General: Steglujan should not be used in patients with type 1 diabetes mellitus.
Acute pancreatitis: Use of dipeptidyl peptidase-4 (DPP-4) inhibitors has been associated with a risk of developing acute pancreatitis. Patients should be informed of the characteristic symptom of acute pancreatitis: persistent, severe abdominal pain. Resolution of pancreatitis has been observed after discontinuation of sitagliptin (with or without supportive treatment), but very rare cases of necrotising or haemorrhagic pancreatitis and/or death have been reported. If pancreatitis is suspected, Steglujan and other potentially suspect medicinal products should be discontinued; if acute pancreatitis is confirmed, Steglujan should not be restarted. Caution should be exercised in patients with a history of pancreatitis.
Hypotension/Volume depletion: Ertugliflozin causes an osmotic diuresis, which may lead to intravascular volume contraction. Therefore, symptomatic hypotension may occur after initiating Steglujan (see Adverse Reactions), particularly in patients with impaired renal function (eGFR less than 60 ml/min/1.73 m2 or CrCl less than 60 ml/min), elderly patients (≥ 65 years), patients on diuretics, or patients on anti-hypertensive therapy with a history of hypotension. Before initiating Steglujan, volume status should be assessed and corrected if indicated. Monitor for signs and symptoms after initiating therapy.
Due to its mechanism of action, ertugliflozin induces an osmotic diuresis and increases serum creatinine and decreases eGFR. Increases in serum creatinine and decreases in eGFR were greater in patients with moderate renal impairment (see Adverse Reactions).
In case of conditions that may lead to fluid loss (e.g., gastrointestinal illness), careful monitoring of volume status (e.g., physical examination, blood pressure measurements, laboratory tests including haematocrit) and electrolytes is recommended for patients receiving Steglujan. Temporary interruption of treatment with Steglujan should be considered until the fluid loss is corrected.
Diabetic ketoacidosis: Rare cases of DKA, including life-threatening and fatal cases, have been reported in clinical trials and post-marketing in patients treated with sodium glucose co-transporter-2 (SGLT2) inhibitors, and cases have been reported in clinical trials with ertugliflozin. In a number of cases, the presentation of the condition was atypical with only moderately increased blood glucose values, below 14 mmol/l (250 mg/dl). It is not known if DKA is more likely to occur with higher doses of ertugliflozin.
The risk of diabetic ketoacidosis must be considered in the event of non-specific symptoms such as nausea, vomiting, anorexia, abdominal pain, excessive thirst, difficulty breathing, confusion, unusual fatigue or sleepiness. Patients should be assessed for ketoacidosis immediately if these symptoms occur, regardless of blood glucose level.
In patients where DKA is suspected or diagnosed, treatment with Steglujan should be discontinued immediately.
Treatment should be interrupted in patients who are hospitalised for major surgical procedures or acute serious medical illnesses. In both cases, treatment with Steglujan may be restarted once the patient's condition has stabilised.
Before initiating Steglujan, factors in the patient history that may predispose to ketoacidosis should be considered.
Patients who may be at higher risk of DKA include patients with a low beta-cell function reserve (e.g., type 2 diabetes patients with low C-peptide or latent autoimmune diabetes in adults (LADA) or patients with a history of pancreatitis), patients with conditions that lead to restricted food intake or severe dehydration, patients for whom insulin doses are reduced and patients with increased insulin requirements due to acute medical illness, surgery, or alcohol abuse. SGLT2 inhibitors should be used with caution in these patients.
Restarting SGLT2 inhibitor treatment in patients with previous DKA while on SGLT2 inhibitor treatment is not recommended, unless another clear precipitating factor is identified and resolved.
The safety and efficacy of Steglujan in patients with type 1 diabetes have not been established and Steglujan should not be used for treatment of patients with type 1 diabetes. Limited data from clinical trials suggest that DKA occurs with common frequency when patients with type 1 diabetes are treated with SGLT2 inhibitors.
Lower limb amputations: An increase in cases of lower limb amputation (primarily of the toe) has been observed in long-term clinical studies with another SGLT2 inhibitor. It is unknown whether this constitutes a class effect. Like for all diabetic patients it is important to counsel patients on routine preventative foot care.
Impairment in renal function: The efficacy of ertugliflozin is dependent on renal function, and efficacy is reduced in patients who have moderate renal impairment and likely absent in patients with severe renal impairment (see Dosage & Administration).
Steglujan should not be initiated in patients with an eGFR below 60 ml/min/1.73 m2 or CrCl below 60 ml/min. Steglujan should be discontinued when eGFR is persistently below 45 ml/min/1.73 m2 or CrCl is persistently below 45 ml/min due to a reduction of efficacy.
Monitoring of renal function is recommended as follows: Prior to Steglujan initiation and periodically during treatment (see Dosage & Administration); More frequently in patients with an eGFR below 60 ml/min/1.73 m2 or a CrCl below 60 ml/min.
Hypoglycaemia with concomitant use with insulin and insulin secretagogues: Ertugliflozin may increase the risk of hypoglycaemia when used in combination with insulin and/or an insulin secretagogue, which are known to cause hypoglycaemia (see Adverse Reactions). Hypoglycaemia has been observed when sitagliptin was used in combination with insulin or a sulphonylurea. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimise the risk of hypoglycaemia when used in combination with Steglujan (see Dosage & Administration and Interactions).
Genital mycotic infections: Ertugliflozin increases the risk of genital mycotic infections. In trials with SGLT2 inhibitors, patients with a history of genital mycotic infections and uncircumcised males were more likely to develop genital mycotic infections (see Adverse Reactions). Patients should be monitored and treated appropriately.
Urinary tract infections: Urinary glucose excretion may be associated with an increased risk of urinary tract infections. The incidence of urinary tract infections was not notably different in the ertugliflozin 5 mg and 15 mg groups (4.0% and 4.1%) and the placebo group (3.9%). Most of the events were mild or moderate and no serious case was reported. Temporary interruption of ertugliflozin should be considered when treating pyelonephritis or urosepsis.
Hypersensitivity reactions: Post-marketing reports of serious hypersensitivity reactions in patients treated with sitagliptin have been reported (see Adverse Reactions). 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 some reports occurring after the first dose. If a hypersensitivity reaction is suspected, Steglujan should be discontinued. Other potential causes for the event should be assessed, and alternative treatment for diabetes initiated.
Bullous pemphigoid: There have been post-marketing reports of bullous pemphigoid in patients taking DPP-4 inhibitors including sitagliptin. If bullous pemphigoid is suspected, Steglujan should be discontinued.
Cardiac failure: Experience in New York Heart Association (NYHA) class I-II is limited, and there is no experience in clinical studies with Steglujan in NYHA class III-IV.
Urine laboratory assessments: Due to the mechanism of action of ertugliflozin, patients taking Steglujan will test positive for glucose in their urine. Alternative methods should be used to monitor glycaemic control.
Interference with 1,5-anhydroglucitol (1,5-AG) assay: Monitoring glycaemic control with 1,5-AG assay is not recommended as measurements of 1,5-AG are unreliable in assessing glycaemic control in patients taking SGLT2 inhibitors. Alternative methods should be used to monitor glycaemic control.
Effects on ability to drive and use machines: Steglujan has no or negligible influence on the ability to drive and use machines. However, when driving or using machines, it should be taken into account that dizziness and somnolence have been reported with sitagliptin. In addition, patients should be alerted to the risk of hypoglycaemia when Steglujan is used in combination with insulin or an insulin secretagogue and to the elevated risk of adverse reactions related to volume depletion, such as postural dizziness (see Dosage & Administration, Precautions, and Adverse Reactions).
Use in Elderly: Elderly patients may be at an increased risk of volume depletion. Patients 65 years and older treated with ertugliflozin, had a higher incidence of adverse reactions related to volume depletion compared to younger patients. Steglujan is expected to have diminished efficacy in elderly patients with renal impairment (see Dosage & Administration and Adverse Reactions).