Ertugliflozin-Metformin

Ertugliflozin-Metformin is a combination medication used as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus who are not adequately controlled on a regimen containing ertugliflozin or metformin, or in patients who are already treated with both ertugliflozin and metformin.

• Ertugliflozin-Metformin is available under the following different brand names: Segluromet

Common side effects of Ertugliflozin-Metformin include:

• genital yeast infections
• diarrhea
• nausea
• vomiting
• gas (flatulence)
• abdominal discomfort
• indigestion
• weakness/lack of energy
• headache
• urinary tract infections (UTIs)
• vaginal itching
• increased urination
• back pain
• weight loss
• thirst

Serious side effects of Ertugliflozin-Metformin include:

• hives
• difficulty breathing
• swelling of the face, lips, tongue, or throat
• burning, painful, frequent, or urgent urination
• pink or bloody urine
• changes in the amount of urine
• swelling of the legs or feet
• unusual vaginal discharge, burning, or itching
• vaginal odor
• redness, itching, or swelling of the penis
• unusual discharge from the penis
• pain, redness, and swelling in or around the genital area
• fever
• feeling unwell
• sudden sweating
• shaking
• fast heartbeat
• hunger
• blurred vision
• dizziness
• tinging of the hands or feet
• increased thirst or urination
• vomiting
• diarrhea
• heavy sweating
• urinating less than usual
• unusual dry mouth
• fainting
• rash
• itching
• severe dizziness

Rare side effects of Ertugliflozin-Metformin include:

• none 

Seek medical care or call 911 at once if you have the following serious side effects:

• Severe headache, confusion, slurred speech, arm or leg weakness, trouble walking, coordination loss, unsteady, very stiff muscles, high fever, profuse sweating, or tremors.
• Serious eye symptoms such as sudden vision loss, blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights.
• Serious heart symptoms include fast, irregular, or pounding heartbeats; fluttering in the chest; shortness of breath; sudden dizziness, lightheadedness, or passing out.

This is not a complete list of side effects and other serious side effects or health problems that may occur because of the use of this drug. Call your doctor for medical advice about serious side effects or adverse reactions. You may report side effects or health problems to FDA at 1-800-FDA-1088.

Adult dosage

Tablet

• 2.5 mg/500 mg
• 2.5 mg/1000 mg
• 7.5 mg/500 mg
• 7.5 mg/1000 mg

Type 2 diabetes mellitus

Adult dosage

• Individualize starting dose based on the patient’s current regimen, while not exceeding the daily dose of ertugliflozin 15 mg and metformin 2000 mg.
• Take two times a day with meals.
• Switching from individual ertugliflozin and/or metformin
• Patients on metformin: Switch to tablets containing 2.5 mg ertugliflozin, with a similar total daily dose of metformin.
• Patients on ertugliflozin: Switch to tablets containing 500 mg metformin, with a similar total daily dose of ertugliflozin.
• Patients already on ertugliflozin and metformin: Switch to tablets containing the same total daily dose of ertugliflozin and a similar daily dose of metformin.
• To reduce GI adverse effects, gradually escalate the dose for those initiating metformin.
• Adjust dose based on effectiveness and tolerability.

Dosage Considerations – Should be Given as Follows: 

• See “Dosages”

If your medical doctor is using this medicine to treat your pain, your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor, healthcare provider, or pharmacist first.

• Ertugliflozin-Metformin has severe interactions with no other drugs.
• Ertugliflozin-Metformin has serious interactions with the following drugs:
  • contrast media (iodinated)
  • ethanol
  • ioversol
  • methylene blue
  • pacritinib
  • ranolazine
  • risdiplam
  • selegiline
  • selegiline transdermal
  • tafenoquine
  • tedizolid
  • tranylcypromine
  • trilaciclib
• Ertugliflozin-Metformin has moderate interactions with at least 191 other drugs
• Ertugliflozin-Metformin has minor interactions with at least 82 other drugs

This information does not contain all possible interactions or adverse effects. Visit the RxList Drug Interaction Checker for any drug interactions. Therefore, before using this product, tell your doctor or pharmacist about all the products you use. Keep a list of all your medications with you and share this information with your doctor and pharmacist. Check with your healthcare professional or doctor for additional medical advice, health questions, or concerns.

Contraindications

• Hypersensitivity to drugs or excipients; reactions such as angioedema or anaphylaxis have occurred
• Severe renal impairment (eGFR below 30 mL/min/1.73 m2), end-stage renal disease, or dialysis
• Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma

Effects of drug abuse

• None

Short-Term Effects

• See “What Are Side Effects Associated with Using Ertugliflozin-Metformin?”

Long-Term Effects

• See “What Are Side Effects Associated with Using Ertugliflozin-Metformin?”

Cautions

• Cases of metformin-associated lactic acidosis reported, including fatalities 
• Necrotizing fasciitis of the perineum (Fournier gangrene) reported with SGLT2 inhibitors; signs and symptoms include tenderness, redness, or swelling of the genitals or the area from the genitals back to the rectum and a fever above 100.4 F or a general feeling of being unwell; if suspected, discontinue SGLT2 inhibitor and start treatment immediately with broad-spectrum antibiotics and surgical debridement if necessary
• Before initiating treatment in patients with one or more of the risk factors, assess their volume status and renal function; causes intravascular volume contraction; symptomatic hypotension may occur after initiating, particularly in patients with renal impairment, with low systolic blood pressure, on diuretics, or who are elderly
• Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated; serious urinary tract infections, including urosepsis and pyelonephritis, requiring hospitalization were reported in patients receiving SGLT2 inhibitors
• Genital mycotic infections may occur; patients with a history of genital mycotic infections and uncircumcised males are more susceptible
• Dose-related increases in LDL-C were reported
• No conclusive evidence of macrovascular risk reduction with empagliflozin or any other antidiabetic agent
• Lower limb amputation
  • An increased risk for lower limb amputation (primarily of the toe) has been observed in clinical studies with another SGLT2 inhibitor; before initiating, consider factors that may predispose the patient to increased risk for amputations (eg, history of prior amputation, peripheral vascular disease, neuropathy, diabetic foot ulcers)
  • Counsel patients about the importance of routine preventative foot care; monitor patients receiving these drugs for signs and symptoms of infection (including osteomyelitis), new pain or tenderness, sores or ulcers involving the lower limbs, and discontinue therapy if these complications occur

Vitamin B12 deficiency

• Vitamin B12 levels may decrease; metformin may interfere with absorption from B12-intrinsic factor complex; such decrease, possibly due to interference with B12 absorption from B12-intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation
• Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels; measure hematologic parameters on an annual basis and vitamin B12 at 2 to 3-year intervals in patients on metformin and manage any abnormalities

Renal impairment

• Obtain an eGFR at least annually in all patients receiving therapy
• Not recommended in patients with an eGFR below 45 mL/min/1.73 m2; renal impairment may occur owing to intravascular volume contraction
• Consider factors that may predispose patients to acute kidney injury, including hypovolemia, chronic renal insufficiency, CHF, and concomitant medications (eg, diuretics, ACE inhibitors, ARBs, NSAIDs)
• Consider temporarily discontinuing ertugliflozin in any setting of reduced oral intake or fluid loss; monitor for signs and symptoms of acute kidney injury, and, if evident, discontinue the drug promptly and institute treatment

Ketoacidosis

• Not indicated for patients with type 1 diabetes mellitus (T1DM); in placebo-controlled trials, the risk for ketoacidosis increased in patients with T1DM who received SGLT2 inhibitors
• Risk for ketoacidosis may be greater with higher doses
• Before initiating therapy, consider factors in the patient’s history that may predispose them to ketoacidosis, including pancreatic insulin deficiency from any cause, including caloric restriction, and alcohol abuse
• Consider temporary discontinuation of the therapy for at least 4 days for patients who undergo scheduled surgery
• Consider monitoring for ketoacidosis and temporarily discontinuing therapy in other clinical situations known to predispose patients to ketoacidosis (eg, prolonged fasting due to acute illness or post-surgery); ensure that the risk factors for ketoacidosis are resolved before restarting therapy
• Educate patients on signs and symptoms of ketoacidosis and instruct patients to discontinue therapy and seek medical attention immediately if signs and symptoms occur

Drug interaction overview

• Closely monitor if coadministered with drugs that affect glycemic control by causing hyperglycemia (eg, thiazides and other diuretics, corticosteroids, phenothiazines, thyroid drugs, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, CCBs, isoniazid)
• Ertugliflozin
  • Hypoglycemia risk increased with insulin and insulin secretagogues (eg, sulfonylureas); a lower dose of insulin or insulin secretagogue may be required
  • Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors, as SGLT2 inhibitors increase urinary glucose excretion and lead to positive urine glucose tests; use alternative methods to monitor glycemic control
  • Monitoring glycemic control with 1,5-AG assay is not recommended, as measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors; use alternative methods to monitor glycemic control
• Metformin
  • Coadministration with carbonic anhydrase inhibitors (topiramate, zonisamide, acetazolamide, dichlorphenamide) may increase the risk for lactic acidosis; these drugs cause a decrease in serum bicarbonate and induce non-anion gap hyperchloremic metabolic acidosis
  • Drugs that interfere with renal tubular transport (OCT2 inhibitors, MATE inhibitors) may increase systemic exposure to metformin and increase the risk for lactic acidosis.
  • Alcohol is known to increase the effect of metformin on lactate metabolism

Pregnancy and Lactation

• Ertugliflozin
  • Based on animal data showing adverse renal effects, the drug is not recommended during the second and third trimesters of pregnancy
  • Data on the drug’s use in pregnant women are limited and are not sufficient to determine a drug-associated risk for adverse developmental outcomes; there are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy
• Metformin
  • Published data from postmarketing studies have not reported a clear association between metformin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin was used during pregnancy
  • However, these studies cannot establish the absence of any metformin-associated risk because of methodological limitations, including small sample size and inconsistent comparator groups
• Lactation
  • Not recommended while breastfeeding
  • Ertugliflozin
    • Unknown if distributed in human breast milk
    • Since human kidney maturation occurs in utero and during the first 2 years of life when lactational exposure may occur, there may be a risk to the developing human kidney
    • Because of the potential for serious adverse reactions in a breastfed infant, advise women that ertugliflozin is not recommended while breastfeeding
  • Metformin
    • Published clinical lactation studies report that metformin is present in human milk, which resulted in infant doses of approximately 0.11-1% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 0.13 and 1
    • However, the studies were not designed to establish the risk associated with the use of metformin during lactation because of the small sample size and limited adverse event data collected in infants