SEGLUROMET®

SEGLUROMET® is a medication used to treat type 2 diabetes in adults. It contains two active ingredients: ertugliflozin and metformin hydrochloride. Ertugliflozin belongs to a class of medications called SGLT2 inhibitors, which work by preventing the kidneys from reabsorbing glucose and instead excreting it in the urine. Metformin, on the other hand, is a biguanide medication that helps to lower blood glucose levels by reducing the amount of glucose produced by the liver and improving insulin sensitivity.

Ertugliflozin: The chemical name of ertugliflozin L-pyroglutamic acid is (1S,2S,3S,4R,5S)-5-(4-chloro-3-(4ethoxybenzyl)phenyl)-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol, compound with (2S)-5oxopyrrolidine-2-carboxylic acid. The molecular formula is C₂₇H₃₂ClNO₁₀and the molecular weight is 566.00.

Ertugliflozin L-pyroglutamic acid is a white to off-white powder that is soluble in ethyl alcohol and acetone, slightly soluble in ethyl acetate and acetonitrile and very slightly soluble in water.

Metformin HCl: Metformin hydrochloride (N,N-dimethylimidodicarbonimidic diamide hydrochloride) is not chemically or pharmacologically related to any other classes of oral antihyperglycemic agents.

Inactive ingredients are povidone, microcrystalline cellulose, crospovidone, sodium lauryl sulfate, and magnesium stearate.

The film coating contains: hypromellose, hydroxypropyl cellulose, titanium dioxide, iron oxide red, and carnauba wax.

SEGLUROMET® (ertugliflozin and metformin hydrochloride) tablets

Mechanism of Action

SEGLUROMET: SEGLUROMET combines two antihyperglycemic agents with complementary mechanisms of action to improve glycemic control in patients with type 2 diabetes mellitus: ertugliflozin, a SGLT2 inhibitor, and metformin hydrochloride, a member of the biguanide class.

Ertugliflozin: SGLT2 is the predominant transporter responsible for reabsorption of glucose from the glomerular filtrate back into the circulation. Ertugliflozin is an inhibitor of SGLT2. By inhibiting SGLT2, ertugliflozin reduces renal reabsorption of filtered glucose and lowers the renal threshold for glucose, and thereby increases urinary glucose excretion.

Metformin HCl: Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes mellitus, lowering both basal and postprandial plasma glucose. Its pharmacologic mechanisms of action are different from other classes of oral antihyperglycemic agents. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Metformin does not produce hypoglycemia in either patients with type 2 diabetes mellitus or normal subjects (except in special circumstances)and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.

INDICATIONS AND USAGE

SEGLUROMET^®is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Limitations of Use

Not recommended in patients with type 1 diabetes mellitus. It may increase the risk of diabetic ketoacidosis in these patients.

DOSAGE AND ADMINISTRATION

Individualize the starting dose of SEGLUROMET, ertugliflozin and metformin hydrochloride (HCI), based on the patient’s current regimen, while not exceeding the maximum recommended daily dose of 15 mg ertugliflozin and 2,000 mg metformin HCl:

In patients on metformin HCI, switch to SEGLUROMET tablets containing 2.5 mg ertugliflozin, with a similar total daily dose of metformin HCl.
In patients on ertugliflozin, switch to SEGLUROMET tablets containing 500 mg metformin HCl, with a similar total daily dose of ertugliflozin.
In patients already treated with ertugliflozin and metformin HCl, switch to SEGLUROMET tablets containing the same total daily dose of ertugliflozin and a similar daily dose of metformin HCI.

Take SEGLUROMET twice daily with meals, with gradual dose escalation for those initiating metformin HCl to reduce the gastrointestinal side effects due to metformin.

Dosing may be adjusted based on effectiveness and tolerability.

Use of SEGLUROMET is not recommended in patients with an eGFR less than 45 mL/min/1.73 m².

Use of SEGLUROMET is contraindicated in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m²), end stage-renal disease (ESRD), or on dialysis.

Discontinuation for Iodinated Contrast Imaging Procedures

Discontinue SEGLUROMET at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR less than 60 mL/min/1.73 m²; in patients with a history of liver disease, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart SEGLUROMET if renal function is stable.

CONTRAINDICATIONS

Hypersensitivity to ertugliflozin, metformin, or any excipient in SEGLUROMET, reactions such as angioedema or anaphylaxis have occurred.
Patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m²), end stage-renal disease (ESRD), or on dialysis.
Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma.

WARNINGS AND PRECAUTIONS

Lactic Acidosis: There have been postmarketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate: pyruvate ratio; metformin plasma levels were generally >5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk.

Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue SEGLUROMET and report these symptoms to their healthcare provider.

Ketoacidosis: Reports of ketoacidosis, a serious life-threatening condition requiring urgent hospitalization, have been identified in clinical trials and postmarketing surveillance in patients with type 1 and type 2 diabetes mellitus receiving sodium glucose co-transporter-2 (SGLT2) inhibitors including ertugliflozin. Fatal cases of ketoacidosis have been reported in patients taking medicines containing SGLT2 inhibitors. In placebo-controlled trials of patients with type 1 diabetes, the risk of ketoacidosis was increased in patients who received SGLT2 inhibitors compared to patients who received placebo. The risk of ketoacidosis may be greater with higher doses. SEGLUROMET is not indicated for the treatment of patients with type 1 diabetes mellitus.

Before initiating SEGLUROMET, consider factors in the patient history that may predispose to ketoacidosis, including pancreatic insulin deficiency from any cause, caloric restriction, and alcohol abuse. For patients who undergo scheduled surgery, consider temporarily discontinuing SEGLUROMET for at least 4 days prior to surgery.

Consider monitoring for ketoacidosis and temporarily discontinuing SEGLUROMET in other clinical situations known to predispose to ketoacidosis (e.g., prolonged fasting due to acute illness or post-surgery). Ensure risk factors for ketoacidosis are resolved prior to restarting SEGLUROMET.

Educate patients on the signs and symptoms of ketoacidosis and instruct patients to discontinue SEGLUROMET and seek medical attention immediately if signs and symptoms occur.

Lower Limb Amputation: In a long-term cardiovascular outcomes study, in patients with type 2 diabetes and established cardiovascular disease, the occurrence of non-traumatic lower limb amputations was reported with event rates of 4.7, 5.7, and 6.0 events per 1,000 patient-years in the placebo, ertugliflozin 5 mg, and ertugliflozin 15 mg treatment arms, respectively.

Amputation of the toe and foot were most frequent (81 out of 109 patients with lower limb amputations). Some patients had multiple amputations, some involving both lower limbs.

Lower limb infections, gangrene, and diabetic foot ulcers were the most common precipitating medical events leading to the need for an amputation. Patients with amputations were more likely to be male, have higher A1C (%) at baseline, have a history of peripheral arterial disease, amputation or peripheral revascularization procedure, diabetic foot, and to have been taking diuretics or insulin.

Volume Depletion: SEGLUROMET can cause intravascular volume contraction which may sometimes manifest as symptomatic hypotension or acute transient changes in creatinine. There have been postmarketing reports of acute kidney injury, some requiring hospitalization and dialysis, in patients with type 2 diabetes mellitus receiving SGLT2 inhibitors, including SEGLUROMET. Patients with impaired renal function (eGFR less than 60 mL/min/1.73 m²), elderly patients, patients with low systolic blood pressure, or patients on loop diuretics may be at increased risk for volume depletion or hypotension. Before initiating SEGLUROMET in patients with one or more of these characteristics, assess volume status and renal function. In patients with volume depletion, correct this condition before initiating SEGLUROMET. Monitor for signs and symptoms of volume depletion, and renal function after initiating therapy.

Urosepsis and Pyelonephritis: There have been postmarketing reports of serious urinary tract infections, including urosepsis and pyelonephritis, requiring hospitalization in patients receiving medicines containing SGLT2 inhibitors. Treatment with medicines containing SGLT2 inhibitors increases the risk for urinary tract infections. Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated.

Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues: Insulin and insulin secretagogues (e.g., sulfonylurea) are known to cause hypoglycemia. SEGLUROMET may increase the risk of hypoglycemia when used in combination with insulin and/or an insulin secretagogue. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with SEGLUROMET.

Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene): Reports of necrotizing fasciitis of the perineum (Fournier’s Gangrene), a rare but serious and life-threatening necrotizing infection requiring urgent surgical intervention, have been identified in postmarketing surveillance in patients with diabetes mellitus receiving SGLT2 inhibitors, including ertugliflozin. Cases have been reported in females and males. Serious outcomes have included hospitalization, multiple surgeries, and death.

Patients treated with SEGLUROMET presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise, should be assessed for necrotizing fasciitis. If suspected, start treatment immediately with broad-spectrum antibiotics and, if necessary, surgical debridement. Discontinue SEGLUROMET, closely monitor blood glucose levels, and provide appropriate alternative therapy for glycemic control.

Genital Mycotic Infections: Ertugliflozin increases the risk of genital mycotic infections. Patients who have a history of genital mycotic infections or who are uncircumcised are more likely to develop genital mycotic infections. Monitor and treat appropriately.

Vitamin B12 Deficiency: In metformin clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B12 levels was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the 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.

DRUG INTERACTIONS

Carbonic Anhydrase Inhibitors: The risk of lactic acidosis may increase due to concomitant use of Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) with metformin. These drugs frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis.

Drugs that Reduce Metformin clearance: The risk of lactic acidosis may increase due to concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2] / multidrug and toxin extrusion [MATE] inhibitors such as ranolazine, vandetanib, dolutegravir, and cimetidine) which increase systemic exposure to metformin.

Consider the benefits and risks of concomitant use.

Alcohol: Potentiate the effect of metformin on lactate metabolism.

Warn patients against excessive alcohol intake while receiving SEGLUROMET.

Insulin and Insulin Secretagogues: The risk of hypoglycemia when ertugliflozin is used in combination with insulin and/or an insulin secretagogue.

A lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with SEGLUROMET.

Drugs that Affect Glycermic control: Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid.

When a patient is receiving SEGLUROMET along with such drugs, the patient should be closely observed to maintain adequate glycemic control.

Lithium: Concomitant use of an SGLT2 inhibitor with lithium may decrease serum lithium concentrations.

Monitor serum lithium concentration more frequently during SEGLUROMET initiation and dosage changes.

Positive Urine Glucose test: SGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose tests.

Monitoring glycemic control with urine glucose tests is not recommended in patients taking SEGLUROMET. Use alternative methods to monitor glycemic control.

Interference with 1,5-anhydroglucitol (1,5-AG) Assay: Measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors.

Monitoring glycemic control with 1,5-AG assay is not recommended. Use alternative methods to monitor glycemic control.

USE IN SPECIFIC POPULATIONS

Pregnancy: Based on animal data showing adverse renal effects, from ertugliflozin, SEGLUROMET is not recommended during the second and third trimesters of pregnancy. Published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage risk.

The limited available data with SEGLUROMET in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy.

Poorly-controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity.

Lactation: There is no information regarding the presence of SEGLUROMET or ertugliflozin in human milk, the effects on the breastfed infant, or the effects on milk production. Limited published studies report that metformin is present in human milk. However, there is insufficient information on the effects of metformin on the breastfed infant and no available information on the effects of metformin on milk production. Ertugliflozinand metformin are present in the milk of lactating rats. 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, based on data with ertugliflozin. Because of the potential for serious adverse reactions in a breastfed infant, advise women that the use of SEGLUROMET is not recommended while breastfeeding.

Females and Males of Reproductive Potential: Discuss the potential for unintended pregnancy with premenopausal women as therapy with metformin may result in ovulation in some anovulatory women.

Pediatric Use: Safety and effectiveness of SEGLUROMET in pediatric patients under 18 years of age have not been established.

Geriatric Use: No dosage adjustment of SEGLUROMET is recommended based on age. Elderly patients are more likely to have decreased renal function. Because renal function abnormalities can occur after initiating ertugliflozin, and metformin is known to be substantially excreted by the kidneys, care should be taken in dose selection in the elderly. Assess renal function in elderly patients prior to initiating dosing and periodically thereafter.

Hepatic Impairment: Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. SEGLUROMET is not recommended in patients with hepatic impairment.

OVERDOSAGE

SEGLUROMET: In the event of an overdose with SEGLUROMET, contact the Poison Control Center. Employ the usual supportive measures as dictated by the patient’s clinical status.

Ertugliflozin: Removal of ertugliflozin by hemodialysis has not been studied.

Metformin HCl: Overdose of metformin hydrochloride has occurred, including ingestion of amounts greater than 50 g (25 times the maximum recommended daily dose). Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin hydrochloride has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases. Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected.

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SEGLUROMET® (ertugliflozin and metformin hydrochloride) tablets

SEGLUROMET®