Dapagliflozin and Metformin
Medically reviewed on March 25, 2018
(dap a gli FLOE zin & met FOR min)
- Dapagliflozin/Metformin HCl
- Metformin and Dapagliflozin
- Metformin Hydrochloride and Dapagliflozin
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet Extended Release 24 Hour, Oral:
Xigduo XR: Dapagliflozin 10 mg [immediate release] and metformin hydrochloride 500 mg [extended release], Dapagliflozin 2.5 mg [immediate release] and metformin hydrochloride 1000 mg [extended release], Dapagliflozin 10 mg [immediate release] and metformin hydrochloride 1000 mg [extended release], Dapagliflozin 5 mg [immediate release] and metformin hydrochloride 1000 mg [extended release]
Xigduo XR: Dapagliflozin 5 mg [immediate release] and metformin hydrochloride 500 mg [extended release] [contains fd&c yellow #6 aluminum lake]
Brand Names: U.S.
- Xigduo XR
- Antidiabetic Agent, Biguanide
- Antidiabetic Agent, Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitor
- Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitor
Dapagliflozin: By inhibiting sodium-glucose cotransporter 2 (SGLT2) in the proximal renal tubules, dapagliflozin reduces reabsorption of filtered glucose from the tubular lumen and lowers the renal threshold for glucose (RTG). SGLT2 is the main site of filtered glucose reabsorption; reduction of filtered glucose reabsorption and lowering of RTG result in increased urinary excretion of glucose, thereby reducing plasma glucose concentrations.
Metformin: Decreases hepatic glucose production, decreases intestinal absorption of glucose, improves insulin sensitivity by increasing peripheral glucose uptake and utilization.
Use: Labeled Indications
Diabetes mellitus, type 2: 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.
History of serious hypersensitivity to dapagliflozin, metformin, or any component of the formulation; moderate to severe renal impairment (eGFR <60 mL/minute/1.73 m2), end-stage renal disease or patients on dialysis; acute or chronic metabolic acidosis (including diabetic ketoacidosis, with or without coma)
Canadian labeling: Additional contraindications (not in US labeling): Serum creatinine levels above the ULN range, unknown renal function, renal disease or dysfunction (eg, serum creatinine ≥136 micromol/L [males] or ≥124 micromol/L [females]) or abnormal CrCl (<60 mL/minute) which may result from conditions such as cardiovascular collapse (shock), acute MI, and septicemia; history of ketoacidosis with or without coma; history of lactic acidosis, irrespective of precipitating factors; excessive alcohol intake (acute or chronic); clinical or laboratory evidence of hepatic disease; cardiovascular collapse; disease states associated with hypoxemia such as cardiorespiratory insufficiency (which are often associated with hyperlactacidemia); stress conditions (eg, severe infection, trauma or surgery, postoperative recovery); severe dehydration; period around iodinated contrast media administration; pregnancy; breastfeeding
Note: If present, correct volume depletion prior to initiation. If converting from a metformin extended release product that is being taken in the evening, skip the last dose before starting the dapagliflozin/metformin combination product.
Diabetes mellitus, type 2: Oral:
Extended-release tablets: Initial: Individualize based on patient's current antidiabetic regimen. Patients not previously receiving dapagliflozin should initiate dapagliflozin at 5 mg once daily. May gradually increase dose based on effectiveness and tolerability; dosing range: dapagliflozin 5 mg/metformin 500 mg once daily to dapagliflozin 10 mg/metformin 2,000 mg once daily. Maximum: dapagliflozin 10 mg/metformin 2,000 mg once daily.
Immediate-release (Canadian product): Initial: Individualize based on patient's current antidiabetic regimen. May gradually increase dose based on effectiveness and tolerability; range: dapagliflozin 5 mg/metformin 850 mg twice daily to dapagliflozin 5 mg/metformin 1000 mg twice daily. Maximum: dapagliflozin 10 mg/metformin 2,000 mg/day.
Refer to adult dosing. The initial and maintenance dosing should be conservative, due to the potential for decreased renal function (monitor).
Dosing: Renal Impairment
eGFR ≥60 mL/minute/1.73 m2: No dosage adjustment necessary.
eGFR <60 mL/minute/1.73 m2: Use is contraindicated.
Hemodialysis: Use is contraindicated.
Dosing: Hepatic Impairment
The manufacturer recommends to avoid metformin since hepatic disease is considered a risk factor for the development of lactic acidosis during metformin therapy. However, continued use of metformin in diabetics with hepatic dysfunction, including cirrhosis, has been used successfully and may be associated with a survival benefit in carefully selected patients; use cautiously in patients at risk for lactic acidosis (eg, renal impairment, alcohol use) (Brackett 2010; Zhang 2014). No dosage adjustment is necessary for dapagliflozin in patients with mild to severe hepatic impairment according to the manufacturer's labeling for dapagliflozin.
Extended-release tablet: Administer in the morning with food (to reduce gastrointestinal side effects). Swallow tablets whole; do not crush, cut, or chew.
Immediate-release tablet (Canadian product): Administer with meals twice daily.
Individualized medical nutrition therapy (MNT) based on ADA recommendations is an integral part of therapy.
Store at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F).
Abemaciclib: May increase the serum concentration of MetFORMIN. Monitor therapy
Alcohol (Ethyl): May enhance the adverse/toxic effect of MetFORMIN. Specifically, alcohol may potentiate the risk of lactic acidosis Avoid combination
Alpha-Lipoic Acid: May enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy
Androgens: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Exceptions: Danazol. Monitor therapy
Bictegravir: May increase the serum concentration of MetFORMIN. Monitor therapy
BuPROPion: May increase the serum concentration of OCT2 Substrates. Monitor therapy
Carbonic Anhydrase Inhibitors: May enhance the adverse/toxic effect of MetFORMIN. Specifically, the risk of developing lactic acidosis may be increased. Exceptions: Brinzolamide; Dorzolamide. Monitor therapy
Cephalexin: May increase the serum concentration of MetFORMIN. Monitor therapy
Cimetidine: May increase the serum concentration of MetFORMIN. Management: Consider alternatives to cimetidine in patients receiving metformin due to a potential for increased metformin concentrations and toxicity (including lactic acidosis). Consider therapy modification
Dalfampridine: MetFORMIN may increase the serum concentration of Dalfampridine. Dalfampridine may increase the serum concentration of MetFORMIN. Monitor therapy
Dofetilide: MetFORMIN may increase the serum concentration of Dofetilide. Monitor therapy
Dolutegravir: May increase the serum concentration of MetFORMIN. Management: Limit the daily metformin dose to 1,000 mg when used with dolutegravir. Monitor for increased metformin effects/toxicities during concomitant use. Consider therapy modification
Glycopyrrolate (Systemic): May increase the serum concentration of MetFORMIN. Monitor therapy
Guanethidine: May enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy
Hyperglycemia-Associated Agents: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy
Hypoglycemia-Associated Agents: Antidiabetic Agents may enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy
Insulins: Sodium-Glucose Cotransporter 2 (SLGT2) Inhibitors may enhance the hypoglycemic effect of Insulins. Management: Consider a decrease in insulin dose when initiating therapy with a sodium-glucose cotransporter 2 inhibitor and monitor patients for hypoglycemia. Consider therapy modification
Iodinated Contrast Agents: May enhance the adverse/toxic effect of MetFORMIN. Renal dysfunction that may be caused by iodinated contrast agents may lead to metformin-associated lactic acidosis. Management: Management advice varies. Refer to the full drug interaction monograph content for details. Exceptions: Diatrizoate Meglumine; Diatrizoate Sodium; Ethiodized Oil. Consider therapy modification
Isavuconazonium Sulfate: May increase the serum concentration of MetFORMIN. Monitor therapy
LamoTRIgine: May increase the serum concentration of MetFORMIN. Management: The lamotrigine Canadian product monograph states that coadministration of these drugs is not recommended. Monitor therapy
Monoamine Oxidase Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy
Ombitasvir, Paritaprevir, and Ritonavir: May enhance the adverse/toxic effect of MetFORMIN. Specifically, the risk for lactic acidosis may be increased. Monitor therapy
Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir: May enhance the adverse/toxic effect of MetFORMIN. Specifically, the risk for lactic acidosis may be increased. Monitor therapy
Ondansetron: May increase the serum concentration of MetFORMIN. Monitor therapy
Patiromer: May decrease the serum concentration of MetFORMIN. Management: Administer metformin at least 3 hours before or 3 hours after patiromer. Consider therapy modification
Pegvisomant: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy
Prothionamide: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy
Quinolones: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Quinolones may diminish the therapeutic effect of Blood Glucose Lowering Agents. Specifically, if an agent is being used to treat diabetes, loss of blood sugar control may occur with quinolone use. Monitor therapy
Ranolazine: May increase the serum concentration of MetFORMIN. Management: Limit the metformin dose to a maximum of 1700 mg/day when used together with ranolazine 1000 mg twice daily. Consider therapy modification
Ritodrine: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy
Salicylates: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy
Selective Serotonin Reuptake Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy
Sulfonylureas: Sodium-Glucose Cotransporter 2 (SLGT2) Inhibitors may enhance the hypoglycemic effect of Sulfonylureas. Management: Consider a decrease in sulfonylurea dose when initiating therapy with a sodium-glucose cotransporter 2 inhibitor and monitor patients for hypoglycemia. Consider therapy modification
Thiazide and Thiazide-Like Diuretics: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy
Topiramate: May enhance the adverse/toxic effect of MetFORMIN. Monitor therapy
Trimethoprim: May increase the serum concentration of MetFORMIN. Monitor therapy
Trospium: MetFORMIN may decrease the serum concentration of Trospium. Monitor therapy
Vandetanib: May increase the serum concentration of MetFORMIN. Monitor therapy
Verapamil: May diminish the therapeutic effect of MetFORMIN. Monitor therapy
Positive test for glucosuria; may interfere with 1,5-anhydroglucitol (1,5-AG) assay; use alternative methods to monitor glycemic control.
See individual monographs for additional adverse effects reported with each agent
1% to 10%:
Central nervous system: Headache (5%), dizziness (3%)
Endocrine & metabolic: Dyslipidemia (2% to 3%)
Infection: Genitourinary fungal infection (female: 9%, includes bacterial vaginosis, female genital tract infection, genital abscess, vaginal infection, vulvovaginal candidiasis; male: 4%, includes balanitis, balanitis [candida], balanoposthitis, posthitis), influenza (3% to 4%)
Gastrointestinal: Nausea (3% to 4%), constipation (3%)
Genitourinary: Urinary tract infection (6%), increased urine output (2% to 3%), dysuria (2%)
Respiratory: Cough (3%), pharyngitis (2% to 3%)
<1%, postmarketing, and/or case reports: Ketoacidosis (FDA Safety Communication, December 4, 2015), pyelonephritis (FDA Safety Communication, December 4, 2015), urosepsis (FDA Safety Communication, December 4, 2015)
Concerns related to adverse effects:
• Bone fractures: An increased incidence of bone fractures has been observed with dapagliflozin in patients with moderate renal impairment (eGFR 30 to 60 mL/minute/1.73 m2).
• Genital mycotic infections: Dapagliflozin may increase the risk of genital mycotic infections (eg, vulvovaginal mycotic infection, vulvovaginal candidiasis, vulvovaginitis, candida balanitis, balanoposthitis). Patients with a history of these infections or uncircumcised males are at greater risk.
• Hypersensitivity reactions: Patients may experience hypersensitivity reactions (eg, angioedema, urticaria), with some being severe, due to dapagliflozin. Discontinue if hypersensitivity occurs and treat as appropriate.
• Hypotension: Dapagliflozin may cause symptomatic hypotension due to intravascular volume depletion especially in patients with renal impairment (eGFR <60 mL/minute/1.73 m2), elderly, patients on other antihypertensives (eg, diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]), or those with low systolic blood pressure. Assess volume status prior to initiation in patients at risk of hypotension and correct if depleted; monitor for signs and symptoms of hypotension after initiation.
• Ketoacidosis: Cases of ketoacidosis (some fatal) have been reported in patients with type 1 and type 2 diabetes mellitus receiving sodium-glucose cotransporter 2 (SGLT2) inhibitors; in some cases, patients have presented with normal or only modestly elevated blood glucose (<250 mg/dL) (Bobart 2016, FDA 2015, Handelsman 2016). Before initiating treatment, consider risk factors that may predispose to ketoacidosis (eg, pancreatic insulin deficiency, dose decreases or discontinuation of insulin, caloric restriction, alcohol abuse, extensive exercise, myocardial infarction, stroke, severe infection, surgery, any other extreme stress event) (Handelsman 2016). The American Association of Clinical Endocrinologists and American College of Endocrinology recommend considering withholding of SGLT2 inhibitors for at least 24 hours prior to events that may precipitate diabetic ketoacidosis (Handelsman 2016), while others have suggested withholding for 3 to 5 days (Bobart 2016). Patients presenting with nausea/vomiting, abdominal pain, generalized malaise, and/or shortness of breath should be assessed immediately for ketoacidosis; discontinue therapy and treat promptly if ketoacidosis is suspected.
• Lactic acidosis: [US Boxed Warning]: Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset is often subtle, accompanied by nonspecific symptoms (eg, malaise, myalgias, respiratory distress, somnolence, abdominal pain); elevated blood lactate levels (>5 mmol/L); anion gap acidosis (without evidence of ketonuria or ketonemia); increased lactate:pyruvate ratio; metformin plasma levels generally >5 mcg/mL. Risk factors for lactic acidosis include patients with renal impairment, concomitant use of certain drugs (eg, carbonic anhydrase inhibitors such as topiramate), ≥65 years, having a radiologic study with contrast, surgery and other procedures, hypoxic states (eg, acute heart failure), excessive alcohol intake, and hepatic impairment. Discontinue immediately if lactic acidosis is suspected; prompt hemodialysis is recommended. Lactic acidosis should be suspected in any patient with diabetes receiving metformin with evidence of acidosis but without evidence of ketoacidosis. Discontinue metformin in patients with conditions associated with dehydration, sepsis, or hypoxemia. The risk of accumulation and lactic acidosis increases with the degree of impairment of renal function.
• Lipid abnormality: Dapagliflozin may increase LDL-cholesterol (C); monitor and treat as needed.
• Renal effects: Acute kidney injury has been reported with dapagliflozin. Prior to initiation, consider risk factors for acute kidney injury (eg, hypovolemia, chronic renal insufficiency, heart failure, use of concomitant medications [eg, diuretics, ACE inhibitors, angiotensin receptor blockers, or NSAIDs]). Temporarily discontinue use with reduced oral intake or fluid losses; discontinue use if acute kidney injury occurs. Additional abnormalities in renal function (decreased eGFR, increased serum creatinine) and adverse effects related to renal function may occur. Assess renal function prior to initiation and periodically during treatment.
• Urinary tract infection: Serious urinary infections, including urosepsis and pyelonephritis requiring hospitalization, have been reported; treatment with SGLT2 inhibitors, including dapagliflozin, increases the risk for urinary tract infections (UTI); monitor for signs and symptoms of UTI and treat as needed.
• Vitamin B12 concentrations: Long-term metformin use is associated with vitamin B12 deficiency; monitor vitamin B12 serum concentrations periodically with long-term therapy. Monitoring of B12 serum concentrations should be considered in all patients receiving metformin and in particular those with peripheral neuropathy or anemia (ADA 2018c).
• Bladder cancer: Newly diagnosed bladder cancer occurred more frequently in dapagliflozin patients; causal relationship could not be established. Do not use in patients with active bladder cancer; weigh the benefits of glycemic control versus the unknown risks for cancer recurrence in patients with a history of bladder cancer.
• Heart failure: Metformin may be used in patients with stable heart failure (HF); avoid use in unstable or hospitalized patients with heart failure (ADA 2018e). Risk of lactic acidosis may be increased secondary to hypoperfusion. In a scientific statement from the American Heart Association, metformin has been determined to be an agent that may exacerbate underlying myocardial dysfunction (magnitude: major) (AHA [Page 2016]). Use of metformin in patients with HF may be associated with reduced mortality and reduction in hospital readmission for HF (Crowley 2017; Eurich 2013).
• Hepatic impairment: The manufacturer recommends to generally avoid use in patients with hepatic impairment due to potential for lactic acidosis. However, continued use of metformin in patients with diabetes with liver dysfunction, including cirrhosis, may be associated with a survival benefit in carefully selected patients (Brackett 2010; Crowley 2017; Zhang 2014).
• Renal impairment: Metformin is substantially excreted by the kidney; assess renal function prior to initiation of therapy and periodically thereafter using estimated glomerular filtration rate (eGFR); the risk of metformin accumulation and lactic acidosis increase with degree of renal impairment. Use of combination product is contraindicated in patients with moderate to severe renal impairment (eGFR <60 mL/minute/1.73 m2). Use of concomitant medications that may affect renal function (ie, affect tubular secretion) may also affect metformin disposition. Metformin should be withheld in patients with dehydration and/or prerenal azotemia.
• Stress-related states: It may be necessary to discontinue metformin and administer insulin if the patient is exposed to stress (fever, trauma, infection, surgery).
Concurrent drug therapy issues:
• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
• Elderly: Use with caution; risk of metformin-associated lactic acidosis increases with age.
• Appropriate use: Not for use in patients with diabetic ketoacidosis (DKA) or patients with type 1 diabetes mellitus.
• Ethanol use: Instruct patients to avoid excessive acute or chronic ethanol use; ethanol may potentiate metformin's effect on lactate metabolism.
• Iodinated contrast: According to the manufacturer, it is recommended to temporarily discontinue metformin at the time of or before iodinated contrast imaging procedures in patients with a history of hepatic disease, alcoholism, or heart failure; or in patients who will receive intra-arterial iodinated contrast. Reevaluate eGFR 48 hours after imaging procedure; restart if renal function is stable. Alternatively, the American College of Radiology (ACR) guidelines recommend that metformin may be used prior to or following administration of iodinated contrast media in patients with no evidence of acute kidney injury (AKI) and with an eGFR ≥30 mL/minute/1.73 m2; ACR guidelines recommend temporary discontinuation of metformin in patients with known AKI or severe chronic kidney disease ([stage IV or V [ie, eGFR <30 mL/minute/1.73 m2]) or who are undergoing arterial catheter studies (ACR 2017).
• Patient education: Diabetes self-management education (DSME) is essential to maximize the effectiveness of therapy.
• Surgical procedures: Metformin should be withheld the day of surgery (all other oral hypoglycemic agents should be withheld the morning of surgery or procedure) (ADA 2018d). Resume only after normal oral intake resumed and normal renal function is verified.
HbA1c (at least twice yearly in patients who have stable glycemic control and are meeting treatment goals; quarterly in patients not meeting treatment goals or with therapy change (ADA 2018a); plasma glucose; LDL-C; renal function (baseline then annually or when clinically indicated); volume status (eg blood pressure, hematocrit, electrolytes); hematologic parameters (annually); genital mycotic infections and UTI; hypersensitivity reactions; vitamin B12 (periodically with long term therapy); folate (if megaloblastic anemia is suspected); signs and symptoms of metabolic acidosis
Pregnancy Risk Factor
Animal reproduction studies have not been conducted with this combination. Metformin crosses the placenta (ADA 2018f). Refer to individual monographs.
• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Patient may experience rhinitis, pharyngitis, diarrhea, nausea, vomiting, tablet shell in stool, or headache. Have patient report immediately to prescriber signs of lactic acidosis (fast breathing, tachycardia, abnormal heartbeat, vomiting, fatigue, shortness of breath, severe loss of strength and energy, severe dizziness, feeling cold, or muscle pain or cramps), signs of fluid and electrolyte problems (mood changes, confusion, muscle pain or weakness, abnormal heartbeat, severe dizziness or passing out, tachycardia, increased thirst, seizures, loss of strength and energy, lack of appetite, urinary retention or change in amount of urine passed, dry mouth, dry eyes, or nausea or vomiting), signs of kidney problems (urinary retention, hematuria, change in amount of urine passed, or weight gain), signs of a urinary tract infection (hematuria, burning or pain when passing urine, polyuria, fever, lower abdominal pain, or pelvic pain), signs of low blood sugar (dizziness, headache, fatigue, feeling weak, shaking, tachycardia, confusion, increased hunger, or sweating), vaginal yeast infection, penile yeast infection, or severe abdominal pain (HCAHPS).
• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.
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Other brands: Xigduo XR