22/23. Sotagliflozin- (INPEFA)- (May 2023)- to treat heart failure
Drug Name:22/23. Sotagliflozin- (INPEFA)- (May 2023)- to treat heart failure
List Of Brands:
Indication Type Description:
Drug Interaction
Indication
Adverse Reaction
Contra-Indications
Dosages/ Overdosage Etc
Patient Information
Pharmacology/ Pharmacokinetics
Pregnancy and lactation
Drug Interaction:
DRUG INTERACTIONS(summary)
Digoxin: Monitor digoxin levels.
Uridine 5'-diphospho-glucuronosyltransferase Inducers (e.g., rifampin): Sotagliflozin exposure is reduced. Consider monitoring of clinical status.
Lithium: Monitor serum lithium concentrations.
DRUG INTERACTIONS-(details)-
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
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..
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.
Indication:
BRIEF SUMMARY
SOTAGLIFLLOZIN- (May 2023)
Indication- To treat heart failure
Composition Tablets: 200 mg and 400 mg
ADR- Most common adverse reactions (incidence = 5%) are urinary tract infection, volume depletion, diarrhea, and hypoglycemia
CI- serious hypersensitivity reaction to INPEFA.
WARNINGS- • Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis- Consider ketone monitoring in patients with type 1 diabetes mellitus and consider ketone monitoring in others at risk for ketoacidosis
Pat inform- . 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
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U.S. FDA APPROVED DRUGS DURING 2023
Sr.No- 22
Adverse Reaction:
ADVERSE REACTIONS-
Most common adverse reactions (incidence = 5%) are urinary tract infection, volume depletion, diarrhea, and hypoglycemia.
Contra-Indications:
CONTRAINDICATIONS-
• History of serious hypersensitivity reaction to INPEFA.
WARNINGS AND PRECAUTIONS-
• Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis:
Consider ketone monitoring in patients with type 1 diabetes mellitus and consider ketone monitoring in others at risk for ketoacidosis, as indicated. Assess for ketoacidosis regardless of presenting blood glucose levels and discontinue INPEFA if ketoacidosis is suspected. Monitor patients for resolution of ketoacidosis before restarting.
• Volume Depletion: Before initiating, correct volume status. Monitor for signs and symptoms of hypotension during therapy.
• Urosepsis and Pyelonephritis: Monitor for signs and symptoms during therapy and treat promptly.
• Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues: Lower dose of insulin or insulin secretagogue may be required.
• Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene): Monitor for pain, tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise. Discontinue INPEFA and treat urgently.
• Genital Mycotic Infections: Monitor and treat as appropriate.
Dosages/ Overdosage Etc:
Patient Information:
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guidw
. 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
Volume Depletion Inform patients that symptomatic hypotension may occur with INPEFA 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.
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
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
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.].
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
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 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.
Pharmacology/ Pharmacokinetics:
CLINICAL PHARMACOLOGY
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.
2. Pharmacodynamics-
Cardiac Electrophysiology- In a randomized, placebo-controlled, active-comparator, crossover study, 58 healthy subjects were administered a single oral dose of sotagliflozin 800 mg or sotagliflozin 2000 mg (5 times the maximum recommended dose), moxifloxacin, and placebo.
No increase in QT corrected for heart rate (QTc) was observed with either 800 mg or 2000 mg sotagliflozin.
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.
Absorption-
The absolute bioavailability of oral sotagliflozin 400 mg dose was approximately 25% (90% confidence interval [CI] 16% to 39%) for area under the concentration-time curve from time 0 to last measurable concentration (AUC0-last).
The contribution of enterohepatic circulation to the overall exposure is estimated to be approximately 50%. The median time to maximum plasma concentration (Tmax) ranged from 1.25 to 3 hours, over a single-dose range of 200 mg to 2000 mg.
Following administration of multiple doses (400 mg and 800 mg), the median Tmax values ranged from 2.5 to 4 hours.
Food Effect-
When sotagliflozin tablets were administered with a high-caloric breakfast compared to fasting conditions, plasma exposure to sotagliflozin as measured by Cmax and AUC0-inf increased by 149% and 50%, respectively.
Multiple doses of sotagliflozin 400 mg given immediately before breakfast, 30 minutes prior to breakfast, and 1-hour before breakfast in healthy subjects showed a consistent effect of sotagliflozin on urine glucose excretion (UGE), insulin, and postprandial glucose (PPG) across all dose schedules.
It is recommended that INPEFA be taken not more than one hour before the first meal of the day.
Distribution-
Both sotagliflozin and its major human metabolite sotagliflozin 3-O-glucuronide exhibited high binding to human plasma proteins in vitro (> 93% bound), which was not dependent on the concentration of sotagliflozin and sotagliflozin 3-O-glucuronide and was not influenced by the degree of renal or hepatic function.
Following administration of a single 400 mg dose of [14C]-sotagliflozin, the mean blood/plasma ratios for total radioactivity were 0.5 and 0.4 for Cmax and AUC0-last, respectively, and the mean whole blood to plasma concentration ratio of sotagliflozin ranged from 0.5 to 0.6. The mean apparent volume of distribution of sotagliflozin following administration of a single 400 mg oral dose of [14C]-sotagliflozin was 9000 L. Reference ID: 5180905 11
Elimination-
Metabolism- Following the administration of a single dose of 400 mg [14C]-sotagliflozin in healthy subjects, sotagliflozin was extensively metabolized predominantly to sotagliflozin 3-O-glucuronide and it represented 94.3% of the radioactivity in plasma.
The key enzymes responsible for the metabolism of sotagliflozin were UGT1A9 and, to a lesser extent, CYP3A4.
Following incubation of sotagliflozin with UGT1A9, the 3-O-glucuronide metabolite of sotagliflozin was the main conjugate observed. No acyl glucuronides of sotagliflozin were identified.
Excretion-
Following the administration of a single dose of 400 mg [14C]-sotagliflozin, 57% and 37% of the radioactivity was recovered in the urine and feces, respectively. These results indicate that the main route of elimination was renal.
The predominant metabolite detected in urine was sotagliflozin 3-O-glucuronide, representing a mean of 33% of the administered radioactive dose. Unchanged [14C]-sotagliflozin was the predominant radioactive peak detected in fecal extracts representing a mean of 23% of the total administered radioactive dose. Sotagliflozin undergoes enterohepatic circulation
. Following administration of 200 mg and 400 mg, mean terminal halflife (T1/2) ranged from 21 to 35 hours for sotagliflozin and from 19 to 26 hours for sotagliflozin 3-O-glucuronide
Effective half-life of sotagliflozin ranged from 5 to 10 hours. Steady state was generally achieved after 5 days of once daily dosing with sotagliflozin 200 mg and 400 mg. In healthy volunteers, mean oral clearance (CL/F) of sotagliflozin ranged from 260 to 370 L/hr following administration of 200 mg and 400 mg sotagliflozin.
The median population PK model predicted CL/F in type 2 diabetes mellitus patients with normal renal function was about 300 L/hr.
Specific Populations-
Renal Impairment- Exposure of sotagliflozin was evaluated in a dedicated PK study in subjects with mild (eGFR 60 to < 90 mL/min/1.73 m²) and moderate (eGFR 30 to < 60 mL/min/1.73 m²) renal impairment and with normal renal function (eGFR = 90 mL/min/1.73 m²).
Exposure to sotagliflozin following a single dose of 400 mg was approximately 70% higher in subjects with mild and up to 170% higher in subjects with moderate renal impairment compared to subjects with normal renal function [see Use in Specific Populations (8.6)].
Hepatic Impairmen-
t In a study with subjects with reduced hepatic function, AUC of sotagliflozin was not increased in mild (Child Pugh A) hepatic impaired subjects but was increased by approximately 3-fold in moderate (Child Pugh B) and approximately 6-fold in severe (Child Pugh C) hepatic impaired subjects compared to subjects with normal hepatic function [see Use in Specific Populations (8.7)].
Effects of Age, Sex, Race, and Body Weight on Pharmacokinetics Based on population PK analysis, age, body weight, sex and race (non-white versus primarily whites) do not have a clinically meaningful effect on the PK of sotagliflozin. Reference ID: 5180905 12
Drug Interactions-
In Vitro Studies- The major human metabolite of sotagliflozin, sotagliflozin 3-O-glucuronide, was shown to have an in vitro potential to inhibit CYP3A4 and CYP2D6 and to induce CYP3A4. Sotagliflozin was shown to have inhibitory effects on P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).
Pregnancy and lactation:
USE IN SPECIFIC POPULATIONS
1. 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 drugassociated 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
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.
2. Lactation Risk Summary-
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).
When a drug is present in animal milk, it is likely to be present in human milk.
Because of the potential for serious adverse reactions in a breastfed infant, advise women that breastfeeding is not recommended while taking INPEFA.
3.Pediatric Use-
The safety and effectiveness of INPEFA in pediatric patients under 18 years of age have not been established.
4. 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
5.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
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.
6. 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 INPEFA have not been established in patients with moderate or severe hepatic impairment
INPEFA is not recommended in patients with moderate or severe hepatic impairment.
OVERDOSAGE-
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.