Dosing and uses of Invokana (canagliflozin)
Adult dosage forms and strengths
tablet
- 100mg
- 300mg
Diabetes Mellitus Type 2
Selective sodium-glucose transporter-2 (SGLT2) inhibitor indicated as an adjunct to diet and exercise to improve glycemic control with type 2 diabetes mellitus
Initial: 100 mg PO qDay taken before the first meal of the day
May increase dose to 300 mg qDay in patients tolerating 100 mg/day who have an eGFR ≥60 mL/min/1.73 m² and require additional glycemic controL
Dosage modifications
Renal impairment
- eGFR ≥60 mL/min/1.73 m²: No dosage adjustment required
- eGFR 45 to <60 mL/min/1.73 m²: Do not exceed 100 mg/day
- eGFR <45 mL/min/1.73 m²: Do not initiate canagliflozin
- Not recommended with eGFR that declines persistently below 45 mL/min/1.73 m²
- eGFR <30 mL/min/1.73 m²: Contraindicated
UGT enzyme inducers
- Coadministration with UGT enzyme inducers (eg, rifampin, phenytoin, phenobarbital, ritonavir): Consider increasing dose to 300 mg qDay in patients tolerating 100 mg/day with eGFR ≥60 mL/min/1.73 m² and require additional glycemic control
- Consider another antihyperglycemic agents if eGFR is 45 to <60 mL/min/1.73 m² and receiving a UGT inducer
Dosing Considerations
Not recommended for treating type 1 diabetes mellitus or diabetic ketoacidosis
Correct volume depletion prior to initiating canagliflozin
Pediatric dosage forms and strengths
Safety and efficacy not established
Invokana (canagliflozin) adverse (side) effects
>10%
Female genital mycotic infections (10.4-11.4%)
1-10%
Increased urination (4.6-5.3%)
Male genital mycotic infections (3.7-4.2%)
Vulvovaginal pruritus (1.6-3%)
Thirst (2.3-2.8%)
Constipation (1.8-2.3%)
Nausea (2.2-2.3%)
Abdominal pain (1.7-1.8%)
Volume depletion
- Overall population (2.3-3.4%)
- Age >75 yr (4.9-8.7%)
- eGFR <60/mL/min/1.73 m³ (4.7-8.1%)
- Use of loop diuretic (3.2-8.8%)
Postmarketing reports
Bone fractures
Higher risk of falls for patients treated within first few weeks of treatment reported
Angioedema
Warnings
Contraindications
Documented hypersensitivity
Severe renal impairment (eGFR <30 mL/min/1.73 m²), end-stage renal disease or patients on dialysis
History of a serious hypersensitivity reaction to canagliflozin, such as anaphylaxis or angioedema
Cautions
Causes intravascular volume contraction and symptomatic hypotension and/or acute kidney injury can occur, particularly if eGFR <60 mL/min/1.73 m², advance age, existing low systolic BP, or taking either diuretics or drugs that interfere with renin-angiotensin-aldosterone system (RAS) (eg, ACE inhibitors, ARBs); before initiating therapy, assess volume status and correct hypovolemia in patients with renal impairment, the elderly, in patients with low systolic blood pressure, or on diuretics, ACE inhibitors, or ARB; monitor for signs and symptoms during therapy
Drug increases serum creatinine and decreases eGFR, patients with hypovolemia are more susceptible to renal function impairment
Consider temporarily discontinuing in settings of reduced oral intake or fluid losses; if acute kidney injury occurs, discontinue and promptly treat; monitor renal function during therapy
Hyperkalemia reported; patients with moderate renal impairment who take potassium-sparing diuretics or drugs that alter RAS are more likely to develop hyperkalemia; monitor potassium levels in patients with impaired renal function and in patients predisposed to hyperkalemia
Hypoglycemia risk increased with insulin and insulin secretagogues, consider a lower dose of insulin or the insulin secretagogue
Genital mycotic infections may occur, patients with history of genital mycotic infections and uncircumcised males are more susceptible
Increases risk of urinary tract infections (UTIs), including life-threatening urosepsis and pyelonephritis that started as UTIs; evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated
Ketoacidosis associated with SGLT2 inhibitors reported; monitor for signs of ketoacidosis and advise patients to seek immediate medical attention for symptoms (eg, difficulty breathing, nausea, vomiting, abdominal pain, confusion, unusual fatigue or sleepiness); assess patients who present with signs and symptoms of metabolic acidosis for ketoacidosis, regardless of blood glucose level; consider risk factors for ketoacidosis prior to initiating therapy; patients may require temporary discontinuation of therapy in clinical situation that may predispose to ketoacidosis
Hypersensitivity reactions (eg, generalized urticaria), some serious, were reported during clinical trials; if it occurs, discontinue therapy and monitor until signs and symptoms resolve
Dose-related increases in LDL-C reported; monitor LDL-C and treat if appropriate
No conclusive evidence of macrovascular risk reduction with canagliflozin or any other antidiabetic agent exists
SGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose tests; use alternative methods to monitor glycemic controL
Increased risk of bone fracture, occurring as early as 12 weeks after treatment initiation, reported; consider factors that contribute to fracture risk prior to initiating therapy
Higher risk of falls for patients treated within first few weeks of treatment reported
Hypersensitivity reactions, including angioedema and anaphylaxis reported with canagliflozin; these reactions generally occurred within hours to days after initiating canagliflozin; if hypersensitivity reactions occur, discontinue therapy; treat and monitor until signs and symptoms resolve
Not recommended for use in severe hepatic impairment (not studied); dose adjustment not necessary in mild or moderate hepatic impairment
Should not be used for the treatment of patients with type 1 diabetes mellitus (insulin dependent
Pregnancy and lactation
Pregnancy category: C
Lactation: Unknown whether distributed in human breast milk; breast feeding women should discontinue canagliflozin or nursing taking into account the importance of the drug to the mother
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Invokana (canagliflozin)
Mechanism of action
Selective sodium-glucose transporter-2 (SGLT2) inhibitor
SGLT-2 inhibition lowers the renal glucose threshold (ie, the plasma glucose concentration which exceed the maximum glucose reabsorption capacity of the kidney); lowering the renal glucose threshold results in increased urinary glucose excretion
Absorption
Bioavailability: 65%
Peak plasma time: 1-2 hr
Distribution
Protein bound: 99% (predominantly to albumin)
Vd: 119 L
Metabolism
O-glucuronidation is the major metabolic elimination pathway, mainly by UGT1A9 and UGT2B4 to 2 inactive O-glucuronide metabolites
CYP3A4-mediated (oxidative) metabolism is minimal (~7%)
Elimination
Half-life: 10.6 hr (100 mg dose); 13.1 hr (300 mg dose)
Total body clearance: 192 mL/min
Excretion
- Feces: 41.5% (canagliflozin), 7% (hydroxylated metabolite), 3.2% (O-glucuronide metabolite)
- Urine: 33% excreted in urine, mainly as O-glucuronide metabolites (30.5%); <1% excreted unchanged
