XIGDUO XR- dapagliflozin propanediol and metformin hydrochloride tablet, film coated, extended release
AstraZeneca Pharmaceuticals LP
WARNING: LACTIC ACIDOSIS
� Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL [see Warnings and Precautions (5.1) ].
� Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., cationic drugs such as topiramate), age 65 years old or greater, having a radiological study with contrast media, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment.
� Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the full prescribing information [see Dosage and Administration (2.2), Contraindications (4), Warnings and Precautions (5.1), Drug Interactions (7), and Use in Specific Populations (8.6, 8.7)].
� If metformin-associated lactic acidosis is suspected, immediately discontinue XIGDUO XR and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended [see Warnings and Precautions (5.1) ].
1 INDICATIONS AND USAGE
XIGDUO XR (dapagliflozin and metformin HCl extended-release) is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both dapagliflozin and metformin is appropriate [see Clinical Studies (14)].
1.1 Limitations of Use
XIGDUO XR is not recommended for patients with type 1 diabetes mellitus or diabetic ketoacidosis.
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dosing
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Healthcare providers should individualize the starting dose of XIGDUO XR based on the patient's current treatment [see Dosage Forms and Strengths (3)].
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XIGDUO XR should be taken once daily in the morning with food with gradual dose escalation to reduce the gastrointestinal (GI) side effects due to metformin.
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XIGDUO XR tablets must be swallowed whole and never crushed, cut, or chewed. Occasionally, the inactive ingredients of XIGDUO XR will be eliminated in the feces as a soft, hydrated mass that may resemble the original tablet.
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Dosing may be adjusted based on effectiveness and tolerability while not exceeding the maximum recommended daily dose of 10 mg dapagliflozin and 2000 mg metformin HCl.
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Patients taking an evening dose of metformin XR should skip their last dose before starting XIGDUO XR.
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In patients with volume depletion, correcting this condition prior to initiation of XIGDUO XR is recommended
DOSAGE FORMS AND STRENGTHS
XIGDUO XR is a combination of dapagliflozin and metformin HCl extended-release. XIGDUO XR tablets are available in the following dosage forms and strengths:
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5 mg/500 mg tablets are orange, biconvex, capsule-shaped, and film-coated tablets with "1070? and "5/500? debossed on one side and plain on the reverse side.
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5 mg/1000 mg tablets are pink to dark pink, biconvex, oval-shaped, and film-coated tablets with "1071? and "5/1000? debossed on one side and plain on the reverse side.
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10 mg/500 mg tablets are pink, biconvex, capsule-shaped, and film-coated tablets with "1072? and "10/500? debossed on one side and plain on the reverse side.
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10 mg/1000 mg tablets are yellow to dark yellow, biconvex, oval-shaped, and film-coated tablets with "1073? and "10/1000? debossed on one side and plain on the reverse side.
4 CONTRAINDICATIONS
XIGDUO XR is contraindicated in patients with:
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Moderate to severe renal impairment (eGFR below 60 mL /min/1.73 m2), end stage renal disease or patients on dialysis [see Warnings and Precautions (5.1) ].
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History of a serious hypersensitivity reaction to dapagliflozin or hypersensitivity to metformin hydrochloride [see Adverse Reactions (6.1) ].
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Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin.
5 WARNINGS AND PRECAUTIONS
? 5.1 Lactic Acidosis
? There have been post-marketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate: pyruvate ratio;metformin plasma levels generally >5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk.
Use with Medications Known to Cause Hypoglycemia
Dapagliflozin
Insulin and insulin secretagogues are known to cause hypoglycemia. Dapagliflozin can increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue [see Adverse Reactions (6.1)]. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when these agents are used in combination with XIGDUO XR.
Metformin hydrochloride
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.
5.7 Vitamin B12 Concentrations
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. This 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 (6.1)].
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 B12measurements at 2- to 3-year intervals may be useful.
5.8 Genital Mycotic Infections
Dapagliflozin increases the risk of genital mycotic infections. Patients with a history of genital mycotic infections were more likely to develop genital mycotic infections [see Adverse Reactions (6.1)]. Monitor and treat appropriately.
5.11 Macrovascular Outcomes
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with XIGDUO XR or any other antidiabetic drug.
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
XIGDUO XR
XIGDUO XR combines two antihyperglycemic agents with complementary mechanisms of action to improve glycemic control in patients with type 2 diabetes: dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, and metformin hydrochloride, a biguanide.
Dapagliflozin
Sodium-glucose cotransporter 2 (SGLT2), expressed in the proximal renal tubules, is responsible for the majority of the reabsorption of filtered glucose from the tubular lumen. Dapagliflozin is an inhibitor of SGLT2. By inhibiting SGLT2, dapagliflozin reduces reabsorption of filtered glucose and lowers the renal threshold for glucose, and thereby increases urinary glucose excretion.
Metformin hydrochloride
Metformin improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Metformin does not produce hypoglycemia in either patients with type 2 diabetes or in healthy subjects, except in unusual circumstances [see Warnings and Precautions (5.6)], and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.
