Inpefa (sotagliflozin)

No dosing information is available for this tab.

Sotagliflozin is administered orally once daily. Sotagliflozin should be administered not more than one hour before the first meal of the day. Tablets should be swallowed whole; tablets should not be cut, crushed, or chewed.

If a dose of sotagliflozin is missed by more than 6 hours, the patient should be instructed to take the next dose as prescribed the next day.

Store sotagliflozin tablets at 20-25degreesC; excursions are permitted between 15-30degreesC.

No dosing information is available for this tab.

Sotagliflozin is extensively metabolized, primarily by uridine diphosphate-glucuronosyl transferase (UGT) 1A9 and to a lesser extent by cytochrome P-450 (CYP) 3A4.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Selected P-Glycoprotein (P-Gp) Inhibitors/Ensartinib

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Ensartinib is a P-glycoprotein (P-gp) substrate. P-gp inhibitors may increase the levels of ensartinib.(1)

CLINICAL EFFECTS: The concurrent administration of a P-glycoprotein (P-gp) inhibitor may result in elevated levels of and toxicity from ensartinib.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of ensartinib states that concurrent use of P-glycoprotein (P-gp) inhibitors should be avoided.(1) The manufacturer of daraxonrasib states P-gp substrates should be administered at least 4 hours apart from daraxonrasib.(4)

DISCUSSION: Ensartinib is a substrate of P-gp. Inhibitors of P-gp may increase toxicity of ensartinib.(1) Inhibitors of P-gp linked to this monograph include: abrocitinib, amiodarone, Asian ginseng (Panax ginseng), asunaprevir, aumolertinib, azithromycin, belumosudil, capmatinib, carvedilol, cimetidine, cyclosporine, danicopan, daraxonrasib, daridorexant, diosmin, eliglustat, flibanserin, fostamatinib, ginkgo biloba, glecaprevir and pibrentasvir, hydroquinidine, ivacaftor, lapatinib, mavorixafor, milk thistle (Silybum marianum), neratinib, osimertinib, propafenone, quercetin, quinidine, ranolazine, rolapitant, silibinin, silymarin, sotagliflozin, tepotinib, tezacaftor, valbenazine, velpatasvir, vemurafenib, venetoclax, vepdegestrant, vilazodone, vimseltinib, and voclosporin.(2,3)

There are no severe interactions for this drug.

Moderate Interaction: Assess the risk to the patient and take action as needed.

Antidiabetic Agents/Gymnema

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Gymnema has been shown to increase the number of insulin-secreting beta cells in animals. It has also been shown to increase the activity of enzymes responsible for glucose uptake and utilization and inhibit peripheral utilization of glucose.(1)

CLINICAL EFFECTS: Use of gymnema may result in decreased requirements of antidiabetic agents.(2-4)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Diabetic patients should be carefully monitored if gymnema is initiated or discontinued from concurrent therapy. The dosage of the patient's antidiabetic agent(s) may need to be adjusted.(2)

DISCUSSION: In a study in 22 non-insulin-dependent patients, patients had decreased blood glucose, glycosylated hemoglobin, and glycosylated plasma proteins during gymnema therapy. Patients were able to decrease the dosage of their conventional antidiabetic therapy and five patients were able to discontinue their conventional antidiabetic therapy.(3) In a study in 27 insulin-dependent patients, patients had decreased insulin requirements, fasting blood glucose, glycosylated hemoglobin, and glycosylated plasma protein levels.(4)

Sglt2 Inhibitors/Loop Diuretics

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: SGLT2 inhibitors cause intravascular volume contraction through osmotic diuresis, which can result in hypotension in patients who are volume depleted from loop diuretic use.(1-7)

CLINICAL EFFECTS: Concurrent use of SGLT2 inhibitors with loop diuretics may result in dehydration, hypotension, and acute renal failure.(1-8)

PREDISPOSING FACTORS: This interaction may be more severe in patients who have a eGFR of less than 60 ml/min/1.73m2, are also taking ACE inhibitors or ARBs and/or NSAIDs, are on a low sodium diet, have low systolic blood pressure prior to initiating SGLT2 inhibitors, and/or are 65 years of age or older.(1-7)

PATIENT MANAGEMENT: Before initiating SGLT2 inhibitors in patients maintained on loop diuretics, assess volume status and correct if needed and also assess renal function. Patients receiving concurrent therapy should be monitored for hypotension and acute renal failure.(1-8)

DISCUSSION: In clinical trials of canagliflozin, volume depletion-related adverse effects were associated with the use of loop diuretics, moderate renal impairment (eGFR 30 ml/min/1.73m2 to less than 60 ml/min/1.73m2), and age 75 years and older. In a pool of eight Phase 3 clinical trials, 2.3% of all patients taking 100 mg of canagliflozin experienced at least one volume depletion-related event, compared to 3.2% of patients taking 100 mg of canagliflozin with a loop diuretic. 3.4% of all patients taking 300 mg of canagliflozin experienced at least one volume depletion-related event, compared to 8.8% of patients taking 300 mg of canagliflozin with a loop diuretic.(1,2) Cases of acute renal failure, most requiring hospitalization, have been reported in patients receiving canagliflozin and dapagliflozin. Twenty-six of 101 cases involved concurrent use of diuretics.(7) In a post-hoc analysis of the EMPEROR-Preserve trial, the combination of empagliflozin and diuretics was associated with a higher incidence of volume depletion events (HR 1.34; 95% CI, 1.13-1.59). The most commonly reported events were hypotension, syncope, and dehydration. Coadministration of diuretics and empagliflozin did not result in a difference in the incidence of acute renal failure, hyperkalemia, or adverse events leading to trial discontinuation (including fatal events) compared to empagliflozin alone. There was also no change in the benefit of empagliflozin for the primary end point of first hospitalization for heart failure or cardiovascular death.(8)

Sodium-Glucose Co-Transporter 2 (Sglt2) Inhibitors/Lithium

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Sodium-glucose cotransporter 2 (SGLT2) inhibitors may increase the renal excretion of lithium by impairing the proximal tubular reabsorption of lithium.(1,2)

CLINICAL EFFECTS: Concurrent use of SGLT2 inhibitors may result in decreased levels and clinical effectiveness of lithium.(1-6)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Lithium levels should be monitored more frequently when starting or changing the dose of SGLT2 inhibitors. The dose of lithium may need to be adjusted.(3-6)

DISCUSSION: A 29 year old patient stabilized on lithium with good therapeutic response was started on empagliflozin on day 10 of lithium therapy. Three days later, lithium level was subtherapeutic. Empagliflozin was stopped. After 1 week, lithium levels returned to therapeutic range. Two days later, the patient had another trial of empagliflozin and again developed subtherapeutic lithium levels.(1) A post hoc analysis of 2 dapagliflozin trials (IMPROVE and DapKid) examined the effects of dapagliflozin on volume status in diabetic patients with albuminuric kidney disease. Lithium excretion, which served as a marker of proximal tubular sodium excretion, was found to increase by 19.6% (p < 0.01).(2)

*History of serious hypersensitivity reaction to sotagliflozin.

There are no contraindication contraindications for this drug.

• Child-pugh class B hepatic impairment
• Child-pugh class C hepatic impairment
• Disease of liver
• Hypovolemia
• Invasive surgical procedure
• Necrotizing fasciitis of perineum or genital area
• Pregnancy
• Type 1 diabetes mellitus
• Urinary tract infection

• Kidney disease with reduction in glomerular filtration rate (GFr)

The most common adverse effects of sotagliflozin (>=5% of patients) reported in clinical studies include urinary tract infection, volume depletion, diarrhea, and hypoglycemia.

More Frequent

• Hypoglycemic disorder

Rare or Very Rare

• Acute kidney injury
• Diabetic ketoacidosis
• Genitourinary tract infections
• Necrotizing fasciitis of perineum or genital area
• Urosepsis

More Frequent

• Diarrhea
• Hypovolemia
• Urinary tract infection

Less Frequent

• Candidal balanitis
• Vulvovaginal candidiasis

Rare or Very Rare

• Dizziness

No enhanced messaging available.

Safety and effectiveness of sotagliflozin have not been established in pediatric patients less than 18 years of age.

There is insufficient evidence with sotagliflozin in pregnant women to evaluate a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Based on findings from animal studies showing renal effects, sotagliflozin is not recommended during the second and third trimester of pregnancy.

In embryo-fetal development studies in rats and rabbits, sotagliflozin was administered for intervals coinciding with the first trimester of organogenesis in humans. Sotagliflozin was not teratogenic when administered at dosages up to 100 mg/kg per day in pregnant rats during embryogenic organogenesis (40 times the human exposure at the maximum recommended human dosage (MHRD)). 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 dosages up to 200 mg/kg per day in pregnant rabbits (9 times the human exposure at MRHD). 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 MRHD of 400 mg once daily caused increased kidney weights and renal pelvis and tubule dilatations that were partially reversible.

There are risks to the mother and fetus associated with untreated heart failure in pregnancy. Pregnant women with heart failure are at increased risk for preterm birth. Clinical classification of heart failure may worsen with pregnancy and lead to maternal death.

There are no data on the presence of sotagliflozin in human milk, the effects on the breast-fed infant, or the effects on milk production. Sotagliflozin is present in rat 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 breast-fed infant, advise women that breastfeeding is not recommended while taking sotagliflozin.

The manufacturer makes no specific dosage recommendations for geriatric patients based solely on age; however, greater sensitivity of some older individuals cannot be ruled out.

In clinical studies with sotagliflozin, no overall differences in efficacy were determined between older and younger patients, and other reported clinical experience has not identified differences in responses between older 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.

In the SOLOIST study, a total of 241 (40%) patients treated with sotagliflozin were between 65 and <75 years of age, and 174 (29%) patients were >=75 years of age. In the SCORED study, a total of 2470 (47%) patients treated with sotagliflozin were between 65 and <75 years of age, and 1240 (23%) were >=75 years of age.