Usual Adult Dose for Diabetes Type 2

Individualize dose based on current regimen:

Initial dose: 1 tablet orally twice a day

• For patients on metformin: Start with tablet containing ertugliflozin 2.5 mg and one-half total daily dose of metformin
• For patients on ertugliflozin: Start with tablet containing one-half daily dose of ertugliflozin and metformin 500 mg
• For patients already treated with ertugliflozin and metformin: Start with the tablet that provides one-half total daily dose of ertugliflozin and one-half of similar daily dose of metformin

Adjust dose based on effectiveness and tolerability
Maximum daily dose: Ertugliflozin 15 mg; Metformin 2000 mg

Comments:

• Volume depletion should be corrected prior to therapy initiation.
• Metformin dose should be gradually increased to reduce gastrointestinal side effects; taking with meals will also reduce gastrointestinal effects.
• This drug is not recommended for patients with type 1 diabetes mellitus as it may increase the risk of diabetic ketoacidosis.

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

Renal Dose Adjustments

eGFR 45 mL/min/1.73 m2 or greater: No dose adjustment recommended
eGFR 30 to less than 45 mL/min/1.73 m2): Not recommended
eGFR 30 mL/min/1.73m2), ESRD, or dialysis: Contraindicated

IODINATED CONTRAST PROCEDURES:

• For patients with eGFR less than 60 mL/min/1.73 m2: Stop this drug at the time of, or before an iodinated contrast imaging procedure; re-evaluate eGFR 48 hours after procedure; restart therapy only if renal function is stable.
• For patients receiving intra-arterial iodinated contrast: Stop this drug at the time of, or before procedure, re-evaluate eGFR 48 hours after procedure; restart therapy only if renal function is stable.

Liver Dose Adjustments

Hepatic impairment: Not recommended

Dose Adjustments

Elderly: Assess renal function more frequently in this population as the risk of metformin-associated lactic acidosis increases with patient age

SURGICAL PROCEDURES:

• Discontinue at least 4 days prior to scheduled surgery; an increase in other glucose lowering agents may be required during this time

IODINATED CONTRAST PROCEDURE:

• Discontinue therapy at time of, or prior to an iodinated contrast procedure for:
• Patients with an eGFR less than 60 mL/min/1.73 m2
• Patients with a history of hepatic impairment, alcoholism, or heart failure
• Patients who will be administered intra-arterial iodinated contrast

Re-evaluate eGFR 48 hours after the imaging procedure; restart only if renal function is stable

Concomitant Use of Insulin and Insulin Secretagogues:

• A lower dose of insulin or an insulin secretagogue may be required to reduce the risk of hypoglycemia

• Concomitant use with drugs that may increase the risk of metformin-associated lactic acidosis (e.g., those that impair renal function, result in significant hemodynamic changes, interfere with acid base balance, or increase metformin accumulation [e.g., cationic drugs]) should be avoided or used with more frequent monitoring

Precautions

US BOXED WARNING: LACTIC ACIDOSIS

• Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis has been characterized by elevated blood lactate levels (greater than 5 mmol/L) anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio, and metformin plasma levels generally greater than 5 mcg/mL.
• Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years or older, having a radiological study with contrast, surgery, and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment; recommendations are provided in the full prescribing guidelines to reduce the risks.
• If metformin-associated acidosis is suspected, immediately discontinue therapy and institute general supportive measures in a hospitalized setting. Prompt hemodialysis is recommended.

CONTRAINDICATIONS:

• Hypersensitivity to the active substances or product excipients; reactions such as angioedema or anaphylaxis have occurred
• Severe renal impairment (eGFR less than 30 mL/min/1.73 m2), ESRD, or dialysis
• Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma

Safety and efficacy have not been established in patients younger than 18 years.

Consult WARNINGS section for additional precautions.

Dialysis

Contraindicated

Other Comments

Administration advice:

• Take orally twice a day with meals
• Gastrointestinal tolerability may be improved by a slow increase in metformin dosage

Missed dose: If a dose is missed, take as soon as remembered unless it is close to the next dose, then skip the missed dose and take the next regularly scheduled dose; do not double next dose

General:

• Correct volume depletion prior to initiating treatment.
• Not recommended for patients with type 1 diabetes mellitus as it may increase risk of diabetic ketoacidosis.
• May need to temporarily stop treatment prior to radiologic studies utilizing iodinated contrast materials and for surgical procedures when restricted food or fluid intake is expected; may resume once adequate renal function is confirmed.

Monitoring:

• Monitor renal function prior to initiating therapy and as clinically indicated
• Assess fluid status prior to initiation and monitor for signs and symptoms of volume depletion during therapy
• Evaluate for the presence of ketoacidosis in symptomatic patients, regardless of blood sugar reading
• Monitor for new pain or tenderness, sores or ulcers, or infections involving the leg or foot
• Assess hematologic parameters annually; periodically asses Vitamin B-12 levels, especially in patients with peripheral neuropathy or anemia

Monitor for genital mycotic infections and urinary tract infections

• Monitor glycemic control

Patient advice:

• Read the US FDA-approved patient labeling (Medication Guide).
• Instruct patients experiencing symptoms of ketoacidosis such as difficulty breathing, nausea, vomiting, abdominal pain, confusion, and unusual fatigue, or sleepiness to stop taking this drug and seek immediate medical attention.
• Inform patients about the risk of lactic acidosis, conditions that might predispose them to its occurrence, and symptoms to watch for and report.
• Patients should be instructed to maintain adequate fluid intake to avoid adverse reactions related to volume depletion such as orthostatic hypotension.
• Patients should understand the importance of adhering to dietary instructions, regular physical exercise, and routine lab monitoring; they should understand how to treat low and high blood sugars and when to seek medical advice (for example, during periods of stress as medical management of glycemic control may change).
• Inform patients that genital mycotic infections, urinary tract infections, and hypersensitivity reactions may occur and they should contact their health care professional if these occur.
• Patients should be instructed to seek immediate medical attention for symptoms of tenderness, redness, or swelling of the genitals or the area from the genitals back to the rectum, especially if they have a fever and are feeling unwell.
• Patients should be instructed to seek medical attention promptly for signs and symptoms of acute kidney injury such as decreased urine, swelling in the legs or feet.
• Patients should be instructed to promptly report new pain or tenderness, sores or ulcers, or infections involving the leg or foot.
• Advise patients that this drug may need to be temporarily stopped if undergoing radiologic studies with intravascular iodinated contrast materials or surgical procedures that will limit food or fluid intake.
• Advise patients on the risks of excessive alcohol intake.
• Women of childbearing potential should be advised to speak to their healthcare provider if they become pregnant, intend to become pregnant, or are breastfeeding.
• Advise premenopausal anovulatory females that this drug may result in an unintended pregnancy due to its effect on ovulation.
• Tell patients that while gastrointestinal symptoms might be common when initiating treatment, gastrointestinal problems after initiation should be reported.