STEGLUJAN®

STEGLUJAN® is a medication that combines two active ingredients, ertugliflozin and sitagliptin, in a single tablet. Ertugliflozin belongs to a class of medications called SGLT2 inhibitors, which work by blocking the reabsorption of glucose in the kidneys and promoting its excretion in the urine. Sitagliptin, on the other hand, is a DPP-4 inhibitor that works by increasing the levels of incretin hormones in the body, which stimulate the production of insulin and lower blood sugar levels. Together, these two medications help to control blood sugar levels in adults with type 2 diabetes mellitus.

Ertugliflozin: The chemical name of ertugliflozin L-pyroglutamic acid is (1S,2S,3S,4R,5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol, compound with (2S)-5-oxopyrrolidine-2-carboxylic acid. The molecular formula is C₂₇H₃₂ClNO₁₀ and 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.

Sitagliptin: Sitagliptin phosphate monohydrate is described chemically as 7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazine phosphate (1:1) monohydrate. The empirical formula is C₁₆H₁₅F₆N₅O•H₃PO₄•H₂O and the molecular weight is 523.32.

Inactive ingredients are microcrystalline cellulose, dibasic calcium phosphate anhydrous, croscarmellose sodium, sodium stearyl fumarate, and magnesium stearate.

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

STEGLUJAN® (ertugliflozin and sitagliptin) tablets

Mechanism of Action

STEGLUJAN: STEGLUJAN 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 sitagliptin, a DPP-4 inhibitor.

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.

Sitagliptin: Sitagliptin is a DPP-4 inhibitor, which is believed to exert its actions in patients with type 2 diabetes mellitus by slowing the inactivation of incretin hormones. Concentrations of the active intact hormones are increased by sitagliptin, thereby increasing and prolonging the action of these hormones. Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. These hormones are rapidly inactivated by the enzyme, DPP-4. The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. By increasing and prolonging active incretin levels, sitagliptin increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.

INDICATIONS AND USAGE

STEGLUJAN® 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.
Has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using STEGLUJAN.

DOSAGE AND ADMINISTRATION

The recommended starting dose of STEGLUJAN is 5 mg ertugliflozin/100 mg sitagliptin once daily, taken in the morning, with or without food.
For patients treated with ertugliflozin who are being switched to STEGLUJAN, the dose of ertugliflozin can be maintained.
For additional glycemic control, the dose may be increased to 15 mg ertugliflozin/100 mg sitagliptin once daily in patients tolerating STEGLUJAN.
Use is not recommended in patients with an eGFR less than 45 mL/min/1.73 m².
Use of STEGLUJAN is contraindicated in patients with severe renal impairment (<30 mL/min/1.73 m²), end-stage renal disease (ESRD) or on dialysis.

CONTRAINDICATIONS

Patients with severe renal impairment (<30 mL/min/1.73 m2), end-stage renal disease (ESRD), or on dialysis.
Hypersensitivity to sitagliptin, ertugliflozin, or any excipient, in STEGLUJAN, reactions such as anaphylaxis or angioedema have occurred.

WARNINGS AND PRECAUTIONS

Pancreatitis: There have been postmarketing reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, in patients taking sitagliptin, a component of STEGLUJAN. After initiation of STEGLUJAN, patients should be observed carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, STEGLUJAN should promptly be discontinued and appropriate management should be initiated. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using STEGLUJAN.

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 medicines containing sodium glucose co-transporter-2 (SGLT2) inhibitors including ertugliflozin. Fatal cases of ketoacidosis have been reported in patients taking 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. STEGLUJAN is not indicated for the treatment of patients with type 1 diabetes mellitus.

Before initiating STEGLUJAN, 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 STEGLUJAN for at least 4 days prior to surgery.

Consider monitoring for ketoacidosis and temporarily discontinuing STEGLUJAN 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 STEGLUJAN.

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

Lower Limb Amputation: In a long-term cardiovascular outcomes study, in patients with type 2diabetes 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 1000 patient-years in the placebo, ertugliflozin5 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.

Acute Renal Failure: There have been postmarketing reports with sitagliptin of worsening renal function, including acute renal failure, sometimes requiring dialysis. A subset of these reports involved patients with renal insufficiency, some of whom were prescribed inappropriate doses of sitagliptin. A return to baseline levels of renal insufficiency has been observed with supportive treatment and discontinuation of potentially causative agents. Consideration can be given to cautiously reinitiating STEGLUJAN if another etiology is deemed likely to have precipitated the acute worsening of renal function.

Sitagliptin has not been found to be nephrotoxic in preclinical studies at clinically relevant doses, or in clinical trials.

Volume Depletion: STEGLUJAN 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 STEGLUJAN. 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 STEGLUJAN 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 STEGLUJAN. 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.

Heart Failure: An association between dipeptidyl peptidase-4 (DPP-4) inhibitor treatment and heart failure has been observed in cardiovascular outcomes trials for two other members of the DPP-4 inhibitor class. These trials evaluated patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease. Consider the debridement. Discontinue STEGLUJAN, 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.

Hypersensitivity Reactions: There have been postmarketing reports of serious hypersensitivity reactions in patients treated with sitagliptin. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. Onset of these reactions occurred within the first 3 months after initiation of treatment with sitagliptin, with some reports occurring after the first dose. If a hypersensitivity reaction is suspected, discontinue STEGLUJAN, assess for other potential causes for the event, and institute alternative treatment for diabetes.

Angioedema has also been reported with other dipeptidyl peptidase-4 (DPP-4) inhibitors. Use caution in a patient with a history of angioedema with another DPP-4 inhibitor because it is unknown whether such patients will be predisposed to angioedema with STEGLUJAN.

Severe and Disabling Arthralgia: There have been postmarketing reports of severe and disabling arthralgia in patients taking DPP-4inhibitors. The time to onset of symptoms following initiation of drug therapy varied from one day to years.

Patients experienced relief of symptoms upon discontinuation of the medication. A subset of patients experienced a recurrence of symptoms when restarting the same drug or a different DPP-4 inhibitor.

Consider DPP-4 inhibitors as a possible cause for severe joint pain and discontinue drug if appropriate.

Bullous Pemphigoid: Postmarketing cases of bullous pemphigoid requiring hospitalization have been reported with DPP-4 inhibitor use. In reported cases, patients typically recovered with topical or systemic immunosuppressive treatment and discontinuation of the DPP-4 inhibitor. Tell patients to report development of blisters or erosions while receiving STEGLUJAN. If bullous pemphigoid is suspected, STEGLUJAN should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment.

DRUG INTERACTIONS

Insulin and Insulin Secretagogues: The risk of hypoglycemia when STEGLUJAN 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 STEGLUJAN.

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

Monitor serum lithium concentration more frequently during STEGLUJAN 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 SGLT2 inhibitors. 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 takingSGLT2 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, STEGLUJAN is not recommended during the second and third trimesters of pregnancy.

The limited available data with ertugliflozin and sitagliptin use during pregnancy 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.

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 STEGLUJAN, in human milk, the effects on the breastfed infant, or the effects on milk production. Ertugliflozin and sitagliptin 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 STEGLUJAN is not recommended while breastfeeding.

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

Geriatric Use: No dosage adjustment of STEGLUJAN 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 sitagliptin is known to be substantially excreted by the kidneys, renal function should be assessed more frequently in elderly patients.

OVERDOSAGE

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

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Gafacom

STEGLUJAN® (ertugliflozin and sitagliptin) tablets

STEGLUJAN®