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General: Jardiance Duo should not be used in patients with type 1 diabetes.
Diabetic ketoacidosis: Cases of diabetic ketoacidosis (DKA), a serious life-threatening condition requiring urgent hospitalization, have been reported in patients treated with empagliflozin, including fatal cases. In a number of reported cases, the presentation of the condition was atypical with only moderately increased blood glucose values, below 14 mmol/l (250 mg/dl).
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. If ketoacidosis is suspected, Jardiance Duo should be discontinued, patient should be evaluated, and prompt treatment should be instituted.
Patients who may be at higher risk of ketoacidosis while taking Jardiance Duo include patients on a very low carbohydrate diet (as the combination may further increase ketone body production), patients with an acute illness, pancreatic disorders suggesting insulin deficiency (e.g. type 1 diabetes, history of pancreatitis or pancreatic surgery), insulin dose reduction (including insulin pump failure), alcohol abuse, severe dehydration, and patients with a history of ketoacidosis. Jardiance Duo should be used with caution in these patients. When reducing the insulin dose caution should be taken. In patients treated with Jardiance Duo consider monitoring for ketoacidosis and temporarily discontinuing Jardiance Duo in clinical situations known to predispose to ketoacidosis (e.g. prolonged fasting due to acute illness or surgery). In these situations, consider monitoring of ketones, even if Jardiance Duo treatment has been interrupted.
Lactic acidosis: Lactic acidosis, a very rare, but serious metabolic complication, most often occurs at acute worsening of renal function or cardiorespiratory illness or sepsis. Metformin accumulation occurs at acute worsening of renal function and increases the risk of lactic acidosis.
In case of dehydration (severe diarrhoea or vomiting, fever or reduced fluid intake), metformin should be temporarily discontinued and contact with a health care professional is recommended.
Medicinal products that can acutely impair renal function (such as antihypertensives, diuretics and NSAIDs) should be initiated with caution in metformin-treated patients.
Other risk factors for lactic acidosis are excessive alcohol intake, hepatic insufficiency, inadequately controlled diabetes, ketosis, prolonged fasting and any conditions associated with hypoxia, as well as concomitant use of medicinal products that may cause lactic acidosis (see Contraindications and Interactions).
Patients and/or care-givers should be informed of the risk of lactic acidosis.
Lactic acidosis is characterised by acidotic dyspnoea, abdominal pain, muscle cramps, asthenia and hypothermia followed by coma. In case of suspected symptoms, the patient should stop taking metformin and seek immediate medical attention.
Diagnostic laboratory findings are decreased blood pH (<7.35), increased plasma lactate levels (> 5 mmol/l), and an increased anion gap and lactate/pyruvate ratio.
Administration of iodinated contrast agent: Intravascular administration of iodinated contrast agents may lead to contrast induced nephropathy, resulting in metformin accumulation and an increased risk of lactic acidosis. Metformin should be discontinued prior to or at the time of the imaging procedure and not restarted until at least 48 hours after, provided that renal function has been re-evaluated and found to be stable, see Dosage & Administration and Interactions.
Necrotizing fasciitis of the perineum (Fournier's gangrene): Postmarketing cases of necrotizing fasciitis of the perineum (also known as Fournier's gangrene), a rare, but serious and life-threatening necrotizing infection, have been reported in female and male patients with diabetes mellitus treated with SGLT2 inhibitors, including empagliflozin. Serious outcomes have included hospitalization, multiple surgeries, and death.
Patients treated with Jardiance Duo who present with pain or tenderness, erythema, swelling in the genital or perineal area, fever, malaise should be evaluated for necrotizing fasciitis. If suspected, Jardiance Duo should be discontinued and prompt treatment should be instituted (including broad-spectrum antibiotics and surgical debridement if necessary).
Renal function: Due to the mechanism of action, the efficacy of empagliflozin is dependent on renal function.
GFR should be assessed before treatment initiation and regularly thereafter, see Dosage & Administration. Jardiance Duo is contraindicated in patients with GFR<60 ml/min and should be temporarily discontinued in the presence of conditions that alter renal function, see Contraindications.
Cardiac function: Patients with heart failure are more at risk of hypoxia and renal impairment. In patients with stable chronic heart failure, Jardiance Duo may be used with a regular monitoring of cardiac and renal function.
For patients with acute and unstable heart failure, Jardiance Duo is contraindicated due to the metformin component (see Contraindications).
Use in patients at risk for volume depletion: Based on the mode of action of SGLT-2 inhibitors, osmotic diuresis accompanying therapeutic glucosuria may lead to a modest decrease in blood pressure. Therefore, caution should be exercised in patients for whom an empagliflozin-induced drop in blood pressure 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, blood pressure measurements, laboratory tests including haematocrit) and electrolytes is recommended for patients receiving empagliflozin. Temporary interruption of treatment with Jardiance Duo should be considered until the fluid loss is corrected.
Urinary tract infections: In the pooled placebo-controlled double-blind trials of 18 to 24 weeks duration, the overall frequency of urinary tract infection reported as adverse event was higher in patients treated with empagliflozin 10 mg plus metformin as compared to patients treated with placebo plus metformin or empagliflozin 25 mg plus metformin (see Side Effects).
Post-marketing cases of complicated urinary tract infections including pyelonephritis and urosepsis have been reported in patients treated with empagliflozin. Temporary interruption of treatment should be considered in patients with complicated urinary tract infections.
Surgery: Jardiance Duo must be discontinued at the time of surgery under general, spinal or epidural anaesthesia. Therapy may be restarted no earlier than 48 hours following surgery or resumption of oral nutrition and provided that renal function has been re-evaluated and found to be stable.
Elevated haematocrit: Haematocrit increase was observed with empagliflozin treatment.
Urine laboratory assessments: Due to its mechanism of action, patients taking Jardiance Duo will test positive for glucose in their urine.
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. Discontinuation of Jardiance Duo may be considered in cases of recurrent urinary tract infections.
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.
Hepatic Injury: Cases of hepatic injury have been reported with empagliflozin in clinical trials. A causal relationship between empagliflozin and hepatic injury has not been established.
Cardiac Failure: Experience in New York Heart Association (NYHA) class I-II is limited, and there is no experience in clinical studies with empagliflozin in NYHA class III-IV. In the EMPA-REG OUTCOME study, 10.1 % of the patients were reported with cardiac failure at baseline. The reduction of cardiovascular death in these patients was consistent with the overall study population.
Vitamin B12 levels: In controlled clinical trials of metformin of 29 weeks duration, a decrease to subnormal levels of previously normal serum Vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, is, however, very rarely associated with anaemia and appears to be rapidly reversible with discontinuation of metformin or Vitamin B12 supplementation. Measurement of haematologic parameters on an annual basis is advised in patients on Jardiance Duo and any apparent abnormalities should be appropriately investigated and managed. Certain individuals (those with inadequate Vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal Vitamin B12 levels. In these patients, routine serum Vitamin B12 measurements at two- to three-year intervals may be useful.
Driving and Using Machines: No studies on the effects on the ability to drive and use machines have been performed.
Jardiance duo has minor influence on the ability to drive and use machines. Patients should be advised to take precautions to avoid hypoglycaemia while driving and using machines, in particular when Jardiance Duo is used in combination with a sulphonyl urea and/or insulin.
Use in Elderly: Patients aged 75 years and older may be at an increased risk of volume depletion, therefore, Jardiance Duo should be prescribed with caution in these patients (see Side Effects). Therapeutic experience in patients aged 85 years and older is limited. Initiation of treatment in this population is not recommended.
As metformin is excreted via the kidney, and elderly patients have a tendency to decreased renal function, elderly patients taking Jardiance Duo should have their renal function monitored regularly.
The effect of empagliflozin on urinary glucose excretion is associated with osmotic diuresis, which could affect the hydration status.
