Inpefa Drug Information
Generic name: SOTAGLIFLOZIN
Sodium-Glucose Cotransporter 2 Inhibitor [EPC]
Uses of Inpefa
is indicated to reduce the risk of cardiovascular death, hospitalization for heart failure, and urgent heart failure visit in adults with: heart failure or type 2 diabetes mellitus, chronic kidney disease, and other cardiovascular risk factors INPEFA is a sodium-glucose cotransporter 2 (SGLT2) inhibitor indicated to reduce the risk of cardiovascular death, hospitalization for heart failure, and urgent heart failure visit in adults with: heart failure or type 2 diabetes mellitus, chronic kidney disease, and other cardiovascular risk factors
Dosage & Administration of Inpefa
Prior to Initiation of
INPEFA Assess volume status and, if necessary, correct volume depletion prior to initiation of INPEFA . Assess renal function prior to initiation of INPEFA and then as clinically indicated . 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.
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 . Down-titrate to 200 mg as necessary. 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.
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 .
Side Effects of Inpefa
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 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
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
Dizziness 2.5 2.6 2.8 3.3 Genital mycotic infection 0.2 0.8 0.9 2.4
Changes in Laboratory Test Values During Treatment Increase in Serum Creatinine and Decrease in eGFR 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 .
Warnings & Cautions for Inpefa
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 ; 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 . 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.
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.
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.
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 .
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 . 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.
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.
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 . 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.
Drug Interactions with Inpefa
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 .
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 .
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.
Pregnancy Safety for Inpefa
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 . 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.
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.
Pediatric Use of Inpefa
Pediatric Use The safety and effectiveness of INPEFA in pediatric patients under 18 years of age have not been established.
Contraindications for Inpefa
is contraindicated in patients with a history of serious hypersensitivity reaction to INPEFA. History of serious hypersensitivity reaction to INPEFA.
Overdosage Information for Inpefa
There were no confirmed reports of symptomatic overdose with sotagliflozin during the clinical development program of INPEFA. In the event of an overdose with INPEFA, contact the Poison Control Center. Employ the usual supportive measures as dictated by the patient's clinical status. The removal of sotagliflozin by hemodialysis has not been studied.
Clinical Studies of Inpefa
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/m 2, and median eGFR was 50 mL/min/1.73 m 2. 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 0.67 ; p = 0.001). ( Table 2 ). Table 2 Treatment Effect for the Primary Composite, Components and Secondary Endpoint in the SOLOIST Study Primary Endpoint a Event Rates per 100 Patient-years Hazard Ratio (95% CI) INPEFA N = 608 Placebo N = 614 a Based on investigator-reported events in all randomized patients, analyzed according to the treatment group allocated by randomization. b Predefined primary endpoint. c Predefined secondary endpoint and tested with multiplicity control. d Time-to-event analysis was performed; event rates are percentages of patients with events.
Total occurrence of cardiovascular death, hospitalization for heart failure, and urgent heart failure visit b 51.3 76.4 0.67 p = 0.001 Primary Endpoint Components Cardiovascular death c,d 8.4 9.4 0.84 Hospitalization for heart failure 33.7 51.9 0.65 Urgent heart failure visit 6.9 12.1 0.60 Secondary Endpoint c Hospitalization for heart failure and urgent heart failure visit c 40.6 63.9 0.64 p = 0.0009 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. 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 Primary composite endpoint was based on investigator-reported events in all randomized patients, analyzed according to the treatment group allocated by randomization.
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). 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) 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 3 Figure 4
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 m 2 ), 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/m 2, median eGFR was 45 mL/min/1.73 m 2 (8% with eGFR < 30, 44% with eGFR 30 to < 45, and 48% with eGFR ≥ 45 mL/min/1.73 m 2 ), 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 ; p < 0.001) ( Table 3 ). Table 3 Treatment Effect for the Primary Composite, Components and Secondary Endpoint in the SCORED Study Primary Endpoint a Event Rates (per 100 Patient-years) Hazard Ratio (95% CI) INPEFA N = 5,292 Placebo N = 5,292 a Based on investigator-reported events in all randomized patients, analyzed according to the treatment group allocated by randomization. b Predefined primary endpoint. c Predefined secondary endpoint and tested with multiplicity control. d Time-to-event analysis was performed; event rates are percentages of patients with events. Total occurrence of cardiovascular death, hospitalization for heart failure, and urgent heart failure visit b 5.6 7.5 0.75 p < 0.001 Primary Endpoint Components Cardiovascular death c,d 2.9 3.2 0.90 Hospitalization for heart failure 2.8 4.2 0.66 Urgent heart failure visit 0.7 0.9 0.73 Secondary Endpoint c Hospitalization for heart failure or urgent heart failure visit c 3.5 5.1 0.67 p = 0.0001 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. 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 Primary composite endpoint was based on investigator-reported events in all randomized patients, analyzed according to the treatment group allocated by randomization. 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). 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) 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 Figure
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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