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General: XIGDUO XR should not be used in patients with type 1 diabetes mellitus (see Indications) or for the treatment of diabetic ketoacidosis (see Ketoacidosis as follows).
Lactic acidosis: Metformin hydrochloride: Lactic acidosis is a very rare, but serious and potentially fatal in the absence of prompt treatment, metabolic complication that can occur due to metformin accumulation. Reported cases of lactic acidosis in patients on metformin have occurred primarily in patients with diabetes with significant renal failure. The incidence of lactic acidosis can and should be reduced by also assessing other associated risk factors such as poorly controlled diabetes, ketosis, prolonged fasting, excessive alcohol intake, hepatic insufficiency, dehydration, any acute conditions associated with hypoxia or impacting renal function.
Medicinal products that can acutely impair renal function, such as antihypertensives, diuretics and nonsteroidal anti-inflammatory drug (NSAIDs), should be initiated with caution in metformin-treated patients.
Patients and/or care-givers should be informed on the risk of lactic acidosis. Lactic acidosis is characterized by symptoms such as acidotic dyspnea, abdominal pain, muscle cramps, asthenia and hypothermia followed by coma. Diagnostic laboratory findings are decreased blood pH, plasma lactate levels above 5 mmol/L, and an increased anion gap and lactate/pyruvate ratio. Lactic acidosis is a medical emergency that must be treated in a hospital setting. If metabolic acidosis is suspected, treatment with XIGDUO XR should be discontinued and the patient hospitalized immediately.
Use in renal impairment: Dapagliflozin increases serum creatinine and decreases eGFR (see Adverse Reactions). Renal function abnormalities can occur after initiating dapagliflozin. 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 dapagliflozin; some reports involved patients younger than 65 years of age.
XIGDUO XR should not be used for the treatment of diabetes in patients with eGFR persistently below 45 mL/min/1.73 m2 as the glycaemic efficacy of dapagliflozin is dependent on renal function (see Dosage & Administration).
Dapagliflozin has not been studied in patients with severe renal impairment (eGFR <30 mL/min/1.73m2 by MDRD) or end stage renal disease (ESRD). Based on the mechanism of action, dapagliflozin was not anticipated to be effective in these populations.
Metformin is excreted by the kidney and the risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal function.
Monitoring of renal function is recommended as follows: prior to initiation of XIGDUO XR and at least yearly thereafter; prior to initiation of concomitant medicines that may reduce renal function and periodically thereafter; for renal function approaching eGFR 45 mL/min/1.73 m2 and in elderly patients, at least 2 to 4 times per year. If renal function falls persistently eGFR < 45 mL/min/1.73 m2, treatment with XIGDUO XR should be discontinued.
Change in clinical status of patients with previously controlled type 2 diabetes: Metformin hydrochloride: A patient with type 2 diabetes previously well controlled on XIGDUO XR who develops laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly for evidence of lactic acidosis. Evaluation should include serum electrolytes and ketones, blood glucose and, if indicated, blood pH, lactate, pyruvate, and metformin levels. If acidosis occurs, XIGDUO XR must be stopped immediately and other appropriate corrective measures initiated.
Use in hepatic impairment: Dapagliflozin: There is limited experience in clinical trials in patients with hepatic impairment. Dapagliflozin exposure is increased in patients with severe hepatic impairment. Dapagliflozin should not be used in patients with severe hepatic impairment (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
Metformin hydrochloride: Since impaired hepatic function has been associated with some cases of lactic acidosis, XIGDUO XR should be avoided in patients with clinical or laboratory evidence of hepatic disease.
Radiologic studies with intravascular iodinated contrast materials: Metformin hydrochloride: Intravascular administration of iodinated contrast agents in radiological studies can lead to an acute decrease in renal function and has been associated with lactic acidosis in patients receiving metformin. Therefore, XIGDUO XR should temporarily be discontinued prior to, or at the time of the procedure and not reinstituted until 48 hours afterwards, and only after renal function has been re-evaluated and found to be normal (see Contraindications).
Acute conditions associated with hypoxia or impacting renal function: Metformin hydrochloride: Cardiovascular collapse (shock), acute congestive heart failure, acute myocardial infarction, and other conditions characterised by hypoxemia have been associated with lactic acidosis and may also cause pre-renal azotemia. Acute conditions such as dehydration, severe infections, and hypoperfusion, have potential to alter renal function. In these situations, metformin must be discontinued.
Surgery: Treatment with XIGDUO XR should be ceased at least 48 hours prior to major surgery (see Lactic acidosis and Diabetic ketoacidosis). An increase in other glucose lowering agents may be required during this time.
Patients scheduled for non-urgent surgery who have not ceased treatment with XIGDUO XR should be assessed and consideration should be given to postponing the procedure.
Treatment with XIGDUO XR may be restarted not earlier than 48 hours following the surgery once the patient's condition has stabilised, oral intake is normal and only after renal function has been evaluated and found to be normal.
Use in Patients at Risk for Volume Depletion and/or Hypotension: Dapagliflozin: The diuretic effect of dapagliflozin is a potential concern for volume depleted patients. Due to its mechanism of action, dapagliflozin induces osmotic diuresis which may lead to the modest decrease in blood pressure observed in clinical studies (see Pharmacology: Pharmacodynamics: Clinical trials under Actions).
When considering initiating dapagliflozin, there may be patients for whom the additional diuretic effect of dapagliflozin is a potential concern either due to acute illness (such as gastrointestinal illness) or a history of hypotension or dehydration with diuretic therapy for patients who may become volume depleted. Initiation of therapy with dapagliflozin is therefore not recommended in these patients.
In case of intercurrent conditions that may lead to volume depletion, such as gastrointestinal illness, heat stress or severe infections, careful monitoring of volume status (e.g. physical examination, blood pressure measurements, laboratory tests including electrolytes) is recommended. Temporary interruption of XIGDUO XR is recommended for patients who develop volume depletion until the depletion is corrected (see Adverse Reactions).
Caution should be exercised in patients for whom a dapagliflozin-induced drop in blood pressure could pose a risk, such as patients with known cardiovascular disease, patients on antihypertensive therapy with a history of hypotension or elderly patients.
Urinary Tract Infections: Dapagliflozin: There have been postmarketing reports of serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalisation in patients receiving sodium-glucose cotransporter 2 (SGLT2) inhibitors, including dapagliflozin. Urinary tract infections were more frequently reported for dapagliflozin 10 mg compared to control in a placebo‐pooled analysis up to 24 weeks (4.7% vs. 3.5%, respectively). Urinary glucose excretion may be associated with an increased risk of urinary tract infection. Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated (see Adverse Reactions). Temporary interruption of dapagliflozin should be considered when treating pyelonephritis or urosepsis. Discontinuation of dapagliflozin may be considered in cases of recurrent urinary tract infections; see Adverse Reactions.
Necrotising fasciitis of the perineum (Fournier’s gangrene): Postmarketing cases of necrotising fasciitis of the perineum (also known as Fournier's gangrene), a rare, but serious and potentially life-threatening necrotising infection, have been reported in female and male patients with diabetes mellitus treated with SGLT2 inhibitors, including dapagliflozin (see Adverse Reactions). Serious outcomes have included hospitalisation, multiple surgeries, and death.
Patients treated with XIGDUO XR who present with pain or tenderness, erythema, swelling in the genital or perineal area, fever, malaise should be evaluated for necrotising fasciitis. If suspected, XIGDUO XR should be discontinued and prompt treatment should be instituted (including broad-spectrum antibiotics and surgical debridement if necessary).
Lower limb amputations: Dapagliflozin: An increase in cases of lower limb amputation (primarily of the toe) has been observed in ongoing long-term, clinical studies with another SGLT2 inhibitor. It is unknown whether this constitutes a class effect. Like for all diabetes patients it is important to counsel patients on routine preventative footcare.
Acute Kidney Injury: There have been postmarketing reports of acute kidney injury, some requiring hospitalization and dialysis; in patients receiving dapagliflozin.
Vitamin B12 Levels: 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 2- to 3-year intervals may be useful.
Excessive alcohol intake: Metformin hydrochloride: Alcohol potentiates the effect of metformin on lactate metabolism. Patients should be warned against excessive alcohol intake, while receiving XIGDUO XR.
Ketoacidosis: XIGDUO XR should not be used for the treatment of diabetic ketoacidosis (DKA).
There have been reports of ketoacidosis, including DKA, a serious life-threatening condition requiring urgent hospitalisation in patients taking dapagliflozin and other SGLT2 inhibitors. Fatal cases of ketoacidosis have been reported in patients taking dapagliflozin.
Patients treated with XIGDUO XR who present with signs and symptoms consistent with ketoacidosis, including nausea, vomiting, abdominal pain, malaise and shortness of breath, should be assessed for ketoacidosis, even if blood glucose levels are below 14 mmol/L (250 mg/dL). If ketoacidosis is suspected, XIGDUO XR should be suspended, the patient should be evaluated and prompt treatment initiated.
Treatment of ketoacidosis generally requires insulin, fluid, potassium and carbohydrate replacement.
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.
Before initiating XIGDUO XR, consider factors in the patient history that may predispose to ketoacidosis.
Factors that predispose patients to ketoacidosis include insulin deficiency from any cause (including insulin pump failure, history of pancreatitis or pancreatic surgery), insulin dose reduction, reduced caloric intake or increased insulin requirements due to infections, low carbohydrate diet, acute illness, surgery, a previous ketoacidosis, dehydration and alcohol abuse. XIGDUO XR should be used with caution in these patients. Consider monitoring patients for ketoacidosis and temporarily discontinuing XIGDUO XR in clinical situations known to predispose to ketoacidosis.
Loss of Control of Blood Glucose: Metformin hydrochloride: When a patient stabilised on any diabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a temporary loss of glycaemic control may occur. At such times, it may be necessary to withhold XIGDUO XR and temporarily administer insulin. XIGDUO XR may be reinstituted after the acute episode is resolved.
Use with Medications Known to Cause Hypoglycaemia: Dapagliflozin: Insulin and insulin secretagogues, such as sulfonylureas, cause hypoglycaemia. Therefore, a lower dose of insulin or the insulin secretagogue may be required to reduce the risk of hypoglycaemia when used in combination with XIGDUO XR (see Adverse Reactions).
Metformin hydrochloride: Hypoglycaemia does not occur in patients receiving metformin alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (such as sulfonylureas and insulin) or ethanol. Elderly, debilitated, or malnourished patients, and those with adrenal or pituitary insufficiency or alcohol intoxication, are particularly susceptible to hypoglycaemic effects. Hypoglycaemia may be difficult to recognise in the elderly and in people who are taking beta-adrenergic blocking drugs.
Cardiac failure: Dapagliflozin: There is no experience in clinical studies with dapagliflozin in NYHA class IV.
Effects on laboratory tests: 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.
Haematocrit: In the pool of 13 short-term placebo-controlled studies (see Adverse Reactions), increases from baseline in mean haematocrit values were observed in dapagliflozin-treated patients starting at Week 1. At Week 24, the mean changes from baseline in haematocrit were -0.33% in the placebo group and 2.30% in the dapagliflozin 10 mg group. By Week 24, haematocrit values >55% were reported in 0.4% of placebo-treated patients and 1.3% of dapagliflozin 10 mg-treated patients.
In the pool of 9 placebo-controlled studies with short-term and long-term data, at week 102, the mean changes in haematocrit values were 2.68% vs. -0.46%, respectively. Results for haematocrit values > 55% during the short-term plus long-term phase (the majority of patients were exposed to treatment for more than one year), were similar to week 24.
Most patients with marked abnormalities of elevated haematocrit or haemoglobin had elevations measured a single time that resolved at subsequent visits.
Serum Inorganic Phosphorus: In the pool of 13 short-term placebo-controlled studies, increases from baseline in mean serum phosphorus levels were reported at Week 24 in dapagliflozin-treated patients compared with placebo-treated patients (mean increase of 0.042 mmol/L versus -0.0013 mmol/L, respectively). Higher proportions of patients with marked laboratory abnormalities of hyperphosphataemia ( ≥ 1.81 mmol/L for age 17-65 years or ≥ 1.65 mmol/L for age ≥ 66 years) were reported on dapagliflozin at Week 24 (0.9% versus 1.7% for placebo and dapagliflozin 10 mg, respectively).
In the pool of 9 placebo-controlled studies with short-term and long-term data, at week 102, reported increases in mean serum phosphorus were similar to week 24 results. During the short-term plus long-term phase laboratory abnormalities of hyperphosphataemia were reported in a higher proportion of patients in the dapagliflozin group compared to placebo (3.0% vs. 1.6%, respectively). The clinical relevance of these findings is unknown.
Lipids: In the 13-study short-term placebo-controlled pool (see Adverse Reactions), small changes from baseline in mean lipid values were reported at week 24 in dapagliflozin 10 mg treated patients compared with placebo. Mean percent change from baseline at week 24 for dapagliflozin 10 mg vs. placebo, respectively was as follows: total cholesterol 2.5% vs. 0.0%; HDL cholesterol 6.0% vs. 2.7%; LDL cholesterol 2.9% vs. -1.0%; triglycerides -2.7% vs. -0.7%. The ratio between LDL cholesterol and HDL cholesterol decreased for both treatment groups at week 24.
In the pool of 9 placebo-controlled studies with short-term and long-term data, the mean percent change from baseline at week 102 for dapagliflozin 10 mg vs. placebo, respectively was as follows: total cholesterol 2.1% vs. -1.5%; HDL cholesterol 6.6% vs. 2.1%; LDL cholesterol 2.9% vs. -2.2%; triglycerides -1.8% vs. -1.8%.
In the cardiovascular outcomes study, no clinical important differences in total cholesterol, HDL cholesterol, LDL cholesterol or triglycerides were seen.
Liver Function Tests: In the 21-study active and placebo-controlled pool (see Adverse Reactions), there was no imbalance across treatment groups in the incidence of elevations of ALT or AST. ALT > 3 x ULN was reported in 1.2% of patients treated with dapagliflozin 10 mg and 1.6% treated with comparator. ALT or AST > 3 x ULN and bilirubin > 2 x ULN was reported in 0.1% of patients on any dose of dapagliflozin, 0.2% of patients on dapagliflozin 10 mg, and 0.1% of patients on comparator.
Effects on ability to drive and to use machines: No studies on the effects on the ability to drive and use machines have been performed with XIGDUO XR or dapagliflozin. It should be taken into account that dizziness has been reported in studies with dapagliflozin.
Patients should be alerted to the risk of hypoglycaemia when XIGDUO XR is used with a sulphonylurea or insulin.
Use in children: Safety and effectiveness of XIGDUO XR in paediatric patients have not been established.
Use in elderly: Because metformin is eliminated by the kidney, and because elderly patients are more likely to have decreased renal function, XIGDUO XR should be used with caution as age increases. The renal function recommendations provided for all patients also apply to elderly patients.
Metformin hydrochloride: Controlled clinical studies of metformin did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients, although other reported clinical experience has not identified differences in responses between the elderly and young patients. Metformin is known to be substantially excreted by the kidney and because the risk of serious adverse reactions to the drug is greater in patients with impaired renal function, metformin should only be used in patients with normal renal function. The initial and maintenance dosing of metformin should be conservative in patients with advanced age due to the potential for decreased renal function in this population. Any dose adjustment should be based on a careful assessment of renal function. (See Contraindications, Precautions and Pharmacology: Pharmacokinetics under Actions.)
