(kan a gli FLOE zin)
Diabetes mellitus, type 2: Treatment of type 2 diabetes mellitus (noninsulin dependent, NIDDM) as an adjunct to diet and exercise to improve glycemic control
History of serious hypersensitivity to canagliflozin or any component of the formulation; severe renal impairment (eGFR <30 mL/minute/1.73 m2); end-stage renal disease or patients on dialysis.
Canadian labeling: Additional contraindications (not in US labeling): eGFR <45 mL/minute/1.73 m2
Note: If present, correct volume depletion prior to initiation.
Diabetes mellitus, type 2: Oral: Initial: 100 mg once daily prior to first meal of the day; may increase to 300 mg once daily (only in patients with eGFR ≥60 mL/minute/1.73 m2)
Dosing adjustment for concomitant therapy with UDP-glucuronosyl transferase (UGT) inducers (eg, rifampin, phenytoin, phenobarbital, ritonavir): Consider increasing the canagliflozin dose to 300 mg once daily in patients currently tolerating canagliflozin 100 mg once daily 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 antihyperglycemic therapy.
Refer to adult dosing.
US labeling:
eGFR ≥60 mL/minute/1.73 m2: No dosage adjustment necessary.
eGFR 45 to <60 mL/minute/1.73 m2: Maximum dose: 100 mg once daily. If patient receiving concurrent UDP-glucuronosyl transferase (UGT) enzyme inducers (eg, rifampin, phenytoin, phenobarbital, ritonavir) and eGFR 45 to <60 mL/minute/1.73 m2 at baseline, consider the use of another antidiabetic agent.
eGFR ≥30 to <45 mL/minute/1.73 m2: Use not recommended for initiation of therapy or when eGFR is persistently <45 mL/minute/1.73 m2.
eGFR <30 mL/minute/1.73 m2: Use is contraindicated.
End-stage renal disease (ESRD): Use is contraindicated.
Hemodialysis: Use is contraindicated.
Canadian labeling:
eGFR ≥60 mL/minute/1.73 m2: No dosage adjustment necessary.
eGFR 45 to <60 mL/minute/1.73 m2: Avoid initiating therapy if eGFR <60 mL/minute/1.73 m2 at baseline. If eGFR persistently falls to 45 to <60 mL/minute/1.73 m2 during therapy, do not exceed 100 mg once daily. If patient receiving concurrent UDP-glucuronosyl transferase (UGT) enzyme inducers (eg, rifampin, phenytoin, phenobarbital, ritonavir) and eGFR 45 to <60 mL/minute/1.73 m2 at baseline, consider the use of another antidiabetic agent.
eGFR <45 mL/minute/1.73 m2: Use is contraindicated.
ESRD: Use is contraindicated.
Hemodialysis: Use is contraindicated.
Mild-to-moderate impairment (Child-Pugh class A, B): No dosage adjustment necessary.
Severe impairment (Child-Pugh class C): Use not recommended (has not been studied).
May be administered with or without food. It is recommended to take before the first meal of the day (may reduce postprandial hyperglycemia via delayed intestinal glucose absorption). Canadian labeling suggests that the tablet should be swallowed whole.
Individualized medical nutrition therapy (MNT) based on ADA recommendations is an integral part of therapy.
Store at 25 ‚ °C (77 ‚ °F); excursions permitted to 15 ‚ °C to 30 ‚ °C (59 ‚ °F to 86 ‚ °F).
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Invokana: 100 mg, 300 mg
ACE Inhibitors: Canagliflozin may enhance the hyperkalemic effect of ACE Inhibitors. Canagliflozin may enhance the hypotensive effect of ACE Inhibitors. Monitor therapy
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
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
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
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
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
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
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 Johns 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
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); renal function and volume status (baseline and periodically during treatment); serum potassium (periodically after initiation in renal impairment and those predisposed to hyperkalemia); serum magnesium and phosphate; LDL-C; genital mycotic infections and UTI; hypersensitivity reactions; blood pressure; signs and symptoms of metabolic acidosis
Positive test for glucosuria; may interfere with 1,5-anhydroglucitol (1,5-AG) assay; use alternative methods to monitor glycemic control.
>10%:
Endocrine & metabolic: Increased serum potassium (>5.4 mEq/mL: 9% to 27%, ≥6.5 mEq/mL: 1% to 2%; dose-related; more risk in patients with moderate renal impairment)
Genitourinary: Genitourinary infection (females: 11% to 12%; including vulvovaginal candidiasis, vulvovaginal mycotic infection, vulvovaginitis, vaginal infection, vulvitis; males: 4%; including balanitis/balanoposthitis, balanitis candida, fungal genital infection)
1% to 10%:
Central nervous system: Falling (1% to 2%), fatigue (2%)
Endocrine & metabolic: Hypoglycemia (4%; monotherapy), increased thirst (2% to 3%)
Gastrointestinal: Abdominal pain (2%), constipation (2%)
Genitourinary: Urinary tract infection (6%), polyuria (5%), vulvovaginal pruritus (2% to 3%)
Hypersensitivity: Hypersensitivity (4%)
Neuromuscular & skeletal: Bone fracture (1% to 2%), weakness ( ≤1%)
Renal: Renal insufficiency (2% to 4%; 18% to 23% in patients with baseline eGFR 30 to <50 mL/minute/1.73 m2)
Frequency not defined:
Endocrine & metabolic: Hypermagnesemia, increased LDL cholesterol, increased serum cholesterol (non-HDL), increased serum phosphate
Hematologic & oncologic: Increased hemoglobin
Neuromuscular & skeletal: Decreased bone mineral density
Renal: Acute renal failure
<1% (Limited to important or life-threatening): Anaphylaxis, angioedema, ketoacidosis, pancreatitis, pyelonephritis, skin photosensitivity, urosepsis
Concerns related to adverse effects:
- Bone fractures: Increased incidence of bone fractures may occur as early as 12 weeks after treatment initiation. Consider patients 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: 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, urticaria) with some being severe; generally occurs within hours to days after therapy initiation. Discontinue canagliflozin if hypersensitivity occurs and treat as appropriate.
- Hypotension: 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.
- Hyperkalemia: 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.
- 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 co-transporter-2 (SGLT2) inhibitors; before initiating treatment, consider risk factors that may predispose to ketoacidosis (eg, pancreatic insulin deficiency from any cause, caloric restriction, and alcohol abuse). 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.
- Lipid abnormality: May cause dose-related LDL-cholesterol (C) elevation; monitor LDL-C and treat as needed.
- Renal effects: Acute kidney injury has been reported; 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). 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) may occur upon initiation and are dose dependent. Monitor renal function frequently in patients with an eGFR <60 mL/minute/1.73 m2 and discontinue therapy if eGFR is persistently <45 mL/minute/1.73 m2.
- Urinary tract infection: Serious urinary infections including urosepsis and pyelonephritis requiring hospitalization have been reported; treatment with SGLT2 inhibitors increase the risk for urinary tract infections (UTI); monitor for signs and symptoms of UTI and treat as needed.
Disease-related concerns:
- Hepatic impairment: Not recommended for use in severe hepatic impairment (has not been studied). Dose adjustment is not necessary in mild or moderate hepatic impairment.
- Renal impairment: Glycemic efficacy may be less and adverse reactions may be higher with moderate renal impairment (eGFR 30 to <50 mL/minute/1.73 m2). Dose-dependent hyperkalemia has been observed; dosage adjustment may be necessary in patients with preexisting renal impairment. Safety and efficacy in severe renal impairment (<30 mL/minute/1.73 m2), ESRD, and in patients receiving dialysis are not established and canagliflozin is contraindicated in these patients.
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: Elderly patients ( ≥65 years) may have an increased risk of symptoms related to intravascular volume depletion (eg, hypotension, orthostatic hypotension, dizziness, syncope, and dehydration) during therapy, especially with the 300 mg dose; elderly patients ≥75 years may experience a more pronounced risk. HbA1c reductions may be less in patients >65 years compared to younger patients.
Other warnings/precautions:
- Appropriate use: Not for use in patients with diabetic ketoacidosis (DKA) or patients with type 1 diabetes mellitus (insulin-dependent, IDDM).
C
Adverse events have been observed in animal reproduction studies. Based on animal data, adverse fetal effects on renal development may occur in humans following in utero exposure during the second and third trimesters.
In women with diabetes, maternal hyperglycemia can be associated with congenital malformations as well as adverse effects in the fetus, neonate, and the mother (ACOG 2005; ADA 2015; Kitzmiller 2008; Metzger 2007). To prevent adverse outcomes, prior to conception and throughout pregnancy maternal blood glucose and HbA1c should be kept as close to target goals as possible but without causing significant hypoglycemia (ACOG 2013; ADA 2015; Blumer 2013; Kitzmiller 2008). Prior to pregnancy, effective contraception should be used until glycemic control is achieved (Kitzmiller 2008). Other agents are currently recommended to treat diabetes in pregnant women (ACOG 2013; Blumer 2013).
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.
Not affected by food; however, administration prior to the first meal of the day may delay intestinal glucose absorption, thereby reducing postprandial hyperglycemia.
Vdss: 83.5 L (intravenous administration)
Major metabolism through O-glucuronidation by UGT1A9 and UGT2B4 to two inactive metabolites; minor oxidative metabolism (~7%) through CYP3A4.
Feces (41.5% as unchanged drug, 7% as hydroxylated metabolite, 3.2% as O-glucuronide metabolite); urine ~33% (30.5% as O-glucuronide metabolites, <1% as unchanged drug)
Within 24 hours (dose-dependent)
Plasma: 1 to 2 hours
Suppression of the renal threshold for glucose (RTG) occurs throughout the 24-hour dosing interval; maximal RTG suppression occurred with the 300 mg dose (RTG decreased from baseline of ~240 mg/dL to a mean of 70 to 90 mg/dL over 24 hours).
Apparent terminal half-life: 100 mg dose: 10.6 hours; 300 mg dose: 13.1 hours
99% mainly to albumin
- 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?)
- Have patient report immediately to prescriber signs of fluid and electrolyte problems (mood changes, confusion, muscle pain or weakness, abnormal heartbeat, severe dizziness or passing out, tachycardia, more thirst, seizures, loss of strength and energy, lack of appetite, urinary retention or change in the amount of urine produced, dry mouth, dry eyes, or nausea or vomiting), 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 kidney problems (urinary retention, hematuria, change in amount of urine passed, or weight gain), signs of a urinary tract infection (hematuria, burning or painful urination, polyuria, fever, lower abdominal pain, or pelvic pain), signs of low blood sugar (dizziness, headache, fatigue, feeling weak, shaking, tachycardia, confusion, hunger, or sweating), vaginal yeast infection, penile yeast infection, pain, sores, ulcers, or signs of infection in the legs or feet, or bone 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.