Canagliflozin

Canagliflozin is used for: Type 2 diabetes mellitus

Adults >18 years: Recommended Dose: 100 mg PO once daily taken before the first meal of the day May increase dose to 300 mg once daily in patients tolerating 100 mg/day who have an eGFR >60 mL/min/1.73 m² and require additional glycemic control. Elderly: In patients >75 years, the starting dose is 100 mg once daily.

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 Discontinue if eGFR declines below 45 mL/min/1.73 m²

History of a serious hypersensitivity reaction and hypersensitivity to canagliflozin. Severe renal impairment (eGFR <30 mL/min/1.73 m2), end stage renal disease or patients on dialysis. Diabetic Ketoacidosis, Type-1 Diabetes.

Causes intravascular volume contraction and symptomatic hypotension can occur, particularly if eGFR <60 mL/min/1.73 m²2, advance age, existing low systolic BP, or taking either diuretics or drugs that interfere with renin-angiotensin-aldosterone system (RAS) (eg, ACE inhibitors, ARBs). Drug increases serum creatinine and decreases eGFR, patients with hypovolemia are more susceptible to renal function impairment. Hyperkalemia reported; patients with moderate renal impairment who take potassium-sparing diuretics or drugs that alter RAS are more likely to develop hyperkalemia. Hypoglycemia risk increased with insulin and insulin secretagogues, adjust dose. Genital mycotic infections may occur, patients with history of genital mycotic infections and uncircumcised males are more susceptible. Hypersensitivity reactions (eg, generalized urticaria), some serious, were reported during clinical trials. Dose-related increases in LDL-C reported. No conclusive evidence of macrovascular risk reduction with canagliflozin or any other antidiabetic agent. SGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose tests; use alternative methods to monitor glycemic control. The FDA continues to investigate reports of ketoacidosis associated with sodium-glucose cotransporter-2 (SGLT2) inhibitors (ie, canagliflozin, dapagliflozin, empagliflozin); 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). 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. 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 Based on animal data showing adverse renal effects, not recommended during the second and third trimesters of pregnancy Data are limited in pregnant women and are not sufficient to determine a drug associated risk for major birth defects or miscarriage Clinical considerations Poorly controlled diabetes in pregnancy increases maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, stillbirth, and delivery complications Poorly controlled diabetes increases fetal risk for major birth defects, stillbirth, and macrosomia related morbidity Lactation No information regarding distribution in human milk or effects on the breastfed infant or milk production Present in milk of lactating rats Since human kidney maturation occurs in utero and during the first 2 yr of life when lactational exposure may occur, there may be risk to the developing human kidney Inform women not to breastfeed while taking canagliflozin

Decreased efficacy w/ rifampicin. Increase AUC & Cmax of digoxin (not clinically meaningful).

Side effects of Canagliflozin : >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%)

Sodium-glucose co-transporter 2 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.