dapagliflozin/metformin (Xigduo XR)

Dosing and uses of Xigduo XR (dapagliflozin/metformin)

• Adult
• Pediatric

 

Adult dosage forms and strengths

dapagliflozin/metformin

tablet, extended-release

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

 

Type 2 Diabetes Mellitus

Individualize starting dose based on patient’s current therapy

Take once daily in morning with food, with gradual dose escalation to reduce the adverse GI effects due to metformin

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)

Patients taking an evening dose of metformin XR should skip their last dose before starting dapagliflozin/metformin the following morning

 

Dosage modifications

Renal impairment

• Obtain eGFR before starting metformin
• eGFR <30 mL/min/1.73 m²: Contraindicated
• eGFR 30-45 mL/min/1.73 m²: Not recommended to initiate treatment
• Monitor eGFR at least annually or more often for those at risk for renal impairment (eg, elderly)
• If eGFR falls below 45mL/min/1.73 m² while taking metformin, risks and benefits of continuing therapy should be evaluated
• If eGFR falls below 30 mL/min/1.73 m²: while taking metformin, discontinue the drug

 

Dosing Considerations

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

Not for type 1 diabetes mellitus or diabetic ketoacidosis

 

Pediatric dosage forms and strengths

Safety and efficacy not established

 

Xigduo XR (dapagliflozin/metformin) adverse (side) 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%)

 

Warnings

Black box warnings

Metformin

• 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, hepatic impairment, and acute CHF)
• 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

Renal impairment (eg, eGFR <30 ml/min/1.73 m²), which may also result from conditions such as shock, acute MI, and septicemia; ESRD; or patients on dialysis

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) has been 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)

Consider more frequent monitoring of 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 (e.g. cationic drugs)

Assess renal function more frequently in elderly 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

Renal impairment; dapagliflozin increases serum creatinine and decreases eGFR; 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

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

Ketoacidosis associated with SGLT2 inhibitors reported; 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

Therapy should not be administered 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

Iodinated contrast imaging procedures

• 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
• Reevaluate eGFR 48 hr after the imaging procedure; restart metformin if renal function is stable

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; if acute kidney injury occurs, discontinue therapy promptly and institute treatment

 

Pregnancy and lactation

Pregnancy category: C

Lactation: Unknown if distributed in human breast milk

In studies performed on the individual components, both dapagliflozin (reaching levels 0.49 time that found in maternal plasma) and metformin are excreted in the milk of lactating rats

Juvenile rats directly exposed to dapagliflozin showed risk to the developing kidney (renal pelvic and tubular dilations) during maturation

 

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.

 

Pharmacology of Xigduo XR (dapagliflozin/metformin)

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

 

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