Steglatro (ertugliflozin pidolate)

Dosage of ertugliflozin L-pyroglutamic acid is expressed in terms of ertugliflozin.

Ertugliflozin is administered orally once daily in the morning with or without food. The fixed combination of ertugliflozin and metformin hydrochloride is administered orally twice daily with meals to reduce the adverse GI effects of the metformin hydrochloride component. The fixed combination of ertugliflozin and sitagliptin is administered orally once daily in the morning with or without food. See the full prescribing information for additional administration instructions for the combination products.

If a dose of ertugliflozin is missed, the missed dose should be taken as soon as it is remembered followed by resumption of the regular schedule. If the missed dose is not remembered until it is almost time for the next dose, the missed dose should be skipped and the regular schedule resumed; the dose should not be doubled to replace a missed dose.

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

No dosing information is available for this tab.

The major metabolic pathway for ertugliflozin is glucuronidation; the drug is principally glucuronidated by uridine diphosphate-glucuronosyltransferase (UGT) isoenzymes 1A9 and 2B7.

There are no contraindication interactions for this drug.

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)

*Hypersensitivity to ertugliflozin or any ingredient in the formulation.

• Chronic kidney disease stage 3B (moderate) GFR 30-44 ml/min
• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min

• Diabetic foot infection
• History of diabetes-related lower-extremity amputation
• Invasive surgical procedure
• Kidney disease with likely reduction in glomerular filtration rate (GFr)
• Necrotizing fasciitis of perineum or genital area
• Peripheral vascular disease
• Pregnancy
• Type 1 diabetes mellitus

• Diabetic peripheral neuropathy
• Hypercholesterolemia
• Hypotension

The most common adverse effects of ertugliflozin (>=5% of patients) reported in clinical trials were female genital mycotic infections.

The most common adverse effects of ertugliflozin in combination with metformin hydrochloride (>=5% of patients) reported in clinical trials were female genital mycotic infections, diarrhea, nausea, vomiting, flatulence, abdominal discomfort, indigestion, asthenia, and headache.

The most common adverse effects of ertugliflozin in combination with sitagliptin (>=5% of patients) reported in clinical trials were female genital mycotic infections, upper respiratory tract infections, nasopharyngitis, and headache.

Less Frequent

• Dehydration
• Genitourinary tract infections

Rare or Very Rare

• Acute kidney injury
• Angioedema
• Diabetic ketoacidosis
• Hypovolemia
• Ketoacidosis
• Necrotizing fasciitis of perineum or genital area
• Pyelonephritis
• Urosepsis

More Frequent

• Vulvovaginal candidiasis

Less Frequent

• Back pain
• Candidal balanitis
• Genital organ pruritus
• Headache disorder
• Hypercholesterolemia
• Hyperphosphatemia
• Hypoglycemic disorder
• Increased hemoglobin
• Increased urinary frequency
• Pharyngitis
• Polydipsia
• Polyuria
• Urinary tract infection
• Vaginitis
• Weight loss
• Xerostomia

Rare or Very Rare

• Hypotension
• Skin rash

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Safety and efficacy of ertugliflozin have not been established in pediatric patients younger than 18 years of age.

There is insufficient evidence with ertugliflozin in pregnant women to evaluate a drug-associated risk of adverse developmental outcomes. Based on the results of reproductive and developmental toxicity studies in animals, ertugliflozin use during pregnancy may affect renal development and maturation, especially during the second and third trimesters of pregnancy.

Poorly controlled diabetes mellitus during pregnancy carries risks to the mother and fetus, including diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, delivery complications, major birth defects, stillbirth, and macrosomia-related morbidity. Ertugliflozin therapy is not recommended in pregnant women during the second and third trimesters of pregnancy.

There is no information regarding the presence of ertugliflozin in human milk, the effects on the breast-fed infant, or the effects on milk production. Ertugliflozin is distributed into milk in rats. 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 risk for serious adverse reactions in a breast-fed infant, ertugliflozin is not recommended for use while breastfeeding.

In clinical trials in patients treated with ertugliflozin, 25.7% of patients were 65 years of age or older and 4.5% were 75 years of age or older. Patients 65 years of age and older who received ertugliflozin had a higher incidence of adverse reactions related to volume depletion compared with younger patients; events were reported in 1.1%, 2.2%, and 2.6% of patients treated with comparator, ertugliflozin 5 mg, and ertugliflozin 15 mg, respectively.

In the VERTIS CV trial, 50.5% of patients treated with ertugliflozin were 65 years of age and older, and 10.8% of patients were 75 years of age and older. Safety and efficacy were generally similar for patients aged 65 years and older compared to patients younger than 65 years.