Glyxambi Special Precautions

General: GLYXAMBI should not be used in patients with type 1 diabetes (see Indications/Uses).
Diabetic ketoacidosis: Rare cases of diabetic ketoacidosis (DKA), including life-threatening and fatal cases, have been reported in patients treated with SGLT2 inhibitors, including empagliflozin. 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 empagliflozin.
The risk of DKA 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 empagliflozin 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 empagliflozin may be restarted when the ketone values are normal and the patient's condition has stabilised.
Before initiating empagliflozin, 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.
GLYXAMBI should not be used for treatment of patients with type 1 diabetes. Data from a clinical trial program in patients with type 1 diabetes showed increased DKA occurrence with common frequency in patients treated with empagliflozin 10 mg and 25 mg as adjunct to insulin compared to placebo.
Surgery: Treatment with GLYXAMBI should be ceased prior to major surgery. An increase in other glucose lowering agents may be required during this time.
Patients scheduled for non-urgent surgery who have not ceased empagliflozin should be assessed and consideration should be given to postponing the procedure. Treatment with GLYXAMBI may be restarted once the patient's condition has stabilised and oral intake is normal.
Hypoglycaemia: In clinical trials of linagliptin or of empagliflozin as part of combination therapy with agents not known to cause hypoglycaemia (e.g. metformin, thiazolidinediones) rates of hypoglycaemia reported with linagliptin or empagliflozin were similar to rates in patients taking placebo (see Adverse Reactions).
Sulfonylureas and insulin are known to cause hypoglycaemia. Therefore, caution is advised when GLYXAMBI is used in combination with a sulfonylurea and/or insulin. A dose reduction of the sulfonylurea or insulin may be considered.
Pancreatitis: Acute pancreatitis has been observed in patients taking linagliptin (see Adverse Reactions). If pancreatitis is suspected, GLYXAMBI should be discontinued.
Use in patients at risk for volume depletion: Based on the mode of action of SGLT2 inhibitors, osmotic diuresis accompanying therapeutic glucosuria may lead to a modest decrease in BP. Therefore, caution should be exercised in patients for whom an empagliflozin-induced drop in BP could pose a risk, such as patients with known cardiovascular disease, patients on anti-hypertensive therapy with a history of hypotension or patients aged 75 years and older.
In case of conditions that may lead to fluid loss (e.g. gastrointestinal illness), careful monitoring of volume status (e.g. physical examination, BP measurements, laboratory tests including haematocrit) and electrolytes is recommended for patients receiving empagliflozin. Temporary interruption of treatment with GLYXAMBI should be considered until the fluid loss is corrected.
Urosepsis and Pyelonephritis: There have been postmarketing reports of serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalisation in patients receiving SGLT2 inhibitors, including empagliflozin. Treatment with SGLT2 inhibitors increases the risk for urinary tract infections. Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated (see Adverse Reactions).
Discontinuation of empagliflozin may be considered in cases of recurrent urinary tract infections.
Necrotizing Fasciitis of the Perineum (Fournier's Gangrene): Reports of necrotizing fasciitis of the perineum (Fournier's Gangrene), a rare but serious and life-threatening necrotizing infection requiring urgent surgical intervention, have been identified in post-marketing surveillance in patients with diabetes mellitus receiving SGLT2 inhibitors, including empagliflozin. Cases have been reported in both females and males. Serious outcomes have included hospitalization, multiple surgeries, and death.
Patients treated with empagliflozin presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise, should be assessed for necrotizing fasciitis. If suspected, start treatment immediately with broad-spectrum antibiotics and, if necessary, surgical debridement. Discontinue empagliflozin, closely monitor blood glucose levels, and provide appropriate alternative therapy for glycemic control.
Lower limb amputations: An increase in cases of lower limb amputation (primarily of the toe) has been observed in a long-term clinical study with another SGLT2 inhibitor. The medicine in that study is not empagliflozin. However, it is unknown whether this constitutes a class effect. In a pooled safety analysis of 12,620 patients with T2DM the frequency of patients with lower limb amputations was similar between empagliflozin and placebo. In the largest placebo-controlled trial in 7020 patients (EMPA-REG OUTCOME trial), in which 88% of all the cases of amputations were reported, lower limb amputations occurred in 1.8% of patients treated with empagliflozin 10 mg, in 2.0% of patients treated with empagliflozin 25 mg, and in 1.8% of patients in the placebo arm. It is important to regularly examine the feet and counsel all diabetic patients on routine preventative footcare.
Bullous pemphigoid: Bullous pemphigoid has been observed in patients taking linagliptin. If bullous pemphigoid is suspected, GLYXAMBI should be discontinued.
Arthralgia: There have been postmarketing reports of joint pain, which may be severe, in patients 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 patients who present with or experience an exacerbation of joint symptoms during treatment with linagliptin.
Combination with glucagon like peptide (GLP-1) analogues: Linagliptin has not been studied in combination with glucagon like peptide 1 (GLP-1) analogues.
Use in renal impairment: Empagliflozin increases serum creatinine and decreases eGFR (see Adverse Reactions). Renal function abnormalities can occur after initiating empagliflozin. Patients with hypovolaemia may be more susceptible to these changes.
There have been postmarketing reports of acute kidney injury, some requiring hospitalisation and dialysis, in patients receiving SGLT2 inhibitors, including empagliflozin; some reports involved patients younger than 65 years of age.
GLYXAMBI is contraindicated for use in patients with eGFR <30 mL/min/1.73 m² (see Patients with renal impairment under Dosage & Administration; and Contraindications).
Therapeutic experience with GLYXAMBI is limited in patients with eGFR <60 mL/min.
Monitoring of renal function: Due to its mechanism of action, the efficacy of empagliflozin is dependent on renal function. Therefore assessment of renal function is recommended: prior to empagliflozin initiation and periodically during treatment, i.e. at least yearly; prior to initiation of concomitant medicines that may reduce renal function and periodically thereafter.
Patients treated with empagliflozin can experience an initial fall in eGFR. More intensive monitoring of renal function is recommended, particularly following treatment initiation, if empagliflozin is used in patients with an eGFR <60 mL/min/1.73 m², especially if the eGFR is <45 mL/min/1.73 m².
GLYXAMBI should be discontinued when the eGFR is below 30 mL/min/1.73 m² or CrCl <30 mL/min (see Contraindications).
Effect on laboratory tests: Urine will test positive for glucose while patients are taking GLYXAMBI due to the nature of the mechanism of action of the SGLT2 inhibitors (see Pharmacology: Pharmacodynamics under Actions).
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. Use alternative methods to monitor glycaemic control.
Effects on ability to drive and use machines: No studies on the effects on the ability to drive and use machines have been performed. If patients experience dizziness, they should avoid potentially hazardous tasks such as driving or operating machinery.
Use in the Elderly: Patients aged 75 years and older may be at increased risk of volume depletion, therefore, GLYXAMBI should be prescribed with caution in these patients (see Adverse Reactions). Therapeutic experience in patients aged 75 years and older is limited. Initiation of therapy with GLYXAMBI in this population is not recommended.
Use in Children: The safety and effectiveness of GLYXAMBI in children below 18 years of age have not been established. GLYXAMBI is not recommended for use in patients under 18 years of age.