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Canagliflozin and Metformin

Pronunciation

(kan a gli FLOE zin & met FOR min)

Index Terms

  • Canagliflozin and Metformin Hydrochloride
  • Canagliflozin/Metformin HCl
  • Invokamet XR
  • Metformin and Canagliflozin

Dosage Forms

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

Tablet, Oral:

Invokamet: Canagliflozin 50 mg and metformin hydrochloride 500 mg, Canagliflozin 150 mg and metformin hydrochloride 500 mg, Canagliflozin 50 mg and metformin hydrochloride 1000 mg, Canagliflozin 150 mg and metformin hydrochloride 1000 mg

Tablet Extended Release 24 Hour, Oral:

Invokamet XR: Canagliflozin 50 mg and metformin hydrochloride 500 mg, Canagliflozin 150 mg and metformin hydrochloride 500 mg, Canagliflozin 50 mg and metformin hydrochloride 1000 mg, Canagliflozin 150 mg and metformin hydrochloride 1000 mg

Brand Names: U.S.

  • Invokamet
  • Invokamet XR

Pharmacologic Category

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

Pharmacology

Canagliflozin: By inhibiting sodium-glucose cotransporter 2 (SGLT2) in the proximal renal tubules, canagliflozin 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, decreasing intestinal absorption of glucose and improves insulin sensitivity (increases 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 canagliflozin and metformin is appropriate.

Contraindications

History of serious hypersensitivity (eg, anaphylaxis, angioedema) to canagliflozin, metformin, or any component of the formulation; moderate to severe renal impairment (eGFR <45 mL/minute/1.73 m2); end-stage renal disease (ESRD) or patients on dialysis; acute or chronic metabolic acidosis (including diabetic ketoacidosis).

Canadian labeling: Additional contraindications (not in US labeling): Renal function unknown, serum creatinine levels above the upper limit of normal range, or renal dysfunction (serum creatinine ≥136 micromol/L in males or ≥124 micromol/L in females or abnormal creatinine clearance <60 mL/minute) which may result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia; unstable and/or insulin-dependent (type I) diabetes mellitus; acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma, history of ketoacidosis with or without coma; history of lactic acidosis (regardless of precipitating factors); excessive alcohol intake (acute or chronic); severe hepatic dysfunction or clinical or laboratory evidence of hepatic disease; cardiovascular collapse and disease states associated with hypoxemia including cardiorespiratory insufficiency, which are often associated with hyperlactacidemia; stress conditions (eg, severe infection, trauma, surgery and postoperative recovery phase); severe dehydration; pregnancy; breast-feeding; period of time around administration of iodinated contrast materials

Dosing: Adult

Diabetes mellitus, type 2: Oral: Initial doses should be individualized based on patient’s current antidiabetic regimen; assess renal function before initiating and periodically thereafter:

Extended-release: Note: Daily dose is 2 tablets once daily. In patients with volume depletion not previously treated with canagliflozin, correct this condition before initiating therapy:

Patients naïve to canagliflozin or metformin: Initial: Canagliflozin 50 mg/metformin 500 mg: 2 tablets (canagliflozin 100 mg/metformin 1,000 mg) once daily. Adjust dose gradually as needed (maximum daily dose: canagliflozin 300 mg/metformin 2,000 mg).

Patients on metformin: Initial: Canagliflozin 100 mg plus similar total dose of metformin once daily. Adjust dose gradually as needed (maximum daily dose: canagliflozin 300 mg/metformin 2,000 mg). Patients taking an evening dose of metformin ER should skip their last dose before starting canagliflozin/metformin ER the following morning.

Patients on canagliflozin: Initial: Metformin 1,000 mg plus similar total dose of canagliflozin once daily. Adjust dose gradually as needed (maximum daily dose: canagliflozin 300 mg/metformin 2,000 mg).

Patients switching from immediate release to ER: Use current total dose. Adjust dose gradually as needed (maximum daily dose: canagliflozin 300 mg/metformin 2,000 mg).

Immediate-release: Note: Daily doses should be in 2 divided doses:

Patients on metformin: Initial: Canagliflozin 50 mg plus similar total dose of metformin daily. Adjust dose gradually as needed (maximum daily dose: canagliflozin 300 mg/metformin 2,000 mg).

Patients on canagliflozin: Initial: Metformin 500 mg daily plus similar total dose of canagliflozin daily. Adjust dose gradually as needed (maximum daily dose: canagliflozin 300 mg/metformin 2,000 mg).

Patients switching from combination therapy of canagliflozin and metformin as separate tablets: Use current total dose. Adjust dose gradually as needed (maximum daily dose: canagliflozin 300 mg/metformin 2,000 mg).

Dosing adjustment for concomitant therapy with UDP-glucuronosyl transferase (UGT) inducers (eg, rifampin, phenytoin, phenobarbital, ritonavir): Consider increasing the dose of canagliflozin/metformin to canagliflozin 300 mg/day in patients currently tolerating canagliflozin 100 mg/day who have eGFR ≥60 mL/minute/1.73 m2 and require additional glycemic control. If patient is receiving concurrent UGT enzyme inducers and has eGFR 45 to <60 mL/minute/1.73 m2, consider alternate therapy.

Dosing: Geriatric

Refer to adult dosing. The initial and maintenance dosing should be conservative, due to the potential for decreased renal function (monitor). Do not use metformin in patients ≥80 years unless normal renal function has been established.

Dosing: Renal Impairment

eGFR ≥60 mL/minute/1.73 m2: No dosage adjustment necessary.

eGFR 45 to <60 mL/minute/1.73 m2: Limit the dose of canagliflozin/metformin to canagliflozin 100 mg/day. If patient is receiving concurrent UGT enzyme inducers (eg, rifampin, phenytoin, phenobarbital, ritonavir) and has eGFR 45 to <60 mL/minute/1.73 m2, consider the use of another antidiabetic agent.

eGFR <45 mL/minute/1.73 m2: Use is contraindicated.

End stage renal disease (ESRD) or hemodialysis: Use is contraindicated.

Dosing: Hepatic Impairment

The manufacturer recommends avoiding metformin because liver disease is considered a risk factor for the development of lactic acidosis during metformin therapy. However, continued use of metformin in patients with diabetes with liver 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).

Administration

Immediate release: Administer twice daily with meals.

Extended release: Administer once daily with morning meal. Swallow tablets whole; do not crush, cut, or chew.

Dietary Considerations

Should be taken with meals. Avoid ethanol. Dietary modification based on ADA recommendations is a part of therapy.

Storage

Store between 20°C and 25°C (68°F and 77°F); excursions are permitted to 15°C to 30°C (59°F to 86°F). Store in original container.

Drug Interactions

ACE Inhibitors: Canagliflozin may enhance the hyperkalemic effect of ACE Inhibitors. Canagliflozin may enhance the hypotensive effect of ACE Inhibitors. Monitor therapy

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

Aliskiren: Canagliflozin may enhance the hyperkalemic effect of Aliskiren. Canagliflozin may enhance the hypotensive effect of Aliskiren. Monitor therapy

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

Amodiaquine: CYP2C8 Inhibitors may increase the serum concentration of Amodiaquine. Avoid combination

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

Angiotensin II Receptor Blockers: Canagliflozin may enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Canagliflozin may enhance the hypotensive effect of Angiotensin II Receptor Blockers. Monitor therapy

BuPROPion: May increase the serum concentration of OCT2 Substrates. Monitor therapy

CarBAMazepine: May decrease the serum concentration of Canagliflozin. Management: Consider increasing canagliflozin dose to 300 mg/day in patients with estimated GFR >60 mL/min/1.73 m2 who tolerate canagliflozin 100 mg/day and require greater glycemic control. Consider alternatives in patients with estimated GFR 45-60 mL/min/1.73 m2. Consider therapy modification

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

Efavirenz: May decrease the serum concentration of Canagliflozin. Management: Consider increasing canagliflozin dose to 300 mg/day in patients with estimated GFR >60 mL/min/1.73 m2 who tolerate canagliflozin 100 mg/day and require greater glycemic control. Consider alternatives in patients with estimated GFR 45-60 mL/min/1.73 m2. Consider therapy modification

Eplerenone: Canagliflozin may enhance the hyperkalemic effect of Eplerenone. Canagliflozin may enhance the hypotensive effect of Eplerenone. Monitor therapy

Fosphenytoin: May decrease the serum concentration of Canagliflozin. Management: Consider increasing canagliflozin dose to 300 mg/day in patients with estimated GFR >60 mL/min/1.73 m2 who tolerate canagliflozin 100 mg/day and require greater glycemic control. Consider alternatives in patients with estimated GFR 45-60 mL/min/1.73 m2. Consider therapy modification

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

Heparin: May enhance the hyperkalemic effect of Canagliflozin. Monitor therapy

Heparin (Low Molecular Weight): May enhance the hyperkalemic effect of Canagliflozin. 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

Loop Diuretics: Canagliflozin may enhance the hypotensive effect of Loop Diuretics. Management: If canagliflozin is combined with a loop diuretic, monitor for symptoms of intravascular volume depletion and hypotension. Canadian product labeling recommends avoiding the combination of canagliflozin and loop diuretics. Consider therapy modification

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

PHENobarbital: May decrease the serum concentration of Canagliflozin. Management: Consider increasing canagliflozin dose to 300 mg/day in patients with estimated GFR >60 mL/min/1.73 m2 who tolerate canagliflozin 100 mg/day and require greater glycemic control. Consider alternatives in patients with estimated GFR 45-60 mL/min/1.73 m2. Consider therapy modification

Phenytoin: May decrease the serum concentration of Canagliflozin. Management: Consider increasing canagliflozin dose to 300 mg/day in patients with estimated GFR >60 mL/min/1.73 m2 who tolerate canagliflozin 100 mg/day and require greater glycemic control. Consider alternatives in patients with estimated GFR 45-60 mL/min/1.73 m2. Consider therapy modification

Potassium-Sparing Diuretics: Canagliflozin may enhance the hyperkalemic effect of Potassium-Sparing Diuretics. Canagliflozin may enhance the hypotensive effect of Potassium-Sparing Diuretics. Monitor therapy

Primidone: May decrease the serum concentration of Canagliflozin. Management: Consider increasing canagliflozin dose to 300 mg/day in patients with estimated GFR >60 mL/min/1.73 m2 who tolerate canagliflozin 100 mg/day and require greater glycemic control. Consider alternatives in patients with estimated GFR 45-60 mL/min/1.73 m2. Consider therapy modification

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

RifAMPin: May decrease the serum concentration of Canagliflozin. Management: Consider increasing canagliflozin dose to 300 mg/day in patients with estimated GFR >60 mL/min/1.73 m2 who tolerate canagliflozin 100 mg/day and require greater glycemic control. Consider alternatives in patients with estimated GFR 45-60 mL/min/1.73 m2. Consider therapy modification

Ritonavir: May decrease the serum concentration of Canagliflozin. Management: Consider increasing canagliflozin dose to 300 mg/day in patients with estimated GFR >60 mL/min/1.73 m2 who tolerate canagliflozin 100 mg/day and require greater glycemic control. Consider alternatives in patients with estimated GFR 45-60 mL/min/1.73 m2. 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

St John's Wort: May decrease the serum concentration of Canagliflozin. Management: Consider increasing canagliflozin dose to 300 mg/day in patients with estimated GFR >60 mL/min/1.73 m2 who tolerate canagliflozin 100 mg/day and require greater glycemic control. Consider alternatives in patients with estimated GFR 45-60 mL/min/1.73 m2. Consider therapy modification

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

Adverse Reactions

See individual monographs for additional adverse effects reported with each agent. Frequencies not always defined

Cardiovascular: Symptomatic hypotension

Endocrine & metabolic: Hypoglycemia (4% to 5%)

Renal: Renal function abnormality

<1% (Limited to important or life-threatening): Ketoacidosis (FDA Safety Communication, December 4, 2015), pyelonephritis (FDA Safety Communication, December 4, 2015), severe hypoglycemia, urosepsis (FDA Safety Communication, December 4, 2015)

ALERT: U.S. Boxed Warning

Lactic acidosis:

Post-marketing 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, carbonic anhydrase inhibitors such as topiramate), age 65 years or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (eg, acute 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 canagliflozin/metformin and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.

Warnings/Precautions

Concerns related to adverse effects:

• Bone fracture: Increased incidence of bone fractures may occur as early as 12 weeks after treatment initiation. Consider patient’s risk of fracture prior to initiation. 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: Canagliflozin 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.

• Hyperkalemia: Canagliflozin may cause hyperkalemia. Patients predisposed to hyperkalemia (including patients with renal impairment or taking potassium-sparing diuretics, ACE inhibitors, and ARBs) are more likely to develop hyperkalemia; monitor serum potassium after initiation in those who are predisposed.

• Hypersensitivity reactions: Hypersensitivity reactions (eg, angioedema, anaphylaxis), some serious, generally occurs within hours to days after therapy initiation. Discontinue therapy if hypersensitivity occurs and treat as appropriate.

• Hypotension: Canagliflozin may cause symptomatic hypotension due to intravascular volume depletion especially in patients with renal impairment (ie, 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, MI, stroke, severe infection, surgery, any other extreme stress event) (Handlelsman 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, carbonic anhydrase inhibitors such as topiramate), ≥65 years, having a radiologic study with contrast, surgery and other procedures, hypoxic states (eg, acute heart failure), excessive alcohol intake, and hepatic impairment. Discontinue immediately if lactic acidosis is suspected; prompt hemodialysis is recommended. Lactic acidosis should be suspected in any patient with diabetes receiving metformin with evidence of acidosis but without evidence of ketoacidosis. Discontinue use in patients with conditions associated with dehydration, hypoperfusion, sepsis, or hypoxemia. Temporarily discontinue therapy in patients with restricted food and fluid intake. The risk of accumulation and lactic acidosis increases with the degree of impairment of renal function.

• Lipid abnormality: Canagliflozin may cause dose-related LDL-cholesterol (C) elevation; monitor LDL-C and treat as needed.

• Renal effects: Acute kidney injury has been reported with canagliflozin; may require hospitalization and dialysis; has occurred in patients <65 years of age. Prior to initiation, consider risk factors for acute kidney injury (eg, hypovolemia, chronic renal insufficiency, heart failure, use of concomitant medications including diuretics, ACE inhibitors, ARBs, and NSAIDs). Monitor patients for signs and symptoms of acute kidney injury; consider temporarily discontinuing use with reduced oral intake or fluid losses; immediately discontinue use if acute kidney injury occurs. Additional abnormalities in renal function (decreased eGFR, increased serum creatinine) may occur. Monitor renal function prior to initiation of therapy and periodically during therapy; dosage adjustment and increased renal function monitoring are recommended in patients with an eGFR <60 mL/minute/1.73 m2; use is contraindicated in patients with an eGFR <45 mL/minute/1.73 m2.

• Urinary tract infection: Serious urinary infections including urosepsis and pyelonephritis requiring hospitalization have been reported with canagliflozin; treatment increases the risk for urinary tract infections (UTI); monitor for signs and symptoms of UTI and treat as needed.

• 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.

Disease-related concerns:

• Heart failure: Use caution in patients with congestive heart failure requiring pharmacologic management, particularly in patients with unstable or acute heart failure; risk of lactic acidosis may be increased secondary to hypoperfusion. In addition, discontinue use in patients who develop hypoxic states (eg, cardiovascular collapse [shock], acute heart failure, acute myocardial infarction, other conditions with hypoxemia) due to risk of lactic acidosis.

• Hepatic impairment: Use of metformin in patients with hepatic impairment has been associated with metformin-associated lactic acidosis. Canagliflozin/metformin is not recommended in patients with hepatic impairment. Avoid use of canagliflozin/metformin ER in patients with clinical or laboratory evidence of hepatic disease.

• Renal impairment: Glycemic efficacy of canagliflozin may be less and adverse reactions may be higher with moderate renal impairment. Metformin is substantially excreted by the kidney; use with caution in patients with renal impairment; use is contraindicated in patients with an eGFR <45 mL/minute/1.73 m2 and in patients with end-stage renal disease (ESRD) or on dialysis. Monitor renal function; may assess more frequently in patients at increased risk of developing renal impairment (eg, elderly patients). Use of concomitant medications that may affect renal function (ie, affect tubular secretion) may also affect metformin disposition. Metformin-associated lactic acidosis occurred more in patients with significant renal impairment; withhold metformin in patients with dehydration and/or prerenal azotemia.

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 metformin associated lactic acidosis increases with age. Elderly patients (≥65 years) may have an increased risk of symptoms related to intravascular volume depletion (eg, hypotension, orthostatic hypotension, postural dizziness, syncope, and dehydration) during canagliflozin therapy. Use with caution in the elderly; monitor frequently.

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 an eGFR 45 to 60 mL/minute/1.73 m2; or 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).

• Patient education: Diabetes self-management education (DSME) is essential to maximize the effectiveness of therapy.

• Stress-related states: It may be necessary to discontinue metformin and administer insulin if the patient is exposed to stress (fever, trauma, infection, surgery).

• Surgical procedures: Therapy should be suspended for any surgical procedures requiring restricted intake of food and fluids due to increased risk for volume depletion, hypotension, and renal impairment.

Monitoring Parameters

Urine (glucose and ketones), fasting blood glucose, hemoglobin A1c (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); serum glucose, fructosamine; hematologic parameters (eg, hemoglobin/hematocrit and red blood cell indices); renal function and volume status (initially and periodically during therapy); vitamin B12 (periodically with long term treatment) and folate (if megaloblastic anemia is suspected); blood pressure; LDL-C; serum potassium; signs and symptoms of genital mycotic infections and UTI; signs and symptoms of metabolic acidosis.

Pregnancy Considerations

Animal reproduction studies have not been conducted with this combination. Metformin crosses the placenta. The manufacturer recommends that alternative therapies be used in pregnant women, especially during the second and third trimesters. Refer to individual agents.

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 polyuria, diarrhea, flatulence, nausea, vomiting, loss of strength and energy, 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 acidosis (confusion, fast breathing, tachycardia, abnormal heartbeat, severe abdominal pain, nausea, vomiting, fatigue, shortness of breath, or loss of strength and energy); 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 the amount of urine passed, dry mouth, dry eyes, or nausea or vomiting); signs of a urinary tract infection (hematuria, burning or painful urination, polyuria, fever, lower abdominal pain, or pelvic pain); signs of kidney problems (urinary retention, hematuria, change in amount of urine passed, or weight gain); signs of low blood sugar (dizziness, headache, fatigue, feeling weak, shaking, tachycardia, confusion, increased hunger, or sweating); pain, sores, ulcers, or signs of infection in the legs or feet; vaginal yeast infection; penile yeast infection; bone pain; 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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