Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use

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.

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 risks and benefits of sitagliptin prior to initiating treatment in patients at risk for heart failure, such as those with a prior history of heart failure and a history of renal impairment, and observe these patients for signs and symptoms of heart failure during therapy. Advise patients of the characteristic symptoms of heart failure and to immediately report such symptoms. If heart failure develops, evaluate and manage according to current standards of care and consider discontinuation of sitagliptin.

Hypotension/Volume depletion
Ertugliflozin causes an osmotic diuresis, which may lead to intravascular volume contraction.
Therefore, symptomatic hypotension may occur after initiating Steglujan (see section 4.8), 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 section 4.8).

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, including 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. Monitoring of ketones is recommended in these patients. Measurement of blood ketone levels is preferred to urine. Treatment with Steglujan may be restarted when the ketone values are normal and 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
In a long-term cardiovascular outcomes study VERTIS CV (eValuation of ERTugliflozin effIcacy and Safety, CardioVascular), a study in patients with type 2 diabetes mellitus and established atherosclerotic cardiovascular disease, non-traumatic lower limb amputations (primarily of the toe) were reported with an incidence of 2.0% (0.57 subjects with event per 100 patient years), 2.1% (0.60 subjects with event per 100 patient years) and 1.6% (0.47 subjects with event per 100 patient years) for ertugliflozin 5 mg, ertugliflozin 15 mg and placebo groups. The event rates of lower limb amputations were 0.75 and 0.96 versus 0.74 events per 100 patient years for ertugliflozin 5 mg and ertugliflozin 15 mg versus placebo, respectively. An increase in cases of lower limb amputation (primarily of the toe) has been observed in long-term clinical studies in type 2 diabetes mellitus with SGLT2 inhibitors. It is not known whether this constitutes a class effect. It is important to counsel patients with diabetes on routine preventative foot care.

Renal impairment
The efficacy of ertugliflozin for glycaemic control is dependent on renal function, and glycaemic efficacy is reduced in patients who have moderate renal impairment and likely absent in patients with severe renal impairment (see section 4.2).

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 section 4.2).
-    More frequently in patients with an eGFR below 60 mL/min/1.73 m2 or a CrCl below 60 mL/min.

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

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 section 4.8). 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 sections 4.2 and 4.5).

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 section 4.8). Patients should be monitored and treated appropriately.

Urinary tract infections
Urinary glucose excretion may be associated with an increased risk of urinary tract infections (see section 4.8). Temporary interruption of ertugliflozin should be considered when treating pyelonephritis or urosepsis.

Necrotising fasciitis of the perineum (Fournier’s gangrene)
Post-marketing cases of necrotising fasciitis of the perineum, (also known as Fournier’s gangrene), have been reported in female and male patients taking SGLT2 inhibitors. This is a rare but serious and potentially life-threatening event that requires urgent surgical intervention and antibiotic treatment.

Patients should be advised to seek medical attention if they experience a combination of symptoms of pain, tenderness, erythema, or swelling in the genital or perineal area, with fever or malaise. Be aware that either uro-genital infection or perineal abscess may precede necrotising fasciitis. If Fournier’s gangrene is suspected, Steglujan should be discontinued and prompt treatment (including antibiotics and surgical debridement) should be instituted.

Hypersensitivity reactions
Post-marketing reports of serious hypersensitivity reactions in patients treated with sitagliptin have been reported (see section 4.8). 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.

Severe and Disabling Arthralgia
There have been postmarketing reports of severe and disabling arthralgia in patients taking DPP-4 inhibitors. 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
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.

Elderly patients
Elderly patients may be at an increased risk of volume depletion and renal impairment. 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 sections 4.2 and 4.8).

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.

Sodium
This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

Effects on Driving

4.7   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 sections 4.2, 4.4, and 4.8).