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Steglatro

Generic Name: Ertugliflozin
Class: Sodium-glucose Cotransporter 2 (SGLT2) Inhibitors
Chemical Name: (1S,2S,3S,4R,5S)-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol
Molecular Formula: C22H25ClO7
CAS Number: 1210344-57-2

Medically reviewed on January 8, 2018

Introduction

Ertugliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, is an antidiabetic agent.

Uses for Steglatro

Ertugliflozin has the following uses:

Ertugliflozin is a sodium glucose co-transporter 2 (SGLT2) inhibitor indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.1

Ertugliflozin has the following limitations of use:

Not for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis.1

Steglatro Dosage and Administration

General

Ertugliflozin is available in the following dosage form(s) and strength(s):

Tablets: 5 mg and 15 mg1

Ertugliflozin also is available in fixed combination with sitagliptin phosphate (Steglujan) and in fixed combination with metformin hydrochloride (Segluromet).

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

  • Recommended starting dose is 5 mg once daily, taken in the morning, with or without food.1

  • Increase dose to 15 mg once daily in those tolerating ertugliflozin and needing additional glycemic control.1

  • Assess renal function before initiating ertugliflozin and periodically thereafter:

    Do not use in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/minute/1.73 m2.

    Initiation is not recommended in patients with an eGFR of 30 to less than 60 mL/minute/1.73 m2.

    Continued use is not recommended in patients with an eGFR persistently between 30 and less than 60 mL/min/1.73 m2.1

Cautions for Steglatro

Contraindications

  • Severe renal impairment, end-stage renal disease, or dialysis.1

  • History of serious hypersensitivity reaction to ertugliflozin.1

Warnings/Precautions

Hypotension

Ertugliflozin causes intravascular volume contraction. Therefore, symptomatic hypotension may occur after initiating ertugliflozin particularly in patients with impaired renal function (eGFR less than 60 mL/min/1.73 m2, elderly patients (≥65 years), in patients with low systolic blood pressure, and in patients on diuretics. Before initiating ertugliflozin, volume status should be assessed and corrected if indicated. Monitor for signs and symptoms of hypotension after initiating therapy.1

Ketoacidosis

Reports of ketoacidosis, a serious life-threatening condition requiring urgent hospitalization, have been identified in clinical trials and postmarketing surveillance in patients with type 1 and type 2 diabetes mellitus receiving sodium glucose co-transporter-2 (SGLT2) inhibitors and cases have been reported in ertugliflozin-treated patients in clinical trials. Across the clinical program, ketoacidosis was identified in 3 of 3,409 (0.1%) of ertugliflozin-treated patients and 0% of comparator-treated patients. Fatal cases of ketoacidosis have been reported in patients taking SGLT2 inhibitors. Ertugliflozin is not indicated for the treatment of patients with type 1 diabetes mellitus.1

Patients treated with ertugliflozin who present with signs and symptoms consistent with severe metabolic acidosis should be assessed for ketoacidosis regardless of presenting blood glucose levels, as ketoacidosis associated with ertugliflozin may be present even if blood glucose levels are less than 250 mg/dL. If ketoacidosis is suspected, ertugliflozin should be discontinued, patient should be evaluated, and prompt treatment should be instituted. Treatment of ketoacidosis may require insulin, fluid and carbohydrate replacement.1

In many of the reported cases, and particularly in patients with type 1 diabetes, the presence of ketoacidosis was not immediately recognized and institution of treatment was delayed because presenting blood glucose levels were below those typically expected for diabetic ketoacidosis (often less than 250 mg/dL). Signs and symptoms at presentation were consistent with dehydration and severe metabolic acidosis and included nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. In some but not all cases, factors predisposing to ketoacidosis such as insulin dose reduction, acute febrile illness, reduced caloric intake due to illness or surgery, pancreatic disorders suggesting insulin deficiency (e.g., type 1 diabetes, history of pancreatitis or pancreatic surgery), and alcohol abuse were identified.1

Before initiating ertugliflozin, consider factors in the patient history that may predispose to ketoacidosis, including pancreatic insulin deficiency from any cause, caloric restriction, and alcohol abuse. In patients treated with ertugliflozin, consider monitoring for ketoacidosis and temporarily discontinuing ertugliflozin in clinical situations known to predispose to ketoacidosis (e.g., prolonged fasting due to acute illness or surgery).1

Acute Kidney Injury and Impairment in Renal Function

Ertugliflozin causes intravascular volume contraction and can cause renal impairment. There have been postmarketing reports of acute kidney injury, some requiring hospitalization and dialysis in patients receiving SGLT2 inhibitors.1

Before initiating ertugliflozin, consider factors that may predispose patients to acute kidney injury including hypovolemia, chronic renal insufficiency, congestive heart failure and concomitant medications (diuretics, ACE inhibitors, ARBs, NSAIDs). Consider temporarily discontinuing ertugliflozin in any setting of reduced oral intake (such as acute illness or fasting) or fluid losses (such as gastrointestinal illness or excessive heat exposure); monitor patients for signs and symptoms of acute kidney injury. If acute kidney injury occurs, discontinue ertugliflozin promptly and institute treatment.1

Ertugliflozin increases serum creatinine and decreases eGFR. Patients with moderate renal impairment (eGFR 30 to less than 60 mL/min/1.73 m2) may be more susceptible to these changes. Renal function abnormalities can occur after initiating ertugliflozin. Renal function should be evaluated prior to initiating ertugliflozin and periodically thereafter. Use of ertugliflozin is not recommended when eGFR is persistently between 30 and less than 60 mL/min/1.73 m2and is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2.1

Urosepsis and Pyelonephritis

There have been postmarketing reports of serious urinary tract infections, including urosepsis and pyelonephritis, requiring hospitalization in patients receiving SGLT2 inhibitors. Cases of pyelonephritis also have been reported in ertugliflozin-treated patients in clinical trials. Treatment with SGLT2 inhibitors increases the risk for urinary tract infections. Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated.1

Lower Limb Amputation

An increased risk for lower limb amputation (primarily of the toe) has been observed in clinical studies with another SGLT2 inhibitor. Across seven Phase 3 clinical trials in the ertugliflozin development program, non-traumatic lower limb amputations were reported in 1 (0.1%) patient in the comparator group, 3 (0.2%) patients in the ertugliflozin 5-mg group, and 8 (0.5%) patients in the ertugliflozin 15-mg group. A causal association between ertugliflozin and lower limb amputation has not been definitively established.1

Before initiating ertugliflozin, consider factors in the patient history that may predispose them to the need for amputations, such as a history of prior amputation, peripheral vascular disease, neuropathy and diabetic foot ulcers. Counsel patients about the importance of routine preventative foot care. Monitor patients receiving ertugliflozin for signs and symptoms of infection (including osteomyelitis), new pain or tenderness, sores or ulcers involving the lower limbs, and discontinue ertugliflozin if these complications occur.1

Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues

Insulin and insulin secretagogues (e.g., sulfonylurea) are known to cause hypoglycemia. Ertugliflozin may increase the risk of hypoglycemia when used in combination with insulin and/or an insulin secretagogue. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with ertugliflozin.1

Genital Mycotic Infections

Ertugliflozin increases the risk of genital mycotic infections. Patients who have a history of genital mycotic infections or who are uncircumcised are more likely to develop genital mycotic infections. Monitor and treat appropriately.1

Increases in Low-density Lipoprotein Cholesterol (LDL-C)

Dose-related increases in LDL-C can occur with ertugliflozin. Monitor and treat as appropriate.1

Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with ertugliflozin.1

Specific Populations

Pregnancy

Risk Summary: Based on animal data showing adverse renal effects, ertugliflozin is not recommended during the second and third trimesters of pregnancy.1 The limited available data with ertugliflozin in pregnant women are not sufficient to determine a drug-associated risk of adverse developmental outcomes. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy.1 In animal studies, adverse renal changes were observed in rats when ertugliflozin was administered during a period of renal development corresponding to the late second and third trimesters of human pregnancy. Doses approximately 13 times the maximum clinical dose caused renal pelvic and tubule dilatations and renal mineralization that were not fully reversible. There was no evidence of fetal harm in rats or rabbits at exposures of ertugliflozin approximately 300 times higher than the maximal clinical dose of 15 mg/day when administered during organogenesis.1 The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with a HbA1c >7 and has been reported to be as high as 20-25% in women with HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.1

Disease-Associated Maternal and/or Embryo/Fetal Risk: Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, stillbirth, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity.1

Animal Data: When ertugliflozin was orally administered to juvenile rats from PND 21 to PND 90, increased kidney weight, renal tubule and renal pelvis dilatation, and renal mineralization occurred at doses greater than or equal to 5 mg/kg (13-fold human exposures, based on AUC). These effects occurred with drug exposure during periods of renal development in rats that correspond to the late second and third trimester of human renal development, and did not fully reverse within a 1-month recovery period.1 In embryo-fetal development studies, ertugliflozin (50, 100 and 250 mg/kg/day) was administered orally to rats on gestation days 6 to 17 and to rabbits on gestation days 7 to 19. Ertugliflozin did not adversely affect developmental outcomes in rats and rabbits at maternal exposures that were approximately 300 times the human exposure at the maximum clinical dose of 15 mg/day, based on AUC. A maternally toxic dose (250 mg/kg/day) in rats (707 times the clinical dose), was associated with reduced fetal viability, and a higher incidence of a visceral malformation (membranous ventricular septal defect). In the pre- and post-natal development study in pregnant rats, ertugliflozin was administered to the dams from gestation day 6 through lactation day 21 (weaning). Decreased post-natal growth (weight gain) was observed at maternal doses ≥100 mg/kg/day (greater than or equal to 331 times the human exposure at the maximum clinical dose of 15 mg/day, based on AUC).1

Lactation

Risk Summary: There is no information regarding the presence of ertugliflozin in human milk, the effects on the breastfed infant, or the effects on milk production. Ertugliflozin is present in the milk of lactating 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 for serious adverse reactions in a breastfed infant, advise women that the use of ertugliflozin is not recommended while breastfeeding.1

Animal Data: The lacteal excretion of radiolabeled ertugliflozin in lactating rats was evaluated 10 to 12 days after parturition. Ertugliflozin derived radioactivity exposure in milk and plasma were similar, with a milk/plasma ratio of 1.07, based on AUC. Juvenile rats directly exposed to ertugliflozin during a developmental period corresponding to human kidney maturation were associated with a risk to the developing kidney (persistent increased organ weight, renal mineralization, and renal pelvic and tubular dilatations).1

Pediatric Use

Safety and effectiveness of ertugliflozin in pediatric patients under 18 years of age have not been established.1

Geriatric Use

No dosage adjustment of ertugliflozin is recommended based on age. Across the clinical program, a total of 876 (25.7%) patients treated with ertugliflozin were 65 years and older, and 152 (4.5%) patients treated with ertugliflozin were 75 years and older. Patients 65 years and older had a higher incidence of adverse reactions related to volume depletion compared to 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. Ertugliflozin is expected to have diminished efficacy in elderly patients with renal impairment.1

Renal Impairment

The safety and efficacy of ertugliflozin have not been established in patients with type 2 diabetes mellitus and moderate renal impairment. Compared to placebo-treated patients, patients with moderate renal impairment treated with ertugliflozin did not have improvement in glycemic control, and had increased risks for renal impairment, renal-related adverse reactions and volume depletion adverse reactions. Therefore, ertugliflozin is not recommended in this population.1

Ertugliflozin is contraindicated in patients with severe renal impairment, ESRD, or receiving dialysis. Ertugliflozin is not expected to be effective in these patient populations.1

No dosage adjustment or increased monitoring is needed in patients with mild renal impairment.1

Hepatic Impairment

No dosage adjustment of ertugliflozin is necessary in patients with mild or moderate hepatic impairment. Ertugliflozin has not been studied in patients with severe hepatic impairment and is not recommended for use in this patient population.1

Common Adverse Effects

The most common adverse reactions associated with ertugliflozin (incidence ≥5%) were female genital mycotic infections.1

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Please see product labeling for drug interaction information.

Actions

Mechanism of Action

SGLT2 is the predominant transporter responsible for reabsorption of glucose from the glomerular filtrate back into the circulation. Ertugliflozin is an inhibitor of SGLT2. By inhibiting SGLT2, ertugliflozin reduces renal reabsorption of filtered glucose and lowers the renal threshold for glucose, and thereby increases urinary glucose excretion.1

Advice to Patients

Advise the patient to read the FDA-approved patient labeling (Medication Guide).1

Instructions

Instruct patients to read the Medication Guide before starting ertugliflozin and to reread it each time the prescription is renewed.1

Inform patients of the potential risks and benefits of ertugliflozin and of alternative modes of therapy. Also inform patients about the importance of adherence to dietary instructions, regular physical activity, periodic blood glucose monitoring and HbA1c testing, recognition and management of hypoglycemia and hyperglycemia, and assessment for diabetes complications. Advise patients to seek medical advice promptly during periods of stress such as fever, trauma, infection, or surgery, as medication requirements may change.1

Instruct patients to take ertugliflozin only as prescribed. If a dose is missed, advise patients to take it as soon as it is remembered unless it is almost time for the next dose, in which case patients should skip the missed dose and take the medicine at the next regularly scheduled time. Advise patients not to take two doses of ertugliflozin at the same time.1

Hypoglycemia with Concomitant Use of Insulin and/or Insulin Secretagogue

Inform patients that the incidence of hypoglycemia may increase when ertugliflozin is added to insulin and/or an insulin secretagogue and that a lower dose of insulin or insulin secretagogue may be required to reduce the risk of hypoglycemia.1

Hypotension

Inform patients that symptomatic hypotension may occur with ertugliflozin and advise them to contact their doctor if they experience such symptoms. Inform patients that dehydration may increase the risk for hypotension, and to have adequate fluid intake.1

Ketoacidosis

Inform patients that ketoacidosis is a serious life-threatening condition. Cases of ketoacidosis have been reported during use of ertugliflozin. Instruct patients to check ketones (when possible) if symptoms consistent with ketoacidosis occur even if blood glucose is not elevated. If symptoms of ketoacidosis (including nausea, vomiting, abdominal pain, tiredness, and labored breathing) occur, instruct patients to discontinue ertugliflozin and seek medical advice immediately.1

Acute Kidney Injury

Inform patients that acute kidney injury has been reported during use of ertugliflozin. Advise patients to seek medical advice immediately if they have reduced oral intake (due to acute illness or fasting) or increased fluid losses (due to vomiting, diarrhea, or excessive heat exposure), as it may be appropriate to temporarily discontinue ertugliflozin use in those settings.1

Monitoring of Renal Function

Inform patients about the importance of regular testing of renal function when receiving treatment with ertugliflozin.1

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 if such symptoms occur.1

Amputation

Inform patients of the potential for an increased risk of amputations. Counsel patients about the importance of routine preventative foot care. Instruct patients to monitor for new pain or tenderness, sores or ulcers, or infections involving the leg or foot and to seek medical advice immediately if such signs or symptoms develop.1

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 infection. Advise them of treatment options and when to seek medical advice.1

Genital Mycotic Infections in Males (e.g., Balanitis or Balanoposthitis)

Inform male patients that yeast infections of the penis (e.g., balanitis or balanoposthitis) may occur, especially in uncircumcised males. 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.1

Fetal Toxicity

Advise pregnant patients of the potential risk to a fetus with treatment with ertugliflozin. Instruct patients to immediately inform their healthcare provider if pregnant or planning to become pregnant.1

Lactation

Advise patients that use of ertugliflozin is not recommended while breastfeeding.1

Laboratory Tests

Due to its mechanism of action, inform patients that their urine will test positive for glucose while taking ertugliflozin.1

Additional Information

AHFS First Release. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Ertugliflozin also is available in fixed combination with sitagliptin phosphate (Steglujan) and in fixed combination with metformin hydrochloride (Segluromet).

Ertugliflozin

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablet, Film Coated

5 mg

Steglatro

Merck Sharp & Dohme Corp.

15 mg

Steglatro

Merck Sharp & Dohme Corp.

AHFS Drug Information. © Copyright 2018, Selected Revisions January 8, 2018. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Merck Sharp & Dohme Corp.. STEGLATRO (ertugliflozin) ORAL prescribing information. ƒ2017 Dec. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e6f3e718-bb99-48f1-ab94-b9f0af05fed6

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