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Dapagliflozin and Metformin

Pronunciation

(dap a gli FLOE zin & met FOR min)

Index Terms

  • Dapagliflozin/Metformin HCl
  • Metformin and Dapagliflozin
  • Metformin Hydrochloride and Dapagliflozin

Dosage Forms

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 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

Pharmacologic Category

  • Antidiabetic Agent, Biguanide
  • Antidiabetic Agent, Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitor
  • Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitor

Pharmacology

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 (noninsulin dependent, NIDDM) when treatment with both dapagliflozin and metformin is appropriate.

Contraindications

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 upper limit of normal range or when renal function is unknown; 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; pregnancy; breast-feeding

Dosing: Adult

Note: 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:

US labeling: Initial: Individualize based on patient’s current antidiabetic regimen. May gradually increase dose based on effectiveness and tolerability; 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.

Canadian labeling: 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.

Dosing: Geriatric

Diabetes mellitus, type 2: Oral: The initial and maintenance dosing should be conservative, due to the potential for decreased renal function. Generally, elderly patients should not be titrated to the maximum dose of metformin. Do not use in patients ≥80 years of age unless normal renal function has been established.

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

US labeling: 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.

Canadian labeling: Use is contraindicated in patients with clinical or laboratory evidence of hepatic disease.

Administration

Oral:

US labeling: Extended release tablets: Administer in the morning with food (to reduce gastrointestinal side effects). Swallow tablets whole; do not crush, cut, or chew.

Canadian labeling: Immediate release tablet: Administer with meals twice daily.

Dietary Considerations

Individualized medical nutrition therapy (MNT) based on ADA recommendations is an integral part of therapy.

Storage

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).

Drug Interactions

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

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 together with dolutegravir. Metformin dose adjustments may also be needed upon discontinuation of dolutegravir. Monitor patient response to metformin closely. Consider therapy modification

Glycopyrrolate (Systemic): May increase the serum concentration of MetFORMIN. 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

Insulin: SGLT2 Inhibitors may enhance the hypoglycemic effect of Insulin. 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; 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

MAO 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

Pegvisomant: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Quinolone Antibiotics: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Quinolone Antibiotics 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

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: SGLT2 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

Test Interactions

Positive test for glucosuria; may interfere with 1,5-anhydroglucitol (1,5-AG) assay; use alternative methods to monitor glycemic control.

Adverse Reactions

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% (Limited to important or life-threatening): Ketoacidosis (FDA Safety Communication, December 4, 2015), pyelonephritis (FDA Safety Communication, December 4, 2015), urosepsis (FDA Safety Communication, December 4, 2015)

ALERT: U.S. Boxed 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 (greater than 5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally greater than 5 mcg/mL.

Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (eg, cationic drugs such as topiramate), 65 years and older, having a radiological study with contrast, surgery and other procedures, hypoxic states (eg, 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.

If metformin-associated lactic acidosis is suspected, immediately discontinue therapy and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.

Warnings/Precautions

Concerns related to adverse effects:

• Bone fractures: Increased incidence of bone fractures may occur. According to the American Diabetes Association guidelines, sodium glucose co-transporter-2 (SGLT2) inhibitors should be avoided in patients with fracture risk factors (ADA 2016a).

• 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: 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, a serious and life-threatening condition resulting in urgent hospitalization, 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; if indicated, consider interruption or discontinuation of therapy.

• 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, cationic drugs 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: Dapagliflozin may increase serum creatinine and decrease eGFR, although in patients with normal or mildly impaired renal function at baseline, serum creatinine and eGFR returned to baseline with continued therapy. Monitor renal function; consider temporary interruption of therapy in patients with reduced oral intake or fluid loss. Discontinue use promptly if acute kidney injury occurs and treat as indicated.

• 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.

Disease-related concerns:

• 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: Use with caution in patients with congestive heart failure requiring pharmacologic management, particularly in patients with unstable acute heart failure; risk of lactic acidosis may be increased secondary to hypoperfusion.

• Hepatic impairment: Avoid use in patients with hepatic impairment due to potential for lactic acidosis.

• Renal impairment: Risk of metformin accumulation and lactic acidosis increase with degree of renal impairment. Use 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. Monitor renal function.

• 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.

Special populations:

• Elderly: Metformin should not be initiated in patients ≥80 years of age unless normal renal function is confirmed. Risk of lactic acidosis increases with age.

Other warnings/precautions:

• Appropriate use: Not for use in patients with diabetic ketoacidosis (DKA) or patients with type 1 diabetes mellitus (insulin-dependent, IDDM).

• Ethanol use: Instruct patients to avoid excessive acute or chronic ethanol use; ethanol may potentiate metformin's effect on lactate metabolism.

• Iodinated contrast: 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 2015).

• Surgical procedures: Metformin therapy should be suspended for any surgical procedures. Resume only after normal oral intake resumed and normal renal function is verified.

• Vitamin B12 concentrations: Metformin may impair vitamin B12 absorption, particularly in those with inadequate vitamin B12 or calcium intake/absorption; very rarely associated with anemia. Rapid reversal of vitamin B12 deficiency may be observed with discontinuation of therapy or supplementation. Monitor vitamin B12 serum concentrations periodically with long-term therapy.

Monitoring Parameters

Blood glucose, 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 2016b); LDL-C; renal function and volume status (baseline then annually or more frequently in at-risk patients and when clinically indicated); hematologic parameters (annually); blood pressure; genital mycotic infections and UTI; hypersensitivity reactions; vitamin B12 (periodically with long term therapy); signs and symptoms of metabolic acidosis

Pregnancy Risk Factor

C

Pregnancy Considerations

The Canadian labeling contraindicates use during pregnancy.

Animal reproduction studies have not been conducted with this combination. Metformin crosses the placenta. Refer to individual monographs.

Patient Education

• 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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