XIGDUO XR

XIGDUO XR is a medication used to treat type 2 diabetes in adults. It contains two active ingredients: dapagliflozin and metformin hydrochloride extended-release. Dapagliflozin is an SGLT2 inhibitor that works by preventing the kidneys from reabsorbing glucose and promoting its excretion in the urine. Metformin is a biguanide medication that reduces the amount of glucose produced by the liver and improves insulin sensitivity.

Dapagliflozin

Dapagliflozin is described chemically as D-glucitol, 1,5-anhydro-1-C-[4-chloro-3-[(4ethoxyphenyl)methyl]phenyl]-, (1S)-, compounded with (2S)-1,2-propanediol, hydrate (1:1:1). The empirical formula is C₂₁H₂₅ClO₆•C₃H₈O₂•H₂O and the formula weight is 502.98.

Metformin hydrochloride

Metformin hydrochloride (N,N-dimethylimidodicarbonimidic diamide hydrochloride) is a white to off-white crystalline compound with a molecular formula of C₄H₁₁N₅•HCl and a molecular weight of 165.63. Metformin hydrochloride is freely soluble in water, slightly soluble in alcohol, and is practically insoluble in acetone, ether, and chloroform. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68.

XIGDUO XR INDICATIONS AND USAGE

XIGDUO XR is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Dapagliflozin is indicated to reduce

the risk of hospitalization for heart failure in adults with type 2 diabetes mellitus and established cardiovascular disease (CVD) or multiple cardiovascular (CV) risk factors.
the risk of cardiovascular death and hospitalization for heart failure in adults with heart failure (NYHA class II-IV) with reduced ejection fraction.
- the risk of sustained estimated glomerular filtration rate decline, end-stage kidney disease, cardiovascular death, and hospitalization for heart failure in adults with chronic kidney disease at risk of progression.

Limitations of Use

XIGDUO XR is not recommended for patients with type 1 diabetes mellitus. It may increase the risk of diabetic ketoacidosis in these patients.
Because of the metformin component, the use of XIGDUO XR is limited to adults with type 2 diabetes mellitus for all indications.
XIGDUO XR is not recommended for the treatment of chronic kidney disease in patients with polycystic kidney disease or patients requiring or with a recent history of immunosuppressive therapy for kidney disease. XIGDUO XR is not expected to be effective in these populations.

XIGDUO XR Mechanism of Action

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 thereby promotes urinary glucose excretion. Dapagliflozin also reduces sodium reabsorption and increases the delivery of sodium to the distal tubule. This may influence several physiological functions including, but not restricted to, lowering both pre-and afterload of the heart and downregulation of sympathetic activity, and decreased intraglomerular pressure which is believed to be mediated by increased tubuloglomerular feedback.

Metformin HCl

Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes mellitus, 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. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may decrease.

XIGDUO XR DOSAGE AND ADMINISTRATION

Prior to Initiation of XIGDUO XR

Assess renal function before initiating XIGDUO XR therapy and periodically thereafter.
Assess volume status and, if necessary, correct volume depletion prior to initiation of XIGDUO XR.

Recommended Administration

Take XIGDUO XR orally once daily in the morning with food.
Swallow XIGDUO XR tablets whole and never crush, cut, or chew.

Recommended Dosage

Individualize the starting dose of XIGDUO XR based upon the patient’s current regimen. Patients taking an evening dose of metformin extended-release should skip their last dose before starting XIGDUO XR.
To improve glycemic control in patients not already taking dapagliflozin, the recommended starting dose for dapagliflozin is 5 mg once daily.
For indications related to heart failure and chronic kidney disease the recommended dose for dapagliflozin is 10 mg once daily.
Dosing may be adjusted based on effectiveness and tolerability while not exceeding the maximum recommended daily dose of 10 mg dapagliflozin and 2,000 mg metformin hydrochloride (HCl) extended-release.

Patients with Renal Impairment

No dose adjustment for XIGDUO XR is needed in patients with an estimated glomerular filtration rate (eGFR) greater than or equal to 45 mL/min/1.73 m².

Initiation of XIGDUO XR is not recommended in patients with an eGFR between 30 and 45 mL/min/1.73 m². Assess the benefit and risk of continuing therapy if eGFR falls persistently below this level.

Dapagliflozin is likely to be ineffective to improve glycemic control in patients with eGFR less than 45 mL/min/1.73 m².
- Metformin initiation is not recommended for patients with eGFR less than 45 mL/min/1.73 m².

XIGDUO XR is contraindicated in patients with an eGFR below 30 mL/min/1.73 m², end-stage renal disease, or on dialysis due to the metformin component.

Discontinuation for Iodinated Contrast Imaging Procedures

Discontinue XIGDUO XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with a history of liver disease, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart XIGDUO XR if renal function is stable.

XIGDUO XR CONTRAINDICATIONS

XIGDUO XR is contraindicated in patients with:

Severe renal impairment (eGFR below 30 mL/min/1.73 m²), end-stage renal disease or patients on dialysis.
History of a serious hypersensitivity reaction to dapagliflozin, such as anaphylactic reactions or angioedema, or hypersensitivity to metformin HCl.
Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin.

XIGDUO XR WARNINGS AND PRECAUTIONS

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.

Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue XIGDUO XR and report these symptoms to their healthcare provider.

Ketoacidosis: Reports of ketoacidosis, a serious life-threatening condition requiring urgent hospitalization have been identified in patients with type 1 and type 2 diabetes mellitus taking sodium-glucose co-transporter 2 (SGLT2) inhibitors, including dapagliflozin. In placebo-controlled trials of patients with type 1 diabetes mellitus, the risk of ketoacidosis was increased in patients who received SGLT2 inhibitors compared to patients who received placebo. Fatal cases of ketoacidosis have been reported in patients taking dapagliflozin. XIGDUO XR is not indicated for the treatment of patients with type 1 diabetes mellitus.

Volume Depletion: Dapagliflozin can cause intravascular volume depletion which may sometimes manifest as symptomatic hypotension or acute transient changes in creatinine. There have been post-marketing reports of acute kidney injury, some requiring hospitalization and dialysis, in patients with type 2 diabetes mellitus receiving SGLT2 inhibitors, including dapagliflozin. Patients with impaired renal function (eGFR less than 60 mL/min/1.73 m²), elderly patients, or patients on loop diuretics may be at increased risk for volume depletion or hypotension. Before initiating XIGDUO XR in patients with one or more of these characteristics, assess volume status and renal function. Monitor for signs and symptoms of hypotension and renal function after initiating therapy.

Urosepsis and Pyelonephritis: Serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalization have been reported in patients receiving SGLT2 inhibitors, including dapagliflozin. 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.

Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues: Insulin and insulin secretagogues (e.g., sulfonylurea) are known to cause hypoglycemia. XIGDUO XR may increase the risk of hypoglycemia when combined with insulin and/or an insulin secretagogue. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with XIGDUO XR

Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene): Reports of necrotizing fasciitis of the perineum (Fournier’s Gangrene), a rare but serious and life-threatening necrotizing infection requiring urgent surgical intervention, have been identified in postmarketing surveillance in patients with diabetes mellitus receiving SGLT2 inhibitors, including dapagliflozin. Cases have been reported in both females and males. Serious outcomes have included hospitalization, multiple surgeries, and death.

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. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation. Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. Measure hematologic parameters on an annual basis and vitamin B12 at 2-to 3-year intervals in patients on XIGDUO XR and manage any abnormalities.

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. Monitor and treat appropriately.

XIGDUO XR DRUG INTERACTIONS

Carbonic Anhydrase Inhibitors: Topiramate or other carbonic anhydrase inhibitors (e.g., zonisam ide, acetazolamide or dichlorphenamide) frequently causes a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with XIGDUO XR may increase the risk for lactic acidosis.

Consider more frequent monitoring of these patients.

Drugs that Reduce Metformin Clearance: Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE] inhibitors, such as ranolazine, vandetanib, dolutegravir, and cimetidine) could increase systemic exposure to metformin and may increase the risk for lactic acidosis.

Consider the benefits and risks of concomitant use.

Alcohol: Alcohol is known to potentiate the effect of metformin on lactate metabolism.

Warn patients against excessive alcohol intake while receiving XIGDUO XR.

Insulin or Insulin Secretagogues: The risk of hypoglycemia may be increased when XIGDUO XR is used concomitantly with insulin or insulin secretagogues (e.g., sulfonylurea).

Concomitant use may require lower doses of insulin or the insulin secretagogue to reduce the risk of hypoglycemia.

Drugs Affecting Glycemic Control: Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These medications include thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid.

When such drugs are administered to a patient receiving XIGDUO XR, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving XIGDUO XR, observe the patient closely for hypoglycemia.

Lithium: Concomitant use of an SGLT2 inhibitor with lithium may decrease serum lithium concentrations.

Monitor serum lithium concentration more frequently during XIGDUO XR initiation and dosage changes.

Positive Urine Glucose Test: SGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose tests.

Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control.

Interference with 1,5-anhydroglucitol (1,5-AG) Assay: Measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors.

Monitoring glycemic control with 1,5-AG assay is not recommended. Use alternative methods to monitor glycemic control.

XIGDUO XR USE IN SPECIFIC POPULATIONS

Pregnancy: Based on animal data showing adverse renal effects, XIGDUO XR is not recommended during the second and third trimesters of pregnancy.

Limited data with XIGDUO XR or dapagliflozin in pregnant women are not sufficient to determine drug-associated risk for major birth defects or miscarriage. Published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage risk. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy.

Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity.

Lactation: There is no information regarding the presence of XIGDUO XR or dapagliflozin in human milk, the effects on the breastfed infant, or the effects on milk production.

Limited published studies report that metformin is present in human milk. However, there is insufficient information on the effects of metformin on the breastfed infant and no available information on the effects of metformin on milk production. Dapagliflozin is present in the milk of lactating rats. However, due to species specific differences in lactation physiology, the clinical relevance of these data are not clear. Since human kidney maturation occurs in utero and during the first 2 years of life when lactational exposure may occur, there may be risk to the developing human kidney.

Because of the potential for serious adverse reactions in breastfed infants, advise women that use of XIGDUO XR is not recommended while breastfeeding.

Females and Males of Reproductive Potential: Discuss the potential for unintended pregnancy with premenopausal women as therapy with metformin may result in ovulation in some anovulatory women.

Pediatric Use: Safety and effectiveness of XIGDUO XR in pediatric patients under 18 years of age have not been established.

Geriatric Use: No XIGDUO XR dosage change is recommended based on age. More frequent assessment of renal function is recommended in elderly patients.

Hepatic Impairment: Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. XIGDUO XR is not recommended in patients with hepatic impairment.

XIGDUO XR OVERDOSAGE

Dapagliflozin

In the event of an overdose, contact the Poison Control Center. The removal of dapagliflozin by hemodialysis has not been studied.

Metformin HCl

Overdose of metformin HCl has occurred, including ingestion of amounts >50 grams. Lactic acidosis has been reported in approximately 32% of metformin overdose cases. Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected.

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XIGDUO XR (dapagliflozin and metformin hydrochloride extended-release)

XIGDUO XR