dapagliflozin/metformin (Rx)

Brand and Other Names:Xigduo XR
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Dosing & Uses

AdultPediatric

Dosing Forms & Strengths

dapagliflozin/metformin

tablet, extended-release

  • 2.5mg/1000mg
  • 5mg/500mg
  • 5mg/1000mg
  • 10mg/500mg
  • 10mg/1000mg

Type 2 Diabetes Mellitus

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

Not already taking dapagliflozin: Initiate dapagliflozin at 5 mg PO qDay

Patients taking an evening dose of metformin XR: Skip last dose of metformin XR before starting dapagliflozin/metformin

Dosage Modifications

Renal impairment

  • Obtain eGFR before starting metformin
  • eGFR ≥45 mL/min/1.73 m²: No dosage adjustment required
  • eGFR 30-45 mL/min/1.73 m²: Not recommended
  • eGFR <30 mL/min/1.73 m²: Contraindicated
  • Monitor eGFR at least annually or more often for those at risk for renal impairment (eg, elderly)

Discontinuation for iodinated contrast imaging procedures

  • Discontinue dapagliflozin/metformin at 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 hr after imaging procedure; restart if renal function is stable

Dosing Considerations

Individualize starting dose based on patient’s current therapy

Adjust dose based on effectiveness and tolerability; not to exceed daily dose of dapagliflozin 10 mg and metformin 2000 mg (ie, 2 tablets of 5mg/1000mg)

Correct volume depletion before initiating in patients not previously treated with dapagliflozin

Limitation of use

Not for type 1 diabetes mellitus or diabetic ketoacidosis

Safety and efficacy not established

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Interactions

Interaction Checker

and dapagliflozin/metformin

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            Adverse Effects

            >10%

            Renal impairment (dapagliflozin)

            • Overall (1.8-6.7%; placebo 1.7-4.2%)
            • Age ≥65 yr (3.1-14%; placebo 2.1-7.9%)
            • eGFR 30-60 mL/min (8-28.3%; placebo 6.5-16.1%)
            • Age ≥65 yr and eGFR 30-60 mL/min (7-35.1%; placebo 4.9-19.1%)

            Metformin

            • Diarrhea (53.2%)
            • Nausea/vomiting (25.5%)
            • Flatulence (12.1%)

            1-10%

            Dapagliflozin

            • Female genital mycotic infections (6.9-8.4%)
            • Urinary tract infection (4.3-5.7%)
            • Increased urination (2.9-3.8%)
            • Male genital mycotic infections (2.7-2.8%)
            • Dyslipidemia (2.1-2.5%)
            • Constipation (1.9-2.2%)
            • Discomfort with urination (2.6-2.1%)
            • Extremity pain (1.7-2%)

            Volume depletion (dapagliflozin)

            • Overall (0.6-1.1%; placebo 0.4-0.7%)
            • Patients on loop diuretics (0-9.7%; 1.8-2.5%)
            • Patients with moderate renal impairment, GFR 30-60 mL/min (0.9-1.9%; placebo 1.5-1.9%)
            • Age ≥65 yr (0.5-1.7%; placebo 0.4-0.8%)

            Metformin

            • Asthenia (9.2%)
            • Indigestion (7.1%)
            • Abdominal discomfort (6.4%)
            • Headache (5.7%)

            Postmarketing Reports

            Lactic acidosis

            Acute kidney injury and impairment in renal function

            Dapagliflozin

            • Ketoacidosis
            • Acute kidney injury
            • Impairment in renal function
            • Urosepsis
            • Pyelonephritis rash

            Metformin hydrochloride

            • Cholestatic, hepatocellular, and mixed hepatocellular liver injury
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            Warnings

            Black Box Warnings

            Lactic acidosis

            • Lactic acidosis caused by metformin accumulation (plasma concentration >5 mcg/mL) is a rare but potentially severe consequence; if it occurs, mortality is ~50%
            • Risk increases with certain conditions (eg, renal impairment, sepsis, dehydration, excess alcohol intake, and hepatic impairment); concomitant use of certain drugs (eg, carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (eg, acute congestive heart failure)
            • Onset is subtle, accompanied only by nonspecific symptoms (eg, malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress)
            • Laboratory abnormalities include low pH, increased anion gap, and elevated blood lactate
            • If lactic acidosis is suspected, discontinue drug and immediately hospitalize the patient
            • Discontinue metformin at the time of or before an iodinated contrast imaging procedure in patients with an eGFR between 30-60 mL/minute/1.73 m²; in patients with a history of liver disease, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinate contrast

            Contraindications

            Severe renal impairment (eg, eGFR <30 ml/min/1.73 m²), end stage renal disease or patients on dialysis, which may also result from conditions such as shock, acute MI, and septicemia

            Acute or chronic metabolic acidosis, including diabetic ketoacidosis (see Black Box Warnings)

            Hypersensitivity

            Cautions

            Lactic acidosis; risk increases with degree of renal dysfunction and age (see Black Box Warnings)

            Before initiating therapy, assess volume status and correct hypovolemia in the elderly, in patients with renal impairment or low systolic blood pressure, and in patients on diuretics; monitor for signs and symptoms during therapy

            Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase risk of lactic acidosis, especially in patients at risk; metformin use in patients with impaired hepatic function has been associated with some cases of lactic acidosis; generally, avoid in patients with hepatic impairment

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

            Shock from various causes (eg, acute CHF, acute MI, and other conditions characterized by hypoxemia) associated with lactic acidosis and may also cause prerenal azotemia

            In diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis recommended to correct acidosis and remove accumulated metformin (metformin hydrochloride is dialyzable, with a clearance of up to 170 mL/minute under good hemodynamic conditions)

            Closely monitor patients taking drugs that may increase risk of metformin associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid base balance or increase metformin accumulation (eg, cationic drugs)

            Elderly patients and patients with impaired renal function may be more susceptible to increases in serum creatinine and decreases eGFR; renal function should be evaluated prior to initiation of therapy and monitored periodically thereafter

            Elderly patients have a greater likelihood of having hepatic or cardiac impairment than younger patients; risk of metformin-associated lactic acidosis increases with patient’s age because elderly patients have greater likelihood of having hepatic, renal, or cardiac impairment than younger patients

            Metformin is known to be substantially excreted by the kidney and risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment; before initiating therapy, obtain an estimated glomerular filtration rate (eGFR)

            Dapagliflozin increases risk of urinary tract infections (UTIs), including life-threatening urosepsis and pyelonephritis that started as UTIs; evaluate for signs and symptoms of urinary tract infections and treat promptly, if indicated

            Fatal cases of ketoacidosis reported in patients taking dapagliflozin; monitor for signs of ketoacidosis and advise patients to seek immediate medical attention for symptoms (eg, difficulty breathing, nausea, vomiting, abdominal pain, confusion, unusual fatigue or sleepiness)

            Assess patients who present with signs and symptoms of metabolic acidosis for ketoacidosis, regardless of blood glucose level; consider risk factors for ketoacidosis prior to initiating therapy; patients may require temporary discontinuation of therapy in clinical situation that may predispose to ketoacidosis

            Cases of metformin-associated lactic acidosis reported in setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia); cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia; discontinue therapy when such events occur

            Dose-related increases in LDL–C reported with dapagliflozin

            Dapagliflozin increases risk for genital mycotic infections

            Before initiating therapy, obtain estimated glomerular filtration rate (eGFR); obtain an eGFR at least annually in all patients receiving therapy; in patients at increased risk for development of renal impairment (e.g., the elderly), renal function should be assessed more frequently

            Do not administer to patients with active bladder cancer and should be administered with caution in patients with a prior history of bladder cancer

            Metformin associated with a decrease to subnormal levels of previously normal serum vitamin B-12 levels, without clinical manifestations; measure hematological parameters annually

            Bone fractures reported in patients with eGFR 30 to less than 60 mL/min/1.73 m2, for treatment durations up to 104 weeks

            Necrotizing fascitis of perineum (Fournier gangrene)

            • Reported with SGLT2 inhibitors
            • Signs and symptoms include tenderness, redness, or swelling of the genitals or the area from the genitals back to the rectum, and have a fever >100.4°F or a general feeling of being unwell
            • If suspected, discontinue SGLT2 inhibitor and start broad-spectrum antibiotics immediately and surgical debridement if necessary

            Hypoglycemia

            • Dapagliflozin can increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue; a lower dose of insulin or insulin secretagogue may be required
            • 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 (eg, sulfonylureas, insulin) or ethanol

            Hypotension and acute renal injury

            • Dapagliflozin causes intravascular volume contraction
            • Symptomatic hypotension and/or acute renal injury can occur after initiating, particularly with eGFR <60 mL/min/1.73 m², in elderly patients, with coadministration with diuretics, or medications that interfere with the renin-angiotensin-aldosterone system (eg, ACE inhibitors, angiotensin receptor blockers), or in patients with low systolic blood pressure
            • Consider temporarily discontinuing therapy in any setting of reduced oral intake (such as acute illness or fasting) or fluid losses (gastrointestinal illness or excessive heat exposure); monitor patients for signs and symptoms of acute kidney injury
            • Withholding of food and fluids during surgical or other procedures may increase risk for volume depletion, hypotension and renal impairment; if acute kidney injury occurs, discontinue therapy promptly and institute treatment
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            Pregnancy & Lactation

            Pregnancy

            Based on animal data showing adverse renal effects, not recommended during the second and third trimesters of pregnancy

            Limited data 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

            Discuss potential for unintended pregnancy with premenopausal women as therapy with metformin may result in ovulation in some anovulatory women

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

            Reproductive potential

            • Discuss potential for unintended pregnancy with premenopausal women as therapy with metformin may result in ovulation in some anovulatory women

            Animal data

            • In animal studies, adverse renal pelvic and tubule dilatations, that were not fully reversible, were observed in rats when dapagliflozin was administered during a period of renal development corresponding to the late second and third trimesters of human pregnancy, at all doses tested; the lowest of which provided an exposure 15-times the 10 mg clinical dose

            Lactation

            There is no information regarding the presence 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

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

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Dapagliflozin: Selective sodium-glucose transporter-2 (SGLT2) inhibitor; SGLT2 is expressed in the proximal renal tubules and is responsible for the majority of the reabsorption of filtered glucose from the tubular lumen; SGLT2 inhibitors reduce glucose reabsorption and lower the renal threshold for glucose, thereby increasing urinary glucose excretion

            Metformin: Biguanide; acts by decreasing endogenous hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization; improves glucose tolerance and lowers both basal and postprandial plasma glucose

            Absorption

            Bioavailability: 78% (dapagliflozin)

            Distribution

            Protein bound: 91% (dapagliflozin); negligible (metformin)

            Metabolism

            Metformin: Excreted unchanged in the urine and does not undergo hepatic metabolism

            Dapagliflozin

            • Metabolism primarily mediated by UGT1A9
            • CYP-mediated metabolism is a minor clearance pathway in humans
            • Extensively metabolized, primarily to yield dapagliflozin 3-O-glucuronide (inactive metabolite)

            Elimination

            Dapagliflozin

            • Half-life: 12.9 hr
            • Excretion: 75% urine (<2% as parent drug); 21% feces (~15% as parent drug)

            Metformin

            • Half-life: 6.2 hr (plasma); 17.6 hr (blood) – Suggests erythrocyte mass may be a compartment of distribution
            • Renal clearance: ~3.5 times greater than CrCl
            • Excretion: 90% urine
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            Administration

            Oral Administration

            Administer once daily in morning with food

            Swallow whole; do not crush, cut, or chew

            Occasionally, the inactive ingredients of the extended-release tablet will be eliminated in the feces as a soft, hydrated mass that may resemble the original tablet

            Storage

            Store at 20-25°C (68-77°F); excursions permitted between 15-30°C (59-86°F)

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            Formulary

            FormularyPatient Discounts

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
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            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
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            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.