Ertugliflozin + Metformin

Ertugliflozin + Metformin is used for: Type 2 Diabetes Mellitus

Type 2 Diabetes Mellitus Indicated as 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 Individualize starting dose based on patient’s current regimen, while not exceeding daily dose of ertugliflozin 15 mg and metformin 2000 mg Take BID with meals 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 same total daily dose of ertugliflozin and a similar daily dose of metformin To reduce GI adverse effects, gradually escalate dose for those initiating metformin Adjust dose based on effectiveness and tolerability Hepatic impairment Not recommended with hepatic impairment Metformin has been associated with some cases of lactic acidosis in patients with hepatic impairment

<18 years: Safety and efficacy not established

Renal impairment eGFR &g;e60 mL/min/1.73 m²: No dosage adjustment necessary eGFR <30 mL/min/1.73 m²: Contraindicated End-stage renal disease or dialysis: Contraindicated eGFR 30-60 mL/min/1.73 m² Initiation of ertugliflozin not recommended Continued use not recommended with persistent eGFR 30-60 mL/min/1.73 m²

Take in the morning qDay, with or without food

Hypersensitivity Severe renal impairment, end-stage renal disease, or dialysis Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma

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

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

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)

Side effects of Ertugliflozin + Metformin : >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)

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