Metformin + Dapagliflozin

Pharmacologic Category

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

Dosing: Adult

Note: If present, correct volume depletion prior to initiation. If converting from a metformin ER product that is being taken in the evening, skip the last dose before starting the dapagliflozin/metformin combination product.

Diabetes mellitus, type 2: Oral:

ER tablets:

For improvement in glycemic control: 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 g once daily. Maximum: dapagliflozin 10 mg/metformin 2 g once daily.

For risk reduction of hospitalization for heart failure: Dapagliflozin 10 mg once daily plus appropriate dose of metformin. Maximum: Dapagliflozin 10 mg/metformin 2 g once daily.

Immediate release (Canadian product):

For improvement in glycemic control: 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 1 g twice daily. Maximum: dapagliflozin 10 mg/metformin 2 g/day.

Dosing: Geriatric

Refer to adult dosing. The initial and maintenance dosing should be conservative, due to the potential for decreased renal function (monitor).

Dosing: Renal Impairment: Adult

eGFR ≥45 mL/minute/1.73 m²: No dosage adjustment necessary.

eGFR 30 to <45 mL/minute/1.73 m²: The manufacturer does not recommend use. However, both dapagliflozin and metformin may be considered for use in select patients with eGFR ≥30 mL/minute/1.73 m²; refer to individual agents.

eGFR <30 mL/minute/1.73 m²: Use is contraindicated.

Hemodialysis: Use is contraindicated.

Dosing: Hepatic Impairment: Adult

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; Crowley 2017; 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.

Calculations

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. Note: Dapagliflozin is also indicated for risk reduction of hospitalization for heart failure in patients with type 2 diabetes mellitus and established cardiovascular disease or multiple cardiovascular risk factors.

Clinical Practice Guidelines

See individual agents.

Administration: Oral

Extended release tablets: 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.

Dietary Considerations

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

Storage/Stability

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).

Medication Patient Education with HCAHPS Considerations

What is this drug used for?

• It is used to lower blood sugar in patients with high blood sugar (diabetes).

• It is used in certain people to lower the risk of having to go to the hospital for heart failure.

Frequently reported side effects of this drug

• Nose irritation

• Throat irritation

• Diarrhea

• Nausea

• Vomiting

• Tablet shell in stool

• Headache

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Acidosis like confusion, fast breathing, fast heartbeat, abnormal heartbeat, severe abdominal pain, nausea, vomiting, fatigue, shortness of breath, or loss of strength and energy

• Lactic acidosis like fast breathing, fast heartbeat, abnormal heartbeat, vomiting, fatigue, shortness of breath, severe loss of strength and energy, severe dizziness, feeling cold, or muscle pain or cramps

• Fluid and electrolyte problems like mood changes, confusion, muscle pain or weakness, abnormal heartbeat, severe dizziness or passing out, fast heartbeat, increased thirst, seizures, loss of strength and energy, lack of appetite, unable to pass urine or change in amount of urine passed, dry mouth, dry eyes, or nausea or vomiting

• Kidney problems like unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain

• Urinary tract infection like blood in the urine, burning or pain when passing urine, passing a lot of urine, fever, lower abdominal pain, or pelvic pain

• Low blood sugar like dizziness, headache, fatigue, feeling weak, shaking, fast heartbeat, confusion, increased hunger, or sweating

• Pain, swelling, or signs of infection in the genitals or rectum

• Vaginal yeast infection

• Penile yeast infection

• Severe abdominal pain

• Signs of a significant reaction like 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. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Medication Guide and/or Vaccine Information Statement (VIS)

An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:

Xigduo XR: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/205649s013lbl.pdf#page=52

Contraindications

History of serious hypersensitivity to dapagliflozin, metformin, or any component of the formulation; severe renal impairment (eGFR <30 mL/minute/1.73 m²), ESRD 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

Warnings/Precautions

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) in one randomized, controlled trial (Kohan 2014). However, a second randomized, controlled trial did not confirm a similar increased risk in patients with eGFR 45 to 60 mL/minute/1.73 m² (Fioretto 2018). In the overall population, dapagliflozin does not appear to increase risk of fractures, though longer-term data may be necessary to clarify risk (Jabbour 2018; Ruanpeng 2017; Tang 2016).

• 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, angiotensin-converting enzyme [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). Before initiating treatment, consider risk factors that may predispose to ketoacidosis (eg, pancreatic insulin deficiency, dose decreases of insulin, caloric restriction, alcohol abuse, acute febrile illness, surgery, any other extreme stress event). Consider temporary discontinuation of therapy at least 3 days prior to surgery or any event which may precipitate ketoacidosis; ensure risk factors are resolved prior to reinitiating therapy. 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 of age, 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.

• Necrotizing fasciitis: Cases of necrotizing fasciitis of the perineum (Fournier gangrene), a rare but serious and potentially fatal infection, have been reported in patients receiving dapagliflozin. Assess patients presenting with fever or malaise along with genital or perianal pain, tenderness, erythema, or swelling for necrotizing fasciitis. Discontinue in patients who develop necrotizing fasciitis and initiate treatment immediately.

• 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 nonsteroidal anti-inflammatory drugs]). 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 infection (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 2019).

Disease-related concerns:

• Bariatric surgery:

– Altered absorption: Use individual components of the formulation as immediate-release (IR) tablets or solution after surgery. Absorption may be altered given the anatomic and transit changes created by gastric bypass and sleeve gastrectomy surgery. Extended-release (ER) tablets may have a reduced effect after gastric bypass or sleeve gastrectomy due to the direct bypass of the stomach and proximal small bowel with gastric bypass or a more rapid gastric emptying and proximal small bowel transit with sleeve gastrectomy (Mechanick 2013; Melissas 2013). After gastric bypass (Roux-en-Y gastric bypass [RYGB]), administration of IR tablets led to increased absorption (AUC_0-∞ increased by 21%) and bioavailability (increased by 50%) (Padwal 2011). Lactate levels decrease after gastric bypass (RYGB)-induced weight loss irrespective of the use of metformin. Routinely lowering metformin dose after gastric bypass is not necessary as long as normal renal function is preserved (Deden 2018).

– Dehydration: Evaluate, correct, and maintain postsurgical fluid requirements and volume status prior to initiating therapy and closely monitor the patient for the duration of therapy; volume depletion and related adverse events (eg, hypotension, orthostatic hypotension, syncope) have occurred. Fluid intake may be more difficult after gastric bypass, sleeve gastrectomy, and gastric band (Mechanick 2013).

– Euglycemic diabetic ketoacidosis: Discontinue therapy 3 to 5 days prior to surgery (Bobart 2016). Postoperatively, assess volume status, caloric intake, and need for diabetes treatment, and withhold antidiabetic medication if type 2 diabetes is in remission. Ketoacidosis has been reported in patients with type 1 and type 2 diabetes on SGLT-2 inhibitors. In some cases, normal or only modestly elevated blood glucose was present (<250 mg/dL) (van Niekerk 2018). Risk factors include significant reduction in insulin, caloric restriction, stress of surgery, and infection.

• Heart failure: Metformin may be used in patients with stable heart failure (HF); avoid use in unstable or hospitalized patients with heart failure (ADA 2019). 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 eGFR; the risks of metformin accumulation and lactic acidosis increase with degree of renal impairment. Glycemic efficacy of dapagliflozin may be decreased in patients with renal impairment. The manufacturer does not recommend use of the combination product when eGFR is <45 mL/minute/1.73 m² and contraindicates use when eGFR <30 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.

Special populations:

• Elderly: Use with caution; risk of metformin-associated lactic acidosis increases with age.

• Hospitalized patients: Use of SGLT2-inhibitors are not routinely recommended for hospitalized patients (ADA 2019).

Other warnings/precautions:

• 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: Consider temporary discontinuation of dapagliflozin-containing products at least 3 days prior to surgery; ensure risk factors for ketoacidosis are resolved prior to reinitiating therapy.

Geriatric Considerations

Intensive glucose control (HbA1c <6.5%) has been linked to increased all-cause and cardiovascular mortality, hypoglycemia requiring assistance, and weight gain in adult type 2 diabetes. How "tightly" to control a geriatric patient's blood glucose needs to be individualized. Such a decision should be based on several factors, including the patient's functional and cognitive status, how well he/she recognizes hypoglycemic or hyperglycemic symptoms, and how to respond to them and other disease states. An HbA1c <7.5% is an acceptable endpoint for a healthy older adult, while <8% is acceptable for frail elderly patients, those with a duration of illness >10 years, or those with comorbid conditions and requiring combination diabetes medications. In patients with advanced microvascular complications and/or a life expectancy <5 years, a target HbA1c of 8% to 9% is reasonable. For elderly patients with diabetes who are relatively healthy, attaining target goals for aspirin use, blood pressure, lipids, smoking cessation, and diet and exercise may be more important than normalized glycemic control.

Pregnancy Considerations

Metformin crosses the placenta (ADA 2020).

Refer to individual monographs for additional information.

Breast-Feeding Considerations

Metformin is present in breast milk (Hale 2002). It is not known if dapagliflozin is present in breast milk.

Due to the potential for serious adverse reactions in the breastfeeding infant, breastfeeding is not recommended by the manufacturer.

Lexicomp Pregnancy & Lactation, In-Depth

Briggs' Drugs in Pregnancy & Lactation

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%, 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)

Allergy and Idiosyncratic Reactions

Biguanide Allergy

Toxicology

Antidiabetic Agents, Biguanides

Metabolism/Transport Effects

Refer to individual components.

Drug Interactions Open Interactions

Abemaciclib: May increase the serum concentration of MetFORMIN. Risk C: Monitor therapy

Alcohol (Ethyl): May enhance the adverse/toxic effect of MetFORMIN. Specifically, alcohol may potentiate the risk of lactic acidosis Risk X: Avoid combination

Alpha-Lipoic Acid: May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy

Androgens: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Exceptions: Danazol. Risk C: Monitor therapy

Bictegravir: May increase the serum concentration of MetFORMIN. Risk C: 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. Risk C: Monitor therapy

Cephalexin: May increase the serum concentration of MetFORMIN. Risk C: 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). Risk D: Consider therapy modification

Dalfampridine: MetFORMIN may increase the serum concentration of Dalfampridine. Dalfampridine may increase the serum concentration of MetFORMIN. Risk C: Monitor therapy

Direct Acting Antiviral Agents (HCV): May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy

Dofetilide: MetFORMIN may increase the serum concentration of Dofetilide. Risk C: Monitor therapy

Dolutegravir: May increase the serum concentration of MetFORMIN. Management: Consider the risks and benefits of this combination. If combined, limit the daily metformin dose to 1,000 mg when used with dolutegravir. Monitor for increased metformin effects/toxicities (including lactic acidosis) during concomitant use. Risk D: Consider therapy modification

Erdafitinib: May increase the serum concentration of OCT2 Substrates. Risk C: Monitor therapy

Glycopyrrolate (Systemic): May increase the serum concentration of MetFORMIN. Risk C: Monitor therapy

Guanethidine: May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy

Hyperglycemia-Associated Agents: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy

Hypoglycemia-Associated Agents: Antidiabetic Agents may enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Risk C: Monitor therapy

Insulins: Sodium-Glucose Cotransporter 2 (SGLT2) 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. Risk D: 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. Risk D: Consider therapy modification

Isavuconazonium Sulfate: May increase the serum concentration of MetFORMIN. Risk C: 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. Risk C: Monitor therapy

Maitake: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy

Monoamine Oxidase Inhibitors: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy

Nonsteroidal Anti-Inflammatory Agents: May enhance the adverse/toxic effect of MetFORMIN. Risk C: Monitor therapy

Ombitasvir, Paritaprevir, and Ritonavir: May enhance the adverse/toxic effect of MetFORMIN. Specifically, the risk for lactic acidosis may be increased. Risk C: Monitor therapy

Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir: May enhance the adverse/toxic effect of MetFORMIN. Specifically, the risk for lactic acidosis may be increased. Risk C: Monitor therapy

Ondansetron: May increase the serum concentration of MetFORMIN. Risk C: Monitor therapy

Patiromer: May decrease the serum concentration of MetFORMIN. Management: Administer metformin at least 3 hours before or 3 hours after patiromer. Risk D: Consider therapy modification

Pegvisomant: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy

Prothionamide: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy

Quinolones: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Quinolones may diminish the therapeutic effect of Agents with Blood Glucose Lowering Effects. Specifically, if an agent is being used to treat diabetes, loss of blood sugar control may occur with quinolone use. Risk C: Monitor therapy

Ranolazine: May increase the serum concentration of MetFORMIN. Management: Limit the metformin dose to a maximum of 1,700 mg per day when used together with ranolazine 1,000 mg twice daily. Monitor patients for metformin toxicities, including lactic acidosis and carefully weigh the risks and benefits of this combination. Risk D: Consider therapy modification

Ritodrine: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy

Salicylates: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy

Selective Serotonin Reuptake Inhibitors: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy

Sulfonylureas: Sodium-Glucose Cotransporter 2 (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. Risk D: Consider therapy modification

Tafenoquine: May increase the serum concentration of MATE1 Substrates. Management: Avoid use of MATE substrates with tafenoquine, and if the combination cannot be avoided, monitor closely for evidence of toxicity of the MATE substrate and consider a reduced dose of the MATE substrate according to that substrate's labeling. Risk D: Consider therapy modification

Tafenoquine: May increase the serum concentration of OCT2 Substrates. Management: Avoid use of OCT2 substrates with tafenoquine, and if the combination cannot be avoided, monitor closely for evidence of toxicity of the OCT2 substrate and consider a reduced dose of the OCT2 substrate according to that substrate's labeling. Risk D: Consider therapy modification

Thiazide and Thiazide-Like Diuretics: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy

Topiramate: May enhance the adverse/toxic effect of MetFORMIN. Risk C: Monitor therapy

Trimethoprim: May increase the serum concentration of MetFORMIN. Risk C: Monitor therapy

Trospium: MetFORMIN may decrease the serum concentration of Trospium. Risk C: Monitor therapy

Vandetanib: May increase the serum concentration of MetFORMIN. Risk C: Monitor therapy

Verapamil: May diminish the therapeutic effect of MetFORMIN. Risk C: 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.

Monitoring Parameters

HbA_1c (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 2019); plasma glucose; renal function (baseline then annually or when clinically indicated); volume status (eg, weight, blood pressure, hematocrit, electrolytes); hematologic parameters (annually); genital mycotic infections and urinary tract infection; hypersensitivity reactions; vitamin B₁₂ every 2 to 3 years; folate (if megaloblastic anemia is suspected); if signs/symptoms of ketoacidosis (eg, nausea/vomiting, abdominal pain, malaise, shortness of breath) confirm diagnosis by direct measurement of blood ketones and arterial pH (measurement of serum bicarbonate or urinary ketones may not be adequate) (AACE [Handelsman 2016]).

Reference Range

Recommendations for glycemic control in patients with diabetes:

Nonpregnant adults (ADA 2019):

HbA_1c: <7% (a more aggressive [<6.5%] or less aggressive [<8%] HbA_1c goal may be targeted based on patient-specific characteristics)

Preprandial capillary blood glucose: 80 to 130 mg/dL (more or less stringent goals may be appropriate based on patient-specific characteristics)

Peak postprandial capillary blood glucose: <180 mg/dL (more or less stringent goals may be appropriate based on patient-specific characteristics)

Older adults (≥65 years of age) (ADA 2019):

HbA_1c: <7.5% (healthy); <8% (complex/intermediate health); <8.5% (very complex/poor health) (individualization may be appropriate based on patient and caregiver preferences)

Preprandial capillary blood glucose: 90 to 130 mg/dL (healthy); 90 to 150 mg/dL (complex/intermediate health); 100 to 180 mg/dL (very complex/poor health)

Bedtime capillary blood glucose: 90 to 150 mg/dL (healthy); 100 to 180 mg/dL (complex/intermediate health); 110 to 200 mg/dL (very complex/poor health)

Nursing Physical Assessment/Monitoring

See individual agents.

Dosage Forms: US

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]

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Xigduo: Dapagliflozin 5 mg and metformin hydrochloride 850 mg, Dapagliflozin 5 mg and metformin hydrochloride 1000 mg

Anatomic Therapeutic Chemical (ATC) Classification

A10BD15

Generic Available (US)

Pricing: US

Tablet, 24-hour (Xigduo XR Oral)

2.5-1000 mg (per each): $10.14

5-500 mg (per each): $20.29

5-1000 mg (per each): $10.14

10-500 mg (per each): $20.29

10-1000 mg (per each): $20.29

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Mechanism of Action

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. Dapagliflozin also reduces sodium reabsorption and increases sodium delivery to the distal tubule, which may decrease cardiac preload/afterload and downregulate sympathetic activity.

Metformin: Decreases hepatic glucose production, decreases intestinal absorption of glucose, improves insulin sensitivity by increasing peripheral glucose uptake and utilization.

Pharmacodynamics/Kinetics

See individual agents.

Combination tablets are considered bioequivalent to coadministration of individual dapagliflozin and metformin extended-release tablets.

Local Anesthetic/Vasoconstrictor Precautions

No information available to require special precautions

Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Dizziness and syncope have been reported; patients may experience orthostatic hypotension as they stand up after treatment; especially if lying in dental chair for extended periods of time. Use caution with sudden changes in position during and after dental treatment.

Dapagliflozin-dependent patients with diabetes (noninsulin dependent, type 2) should be questioned by the dental professional at each dental visit to assess their risk for stress-induced hypoglycemia. The dental professional should inquire about the patient’s routine (ie, work, sleep schedule, eating patterns), history of hypoglycemia, time of last medication dose, last meal, and most recent blood sugar assessment. Keep a supply of glucose tablets and other carbohydrates in the office to prepare for a hypoglycemic event. Seek medical attention when necessary (American Diabetes Association 2016).

Effects on Bleeding

No information available to require special precautions

Related Information

Index Terms

Dapagliflozin/Metformin HCl; Metformin and Dapagliflozin; Metformin Hydrochloride and Dapagliflozin

FDA Approval Date

October 30, 2014

References

American College of Radiology Committee on Drugs and Contrast Media. ACR Manual on Contrast Media. Version 10.3. https://www.acr.org/Clinical-Resources/Contrast-Manual. Published 2017. Accessed January 3, 2018.

American Diabetes Association (ADA). Diabetes Care. 2019;42(suppl 1):S1-S193. http://care.diabetesjournals.org/content/42/Supplement_1. Accessed January 9 2019.

American Diabetes Association (ADA). Standards of medical care in diabetes–2020. Diabetes Care. 2020;43(suppl 1):S1-S212. https://care.diabetesjournals.org/content/43/Supplement_1. Accessed January 22, 2020.

Bobart SA, Gleason B, Martinez N, Norris K, Williams SF. Euglycemic ketoacidosis caused by sodium-glucose cotransporter 2 inhibitors: a case report. Ann Intern Med. 2016;165(7):530-532.[PubMed 27699391]

Brackett CC. Clarifying metformin's role and risks in liver dysfunction. J Am Pharm Assoc (2003). 2010;50(3):407-410.[PubMed 20452916]

Crowley MJ, Diamantidis CJ, McDuffie JR, et al. Clinical outcomes of metformin use in populations with chronic kidney disease, congestive heart failure, or chronic liver disease: a systematic review. Ann Intern Med. 2017;166(3):191-200. doi: 10.7326/M16-1901.[PubMed 28055049]

Deden LN, Aarts EO, Aelfers SCW, et al. Risk of metformin-associated lactic acidosis (MALA) in patients after gastric bypass surgery. Obes Surg. 2018;28(4):1080-1085. doi: 10.1007/s11695-017-2974-1.[PubMed 29058235]

Eurich DT, Weir DL, Majumdar SR, et al. Comparative safety and effectiveness of metformin in patients with diabetes mellitus and heart failure: systematic review of observational studies involving 34,000 patients. Circ Heart Fail. 2013;6(3):395-402. doi: 10.1161/CIRCHEARTFAILURE.112.000162.[PubMed 23508758]

Farxiga (dapagliflozin) [prescribing information]. Wilmington, DE: AstraZeneca; March 2015.

FDA Drug Safety Communication: FDA revises labels of SGLT2 inhibitors for diabetes to include warnings about too much acid in the blood and serious urinary tract infections. Food and Drug Administration website. http://www.fda.gov/Drugs/DrugSafety/ucm475463.htm. Published December 4, 2015. Accessed October 2016.

Fioretto P, Del Prato S, Buse JB, et al; DERIVE Study Investigators. Efficacy and safety of dapagliflozin in patients with type 2 diabetes and moderate renal impairment (chronic kidney disease stage 3A): the DERIVE study [published correction appears in Diabetes Obes Metab. 2019;21(1):203]. Diabetes Obes Metab. 2018;20(11):2532-2540. doi: 10.1111/dom.13413.[PubMed 29888547]

Hale TW, Kristensen JH, Hackett LP, et al. Transfer of Metformin Into Human Milk. Diabetologia. 2002;45(11):1509-1514.[PubMed 12436333]

Handelsman Y, Henry RR, Bloomgarden ZT, et al. American Association of Clinical Endocrinologists and American College of Endocrinology Position Statement on the Association of SGLT-2 Inhibitors and Diabetic Ketoacidosis. Endocr Pract. 2016;22(6):753-762.[PubMed 27082665]

Jabbour S, Seufert J, Scheen A, Bailey CJ, Karup C, Langkilde AM. Dapagliflozin in patients with type 2 diabetes mellitus: a pooled analysis of safety data from phase IIb/III clinical trials. Diabetes Obes Metab. 2018;20(3):620-628. doi: 10.1111/dom.13124.[PubMed 28950419]

Kohan DE, Fioretto P, Tang W, List JF. Long-term study of patients with type 2 diabetes and moderate renal impairment shows that dapagliflozin reduces weight and blood pressure but does not improve glycemic control. Kidney Int. 2014;85(4):962-971. doi: 10.1038/ki.2013.356.[PubMed 24067431]

Mechanick JI, Youdim A, Jones DB, et al. Clinical practice guidelines for the perioperative nutritional, metabolic, and nonsurgical support of the bariatric surgery patient--2013 update: cosponsored by American Association of Clinical Endocrinologists, the Obesity Society, and American Society for Metabolic & Bariatric Surgery. Surg Obes Relat Dis. 2013;9(2):159-191. doi: 10.1016/j.soard.2012.12.010.[PubMed 23537696]

Melissas J, Leventi A, Klinaki I, et al. Alterations of global gastrointestinal motility after sleeve gastrectomy: a prospective study. Ann Surg. 2013;258(6):976-982. doi: 10.1097/SLA.0b013e3182774522.[PubMed 23160151]

Padwal RS, Gabr RQ, Sharma AM, et al. Effect of gastric bypass surgery on the absorption and bioavailability of metformin. Diabetes Care. 2011;34(6):1295-1300. doi: 10.2337/dc10-2140.[PubMed 21478461]

Page RL 2nd, O'Bryant CL, Cheng D, et al.; American Heart Association Clinical Pharmacology and Heart Failure and Transplantation Committees of the Council on Clinical Cardiology; Council on Cardiovascular Surgery and Anesthesia; Council on Cardiovascular and Stroke Nursing; and Council on Quality of Care and Outcomes Research. Drugs That May Cause or Exacerbate Heart Failure: A Scientific Statement From the American Heart Association. Circulation. 2016;134(6):e32-69. doi:10.1161/CIR.0000000000000426.[PubMed 27400984]

Ruanpeng D, Ungprasert P, Sangtian J, Harindhanavudhi T. Sodium-glucose cotransporter 2 (SGLT2) inhibitors and fracture risk in patients with type 2 diabetes mellitus: a meta-analysis. Diabetes Metab Res Rev. 2017;33(6). doi: 10.1002/dmrr.2903.[PubMed 28440590]

Tang HL, Li DD, Zhang JJ, et al. Lack of evidence for a harmful effect of sodium-glucose co-transporter 2 (SGLT2) inhibitors on fracture risk among type 2 diabetes patients: a network and cumulative meta-analysis of randomized controlled trials. Diabetes Obes Metab. 2016;18(12):1199-1206. doi: 10.1111/dom.12742.[PubMed 27407013]

van Niekerk C, Wallace J, Takata M, Yu R. Euglycaemic diabetic ketoacidosis in bariatric surgery patients with type 2 diabetes taking canagliflozin [published online August 20, 2018]. BMJ Case Rep. doi: 10.1136/bcr-2017-221527.[PubMed 30131409]

Xigduo (dapagliflozin and metformin) [product monograph]. Mississauga, Ontario, Canada: AstraZeneca Canada Inc; July 2019.

Xigduo XR (dapagliflozin and metformin) [prescribing information]. Wilmington, DE: AstraZeneca; January 2020.

Zhang X, Harmsen WS, Mettler TA, et al. Continuation of metformin use after a diagnosis of cirrhosis significantly improves survival of patients with diabetes. Hepatology. 2014;60(6):2008-2016.[PubMed 24798175]

Brand Names: International

Diglifloz Plus (EG); Ebymect (BE, ES, IE); Xigduo (AT, BE, CZ, DE, DK, EE, ES, FI, GB, HR, HU, IE, LT, LU, LV, MT, NL, NO, PL, PT, RO, SE, SI, SK); Xigduo XR (AE, AU, BB, BR, CR, DO, GT, HK, HN, ID, IL, IN, KR, KW, LB, MY, NI, NZ, PA, PH, SG, SV, TH)

Last Updated 2/27/20

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