within 4 weeks of starting therapy and then stabilize regardless of baseline kidney function. Changes that do not fit this pattern should prompt further evaluation to exclude the possibility of acute kidney injury. In studies that included patients with type 2 diabetes mellitus with moderate renal impairment, the acute effect on eGFR reversed after treatment discontinuation, suggesting acute hemodynamic changes may play a role in the renal function changes observed with INPEFA [see Warnings and Precautions (5.2) and Use in Specific Populations (8.6)].
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)].
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)].
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.
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.
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.
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.
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.
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 AUC0-inf values.
The safety and effectiveness of INPEFA in pediatric patients under 18 years of age have not been established.
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)].
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.
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.
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