Canagliflozin (Invokana) is an antidiabetic medicine that reduces blood sugars by inhibiting the reabsorption of glucose from the kidney tubules. This results in glucose loss in the urine along with water (as a result of osmotic diuresis). So, apart from reducing blood glucose, it also has beneficial effects in patients with volume overloaded states such as heart failure.

It is used to treat Diabetes type 2 as an adjunct to diet and exercise for glycemic control, reducing the risks of major cardiovascular events( like cardiovascular death, nonfatal Myocardial infarction, and nonfatal stroke) in adults with diabetes type 2 and established cardiovascular disease.

Canagliflozin dose in adults:

• It is used in the treatment of type 2 Diabetes mellitus in a dose of:
  • 100 mg orally once a day before the first meal of the day.
  • The dose may be increased to 300 mg once a day. in patients with normal renal functions (eGFR of 60 mL/minute/1.73 m² or more)

Canagliflozin Dose in Children

Not recommended for use in children.

Pregnancy Risk Factor C

• In animal studies, canagliflozin has been shown to have adverse effects on renal development.
• Contrariwise, maternal hyperglycemia can also be linked to congenital malformations and other adverse fetal or maternal events.
• Maternal hyperglycemia must be treated with insulin, or other approved and recommended anti-hyperglycemic medicines.

Canagliflozin use during breastfeeding:

• canagliflozin is not recommended for use during breastfeeding.

Canagliflozin dose in Renal Disease:

• CrCl of 60 mL/minute/1.73 m² or more :
  • Dose adjustment is not necessary.
• CrCl of 45 to 60 mL/minute/1.73 m² :
  • 100 mg once a day. It should be avoided in patients receiving concurrent UDP-glucuronosyl transferase (UGT) enzyme inducers, like rifampin, phenytoin, and phenobarbital, ritonavir.
• CrCl of 30 - 45 mL/minute/1.73 m² :
  • It should not be initiated in patients with a persistently low CrCl (of less than 45 ml/min)
• CrCl of less than 30 mL/minute/1.73 m² or ESRD, or patients on hemodialysis:
  • Use is contraindicated.

Canagliflozin dose in hepatic impairment:

• Mild to moderate impairment (Child-Pugh class A or B):
  • Dose adjustment is not necessary.
• Severe impairment (Child-Pugh class C):
  • It is not recommended in severe hepatic impairment.

Common Side Effects Of Canagliflozin Include:

• Endocrine & metabolic:
  • Increased serum potassium
• Infection:
  • Genitourinary fungal infection
• Renal:
  • Renal insufficiency

Less Common Side Effects Of Canagliflozin Include:

• Central nervous system:
  • Falling
  • Fatigue
• Endocrine & metabolic:
  • Hypoglycemia
  • Hypovolemia
  • Increased thirst
• Gastrointestinal:
  • Abdominal pain
  • Constipation
  • Nausea
• Genitourinary:
  • Urinary tract infection
  • Increased urine output
  • Vulvovaginal pruritus
• Hematologic & oncologic:
  • Increased hemoglobin
• Hypersensitivity:
  • Hypersensitivity reaction
• Neuromuscular & skeletal:
  • Asthenia

Frequency not defined:

• Endocrine & metabolic:
  • Hypermagnesemia
  • Increased serum cholesterol
  • Increased serum phosphate
• Neuromuscular & skeletal:
  • Bone fracture
  • Decreased bone mineral density
• Renal:
  • Increased serum creatinine

Contraindication to Canagliflozin include:

• Severe allergic reactions to canagliflozin and any component of this formulation
• End-stage renal disease, patients on dialysis or severe renal impairment with a CrCl less than 30 mg/minute/1.73m2.

Warnings & Precautions

• Bone fractures:
  • The CANVAS trial revealed an increase in bone fractures, especially among elderly patients with cardiovascular or renal disease.

• Genital mycotic infections:
  • Canagliflozin and SGLT 2 inhibitors increase the risk of urogenital infections such as vulvovaginal yeast infection, vulvovaginal candidiasis vulvovaginal candidiasis vulvovaginitis and balanoposthitis.
  • Patients with a history of genital infection and uncircumscribed males are particularly at risk.

• Hypersensitivity reactions:
  • Within hours or days of the initiation, patients may experience angioedema or anaphylaxis.

• Hypotension:
  • This can cause hypotension in volume-depleted patients, patients with renal impairment, elderly patients, and patients taking antihypertensive medications like ACE inhibitor, Angiotensin receptor blocking drugs, or diuretics.

• Hyperkalemia:
  • Hyperkalemia is a common condition in patients with renal impairment, those who take potassium-sparing diuretics and ACE inhibitors, as well as ARBs.
  • After canagliflozin is started, it is important to monitor serum potassium.

• Ketoacidosis:
  • Even with small increases in blood glucose, the use of SGLT 2 inhibitors has been linked to diabetic ketoacidosis.
  • The AACE and the ACE recommend that you withhold therapy for 24 hours prior to or during events that could lead to diabetic ketoacidosis.

• Lipid abnormality:
  • It may result in elevation of LDL-C cholesterol that should be monitored periodically.

• Lower limb amputation: [US Boxed Warning]:
  • Canagliflozin use has been linked to an increased risk for limb amputations.
  • Patients are more likely to get infections such as diabetic foot ulcers, Gangrene, and lower-limb infections, which eventually lead to amputations. These infections typically involve the toe, middlefoot, or lesser frequently the leg.
  • If there are any signs of gangrene, such as cellulitis or ulceration, patients should stop taking the drug immediately.

• Necrotizing fasciitis:
  • Necrotizing fasciitis (also known as Fournier gangrene) is a serious, but rare, infection that can lead to death.
  • The incidences of genital infections, including Fournier's gangrene, have increased with the introduction of SGLT 2 inhibitors.
  • Patients should be evaluated and canagliflozin stopped immediately if they experience symptoms such as fever, malaise or perianal pains, erythema and swelling.
  • Patients with fever, malaise, tenderness or swelling due to necrotizing fasciitis should be evaluated.
  • Necrotizing fasciitis patients should be treated immediately.

• Renal effects:
  • It causes volume contraction which increases the risk of acute kidney failure.
  • After initiating the procedure, patients should be closely monitored for signs of renal dysfunction, particularly if there are risk factors such as volume depletion, chronic kidney insufficiency, heart disease, and use concomitant medications, such as diuretics, ACE inhibitors or angiotensin receptor blocking drugs, or NSAIDs.
• Urinary tract infection:
  • Urinary tract infections can be serious, including urosepsis or pyelonephritis. These infections may need hospitalization and prolonged intravenous antibiotics.
• Hepatic impairment:
  • It should only be used in mild to moderate cases of hepatic impairment.

Monitor:

• Blood glucose
• Glycated hemoglobin twice yearly in patients with controlled diabetes and every 3 monthly in patients not achieving the glycemic goals.
• Renal function
• Volume status
• Serum potassium
• Serum magnesium and phosphate
• LDL-C
• Genital mycotic infections and UTI
• Hypersensitivity reactions
• Bood pressure
• Lower limb and feet for ulcers and infection
• clinical features of ketoacidosis like nausea & vomiting, abdominal pain, malaise, and shortness of breath.

How to administer Canagliflozin?

• Can be taken with or without food
• It is best to take it before your first meal of the day. This may reduce postprandial hyperglycemia due to delayed intestinal glucose absorption.

Mechanism of action of Canagliflozin:

• It blocks sodium-glucose transporter 2 (SGLT2) from the proximal renal tubes, preventing reabsorption and filtration of filtered glucose from tubular lumen.
• Osmotic diuresis causes water loss by filtering out glucose from the urine.
• This effect can be used and has positive effects on volume-overloaded patients such as heart failure. However, it could also cause volume depletion or dehydration.
• Recurrent infections of the urinary tract can also be caused by glucose loss in the urine. This could prove to be a problem for diabetic patients.

The Onset of action is within 24 hours and is dose-dependent and its effects may last throughout the day. Absorption of the drug is not affected by food. Administration before breakfast or the first meal may result in a delay in the intestinal glucose absorption. This may reduce the postmeals hyperglycemia. 99% of the drug is bound to proteins primarily albumin It is metabolized through O-glucuronidation by UGT1A9 and UGT2B4 to two inactive metabolites. It has a Bioavailability of about 65% and the  half-life elimination after taking the 100 mg dose is 10.6 hours and after the 300 mg dose is 13.1 hours The Time to peak plasma concentration is  1 - 2 hours. It is excreted via Feces.

Canagliflozin international brand names:

• Canaflo
• Canaglif
• Canaglu
• Invocana
• Invokana
• Ivoglita
• Parkflozin
• Sulicent

Canagliflozin Brands in Pakistan:

Canagliflozin is not available in Pakistan