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Lactic Acidosis: Metformin hydrochloride: Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with XIGDUO XR; when it occurs, it is fatal in approximately 50% of cases. Lactic acidosis may also occur in association with a number of pathophysiologic conditions, including diabetes mellitus, and whenever there is significant tissue hypoperfusion and hypoxemia. Lactic acidosis is characterized by elevated blood lactate levels (>5 mmol/L), decreased blood pH, electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels >5 μg/mL are generally found.
The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is very low (approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000 patient-years). In more than 20,000 patient-years exposure to metformin in clinical trials, there were no reports of lactic acidosis. Reported cases have occurred primarily in diabetic patients with significant renal insufficiency, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications. Patients with congestive heart failure requiring pharmacologic management, in particular those with unstable or acute congestive heart failure who are at risk of hypoperfusion and hypoxemia, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal dysfunction and the patient's age. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patients taking metformin and by use of the minimum effective dose of metformin. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. Metformin treatment should not be initiated in patients ≥80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced, as these patients are more susceptible to developing lactic acidosis. In addition, metformin should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis. Because impaired hepatic function may significantly limit the ability to clear lactate, metformin should generally be avoided in patients with clinical or laboratory evidence of hepatic disease. Patients should be cautioned against excessive alcohol intake when taking metformin since alcohol potentiates the effects of metformin hydrochloride on lactate metabolism. In addition, metformin should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure.
The onset of lactic acidosis often is subtle and accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. There may be associated hypothermia, hypotension, and resistant bradyarrhythmias with more marked acidosis. The patient and the patient's physician must be aware of the possible importance of such symptoms and the patient should be instructed to notify the physician immediately if they occur. Metformin should be withdrawn until the situation is clarified. Serum electrolytes, ketones, blood glucose, and if indicated, blood pH, lactate levels, and even blood metformin levels may be useful. Once a patient is stabilized on any dose level of metformin, gastrointestinal symptoms, which are common during initiation of therapy, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease.
Levels of fasting venous plasma lactate above the upper limit of normal, but less than 5 mmol/L, in patients taking metformin do not necessarily indicate impending lactic acidosis and may be explainable by other mechanisms, such as poorly controlled diabetes or obesity, vigorous physical activity, or technical problems in sample handling.
Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia).
Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a patient with lactic acidosis who is taking metformin, the drug should be discontinued immediately and general supportive measures promptly instituted. Because metformin hydrochloride is dialyzable (with a clearance of up to 170 mL/min under good hemodynamic conditions), prompt hemodialysis is recommended to correct the acidosis and remove the accumulated metformin. Such management often results in prompt reversal of symptoms and recovery.
Use in Patients with Renal Impairment: Dapagliflozin: The efficacy of dapagliflozin is dependent on renal function. XIGDUO XR should not be used in patients with moderate to severe renal impairment (CrCl <60 mL/min by Cockcroft-Gault). Therefore, as in all diabetic patients, renal function should be evaluated prior to initiation of XIGDUO XR and periodically thereafter (see Dosage & Administration, Contraindications, Precautions and Adverse Reactions).
Dapagliflozin has not been studied in patients with severe renal impairment (eGFR<30 mL/min/1.73m2 by MDRD or CrCl ≤ 30 mL/min by Cockcroft-Gault) or end-stage renal disease (ESRD) and should, therefore, not be used in this population.
Metformin hydrochloride: Metformin is known to be substantially excreted by the kidney and the risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal function. Thus, patients with serum creatinine levels above the upper limit of normal for their age should not receive XIGDUO XR. In the elderly, XIGDUO XR should be carefully titrated to establish the minimum dose for adequate glycemic effect because aging is associated with reduced renal function. In elderly patients, particularly those ≥80 years of age, renal function should be monitored regularly and, generally, XIGDUO XR should not be titrated to the maximum dose of the metformin component.
Before initiation of XIGDUO XR therapy, and at least annually thereafter, renal function should be assessed and verified as normal. In patients in whom development of renal dysfunction is anticipated, renal function should be assessed more frequently and XIGDUO XR discontinued if evidence of renal impairment is present.
Special caution should be exercised in situations where renal function may become impaired, for example when initiating antihypertensive or diuretic therapy, or when starting treatment with a nonsteroidal anti-inflammatory drug (NSAID).
Use in patients with hepatic impairment: Metformin hydrochloride: Since impaired hepatic function has been associated with some cases of lactic acidosis, XIGDUO XR should generally be avoided in patients with clinical or laboratory evidence of hepatic disease.
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.
Alcohol intake: Metformin hydrochloride: Alcohol is known to potentiate the effect of metformin on lactate metabolism. Therefore, patients should be warned against excessive alcohol intake, acute or chronic, while receiving XIGDUO XR.
Ketoacidosis: There have been post marketing reports of ketoacidosis, including diabetic ketoacidosis, in patients with type 1 and type 2 diabetes mellitus taking XIGDUO XR and other SGLT2 inhibitors, although a causal relationship has not been established. XIGDUO XR is not indicated for the treatment of patients with type 1 diabetes mellitus.
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, discontinuation or temporary interruption of XIGDUO XR should be considered and the patient should be promptly evaluated.
Predisposing factors to ketoacidosis include a low beta-cell function reserve resulting from pancreatic disorders (e.g., type 1 diabetes, history of pancreatitis or pancreatic surgery), insulin dose reduction, reduced caloric intake or increased insulin requirements due to infections, illness or surgery and alcohol abuse. XIGDUO XR should be used with caution in these patients.
Vitamin B12 levels: Metformin Hydrochloride: In controlled clinical trials of metformin of 29-week 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 anemia and appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on XIGDUO XR and any apparent abnormalities should be appropriately investigated and managed [see Adverse Reactions].
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.
Surgical Procedures: Metformin hydrochloride: As Xigduo XR contains metformin hydrochloride, the treatment should be discontinued 48 hours before elective surgery with general, spinal or epidural anesthesia. Xigduo XR should not usually be resumed earlier than 48 hours afterwards and only after renal function has been re-evaluated and found to be normal.
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 ketoacidosis or 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.
Concomitant Medications Affecting Renal Function or Metformin Disposition: Metformin Hydrochloride: Concomitant medication(s) that may affect renal function or result in significant hemodynamic change or may interfere with the disposition of metformin, such as cationic drugs [see Interactions] that are eliminated by renal tubular secretion, should be used with caution.
Radiologic Studies with Intravascular Iodinated Contrast Materials: Metformin hydrochloride: Intravascular contrast studies with iodinated materials can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving metformin. Therefore, in patients in whom any such study is planned, XIGDUO XR should be temporarily discontinued at the time of or prior to the procedure, and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been re-evaluated and found to be normal.
Hypoxic states: Metformin hydrochloride: Cardiovascular collapse (shock) from whatever cause, acute congestive heart failure, acute myocardial infarction, and other conditions characterized by hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur in patients on XIGDUO XR therapy, the drug should be promptly discontinued.
Loss of control of blood glucose: Metformin hydrochloride: When a patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a temporary loss of glycemic 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 in patients at risk for volume depletion: Dapagliflozin: The diuretic effect of dapagliflozin is a potential concern for volume depleted patients. Dapagliflozin is not recommended for use in patients receiving loop diuretics or who are volume depleted.
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.
For patients receiving dapagliflozin, 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 haematocrit) and 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.
Use with Medications Known to Cause Hypoglycemia: Insulin and insulin secretagogues, such as sulfonylureas, cause hypoglycemia. Therefore, a lower dose of insulin or the insulin secretagogue may be required to reduce the risk of hypoglycemia when used in combination with dapagliflozin (see Adverse Reactions).
Hypoglycemia 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 hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly and in people who are taking beta-adrenergic blocking drugs.
Urosepsis and Pyelonephritis: There have been post marketing reports of serious urinary tract infections, including urosepsis and pyelonephritis, requiring hospitalization in patients receiving XIGDUO XR and other SGLT2 inhibitors. 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).
Macrovascular outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with XIGDUO XR or any other antidiabetic drug. In a prospective meta-analysis of 21 clinical studies, dapagliflozin use was not associated with an increased risk for adverse cardiovascular events (see Adverse Reactions).
Lower limb amputations: Dapagliflozin: In one long-term clinical study with another SGLT2 inhibitor, an increase in cases of lower limb amputation (primarily of the toe) has been observed. The medicine in that study is not dapagliflozin. However, it is unknown whether this constitutes a class effect. It is important to regularly examine the feet and counsel all diabetic patients on routine preventative footcare.
Cardiac failure: Experience in NYHA class I-II is limited, and there is no experience in clinical studies with dapagliflozin in NYHA class III-IV.
Use in patients treated with pioglitazone: While a causal relationship between dapagliflozin and bladder cancer is unlikely, as a precautionary measure, dapagliflozin is not recommended for use in patients concomitantly treated with pioglitazone. Available epidemiological data for pioglitazone suggest a small increased risk of bladder cancer in diabetic patients treated with pioglitazone.
Use in patients with diabetes and cardiovascular disease: In two 24-week, placebo-controlled studies with 80-week extension periods, a total of 1887 patients with type 2 diabetes and cardiovascular disease (CVD) were treated with dapagliflozin 10 mg or placebo. Patients with established CVD and inadequate glycemic control (HbA1c ≥7.0% and ≤10.0%), despite pre-existing, stable treatment with oral antidiabetic therapy (OADs) or insulin (alone or in combination) prior to entry, were eligible for these studies and were stratified according to age (<65 years or ≥65 years), insulin use (no or yes), and time from most recent qualifying cardiovascular event (>1 year or <1 year prior to enrollment). Across the 2 studies, 942 patients were treated with dapagliflozin 10 mg and 945 with placebo. Ninety-six percent (96%) of patients treated with dapagliflozin across the 2 studies had hypertension at entry, the majority for more than 10 years duration; the most common qualifying cardiovascular events were coronary heart disease (75%) and stroke (22%). Approximately 19% of patients received loop diuretics at entry and 15% had congestive heart failure (2% had NYHA Class III). Approximately 37% of patients treated with dapagliflozin 10 mg also received metformin plus one additional OAD at entry, (sulfonylurea, thiazolidinedione, DPP4 inhibitor, or other OAD with or without insulin at entry) 38% received insulin plus at least one OAD, and 18% received insulin alone.
Treatment with dapagliflozin 10 mg as add-on to pre-existing antidiabetic treatments over 24 weeks provided significant improvement in coprimary endpoints of HbA1c and composite clinical benefit compared with placebo in this population. Significant reductions in total body weight and seated systolic blood pressure were also seen (see Pharmacology: Pharmacodynamics under Actions). These benefits extended up to 104 weeks of treatment. The safety profile of dapagliflozin in these studies was consistent with that of dapagliflozin in the general clinical study population through 104 weeks of treatment (see Adverse Reactions).
In a separate analysis of patients on metformin alone (with or without insulin) in these two studies, similar improvements in HbA1c and percent body weight reduction to those seen in the total study population were seen in patients treated with dapagliflozin 10 mg plus metformin alone compared with placebo plus metformin alone at Week 24. A mean reduction in seated systolic blood pressure was observed, consistent with that seen in the total study population, in patients treated with dapagliflozin 10 mg plus metformin alone compared with placebo plus metformin alone at Week 24 in study 1, but not in study 2.
Effects on ability to drive and use machines: No studies on the effects on the ability to drive and use machines have been performed.
It should be taken into account that dizziness has been reported in studies with dapagliflozin.
Use in Children: Safety and effectiveness of XIGDUO XR in pediatric patients have not been established.
Use in the 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.
Dapagliflozin: Elderly patients are more likely to have impaired renal function, and/or to be treated with antihypertensive medicinal products that may cause changes in renal function such as angiotensin converting enzyme inhibitors (ACE-I) and angiotensin II type 1 receptor blockers (ARB). The same recommendations for renal function apply to elderly patients as to all patients.
In subject ≥65 year of age, a higher proportion of subjects treated with dapagliflozin had adverse events related to renal impairment or failure compared with placebo. The most commonly reported adverse event related to renal function was increased blood serum creatinine increases, the majority of which were transient and reversible.
Elderly patients may be at a greater risk for volume depletion and are more likely to be treated with diuretics. In subjects ≥65 year of age, a higher proportion of subjects treated with dapagliflozin had adverse events related to volume depletion (see Adverse Reactions).
Therapeutic experience in patients 75 years and older is limited. Initiation of dapagliflozin therapy in this population is not recommended.
Metformin hydrochloride: Controlled clinical studies of metformin did not include sufficient numbers of elderly patients to determine whether they respond differently than 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 of XIGDUO XR should be based on a careful assessment of renal function.
