ertugliflozin/sitagliptin

Ertugliflozin/sitagliptin is a combination medication used to improve glycemic control in adults with type 2 diabetes mellitus, as an adjunct to diet and exercise. The two components of the combination drug work in different ways to reduce blood glucose levels. Ertugliflozin reduces glucose reabsorption in the kidney and sitagliptin prolongs the activity of incretin hormones which reduce glucose production and increase the uptake of glucose from the blood to be used for cellular energy. The combination is more effective than either of the drugs as a single agent.

• Ertugliflozin: Ertugliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor drug. SGLT2 is a protein molecule that is responsible for the majority of glucose reabsorption in the kidneys. Ertugliflozin inhibits SGLT2, reduces reabsorption of glucose in the kidney, lowers renal threshold for glucose and increases urinary glucose excretion.
• Sitagliptin: After a meal, the intestines release incretin hormones known as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Incretin hormones stimulate insulin release from the pancreas, reduce glucagon secretion and glucose production in the liver. Dipeptidyl peptidase-4 (DPP-4) enzyme, present in many tissues, inactivates the incretin hormones within minutes. Sitagliptin inhibits DPP-4 enzyme and prolongs the activity of incretin hormones.

• Do not use ertugliflozin/sitagliptin to treat patients with hypersensitivity to ertugliflozin, sitagliptin or any other component of the formulation.
• Do not use ertugliflozin/sitagliptin in patients with severe impairment of kidney function or end-stage renal disease (ESRD), or in patients on dialysis.
• Sitagliptin use has been associated with fatal and non-fatal acute pancreatitis, including hemorrhagic or necrotizing pancreatitis.
  • Monitor the patient and discontinue ertugliflozin/sitagliptin immediately if the patient develops signs and symptoms of pancreatitis, and institute appropriate treatment.
  • It is not known if patients with a history of pancreatitis are at a higher risk for developing pancreatitis.
• Ketoacidosis, a life-threatening and sometimes fatal complication of diabetes mellitus has been reported following treatment with SGLT-2 inhibitors, including ertugliflozin.
  • Risk of ketoacidosis is greater with higher doses and in patients with type I diabetes mellitus. Ertugliflozin/sitagliptin is not indicated for patients with type I diabetes mellitus.
  • Consider a patient's risk for developing ketoacidosis and ensure risk factors are resolved before initiating treatment with ertugliflozin/sitagliptin.
  • Monitor patients and assess those who develop signs and symptoms of metabolic acidosis for presence of ketoacidosis. Discontinue treatment if ketoacidosis is suspected, evaluate and treat appropriately.
  • In patients undergoing elective surgery, consider temporary discontinuation of ertugliflozin/sitagliptin at least 4 days before surgery.
  • Consider monitoring for ketoacidosis and temporarily discontinuing ertugliflozin/sitagliptin in clinical situations that may predispose a patient to ketoacidosis, such as prolonged fasting due to acute illness or post-surgery.
  • Educate patients on symptoms of ketoacidosis and advise them to report such symptoms immediately.
• In some studies in patients with type II diabetes and established cardiovascular disease, non-traumatic lower limb amputations have been reported, including multiple amputations involving both limbs in some cases.
  • Lower limb infections, gangrene and diabetic foot ulcers were the most common factors for the requirement of amputation.
  • Amputations are more likely in patients who are males, have higher baseline HbA1C, have a history of peripheral arterial disease, amputation or peripheral revascularization procedure, diabetic foot, or have been taking diuretics or insulin.
  • Consider the patient's risk for amputation requirement before initiating treatment with ertugliflozin/sitagliptin.
  • Advise patients on the importance of preventive foot care.
  • Monitor patients for signs and symptoms of infection, new pain or soreness, ulcers or sores in the lower limbs, and advise patients to report these symptoms. Discontinue ertugliflozin/sitagliptin if the patient develops such symptoms.
• Worsening kidney function, including acute kidney failure, has been reported in a few patients, some of whom were prescribed inappropriate doses of sitagliptin. In clinical trials sitagliptin did not show toxicity to the kidney in clinically relevant doses.
  • Kidney function returned to baseline levels with discontinuation of potential causative drugs and supportive treatment.
  • If worsening of kidney function is determined to be of an origin other than sitagliptin, consider reinitiation ertugliflozin/sitagliptin with caution.
• Ertugliflozin/sitagliptin contracts blood volume and can cause symptomatic hypotension, transient changes in creatinine and acute kidney injury.
  • Patients with kidney function impairment, patients on loop diuretics, elderly patients and patients with low systolic blood pressure are at a greater risk.
  • Check blood volume status and correct, if necessary, in patients at risk for volume depletion.
  • Monitor for signs and symptoms of volume depletion during therapy.
• Treatment with SGLT-2 inhibitors, including ertugliflozin, is associated with urinary tract infections (UTIs). Monitor patients for signs and symptoms of UTIs and treat promptly.
• Treatment with DPP-4 inhibitor class of medications has been associated with heart failure.
  • Consider risks and benefits before initiating ertugliflozin/sitagliptin treatment in patients at risk for heart failure and monitor them during therapy.
  • Apprise patients on characteristic heart failure symptoms and advise them to report such symptoms immediately.
  • If a patient develops heart failure symptoms, evaluate and manage appropriately and consider discontinuing ertugliflozin/sitagliptin.
• Ertugliflozin/sitagliptin treatment can cause hypoglycemia and the risk is higher when used in combination with insulin or insulin secretagogue drugs such as sulfonylureas. Adjust the dosage of insulin or insulin secretagogue appropriately.
• A rare but serious life-threatening bacterial genital infection, necrotizing fasciitis of the perineum (Fournier’s gangrene), that has required surgical intervention, has been reported in patients treated with SGLT2 inhibitors, including ertugliflozin.
  • Educate patients on symptoms of necrotizing fasciitis and advise them to report symptoms immediately.
  • If necrotizing fasciitis is suspected, promptly institute appropriate treatment, including broad-spectrum antibiotics, and debridement, if necessary. 
  • Discontinue ertugliflozin/sitagliptin in these patients, monitor glucose levels closely and provide alternate treatment for glycemic control.
• Ertugliflozin increases the risk for genital fungal (mycotic) infections, particularly in patients with a history of genital mycotic infections and in uncircumcised males. Monitor the patient for mycotic infections and treat them appropriately.
• Some patients have reported serious hypersensitivity reactions, including angioedema, anaphylaxis and exfoliative skin conditions such as Stevens-Johnson syndrome, generally within the first 3 months after initiation of sitagliptin, and in some cases, after the first dose.
  • Use ertugliflozin/sitagliptin with caution in patients with a history of hypersensitivity reaction to other dipeptidyl peptidase-4 (DPP-4) inhibitors.
  • Advise patients to report hypersensitivity reactions immediately.
  • In the event of hypersensitivity reaction, discontinue ertugliflozin/sitagliptin, assess for potential causes, provide appropriate treatment for hypersensitivity, and institute alternate treatment for diabetes.
• DPP-4 inhibitors, including sitagliptin, can cause severe and disabling joint pain (arthralgia) that may occur immediately after initiation of therapy, or even after years. 
  • In clinical trials, patients experienced symptom relief upon discontinuation of sitagliptin and some patients had recurrence of symptoms with reinitiation of the same or a different DPP-4 inhibitor.
  • Consider sitagliptin as a possible cause if a patient develops arthralgia, and discontinue if appropriate.
• Some patients taking DPP-4 inhibitors have developed bullous pemphigoid, a rare skin disorder. Advise patients to report development of blisters and erosions. If bullous pemphigoid is suspected, discontinue ertugliflozin/sitagliptin and refer to a dermatologist for appropriate diagnosis and treatment.

Common side effects of ertugliflozin/sitagliptin include:

• Low blood glucose level (hypoglycemia)
• Nose and throat inflammation (nasopharyngitis)
• Headache
• Back pain

Common side effects of ertugliflozin include:

• Urinary tract infections
• Female genital mycotic infections
• Male genital mycotic infections
• Decrease in weight
• Increased urination
• Thirst
• Vaginal itching (pruritus)
• Ketoacidosis
• Blood volume depletion and associated effects including:
  • Dehydration
  • Postural dizziness
  • Feeling faint (presyncope)
  • Fainting (syncope)
  • Low blood pressure (hypotension)
  • Drop in blood pressure when standing up from sitting or lying down (orthostatic hypotension)
• Increase in serum creatinine
• Decrease in estimated glomerular filtration rate (eGFR)
• Increase in LDL cholesterol
• Increase in hemoglobin
• Increase in serum phosphate
• Necrotizing fasciitis of the perineum (Fournier’s gangrene)
• Swelling beneath the skin and in mucous tissue (angioedema)
• Kidney infections including:
  • Urosepsis
  • Pyelonephritis
• Lower limb amputation

Common side effects of sitagliptin:

• Upper respiratory tract infection
• Nausea
• Diarrhea
• Constipation
• Abdominal pain
• Heart failure
• Swelling of extremities (peripheral edema)
• Inflammation of the pancreas (pancreatitis)
• Increase in neutrophil immune cells
• Hypersensitivity reactions including:
  • Rash
  • Hives (urticaria)
  • Itching (pruritus)
  • Angioedema
  • Inflammation of blood vessels in the skin (cutaneous vasculitis)
  • Stevens-Johnson syndrome
  • Severe allergic reaction (anaphylaxis)
• Elevation of liver enzymes
• Worsening of kidney function
• Acute kidney failure
• Severe and disabling joint pain (arthralgia)
• Bullous pemphigoid
• Pain in extremity
• Muscle pain (myalgia)
• Muscle breakdown (rhabdomyolysis)
• Mouth ulceration
• Oral inflammation (stomatitis)

Call your doctor immediately if you experience any of the following symptoms or serious side effects while using this drug:

• Serious heart symptoms include fast or pounding heartbeats, fluttering in your chest, shortness of breath, and sudden dizziness;
• Severe headache, confusion, slurred speech, severe weakness, vomiting, loss of coordination, feeling unsteady;
• Severe nervous system reaction with very stiff muscles, high fever, sweating, confusion, fast or uneven heartbeats, tremors, and feeling like you might pass out; or
• Serious eye symptoms include blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights.

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

Tablet

• 5 mg/100 mg
• 15 mg/100 mg

Adult:

Type 2 Diabetes Mellitus

• Indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both ertugliflozin and sitagliptin is appropriate
• 5 mg/100 mg orally once daily in morning initially; if additional glycemic control is needed and starting dose is tolerated, may increase to maximum dose of 15 mg/100 mg
• Patients on ertugliflozin: Maintain ertugliflozin dose when switched to combination

Dosage Modifications

• Concomitant use with insulin and insulin secretagogues may increase the risk of hypoglycemia; lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with ertugliflozin

Renal impairment

• eGFR 45 mL/minute/1.73 m² or above: No dosage adjustment necessary
• eGFR below 45 mL/minute/1.73 m²: Not recommended
• Severe (eGFR below 30 mL/minute/1.73 m2), end-stage renal disease, or dialysis: Contraindicated

Hepatic impairment

• Mild-to-moderate: No dosage adjustment necessary
• Severe: Not recommended

Dosing Considerations

• Assess renal function before initiating and as clinically indicated
• In patients with volume depletion, correct this condition before initiating

Limitations of use

• Not recommended in patients with type 1 diabetes mellitus; may increase risk of diabetic ketoacidosis in these patients
• Not studied in patients with history of pancreatitis; unknown if drug increases risk for pancreatitis

Geriatric:

• Adults 65 years and above: No dosage adjustment necessary
• Patients aged 65 years or above had a higher incidence of adverse reactions related to volume depletion compared with younger patients
• 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

Pediatric:

• Safety and efficacy not established

Overdose

• There is limited information on ertugliflozin/sitagliptin overdose. Ertugliflozin/sitagliptin overdose may be treated with supportive measures, including elimination of undigested drug from the gastrointestinal tract, and ECG monitoring.
• Removal of ertugliflozin by hemodialysis has not been studied. Sitagliptin may be removed by hemodialysis to a modest extent. Prolonged hemodialysis may be considered if required. It is not known if sitagliptin can be removed by peritoneal dialysis.

Inform your doctor of all medications you are currently taking, who can advise you on any possible drug interactions. Never begin taking, suddenly discontinue, or change the dosage of any medication without your doctor’s recommendation.

• Ertugliflozin/sitagliptin has no listed severe interactions with other drugs.
• Serious interactions of ertugliflozin/sitagliptin include:
  • erdafitinib
  • ethanol
  • lasmiditan
  • sotorasib
  • tepotinib
• Ertugliflozin/sitagliptin has moderate interactions with at least 86 different drugs.
• Ertugliflozin/sitagliptin has mild interactions with at least 75 different drugs.

The drug interactions listed above are not all of the possible interactions or adverse effects. For more information on drug interactions, visit the RxList Drug Interaction Checker.

It is important to always tell your doctor, pharmacist, or health care provider of all prescription and over-the-counter medications you use, as well as the dosage for each, and keep a list of the information. Check with your doctor or health care provider if you have any questions about the medication.

• The limited available data with the use of ertugliflozin/sitagliptin are not sufficient to determine a drug-associated risk for major birth defects and miscarriage.
• Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, stillbirth and delivery complications, and fetal risks of birth defects and abnormally large growth (macrosomia).
• Based on animal studies that show adverse kidney effects from ertugliflozin, use of ertugliflozin/sitagliptin is not recommended during the second and third trimesters of pregnancy.
• There is no information on the presence of ertugliflozin and sitagliptin in breastmilk, or their effects on milk production or the breastfed infant. Ertugliflozin and sitagliptin are present in rat milk.
• Exposure to ertugliflozin can adversely affect developing kidneys because human kidney matures in the uterus and in the first 2 years of life. Use of ertugliflozin/sitagliptin is not recommended in nursing mothers because of the potential for serious adverse reactions, including renal adverse effects, in the breastfed infant.
• There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to sitagliptin during pregnancy. Healthcare providers are encouraged to report any prenatal exposure to ertugliflozin/sitagliptin (Steglujan) by calling the Pregnancy Registry at 1-800-986-8999.

• Take ertugliflozin/sitagliptin exactly as prescribed.
• You will need regular tests while on treatment with ertugliflozin/sitagliptin. Follow up with your physician and do not miss your appointments.
• Discontinue ertugliflozin/sitagliptin and report to your healthcare provider immediately if you develop:
  • Symptoms of pancreatitis, which can include persistent severe abdominal pain with or without vomiting
  • Symptoms of ketoacidosis, a life-threatening condition with symptoms that include nausea, vomiting, abdominal pain, tiredness, and difficulty breathing
  • Heart failure symptoms such as shortness of breath, rapid increase in weight and swelling of ankles and feet
  • Symptoms of low blood pressure
  • Severe joint pain
  • Hypersensitivity reactions
  • Blisters or erosions in the skin
• Follow proper foot care measures as advised by your physician, to prevent diabetic foot sores and ulcers. Report to your physician immediately if you have new pain or tenderness, ulcers, sores or infection in your leg or foot.
• Drink adequate fluids while receiving ertugliflozin/sitagliptin treatment and seek medical care if you develop symptoms of dehydration such as dizziness or weakness, any kidney-related symptoms or urinary infection.
• Report to your physician immediately if you develop any signs of genital yeast infection or other genital infections.
• Store ertugliflozin/sitagliptin safely out of reach of children.
• In the event of overdose, seek medical help or contact Poison Control.