Note: Hypovolemia, if present, should be corrected prior to initiation. May require a gradual dose reduction of insulin and/or insulin secretagogues (sulfonylureas, meglitinides) to avoid hypoglycemia (AACE/ACE [Garber 2020]). Temporarily discontinue use with reduced oral intake or fluid losses.
Diabetes mellitus, type 2, treatment:
Note: May be used as an adjunctive agent or alternative monotherapy for select patients, including those in whom initial therapy with lifestyle intervention and metformin failed, or who cannot take metformin. May be preferred in patients with atherosclerotic cardiovascular disease, heart failure, or diabetic kidney disease given demonstrated cardiovascular and renal benefits (ADA 2021; DeSantis 2020; Neal 2017; Perkovic 2019).
Hyperglycemia: Oral: Initial: 100 mg once daily prior to first meal of the day; may increase to 300 mg once daily after 4 to 12 weeks if needed to achieve glycemic goals (DeSantis 2020; manufacturer's labeling).
Atherosclerotic cardiovascular disease: Oral: 100 or 300 mg once daily. Note: Risk reduction for major adverse cardiovascular events has been demonstrated in patients with type 2 diabetes mellitus and established atherosclerotic cardiovascular disease (Neal 2017; Zelniker 2019).
Diabetic kidney disease: Oral: 100 mg once daily prior to the first meal of the day in patients with urinary albumin excretion >300 mg/day; no further dose titration is necessary for renal benefit. Note: Some experts also use this regimen off label in patients without severely increased albuminuria (eg, urinary albumin excretion ≤300 mg/day); benefits and harms may be more closely balanced due to smaller absolute benefit (Neal 2017; Perkovic 2018; Perkovic 2020). Because sodium-glucose cotransporter 2 inhibitors have less glycemic benefit as eGFR declines, another agent may be needed to achieve glycemic goals (Wexler 2020).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
Altered kidney function:
eGFR ≥60 mL/minute/1.73 m2: No dosage adjustment necessary.
eGFR 30 to <60 mL/minute/1.73 m2: 100 mg once daily.
eGFR <30 mL/minute/1.73 m2 with:
Urinary albumin excretion >300 mg/day: The manufacturer's labeling does not recommend initiation of therapy; however, patients previously established on canagliflozin may continue 100 mg once daily.
Urinary albumin excretion ≤300 mg/day: The manufacturer's labeling does not recommend initiation of therapy in patients without severely increased albuminuria. Canagliflozin should not be initiated in patients with an eGFR <25 to 30 mL/minute/1.73 m2; in patients previously established on canagliflozin, some experts continue use off label at a dose of 100 mg once daily (Neal 2017; Perkovic 2018; Perkovic 2020).
Hemodialysis, intermittent (thrice weekly): Not dialyzable: Use is contraindicated (manufacturer's labeling).
Peritoneal dialysis: Unlikely to be dialyzable (highly protein bound): Use is contraindicated (manufacturer's labeling).
CRRT: Avoid use (expert opinion).
PIRRT (eg, sustained, low-efficiency diafiltration): Avoid use (expert opinion).
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).
Refer to adult dosing.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Invokana: 100 mg, 300 mg
No
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Invokana: 100 mg, 300 mg
An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/204042s039lbl.pdf#page=48, must be dispensed with this medication.
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).
Diabetes mellitus, type 2, treatment: As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus; risk reduction of major cardiovascular events (cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke) in adults with type 2 diabetes mellitus and established cardiovascular disease; risk reduction of end-stage kidney disease, doubling of serum creatinine, cardiovascular death, and hospitalization for heart failure in adults with type 2 diabetes mellitus and diabetic nephropathy with urinary albumin excretion >300 mg/day.
Cases of acute kidney injury (AKI) have been reported in patients receiving sodium-glucose cotransporter 2 (SGLT2) inhibitors (specifically canagliflozin and dapagliflozin), including cases that have required hospitalization and dialysis (Ref). While canagliflozin may cause reversible kidney-related adverse events (eg, increased serum creatinine, decreased estimated GFR [eGFR]) during the first weeks of therapy, an overall reduction in the risk of AKI and kidney-related serious adverse events was demonstrated in patients who received canagliflozin during the CREDENCE trial (Ref). As evidence mounts for the positive effects of these agents on long-term kidney outcomes and a possible reduction in the incidence of AKI, clinicians will need to weigh the potential risk of AKI with the overall benefit of these agents (Ref).
Mechanism: Dose-related; related to the pharmacologic action. SGLT2 inhibition causes increased excretion of glucose and sodium, thereby resulting in an osmotic diuresis; the subsequent hyperosmolarity and volume contraction may increase the risk of AKI. Glucose in the urine may be reabsorbed by glucose transporters in exchange for uric acid, resulting in uricosuria and associated crystal-dependent and -independent damage. Lastly, SGLT2 inhibition results in increased fructose generation; the metabolism of fructose may lead to increased uric acid, oxidative stress, and the release of chemokines, thus causing local tubular injury and inflammation (Ref).
On the other hand, canagliflozin may confer some protection against AKI. Proposed mechanisms based on animal studies regarding the beneficial effects of SGLT2 inhibition on AKI include improved kidney cortical oxygen tension, tubular cell integrity, and tubular albumin reabsorption (Ref); in addition, improved cardiac function may be related to improved kidney function (Ref).
Onset: Varied. With regard to decreases in eGFR, in the CREDENCE study, administration of canagliflozin caused early decline in eGFR which tended to stabilize after ~4 weeks (Ref).
Risk factors:
• Preexisting risk factors for AKI (eg, hypovolemia, chronic kidney insufficiency, heart failure, use of concomitant medications [eg, diuretics, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs]).
An increased incidence of bone fracture was reported in the CANVAS clinical trial program (comprised of the CANVAS and CANVAS-R trials). The similarly designed CANVAS-R trial (n=5,812) did not show an increased fracture risk when analyzed separately from the CANVAS trial (n=4,330); reasons for these conflicting data within the CANVAS program are not clear (Ref). Meta-analyses and pooled analyses (excluding CANVAS trial) have not demonstrated a risk of increased fractures (Ref), and fracture risk was not increased in the CREDENCE trial (Ref).
Onset: Delayed; fractures were observed as early as 12 weeks after treatment initiation in the CANVAS trial (Ref).
Canagliflozin may cause increased serum potassium. In the CREDENCE trial, use of canagliflozin 100 mg daily in patients with a mean eGFR ~56 ± 18 mL/minute/1.73 m2 did not increase the risk of hyperkalemia compared to placebo (Ref).
Risk factors:
• Impaired kidney function (Ref)
• Higher doses (eg, 300 mg daily) (Ref)
• Concomitant use of potassium-sparing diuretics, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers (Ref)
Hypersensitivity reactions, including angioedema, urticaria, anaphylaxis and skin rash, have been reported in patients receiving sodium-glucose cotransporter 2 (SGLT2) inhibitors.
Mechanism: Not clearly established. Multiple potential mechanisms including:
• Non–dose-related; immunologic: IgE-mediated or direct mast cell stimulation (Ref)
• Dose-related; related to the pharmacologic action: Elevated levels of bradykinin (Ref)
Onset: Varied; generally occurs hours to days after treatment initiation.
Risk factors:
• Prior serious hypersensitivity reaction to canagliflozin
• Cross-reactivity: Although other SGLT2 have also been associated with hypersensitivity reactions, there are no reports of cross-reactions between these agents
Sodium-glucose cotransporter 2 (SGLT2) inhibitors may cause events consistent with hypovolemia, including symptomatic hypotension, syncope, and dehydration (Ref). Overall, a reduction in both systolic and diastolic blood pressure (-4 to -6/-1 to -2 mm Hg) has been documented for SGLT2 inhibitors (Ref).
Mechanism: Dose-related; related to the pharmacologic action. Inhibition of SGLT2 causes an increase in the excretion of glucose and sodium, thereby resulting in an osmotic diuresis and intravascular volume contraction (Ref).
Onset: Varied; timing is impacted by volume status (eg, reduced oral intake, fluid losses) and concomitant use of medications known to impact volume status or blood pressure (eg, diuretics, angiotensin-converting enzyme [ACE] inhibitors, angiotensin receptor blockers [ARBs]) (Ref).
Risk factors:
• Kidney impairment (ie, eGFR <60 mL/minute/1.73 m2)
• Older adults
• Concomitant use of antihypertensives (eg, diuretics, ACE inhibitors, ARBs)
• Preexisting low systolic blood pressure
• Reduced oral intake or increased fluid losses
Sodium-glucose cotransporter 2 (SGLT2) inhibitors, including canagliflozin, have been associated with an increased risk of genitourinary fungal infection (eg, vulvovaginal mycotic infection, vulvovaginal candidiasis, vulvovaginitis, candida balanitis, balanoposthitis) and, to a lesser extent, urinary tract infections, including severe cases of urinary tract infection with sepsis and pyelonephritis requiring hospitalization (Ref). These events are generally mild in intensity, respond to treatment, and do not lead to discontinuation (Ref). Additionally, rare but serious and potentially fatal cases of necrotizing fasciitis (perineum) (ie, Fournier gangrene) have been reported (Ref).
Mechanism: Dose-related; related to the pharmacologic action. Patients with diabetes are more prone to urinary tract and genital infections, potentially due to glucosuria-induced bacterial growth, increased adherence of bacteria to the uroepithelium, and altered immune function (Ref). Because SGLT2 inhibitors increase urinary excretion of glucose, it has been hypothesized that these agents further increase the risk of these infections (Ref).
Onset: Varied; available literature suggests that the increased risk of genital infection may be apparent within the first month of SGLT2 inhibitor therapy and remain elevated throughout the course of therapy (Ref); Fournier gangrene may have an average onset of 9 months (range: 5 days to 49 months) (Ref).
Risk factors:
• Diabetes and/or uncontrolled hyperglycemia (Ref)
• Older adults
• Prior history of these types of infections (Ref)
• Females (Ref)
• Uncircumcised males (increased risk for genital infections) (Ref)
Cases of ketoacidosis have been reported in patients with type 1 and type 2 diabetes mellitus receiving sodium-glucose cotransporter 2 (SGLT2) inhibitors, including canagliflozin (Ref).
In some cases, patients have presented with normal or only modestly elevated blood glucose (<250 mg/dL), which can lead to misdiagnosis, prevent timely initiation of treatment, and negatively influence duration of illness (Ref). In addition, SGLT2 inhibitor-mediated increases in urinary glucose loss may persist for several days after discontinuation which may impact duration of illness in patients who develop ketoacidosis (Ref).
Mechanism: Dose-related; related to the pharmacologic action. Several mechanisms have been proposed centered on increased ketone body production and reabsorption. Because SGLT2 inhibitors decrease urinary excretion of ketone bodies and decrease blood glucose in an insulin-independent manner, plasma glucose and urine ketone concentrations may be lower than what is typically expected in classic presentations of diabetic ketoacidosis (Ref).
Onset: Varied; timing is often impacted by the onset of metabolically stressful events (eg, surgery, extensive exercise, myocardial infarction [MI], stroke, severe infections, prolonged fasting) (Ref).
Risk factors:
• Patients with diabetes who are insulin deficient (eg, latent autoimmune diabetes in adults, type 1 diabetes, or some patients with long-standing type 2 diabetes) (Ref)
• Metabolically stressful events (eg, surgery, extensive exercise, MI, stroke, severe infections, prolonged fasting) (Ref)
• Presence of other risk factors that may predispose a patient to ketoacidosis (eg, pancreatic insulin deficiency, dose decreases of insulin, caloric restriction, alcohol abuse, acute febrile illness, surgery, or any other extreme stress event)
There are conflicting data involving the risk of lower limb amputations with sodium-glucose cotransporter 2 (SGLT2) inhibitor therapy; canagliflozin, specifically, has been of concern (Ref). Canagliflozin was associated with almost a 2-fold increased risk of lower limb amputations compared to placebo in the CANVAS and CANVAS-R trials, which included patients with type 2 diabetes at high cardiovascular risk (Ref). However, no difference between placebo and canagliflozin was observed in the CREDENCE trial with regards to amputation risk; although the trial was terminated early due to kidney and cardiovascular benefit (Ref).
During the CANVAS and CANVAS-R trials, amputations observed involved the toe, midfoot, or less frequently the leg (above or below the knee); lower limb infections, gangrene, and diabetic foot ulcers were the most common precipitating factors (Ref).
Mechanism: Not clearly established (Ref).
Risk factors:
• Preexisting risk factors for amputation (eg, prior amputation, peripheral vascular disease, neuropathy, diabetic foot ulcers, cardiovascular disease) (Ref)
• Age ≥65 years (Ref)
• Lack of preventative foot care
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%: Infection: Genitourinary fungal infection (females: 11% to 12%; males: 4%; patients who developed infections were more likely to experience recurrence) (table 1)
|
Drug (Canagliflozin) |
Placebo |
Population |
Dose |
Indication |
|---|---|---|---|---|
|
12% |
3% |
Females |
300 mg/day |
Glycemic control |
|
11% |
3% |
Females |
100 mg/day |
Glycemic control |
|
4% |
0.7% |
Males |
300 mg/day |
Glycemic control |
|
4% |
0.7% |
Males |
100 mg/day |
Glycemic control |
1% to 10%:
Cardiovascular: Hypotension (3%) (table 2)
|
Drug (Canagliflozin) |
Placebo |
Dosage Form |
Indication |
Comments |
|---|---|---|---|---|
|
3% |
2% |
100 mg/day |
Reduce the risk of end-stage kidney disease, doubling of serum creatinine, cardiovascular death, and hospitalization for heart failure |
In patients with type 2 diabetes mellitus and diabetic nephropathy with albuminuria |
Endocrine & metabolic: Hypoglycemia (4%), hypovolemia (2% to 3%) (table 3), increased serum potassium (eGFR 45 to <60 mL/minute/1.73 m2: >5.4 mEq/L: 5% to 9%; ≥6.5 mEq/L: 1%) (table 4), increased thirst (2% to 3%)
|
Drug (Canagliflozin) |
Placebo and Active Comparator |
Dose |
Indication |
|---|---|---|---|
|
3% |
2% |
300 mg/day |
Glycemic control |
|
2% |
2% |
100 mg/day |
Glycemic control |
|
Drug (Canagliflozin) |
Placebo |
Dosage Form |
Indication |
Comments |
|---|---|---|---|---|
|
9% |
5% |
300 mg/day |
Glycemic control |
Patient population: eGFR 45 to <60 mL/minute/1.73 m2; increased serum potassium defined as increases in serum potassium to >5.4 mEq/L and 15% above baseline |
|
5% |
5% |
100 mg/day |
Glycemic control |
Patient population: eGFR 45 to <60 mL/minute/1.73 m2; increased serum potassium defined as increases in serum potassium to >5.4 mEq/L and 15% above baseline |
|
1% |
0.4% |
300 mg/day |
Glycemic control |
Patient population: eGFR 45 to <60 mL/minute/1.73 m2; increased serum potassium defined as increases in serum potassium to ≥6.5 mEq/L |
|
0% |
0.4% |
100 mg/day |
Glycemic control |
Patient population: eGFR 45 to <60 mL/minute/1.73 m2; increased serum potassium defined as increases in serum potassium to ≥6.5 mEq/L |
Gastrointestinal: Abdominal pain (2%), constipation (2%)
Genitourinary: Increased urine output (5%), urinary tract infection (6%), vulvovaginal pruritus (2% to 3%)
Hematologic & oncologic: Increased hemoglobin (3% to 4%)
Hypersensitivity: Hypersensitivity reaction (4%; severe hypersensitivity reaction: <1%)
Nervous system: Falling (2%)
Neuromuscular & skeletal: Asthenia (1%)
Miscellaneous: Limb injury (toe, foot, lower limb amputations: 2% to 4%)
<1%:
Dermatologic: Skin photosensitivity
Gastrointestinal: Pancreatitis
Genitourinary: Phimosis
Frequency not defined:
Endocrine & metabolic: Increased LDL cholesterol, increased serum cholesterol (non-HDL)
Neuromuscular & skeletal: Decreased bone mineral density
Postmarketing:
Dermatologic: Pruritus (Vasapollo 2018)
Endocrine & metabolic: Ketoacidosis (Sloan 2018)
Genitourinary: Urinary tract infection with sepsis (Gupta 2018)
Hypersensitivity: Anaphylaxis, angioedema
Infection: Necrotizing fasciitis (perineum) (Elbeddini 2020)
Neuromuscular & skeletal: Bone fracture (Zhou 2019)
Renal: Acute kidney injury (Phadke 2020), decreased estimated GFR (eGFR) (FDA 2016), increased serum creatinine (FDA 2016), pyelonephritis (Gupta 2018)
Serious hypersensitivity (eg, anaphylaxis, angioedema) to canagliflozin or any component of the formulation; patients on dialysis.
Disease-related concerns:
• Bariatric surgery:
– Altered absorption: Absorption may be altered given the anatomic and transit changes created by gastric bypass and sleeve gastrectomy surgery (Mechanick 2020; Melissas 2013).
– 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 2020).
– 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 SGLT2 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.
• Infection, acute: Discontinue therapy if any of the following occur: signs and symptoms of new infection (including osteomyelitis), new pain or tenderness, or sores/ulcers involving the lower limbs (FDA Safety Communication 2017).
• Renal impairment: Glycemic efficacy may be decreased in renal impairment. Dosage adjustment may be required, see "Dosing: Altered Kidney Function" for more information.
Special populations:
• Older adult: Elderly patients (≥65 years of age) 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 of age may experience a more pronounced risk. HbA1c reductions may be less in patients >65 years of age compared to younger patients.
Other warnings/precautions:
• Appropriate use: Not for use in patients with diabetic ketoacidosis or patients with type 1 diabetes mellitus.
• Hospitalized patients: Use of SGLT2 inhibitors is not routinely recommended for hospitalized patients (ADA 2021).
• Surgical procedures: Consider temporary discontinuation of therapy at least 3 days prior to surgery; ensure risk factors for ketoacidosis are resolved prior to reinitiating therapy.
Substrate of CYP3A4 (minor), MRP2, P-glycoprotein/ABCB1 (minor), UGT1A9, UGT2B4; Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
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. Risk C: Monitor therapy
Beta-Blockers (Beta1 Selective): May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy
Beta-Blockers (Nonselective): May enhance the hypoglycemic effect of Antidiabetic Agents. Beta-Blockers (Nonselective) may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Bortezomib: May enhance the therapeutic effect of Antidiabetic Agents. Bortezomib may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Digoxin: Canagliflozin may increase the serum concentration of Digoxin. Risk C: Monitor therapy
Direct Acting Antiviral Agents (HCV): May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy
Etilefrine: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Fosphenytoin: May decrease the serum concentration of Canagliflozin. Management: Consider increasing canagliflozin dose to 200 mg/day in patients tolerating 100 mg/day. A further increase to 300 mg/day can be considered in patients with an estimated glomerular filtration rate (GFR) of 60 mL/min/1.73 m2 or greater. Risk D: Consider therapy modification
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
Lithium: Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors may decrease the serum concentration of Lithium. Risk C: Monitor therapy
Loop Diuretics: Canagliflozin may enhance the hypotensive effect of Loop Diuretics. 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
Nirmatrelvir and Ritonavir: May decrease the serum concentration of Canagliflozin. Risk C: Monitor therapy
Pegvisomant: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
PHENobarbital: May decrease the serum concentration of Canagliflozin. Management: Consider increasing canagliflozin dose to 200 mg/day in patients tolerating 100 mg/day. A further increase to 300 mg/day can be considered in patients with an estimated glomerular filtration rate (GFR) of 60 mL/min/1.73 m2 or greater. Risk D: Consider therapy modification
Phenytoin: May decrease the serum concentration of Canagliflozin. Management: Consider increasing canagliflozin dose to 200 mg/day in patients tolerating 100 mg/day. A further increase to 300 mg/day can be considered in patients with an estimated glomerular filtration rate (GFR) of 60 mL/min/1.73 m2 or greater. Risk D: Consider therapy modification
Primidone: May decrease the serum concentration of Canagliflozin. Management: Consider increasing canagliflozin dose to 200 mg/day in patients tolerating 100 mg/day. A further increase to 300 mg/day can be considered in patients with an estimated glomerular filtration rate (GFR) of 60 mL/min/1.73 m2 or greater. Risk D: Consider therapy modification
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
RifAMPin: May decrease the serum concentration of Canagliflozin. Management: Consider increasing canagliflozin dose to 200 mg/day in patients tolerating 100 mg/day. A further increase to 300 mg/day can be considered in patients with an estimated glomerular filtration rate (GFR) of 60 mL/min/1.73 m2 or greater. Risk D: Consider therapy modification
Ritodrine: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Ritonavir: May decrease the serum concentration of Canagliflozin. Management: Consider increasing canagliflozin dose to 200 mg/day in patients tolerating 100 mg/day. A further increase to 300 mg/day can be considered in patients with an estimated glomerular filtration rate (GFR) of 60 mL/min/1.73 m2 or greater. Risk D: Consider therapy modification
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
Thiazide and Thiazide-Like Diuretics: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Sodium-glucose cotransporter 2 (SGLT2) inhibitors are not recommended for patients with type 2 diabetes mellitus planning to become pregnant. Patients who could become pregnant should use effective contraception during therapy. Transition to a preferred therapy should be initiated prior to conception and contraception should be continued until glycemic control is achieved (ADA 2021; Alexopoulos 2019; Egan 2020)
Due to adverse effects on renal development observed in animal studies, the manufacturer does not recommend use of canagliflozin during the second and third trimesters of pregnancy.
Poorly controlled diabetes during pregnancy can be associated with an increased risk of adverse maternal and fetal outcomes, including diabetic ketoacidosis, preeclampsia, spontaneous abortion, preterm delivery, delivery complications, major malformations, stillbirth, and macrosomia. 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 (ADA 2021; Blumer 2013).
Agents other than canagliflozin are currently recommended to treat diabetes mellitus in pregnancy (ADA 2021).
It is not known if canagliflozin is present in breast milk.
Due to the potential for serious adverse reactions in the breastfeeding infant, breastfeeding is not recommended by the manufacturer.
Individualized medical nutrition therapy (MNT) based on ADA recommendations is an integral part of therapy.
Blood glucose; renal function (baseline and as clinically needed, especially in patients with preexisting renal impairment); volume status (eg, BP, hematocrit, electrolytes; baseline and periodically during treatment); serum potassium (periodically after initiation in renal impairment and those predisposed to hyperkalemia); genital mycotic infections and urinary tract infection; signs/symptoms of necrotizing fasciitis (eg, fever and malaise along with genital or perianal pain, tenderness, erythema, or swelling), hypersensitivity reactions; BP; lower limb and feet (sores, ulcers, infection); 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]).
HbA1c: Monitor at least twice yearly in patients who have stable glycemic control and are meeting treatment goals; monitor quarterly in patients in whom treatment goals have not been met, or with therapy change. Note: In patients prone to glycemic variability (eg, patients with insulin deficiency), or in patients whose HbA1c is discordant with serum glucose levels or symptoms, consider evaluating HbA1c in combination with blood glucose levels and/or a glucose management indicator (ADA 2021; KDIGO 2020).
Recommendations for glycemic control in patients with diabetes:
Nonpregnant adults (ADA 2021):
HbA1c: <7% (a more aggressive [<6.5%] or less aggressive [<8%] HbA1c goal may be targeted based on patient-specific characteristics). Note: In patients using a continuous glucose monitoring system, a goal of time in range >70% with time below range <4% is recommended and is similar to a goal HbA1c <7%.
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 (~1 to 2 hours after a meal): <180 mg/dL (more or less stringent goals may be appropriate based on patient-specific characteristics).
Older adults (≥65 years of age) (ADA 2021):
Note: Consider less strict targets in patients who are using insulin and/or insulin secretagogues (sulfonylureas, meglitinides) (ES [LeRoith 2019]).
HbA1c: <7% to 7.5% (healthy); <8% to 8.5% (complex/intermediate health). Note: Individualization may be appropriate based on patient and caregiver preferences and/or presence of cognitive impairment. In patients with very complex or poor health (ie, limited remaining life expectancy), consider making therapy decisions based on avoidance of hypoglycemia and symptomatic hyperglycemia rather than HbA1c level.
Preprandial capillary blood glucose: 80 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: 80 to 180 mg/dL (healthy); 100 to 180 mg/dL (complex/intermediate health); 110 to 200 mg/dL (very complex/poor health).
Classification of hypoglycemia (ADA 2021):
Level 1: 54 to 70 mg/dL; hypoglycemia alert value; initiate fast-acting carbohydrate (eg, glucose) treatment.
Level 2: <54 mg/dL; threshold for neuroglycopenic symptoms; requires immediate action.
Level 3: Hypoglycemia associated with a severe event characterized by altered mental and/or physical status requiring assistance.
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.
Onset of action: Within 24 hours (dose-dependent)
Duration of action: 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).
Absorption: Not affected by food; however, administration prior to the first meal of the day may delay intestinal glucose absorption, thereby reducing postprandial hyperglycemia.
Distribution: Vdss: 83.5 L (intravenous administration)
Protein binding: 99% mainly to albumin
Metabolism: Major metabolism through O-glucuronidation by UGT1A9 and UGT2B4 to two inactive metabolites; minor oxidative metabolism (~7%) through CYP3A4.
Bioavailability: ~65%
Half-life elimination: Apparent terminal half-life: 100 mg dose: 10.6 hours; 300 mg dose: 13.1 hours
Time to peak, plasma: 1 to 2 hours
Excretion: 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)
Tablets (Invokana Oral)
100 mg (per each): $22.80
300 mg (per each): $22.80
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