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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 (see Dosage & Administration), caution should be taken. For patients who undergo scheduled surgery, consider temporarily discontinuing JARDIANCE DUO for at least 3 days prior to surgery.
Consider monitoring for ketoacidosis and temporarily discontinuing JARDIANCE DUO in other clinical situations known to predispose to ketoacidosis (e.g., prolonged fasting due to acute illness or post-surgery). In these situations, consider monitoring of ketones, even if Jardiance Duo treatment has been interrupted. Ensure risk factors for ketoacidosis are resolved prior to restarting JARDIANCE DUO.
Educate patients on the signs and symptoms of ketoacidosis and instruct patients to discontinue JARDIANCE DUO and seek medical attention immediately if signs and symptoms occur.
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 diarrhea 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 functions.
GFR should be assessed before treatment initiation and regularly thereafter, see Dosage & Administration. Jardiance Duo is contraindicated in patients with GFR <30 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 Adverse Reactions).
Postmarketing 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.
Vitamin B12: The risk of low vitamin B12 levels increases with increasing metformin dose, treatment duration, and/or in patients with risk factors known to cause vitamin B12 deficiency. In case of suspicion of vitamin B12 deficiency (such as anaemia or neuropathy), vitamin B12 serum levels should be monitored. Periodic vitamin B12 monitoring could be necessary in patients with risk factors for vitamin B12 deficiency. Metformin therapy should be continued for as long as it is tolerated and not contraindicated and appropriate corrective treatment for vitamin B12 deficiency provided in line with current clinical guidelines.
Driving and Using Machines: No studies on the effects on the ability to drive and use machines have been performed.
Use in the 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 Adverse Reactions). 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.
