ertugliflozin/metformin (Rx)

>10% (Ertugliflozin)

Female genital mycotic infections (9.1-12.2%)

1-10% (Ertugliflozin)

Volume depletion adverse effects (1.9-4.4%)

Male genital mycotic infections (3.7-4.2%)

Urinary tract infections (4-4.1%)

Headache (2.9-3.5%)

Vaginal pruritus (2.4-2.8%)

Increased urination (2.4-2.7%)

Nasopharyngitis (2-2.5%)

Back pain (1.7-2.5%)

Renal adverse effects (1.3-2.5%)

Weight decreased (1.2-2.4%)

Thirst (1.4-2.7%)

>5% (Metformin)

Initiating drug

• Diarrhea
• Nausea
• Vomiting
• Flatulence
• Abdominal discomfort
• Indigestion
• Asthenia
• Headache

Long-term use

• Decreased vitamin B-12 absorption, which may very rarely result in significant deficiency (eg, megaloblastic anemia)

Contraindications

Hypersensitivity

Severe renal impairment, end-stage renal disease, or dialysis

Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma

Cautions

Cases of metformin-associated lactic acidosis reported, including fatalities (see Black Box Warnings and Contraindications)

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 have 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

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

Ketoacidosis, a serious life-threatening condition requiring urgent hospitalization, reported; before initiating, consider factors that may predispose patient to ketoacidosis, including pancreatic insulin deficiency from any cause, caloric restriction, and alcohol abuse; monitor for ketoacidosis and temporarily discontinue in clinical situations known to predispose to ketoacidosis (eg, prolonged fasting owing to acute illness or surgery)

Renal impairment may occur owing to intravascular volume contraction; before initiating, 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 drug promptly and institute treatment (see Contraindications and Dosage Modifications)

Serious urinary tract infections, including urosepsis and pyelonephritis, requiring hospitalization reported in patients receiving SGLT2 inhibitors

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 patient to increased risk of amputations (eg, history of prior amputation, peripheral vascular disease, neuropathy, diabetic foot ulcers)

Genital mycotic infections may occur; patients with history of genital mycotic infections and uncircumcised males are more susceptible

Dose-related increases in LDL-C reported

Vitamin B12 levels may decrease; metformin may interfere with absorption from B12-intrinsic factor complex

No conclusive evidence of macrovascular risk reduction with empagliflozin or any other antidiabetic agent

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 risk for lactic acidosis; these drug 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 risk for lactic acidosis
  • Alcohol is known to increase effect of metformin on lactate metabolism

Pregnancy

Ertugliflozin

• Based on animal data showing adverse renal effects, not recommended during the second and third trimesters of pregnancy
• Data are limited in pregnant women and 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

• Animal data

  • 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 ~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 ~300 times higher than the maximal clinical dose of 15 mg/day when administered during organogenesis

Metformin

• Published data from postmarketing studies have not reported a clear association with metformin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin was used during pregnancy
• However, these studies cannot definitely establish the absence of any metformin-associated risk because of methodological limitations, including small sample size and inconsistent comparator groups

• Animal data

  • Metformin did not adversely affect development outcomes when administered to rats and rabbits at doses up to 600 mg/kg/day
  • This represents an exposure of about 2 and 6 times the maximum recommended human dose of 2,000 mg based on body surface area comparisons for rats and rabbits, respectively
  • Determination of fetal concentrations demonstrated a partial placental barrier to metformin

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 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 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 definitely establish the risk of use of metformin during lactation because of small sample size and limited adverse event data collected in infants

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Ertugliflozin: Selective sodium-glucose transporter-2 (SGLT2) inhibitor; lowers the renal glucose threshold (ie, the plasma glucose concentration which exceed the maximum glucose reabsorption capacity of the kidney); lowering the renal glucose threshold results in increased urinary glucose excretion

Metformin: Decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization; improves glucose tolerance by lowering both basal and postprandial plasma glucose

Absorption

Ertugliflozin

• Peak plasma time: 1 hr (fasting); 2 hr (high-fat, high-caloric meal)
• Peak plasma concentration, steady-state: 81.3 ng/mL (5 mg qDay); 268 ng/mL (15 mg qDay)
• AUC, steady-state: 398 ng⋅hr/mL (5 mg qDay); 1,193 ng⋅hr/mL (15 mg qDay)
• Steady-state reached after 4-6 days
• Bioavailability, 15-mg dose: ~100%

Metformin

• Steady-state reached after 24-48 hr
• Bioavailability, 500-mg dose: 50-60%
• Food decreases extent of and slightly delays absorption

Distribution

Ertugliflozin

• Vd, steady-state: 85.5 L
• Protein binding: 93.6%
• Blood-to-plasma concentration ratio of ertugliflozin: 0.66

Metformin

• Vd: 654 L
• Protein binding: Negligible

Metabolism

Ertugliflozin

• Major metabolic pathway for ertugliflozin is UGT1A9 and UGT2B7-mediated O-glucuronidation to 2 glucuronides (pharmacologically inactive at clinically relevant concentrations)
• CYP-mediated (oxidative) metabolism of ertugliflozin is minimal (12%)

Metformin

• Does not undergo hepatic nor biliary metabolism

Excretion

Ertugliflozin

• Half-life: 16.6 hr
• Clearance: 11.2 L/hr
• Excretion, oral [14C]-ertugliflozin solution: Feces (40.9%); urine (50.2%)
• Excretion, unchanged ertugliflozin: Feces (33.8%); urine (1.5%)

Metformin

• Half-life: 17.6 hr (blood); 6.2 hr (plasma)
• Excretion: ~90% urine (unchanged)

Oral Administration

Take in the morning qDay, with or without food

Missed dose

• Take it as soon as you remember
• If it is almost time for scheduled next dose, skip missed dose and take the next regularly scheduled time
• Do not take 2 doses at the same time

Storage

Store at room temperature between 68-77°F (20-25°C); excursions permitted between 59-86°F (15-30°C)

Keep tablets dry

Store blister packs in the original package