Canagliflozin

Usage

• Canagliflozin is prescribed for the treatment of type 2 diabetes mellitus, to improve glycemic control as an adjunct to diet and exercise. It is also indicated to reduce the risk of major adverse cardiovascular events (MACE) in adults with type 2 diabetes and established cardiovascular disease. Additionally, it’s used to reduce the risk of end-stage kidney disease (ESKD), worsening of kidney function, cardiovascular death, and hospitalization for heart failure in adults with type 2 diabetes and chronic kidney disease.
• Pharmacological classification: Sodium-glucose co-transporter 2 (SGLT2) inhibitor.
• Mechanism of action: Canagliflozin inhibits SGLT2 in the kidneys, reducing glucose reabsorption and increasing urinary glucose excretion, thereby lowering blood glucose levels.

Alternate Names

• International/Regional Variations: The generic name Canagliflozin is generally consistent internationally.
• Brand Names: Invokana, Invokamet (canagliflozin and metformin combination).

How It Works

• Pharmacodynamics: Canagliflozin primarily lowers blood glucose by increasing urinary glucose excretion. It also has modest effects on blood pressure and weight loss.
• Pharmacokinetics: Canagliflozin is orally administered and well-absorbed. It’s metabolized primarily via glucuronidation, with a small portion metabolized by CYP3A4 (but it’s not an inhibitor or inducer of CYP enzymes). Primarily eliminated via renal excretion (approximately 42% as unchanged drug) and fecal excretion.
• Mode of action: Canagliflozin selectively inhibits SGLT2 in the proximal renal tubules. This blocks glucose reabsorption, leading to increased urinary glucose excretion and a decrease in plasma glucose levels.
• Receptor binding/Enzyme inhibition: Canagliflozin selectively binds to and inhibits SGLT2.
• Elimination pathways: Primarily renal excretion, with some fecal excretion.

Dosage

Standard Dosage

Adults:

• Initial: 100 mg orally once daily, taken before the first meal of the day.
• Maintenance: May be increased to 300 mg once daily in patients tolerating the lower dose, based on glycemic control and clinical response.

Children:

• Use and dosage must be determined by a doctor. Safety and efficacy haven’t been fully established in children under 18.

Special Cases:

• Elderly Patients: Generally, no dose adjustment is required. However, start with a lower dose and monitor renal function closely, as elderly patients may be more susceptible to adverse effects like dehydration.

• Patients with Renal Impairment: Dosage adjustments are based on eGFR.

  • eGFR 45 to <60 mL/min/1.73 m²: 100 mg once daily.
  • eGFR 30 to <45 mL/min/1.73 m²: 100 mg once daily.
  • eGFR <30 mL/min/1.73 m²: Not recommended.

• Patients with Hepatic Dysfunction: No dosage adjustment is needed for mild or moderate hepatic impairment. Use with caution in severe hepatic impairment.

• Patients with Comorbid Conditions: Consider interactions and necessary adjustments for patients with conditions like heart failure or other metabolic disorders.

Clinical Use Cases

Canagliflozin’s usage in settings like intubation, surgical procedures, mechanical ventilation, ICU, or emergency situations is generally not directly applicable. Its primary role is in chronic disease management. If a patient on Canagliflozin faces any of these situations, careful blood glucose monitoring and potential medication adjustments in consultation with a nephrologist or endocrinologist are needed.

Dosage Adjustments

• Dose modifications are necessary based on eGFR (as described above).
• Also, adjust dose based on patient tolerance and glycemic response.

Side Effects

Common Side Effects

• Genital mycotic infections (e.g., vulvovaginal candidiasis, balanitis).
• Urinary tract infections.
• Increased urination.
• Thirst.

Rare but Serious Side Effects

• Diabetic ketoacidosis (DKA), even with near-normal blood glucose.
• Lower limb amputation.
• Necrotizing fasciitis of the perineum (Fournier’s gangrene).
• Acute kidney injury.
• Serious allergic reactions.
• Hypotension.

Long-Term Effects

• Bone fractures.
• Possible increased risk of bladder cancer.

Adverse Drug Reactions (ADR)

• Any signs of serious allergic reactions (e.g., angioedema, rash).
• Symptoms of DKA (e.g., nausea, vomiting, abdominal pain, rapid breathing).
• Signs of severe genital infection (e.g., fever, pain, swelling).

Contraindications

• Hypersensitivity to canagliflozin.
• Type 1 diabetes.
• End-stage renal disease (ESRD) or patients on dialysis.
• Severe hepatic impairment.
• Pregnancy (second and third trimesters).

Drug Interactions

• Insulin and other antidiabetic agents: Increased risk of hypoglycemia.
• Diuretics: Increased risk of dehydration and hypotension.
• UGT inducers (e.g., rifampin, phenytoin): Decreased efficacy of canagliflozin.
• Other medications: Consult a comprehensive drug interaction database for a full list, as many interactions exist.
• Alcohol: Increased risk of hypoglycemia.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: Contraindicated in the second and third trimesters. Use in the first trimester only if the potential benefit outweighs the potential risk to the fetus.
• Fetal risks: Renal abnormalities in animal studies.
• Breastfeeding: Not recommended due to potential exposure of the infant.

Drug Profile Summary

• Mechanism of Action: SGLT2 inhibitor, increasing urinary glucose excretion.
• Side Effects: Genital/urinary infections, increased urination, thirst, DKA (rare), hypotension.
• Contraindications: Type 1 diabetes, ESRD, severe hepatic impairment, pregnancy (2nd/3rd trimesters).
• Drug Interactions: Insulin, diuretics, UGT inducers.
• Pregnancy & Breastfeeding: Contraindicated in 2nd/3rd trimesters; not recommended while breastfeeding.
• Dosage: Adults: 100-300 mg once daily; dose adjustments based on renal function.
• Monitoring Parameters: Blood glucose, renal function (eGFR, creatinine), blood pressure, signs of infection.

Popular Combinations

• Metformin: Canagliflozin is often combined with metformin for additive glucose-lowering effects.

Precautions

• General Precautions: Monitor renal function, blood glucose, blood pressure, and signs of infection.
• Specific Populations: Dosage adjustments needed for renal impairment. Avoid in pregnancy (2nd/3rd trimesters) and during breastfeeding. Use with caution in the elderly.
• Lifestyle Considerations: Diet and exercise are essential components of diabetes management. Counsel patients on proper hydration to minimize the risk of dehydration.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Canagliflozin?

A: The initial dose is 100 mg once daily, taken before the first meal. This can be increased to 300 mg once daily if tolerated and if further glycemic control is needed. Dosage adjustments are required for patients with renal impairment.

Q2: What are the common side effects of Canagliflozin?

A: Common side effects include genital mycotic infections, urinary tract infections, increased urination, and thirst.

Q3: How does Canagliflozin work?

A: Canagliflozin inhibits SGLT2 in the kidneys, reducing glucose reabsorption and increasing urinary glucose excretion.

Q4: Can Canagliflozin be used in patients with type 1 diabetes?

A: No, canagliflozin is contraindicated in type 1 diabetes.

Q5: What are the serious side effects of Canagliflozin?

A: Serious side effects include DKA, lower limb amputation, necrotizing fasciitis of the perineum, acute kidney injury, and severe allergic reactions.

Q6: What are the contraindications for using Canagliflozin?

A: Contraindications include hypersensitivity, type 1 diabetes, ESRD, severe hepatic impairment, and pregnancy (second and third trimesters).

Q7: Does Canagliflozin interact with other medications?

A: Yes, canagliflozin interacts with several medications, including insulin, diuretics, and UGT inducers. It is essential to check for drug interactions before starting canagliflozin.

Q8: Can Canagliflozin be used during pregnancy or breastfeeding?

A: Canagliflozin is contraindicated during the second and third trimesters of pregnancy. It’s not recommended during breastfeeding.

Q9: How should I monitor patients on Canagliflozin?

A: Monitor blood glucose, renal function (eGFR and creatinine), blood pressure, and watch for signs of infection, especially genital and urinary tract infections.

Q10: What should patients know about taking Canagliflozin?

A: Patients should be educated on the importance of adhering to diet and exercise recommendations, maintaining adequate hydration, and promptly reporting any signs of infection or unusual symptoms to their healthcare provider. They should also be aware of the potential for drug interactions.