Ertugliflozin / sitagliptin

• Ertugliflozin / sitagliptin is indicated as an adjunct to healthy eating and physical activity to improve glycaemic management in adults with type 2 diabetes mellitus when treatment with both ertugliflozin and sitagliptin is appropriate.

 For the latest PBS indications for Ertugliflozin / sitagliptin, please see

https://www.pbs.gov.au/medicine/item/11561L-11579K

• The recommended starting dose of ertugliflozin / sitagliptin is 5 mg ertugliflozin/100 mg sitagliptin once daily, taken in the morning, with or without food.
• In those tolerating ertugliflozin / sitagliptin, the dose may be increased to 15 mg ertugliflozin/100 mg sitagliptin once daily if additional glycaemic management is needed.
• For those treated with ertugliflozin who are being switched to ertugliflozin / sitagliptin, the dose of ertugliflozin can be maintained.
• Renal impairment: Assessment of renal function is recommended prior to initiation of ertugliflozin / sitagliptin and periodically thereafter (i.e., at least yearly; prior to initiation of concomitant medicines that may reduce renal function and periodically thereafter; and more frequently in those with an eGFR below 60 mL/min/1.73 m2).

Initiation of ertugliflozin / sitagliptin is not recommended in individuals with an eGFR less than 45 mL/min/1.73 m2.

In those with an eGFR 45 to less than 60 mL/min/1.73 m2 tolerating ertugliflozin / sitagliptin containing 5 mg ertugliflozin titrate to ertugliflozin / sitagliptin containing 15 mg ertugliflozin as needed for glycaemic management. Discontinue ertugliflozin / sitagliptin if eGFR falls persistently below 45 mL/min/1.73 m2.

• Hepatic impairment No dose adjustment of ertugliflozin / sitagliptin is necessary in individuals with mild or moderate hepatic impairment. Ertugliflozin / sitagliptin has not been studied in people with severe hepatic impairment and is not recommended for use in these individuals.

No dose adjustment is required based on age.

Safety and effectiveness of ertugliflozin / sitagliptin in those under 18 years of age have not been established.

• History of a hypersensitivity reaction to ertugliflozin, or sitagliptin or to any of the excipients.
• Individuals with chronic kidney disease (CKD) receiving dialysis; eGFR < 30 mL/min/1.73m2 or eGFR persistently < 45 mL/min/1.73m2 (CKD stage 3B, 4 and 5).

General:

Ertugliflozin / sitagliptin should not be used in those with type 1 diabetes mellitus or for the treatment of ketoacidosis.

Sitagliptin:

• Pancreatitis

-There have been reports of acute pancreatitis, including fatal and non-fatal haemorrhagic or necrotizing pancreatitis in individuals taking sitagliptin, a component of ertugliflozin / sitagliptin. Individuals should be informed of the characteristic symptoms of acute pancreatitis including persistent, severe abdominal pain. Resolution of pancreatitis has been observed after discontinuation of sitagliptin. If pancreatitis is suspected, ertugliflozin / sitagliptin and other potentially suspect medicinal products should be discontinued.

Note: Diabetes MedsCheck with counselling on side effect profile and referral to healthcare team as required.

• Hypersensitivity reactions:

-There have been post marketing reports of serious hypersensitivity reactions in those treated with sitagliptin. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. 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 ertugliflozin / sitagliptin, assess for other potential causes for the event, and institute alternative treatment for diabetes.

• Arthralgia

-There have been post-marketing reports of joint pain, which may be severe, in people taking DPP-4 inhibitors. Onset of symptoms following initiation of treatment may be rapid or may occur after longer periods. Discontinuation of therapy should be considered in those who present with or experience an exacerbation of joint symptoms during treatment with DPP-4 inhibitors.

• Bullous pemphigoid:

-Post marketing cases of bullous pemphigoid requiring hospitalisation have been reported with DPP-4 inhibitor use. In reported cases, individuals typically recovered with topical or systemic immunosuppressive treatment and discontinuation of the DPP-4 inhibitor. Counsel individuals to report development of blisters or erosions while receiving ertugliflozin / sitagliptin. If bullous pemphigoid is suspected, ertugliflozin / sitagliptin should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment.

• Ertugliflozin
• Hypotension/Volume depletion

-Ertugliflozin, can cause intravascular volume contraction that may sometimes manifest as symptomatic hypotension or acute transient changes in creatinine. Those with impaired renal function (eGFR less than 60 mL/min/1.73 m2), the elderly (≥65 years), or people on diuretics may be at increased risk for volume depletion or hypotension. Before initiating ertugliflozin / sitagliptin in individuals with one or more of these characteristics, intravascular volume status should be assessed, and people advised on the importance of adequate hydration. Monitor intravascular volume status in addition to blood pressure and renal function after initiating therapy. In case of conditions that may lead to fluid loss (e.g., gastrointestinal illness, heat stress or severe infections), careful monitoring of volume status (e.g., physical examination, blood pressure measurements, laboratory tests including haematocrit) and electrolytes is recommended for individuals receiving ertugliflozin / sitagliptin Temporary interruption of ertugliflozin / sitagliptin should be considered until the fluid loss is corrected.

Note: Diabetes Medscheck- Counsel on side effect profile, blood pressure monitoring in pharmacy with referral to appropriate health care professional if blood pressure is unstable.

• Ketoacidosis

-Ertugliflozin / sitagliptin should not be used for the treatment of ketoacidosis. Reports of ketoacidosis, a serious life-threatening condition requiring urgent hospitalisation, have been identified in clinical trials and post marketing surveillance in those receiving sodium glucose co-transporter-2 (SGLT2) inhibitors. Fatal cases of ketoacidosis have been reported in individuals taking SGLT2 inhibitors. Ertugliflozin / sitagliptin is not indicated for the treatment of people with type 1 diabetes mellitus. Individuals treated with ertugliflozin / sitagliptin who present with signs and symptoms consistent with severe metabolic acidosis should be promptly assessed for ketoacidosis regardless of presenting blood glucose levels, as ketoacidosis associated with SGLT2 inhibitors may be present even if blood glucose levels are less than 14 mmol/L. If ketoacidosis is suspected, ertugliflozin / sitagliptin should be discontinued, the person should be evaluated, and prompt treatment should be instituted. Treatment of ketoacidosis generally requires insulin, fluid, potassium, and carbohydrate replacement. Signs and symptoms of ketoacidosis may include excessive thirst, nausea, vomiting, abdominal pain, generalised malaise, and shortness of breath. Restarting SGLT2 inhibitor treatment in those with previous ketoacidosis while on SGLT2 inhibitor treatment is not recommended unless another clear precipitating factor is identified and resolved. Before initiating ertugliflozin / sitagliptin, consider factors in the history that may predispose to ketoacidosis. Factors that predispose patients to ketoacidosis include a low carbohydrate diet, dehydration, acute illness, surgery, a previous ketoacidosis, insulin dose reduction, malnourishment / reduced caloric intake or increased insulin requirements due to infections, insulin deficiency from any cause (including history of pancreatitis or pancreatic surgery, alcohol abuse). Ertugliflozin / sitagliptin should be used with caution in these individuals. Consider monitoring for ketoacidosis and temporarily discontinuing ertugliflozin / sitagliptin in clinical situations known to predispose to ketoacidosis.

Note: Diabetes MedsCheck with referral to healthcare team especially credentialled diabetes educator for counselling on monitoring of ketones and what to do should ketones present in elevated numbers.

• Surgery

-Treatment with ertugliflozin / sitagliptin should be ceased prior to major surgery. An increase in other glucose lowering agents may be required during this time. Those scheduled for non-urgent surgery who have not ceased ertugliflozin should be assessed and consideration should be given to postponing the procedure. Treatment with ertugliflozin / sitagliptin may be restarted once a person’s condition has stabilised and oral intake is normal.

Note: Diabetes MedsCheck with education on sick day management with referral to health care team.

• Genital infections

-Ertugliflozin increases the risk of genital infections. In trials with SGLT2 inhibitors, individuals with a history of genital infections and uncircumcised males were more likely to develop genital infections,

Note: Diabetes MedsCheck with education on side effect profile

• Necrotising fasciitis of the perineum:

-Post marketing cases of necrotising fasciitis of the perineum (also known as Fournier’s gangrene), a rare, but serious and life-threatening necrotising infection, have been reported in females and males with diabetes mellitus treated with SGLT2 inhibitors. Serious outcomes have included hospitalisation, multiple surgeries, and death. Those treated with ertugliflozin / sitagliptin who present with pain or tenderness, erythema, swelling in the genital or perineal area, fever, and malaise should be evaluated for necrotising fasciitis. If suspected, ertugliflozin / sitagliptin should be discontinued, and prompt treatment should be instituted (including broad-spectrum antibiotics and surgical debridement if necessary). Caution is advised in individuals at increased risk of genital infections including those with recurrent or pre-existing urogenital infections, obesity, immunosuppressed states, smoking, alcohol abuse, end-stage renal or liver failure, and HbA1c >10%.

Note: Diabetes MedsCheck with education on side effects profile.

• Volume depletion
• Ketoacidosis
• Impairment in renal function.

-Use of ertugliflozin was associated with increases in serum creatinine and decreases in eGFR, Individuals with moderate renal impairment at baseline had larger mean changes; these changes were observed to reverse after treatment discontinuation, suggesting acute haemodynamic changes play a role in the renal function abnormalities observed with ertugliflozin.

• Genital infections
• Urinary tract infections
• Pancreatitis
• Arthralgia
• Bullous pemphigoid
• Nasal congestion

Note: Diabetes MedsCheck with education on side effect profile