Ertugliflozin

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Steglatro: 5 mg, 15 mg

Pharmacology

Mechanism of Action

By inhibiting sodium-glucose cotransporter 2 (SGLT2) in the proximal renal tubules, ertugliflozin reduces reabsorption of filtered glucose from the tubular lumen and lowers the renal threshold for glucose (RT_G). SGLT2 is the main site of filtered glucose reabsorption; reduction of filtered glucose reabsorption and lowering of RT_G result in increased urinary excretion of glucose, thereby reducing plasma glucose concentrations.

Pharmacokinetics/Pharmacodynamics

Distribution

V_dss: 85.5 L

Metabolism

Primarily by UGT1A9 and UGT2B7-mediated O-glucuronidation to metabolites that are inactive at clinically relevant concentrations; CYP-mediated metabolism is minimal

Excretion

Urine (40.9%; 1.5% as unchanged drug); feces (50.2%; 33.8% as unchanged drug)

Time to Peak

Plasma: 1 hour (fasting); 2 hours (administered with high-fat, high-calorie meal)

Half-Life Elimination

16.6 hours

Protein Binding

93.6%

Use: Labeled Indications

Diabetes mellitus, type 2: As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus

Contraindications

History of serious hypersensitivity reaction to ertugliflozin or any component of the formulation; severe renal impairment, end-stage renal disease, or dialysis

Dosage and Administration

Dosing: Adult

Note: If present, correct volume depletion prior to initiation.

Diabetes mellitus, type 2: Oral: Initial: 5 mg once daily; if initial dose is tolerated and further glycemic control is required, may increase to 15 mg once daily (maximum: 15 mg/day)

Dosing: Geriatric

Refer to adult dosing.

Administration

Oral: Administer in the morning without regard to meals.

Dietary Considerations

Individualized medical nutrition therapy (MNT) based on American Diabetes Association (ADA) recommendations is an integral part of therapy.

Storage

Store at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C to 30°C (between 59°F to 86°F). Protect from moisture.

Drug Interactions

Alpha-Lipoic Acid: May enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy

Androgens: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Exceptions: Danazol. Monitor therapy

Direct Acting Antiviral Agents (HCV): May enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy

Guanethidine: May enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy

Hyperglycemia-Associated Agents: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Hypoglycemia-Associated Agents: Antidiabetic Agents may enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy

Insulins: Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors may enhance the hypoglycemic effect of Insulins. Management: Consider a decrease in insulin dose when initiating therapy with a sodium-glucose cotransporter 2 inhibitor and monitor patients for hypoglycemia. Consider therapy modification

Maitake: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Monoamine Oxidase Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Pegvisomant: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Prothionamide: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Quinolones: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Quinolones may diminish the therapeutic effect of Blood Glucose Lowering Agents. Specifically, if an agent is being used to treat diabetes, loss of blood sugar control may occur with quinolone use. Monitor therapy

Ritodrine: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Salicylates: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Selective Serotonin Reuptake Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Sulfonylureas: Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors may enhance the hypoglycemic effect of Sulfonylureas. Management: Consider a decrease in sulfonylurea dose when initiating therapy with a sodium-glucose cotransporter 2 inhibitor and monitor patients for hypoglycemia. Consider therapy modification

Thiazide and Thiazide-Like Diuretics: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Test Interactions

Positive test for glucosuria; may interfere with 1,5-anhydroglucitol (1,5-AG) assay; use alternative methods to monitor glycemic control.

Adverse Reactions

Incidences may include ertugliflozin used as add on therapy.

>10%: Genitourinary: Genitourinary fungal infection (females: 9% to 12%; males: 4%)

1% to 10%:

Central nervous system: Headache (3% to 4%)

Endocrine & metabolic: Hypovolemia (2% to 4%), hypoglycemia (3%), increased thirst (1% to 3%), weight loss (2%), severe hypoglycemia (1%)

Genitourinary: Increased urine output (2% to 3%), vulvovaginal pruritus (2% to 3%)

Neuromuscular & skeletal: Back pain (3%)

Renal: Renal insufficiency (1% to 3%)

Respiratory: Nasopharyngitis (3%)

Frequency not defined:

Endocrine & metabolic: Increased LDL cholesterol, increased serum phosphate

Genitourinary: Decreased estimated GFR (eGFR)

Renal: Increased serum creatinine

<1%, postmarketing, and/or case reports: Acute renal failure, increased hemoglobin, ketoacidosis, pyelonephritis, urinary tract infection, urinary tract infection with sepsis

Warnings/Precautions

Concerns related to adverse effects:

• Bone fractures: An increased incidence of bone fractures has been observed with other sodium-glucose cotransporter 2 (SGLT-2) inhibitors in some clinical trials. A placebo-controlled trial with ertugliflozin conducted over 2 years did not demonstrate an increased fracture risk; similar changes in bone mineral density (BMD) were observed between groups, except at the hip where a greater decrease in BMD was observed with ertugliflozin (Gallo 2019).

• Genital mycotic infections: May increase the risk of genital mycotic infections (eg, vulvovaginal mycotic infection, vulvovaginal candidiasis, vulvovaginitis, candida balanitis, balanoposthitis). Patients with a history of these infections or uncircumcised males are at greater risk.
• Hypotension: May cause symptomatic hypotension due to intravascular volume depletion especially in patients with renal impairment (ie, eGFR <60 mL/minute/1.73 m²), elderly, patients on other antihypertensives (eg, diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]), or those with low systolic blood pressure. Assess volume status prior to initiation in patients at risk of hypotension and correct if depleted; monitor for signs and symptoms of hypotension after initiation.
• Ketoacidosis: Cases of ketoacidosis (some fatal) have been reported in patients with type 1 and type 2 diabetes mellitus receiving SGLT-2 inhibitors; in some cases, patients have presented with normal or only modestly elevated blood glucose (<250 mg/dL) (Bobart 2016; FDA 2015; Handelsman 2016). Before initiating treatment, consider risk factors that may predispose to ketoacidosis (eg, pancreatic insulin deficiency, dose decreases or discontinuation of insulin, caloric restriction, alcohol abuse, extensive exercise, MI, stroke, severe infection, surgery, any other extreme stress event) (Handelsman 2016). The American Association of Clinical Endocrinologists and American College of Endocrinology recommend considering withholding of SGLT-2 inhibitors for at least 24 hours prior to events that may precipitate diabetic ketoacidosis (Handelsman 2016), while others have suggested withholding for 3 to 5 days (Bobart 2016). Patients presenting with nausea/vomiting, abdominal pain, generalized malaise, and/or shortness of breath should be assessed immediately for ketoacidosis; discontinue therapy and treat promptly if ketoacidosis is suspected.
• Lipid abnormality: May cause dose-related LDL-C elevation; monitor LDL-C and treat as needed.
• Lower limb amputation: An increased risk for lower limb amputation (primarily of the toe) has been observed with another SGLT-2 inhibitor. In clinical trials, the incidence of non-traumatic lower limb amputations observed with ertugliflozin was ≤0.5% though a causal relationship has not been confirmed. Prior to initiation consider risk factors for amputation including prior amputation, peripheral vascular disease, neuropathy, and diabetic foot ulcers. Counsel patients about the importance of preventative foot care. Monitor for, and discontinue therapy if any of the following occur: Signs and symptoms of new infection (including osteomyelitis), new pain or tenderness, or sores/ulcers involving the lower limbs.
• Necrotizing fasciitis: Cases of necrotizing fasciitis of the perineum (Fournier gangrene), a rare but serious and potentially fatal infection, have been reported in patients receiving SGLT-2 inhibitors. Assess patients presenting with fever or malaise along with genital or perianal pain, tenderness, erythema, or swelling for necrotizing fasciitis. Discontinue in patients who develop necrotizing fasciitis and initiate treatment immediately.
• Renal effects: Acute kidney injury has been reported. Prior to initiation, consider risk factors for acute kidney injury (eg, hypovolemia, chronic renal insufficiency, heart failure, use of concomitant medications [eg, diuretics, ACE inhibitors, angiotensin receptor blockers, NSAIDs]). Temporarily discontinue use with reduced oral intake or fluid losses; discontinue use if acute kidney injury occurs. Additional abnormalities in renal function (decreased eGFR, increased serum creatinine) and adverse effects related to renal function may occur. Assess renal function prior to initiation and periodically during treatment.
• Urinary tract infection: Serious urinary infections, including urosepsis and pyelonephritis, requiring hospitalization have been reported; treatment with SGLT-2 inhibitors increases the risk for urinary tract infections (UTI); monitor for signs and symptoms of UTI and treat as needed.

Disease-related concerns:

• Bariatric surgery:

– Altered absorption: Absorption may be altered given the anatomic and transit changes created by gastric bypass and sleeve gastrectomy surgery (Mechanick 2013; Melissas 2013).

– Dehydration: Evaluate, correct, and maintain postsurgical fluid requirements and volume status prior to initiating therapy and closely monitor the patient for the duration of therapy; volume depletion and related adverse events (eg, hypotension, orthostatic hypotension, syncope) have occurred. Fluid intake may be more difficult after gastric bypass, sleeve gastrectomy, and gastric band (Mechanick 2013).

– Euglycemic diabetic ketoacidosis: Discontinue therapy 3 to 5 days prior to surgery (Bobart 2016). Postoperatively, assess volume status, caloric intake, and need for diabetes treatment and withhold antidiabetic medication if type 2 diabetes is in remission. Ketoacidosis has been reported in patients with type 1 and type 2 diabetes on SGLT-2 inhibitors. In some cases, normal or only modestly elevated blood glucose was present (<250 mg/dL) (van Niekerk 2018). Risk factors include significant reduction in insulin, caloric restriction, stress of surgery, and infection.

• Hepatic impairment: Not recommended for use in severe hepatic impairment (has not been studied).
• Renal impairment: Glycemic efficacy may be decreased in renal impairment. Assess renal function prior to initiation and periodically during treatment. Use is not recommended when eGFR is persistently 30 to <60 mL/minute/1.73 m² due to lack of efficacy, and use is contraindicated in patients with an eGFR <30 mL/minute/1.73 m², ESRD, or maintained on dialysis.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: Elderly patients may be predisposed to symptoms related to intravascular volume depletion (eg, hypotension, orthostatic hypotension, dizziness, syncope, dehydration) and renal impairment or failure.

Other warnings/precautions:

• Appropriate use: Not for use in patients with diabetic ketoacidosis or patients with type 1 diabetes mellitus.

Monitoring Parameters

Blood glucose, HbA_1c (at least twice yearly in patients who have stable glycemic control and are meeting treatment goals; quarterly in patients not meeting treatment goals or with therapy change [ADA 2019]); renal function (baseline and periodically during treatment); volume status (eg, blood pressure, hematocrit, electrolytes); phosphate; LDL-C; genital mycotic infections and urinary tract infection; hypersensitivity reactions; blood pressure; lower limb and feet (sores, ulcers, infection); if signs/symptoms of ketoacidosis (eg, nausea/vomiting, abdominal pain, malaise, shortness of breath), confirm diagnosis by direct measurement of blood ketones and arterial pH (measurement of serum bicarbonate or urinary ketones may not be adequate) (AACE [Handelsman 2016])

Pregnancy

Pregnancy Considerations

Due to adverse effects on renal development observed in animal studies, the manufacturer does not recommend use of ertugliflozin during the second and third trimesters of pregnancy

Poorly controlled diabetes during pregnancy can be associated with an increased risk of adverse maternal and fetal outcomes, including diabetic ketoacidosis, preeclampsia, spontaneous abortion, preterm delivery, delivery complications, major birth defects, stillbirth, and macrosomia. To prevent adverse outcomes, prior to conception and throughout pregnancy, maternal blood glucose and HbA_1c should be kept as close to target goals as possible but without causing significant hypoglycemia (ADA 2020; Blumer 2013).

Agents other than ertugliflozin are currently recommended to treat diabetes mellitus in pregnancy (ADA 2020).

Patient Education

What is this drug used for?

• It is used to lower blood sugar in patients with high blood sugar (diabetes).

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Fluid and electrolyte problems like mood changes, confusion, muscle pain or weakness, abnormal heartbeat, severe dizziness, passing out, fast heartbeat, increased thirst, seizures, loss of strength and energy, lack of appetite, unable to pass urine or change in amount of urine passed, dry mouth, dry eyes, or nausea or vomiting.
• Acidosis like confusion, fast breathing, fast heartbeat, abnormal heartbeat, severe abdominal pain, nausea, vomiting, fatigue, shortness of breath, or loss of strength and energy.
• Urinary tract infection like blood in the urine, burning or painful urination, passing a lot of urine, fever, lower abdominal pain, or pelvic pain.
• Kidney problems like unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain.
• Vaginal yeast infection
• Penile yeast infection
• Low blood sugar like dizziness, headache, fatigue, feeling weak, shaking, fast heartbeat, confusion, increased hunger, or sweating.
• Pain, swelling, or signs of infection in the genitals or rectum
• Lower extremity pain, tenderness, sores, or infection
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.