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Contraindications and Side Effects

Updated

Contraindications for Canagliflozin

Purpose

To provide a comprehensive and concise reference on the contraindications for the use of Canagliflozin in clinical practice, ensuring patient safety and adherence to prescribing guidelines.

Overview

Canagliflozin is a sodium-glucose co-transporter 2 (SGLT2) inhibitor approved for managing Type 2 diabetes mellitus. While it offers numerous benefits, its use is contraindicated in specific populations due to potential risks.

1. Severe Renal Impairment (eGFR < 30 mL/min/1.73 m²)

  • Why is this a contraindication? Canagliflozin relies on kidney function to increase glucose excretion. In severe renal impairment, its efficacy is significantly reduced, and there is a higher risk of adverse effects such as electrolyte imbalances or dehydration.
  • Who is this pertinent to? Patients with chronic kidney disease (CKD), end-stage renal disease (ESRD), or those on dialysis.
  • Management:
    • Do not initiate Canagliflozin in patients with eGFR < 30 mL/min/1.73 m².
    • Monitor renal function (eGFR, serum creatinine) before starting treatment and periodically during therapy.
    • Consider alternative therapies for glucose or metabolic management.

2. Diabetic Ketoacidosis (DKA)

  • Why is this a contraindication? Canagliflozin can increase fat oxidation and ketone production, which may precipitate or worsen diabetic ketoacidosis, even in patients with normal blood glucose levels (euglycemic DKA).
  • Who is this pertinent to? Patients with a history of DKA or individuals with type 1 diabetes (off-label usage risk).
  • Management:
    • Avoid use in patients with a history of ketoacidosis.
    • Educate patients on recognizing DKA symptoms: nausea, vomiting, abdominal pain, and confusion.
    • Discontinue treatment immediately if DKA symptoms arise and provide prompt medical evaluation.

3. History of Hypersensitivity Reactions

  • Why is this a contraindication? Canagliflozin may trigger immune-mediated reactions such as angioedema, anaphylaxis, rash, or urticaria. Severe hypersensitivity can be life-threatening.
  • Who is this pertinent to? Patients with a history of severe hypersensitivity reactions to Canagliflozin or any SGLT-2 inhibitor.
  • Management:
    • Do not prescribe Canagliflozin to patients with a known hypersensitivity to the drug.
    • Educate patients to report any symptoms of rash, swelling, or difficulty breathing immediately.
    • For severe reactions, discontinue therapy and provide appropriate emergency care.

4. Active Foot Ulcers or Severe Infections

  • Why is this a contraindication? Canagliflozin has been associated with an increased risk of lower limb amputations in patients with active foot ulcers or severe infections, particularly in individuals with peripheral vascular disease or diabetes.
  • Who is this pertinent to? Patients with active diabetic foot ulcers, gangrene, severe infections, or a history of lower limb amputation.
  • Management:
    • Do not initiate therapy until ulcers or infections are resolved.
    • Perform regular foot examinations for all patients at risk.
    • Consider alternative treatments for high-risk individuals.

5. Volume Depletion or Severe Hypotension

  • Why is this a contraindication? Canagliflozin causes osmotic diuresis, which may worsen volume depletion and lead to severe hypotension, particularly in vulnerable populations.
  • Who is this pertinent to? Patients with dehydration, orthostatic hypotension, or those on high-dose diuretics.
  • Management:
    • Assess volume status before initiating treatment.
    • Rehydrate patients before starting therapy and monitor blood pressure closely.
    • Avoid in individuals with severe volume depletion or symptomatic hypotension.

6. Severe Hepatic Impairment

  • Why is this a contraindication? While rare, Canagliflozin may exacerbate liver dysfunction, and its safety in patients with severe hepatic impairment has not been established.
  • Who is this pertinent to? Patients with severe liver disease, cirrhosis, or elevated liver enzymes.
  • Management:
    • Avoid use in patients with severe hepatic impairment.
    • Monitor liver function tests (LFTs) if there is concern for hepatic dysfunction.

7. Patients Taking Potassium-Sparing Medications

  • Why is this a contraindication? Canagliflozin can contribute to hyperkalemia, and combining it with potassium-sparing diuretics, ACE inhibitors, ARBs, or potassium supplements increases this risk.
  • Who is this pertinent to? Patients on medications like spironolactone, eplerenone, ACE inhibitors, ARBs, or potassium supplements.
  • Management:
    • Assess serum potassium levels before starting therapy and monitor periodically.
    • Avoid combining Canagliflozin with potassium-sparing drugs unless clinically necessary and closely monitored.

 

Side Effects of Canagliflozin

Common Side Effects

  1. Genitourinary Infections:

    • Female Genital Mycotic Infections: Vulvovaginal candidiasis, vulvitis, and vaginal infections.
    • Male Genital Mycotic Infections: Balanitis or balanoposthitis.
    • Urinary Tract Infections: Including cystitis, pyelonephritis, and urosepsis.
    • Management: Counsel patients on hygiene, recognize early symptoms, and treat infections promptly with antifungal or antibiotic therapy.
    • Tips for Prevention
      • Maintain good hygiene: Wash the genital area daily and dry thoroughly after bathing.
      • Avoid wearing tight-fitting or synthetic underwear; opt for breathable cotton fabrics.
      • Stay hydrated to help flush out bacteria from the urinary tract.
    • Contact your healthcare provider at the first sign of infection. Early treatment with antifungal or antibiotic medications can resolve most infections quickly.
    • Reach out to patients before assigning intake to explain risk of UTI or mycotic infection:

      • For women: “Thank you for sharing your history of urinary tract infections (UTIs) or genital yeast infections. It’s important to note that Canagliflozin can increase the risk of these infections, particularly in women. Clinical studies have shown that up to 11–15% of women taking Canagliflozin experience genital yeast infections compared to about 2–3% in those not on the medication. Women with a history of infections are about 2.5 times more likely to experience a recurrence.

        Most of these infections occur within the first 3–6 months of treatment and are usually mild and treatable with antifungal medications. To help reduce your risk, we recommend staying hydrated, maintaining good personal hygiene, and monitoring for symptoms such as itching, irritation, or abnormal discharge.

        We want you to feel comfortable and informed as you consider this treatment. Would you like to proceed with the Canagliflozin protocol, or would you prefer to discuss other options?”

      • For men: ”Thank you for sharing your history of urinary tract infections (UTIs) or genital infections. It’s important to understand that Canagliflozin can increase the risk of these infections, even in men. Clinical studies show that about 3.7–6% of men taking Canagliflozin experience genital yeast infections compared to less than 1% of men not taking the medication. While the overall risk is lower compared to women, it is still elevated, especially for individuals with a history of infections.

        Most infections occur within the first 3–6 months of treatment and are usually mild and treatable with antifungal medications. To minimize your risk, we recommend staying well-hydrated, practicing good hygiene, and watching for symptoms like redness, itching, irritation, or rash.

        We want to ensure you’re comfortable with this information before starting the treatment. Would you like to proceed with the Canagliflozin protocol, or would you prefer to discuss alternative options?"

  2. Increased Urination:

    • Frequent urination due to osmotic diuresis caused by increased glucose excretion.
    • Management: Ensure adequate hydration, particularly in elderly or volume-depleted patients.
      • Drink plenty of water throughout the day; aim for at least 8–10 glasses unless otherwise advised.
      • Avoid excessive alcohol or caffeine, as these can worsen dehydration.

  3. Hypoglycemia:

    • More likely when Canagliflozin is used with insulin or insulin secretagogues.
    • Management: Adjust concomitant diabetes medications and monitor blood glucose levels.
      • Eat regular, balanced meals and include complex carbohydrates.
      • Monitor your blood sugar levels as recommended by your healthcare provider.
      • Carry a quick source of sugar (e.g., glucose tablets or juice) to treat symptoms of low blood sugar.
    • What to Watch For:
      • Early symptoms include shakiness, sweating, confusion, and rapid heartbeat.
    • What to Do:
      • If you experience symptoms, consume a fast-acting sugar source immediately and follow up with a meal or snack.

  4. Mild Dehydration:

    • Symptoms include thirst, dry mouth, and dizziness.
    • Management: Advise patients to increase fluid intake.

Less Common but Significant Side Effects

  1. Electrolyte Imbalances (Hyperkalemia)
    • Who is this pertinent to? Patients with renal impairment, those taking potassium-sparing diuretics, ACE inhibitors, ARBs, or potassium supplements.
    • Why does this occur? Canagliflozin increases glucose excretion through the kidneys, which can also impact electrolyte balance, leading to elevated potassium levels, particularly in those with reduced kidney function.
    • How likely is it? Hyperkalemia is uncommon but more likely in patients with impaired kidney function.
    • Precautions:
      • Monitor serum potassium regularly, especially in high-risk groups.
      • Avoid combining with other potassium-elevating medications without close supervision.
      • Maintain adequate hydration to support kidney function.
    • Management: Discontinue immediately if a reaction occurs and seek emergency care.
  2. Hypotension
    • Who is this pertinent to? Elderly patients, individuals on diuretics, or those with volume depletion (e.g., from dehydration).
    • Why does this occur? Canagliflozin acts as an osmotic diuretic by increasing glucose and water excretion in the urine, which can reduce blood volume and cause a drop in blood pressure.
    • How likely is it? Uncommon but more likely in patients predisposed to volume depletion.
    • Precautions:
      • Encourage adequate hydration to counteract fluid loss.
      • Monitor blood pressure regularly and adjust diuretics if needed.
    • Management: Discontinue immediately if a reaction occurs and seek emergency care.
  3. Bone Fractures
    • Who is this pertinent to? Patients with osteoporosis, low bone mineral density, or a history of fractures.
    • Why does this occur? Canagliflozin may reduce bone mineral density, likely due to its diuretic effect causing mild calcium loss through the urine. This can weaken bone structure over time.
    • How likely is it? Uncommon but most frequently observed within the first 12 weeks of treatment.
    • Precautions:
      • Assess fracture risk prior to initiation.
      • Ensure adequate calcium and vitamin D intake to support bone health.
      • Monitor bone density periodically in at-risk populations.
    • Management: Discontinue immediately if a reaction occurs and seek emergency care.
  4. Ketoacidosis
    • Who is this pertinent to? Patients with diabetes (type 1 or type 2), prolonged fasting, illness, or reduced insulin levels.
    • Why does this occur? Canagliflozin increases fat oxidation by reducing glucose availability, which can lead to excessive ketone production, even in patients with normal blood glucose levels (euglycemic ketoacidosis).
    • How likely is it? Rare but serious if it occurs.
    • Precautions:
      • Educate patients on symptoms: nausea, vomiting, abdominal pain, and confusion.
      • Avoid initiating therapy during acute illness or periods of stress.
      • Discontinue immediately if symptoms arise and seek prompt medical care.
    • Management: Discontinue immediately if a reaction occurs and seek emergency care.
  5. Lower Limb Amputation
    • Who is this pertinent to? Patients with peripheral vascular disease, diabetic foot ulcers, or a history of amputations.
    • Why does this occur? Canagliflozin may impair blood flow or contribute to dehydration, increasing the risk of ulcers, infections, and amputations in patients with pre-existing peripheral vascular disease or diabetic foot complications.
    • How likely is it? Uncommon but significant in high-risk populations.
    • Precautions:
      • Perform regular foot examinations and encourage proper foot care.
      • Monitor for early signs of ulcers, infections, or poor healing.
      • Consider alternative therapies in patients at high risk.
    • Management: Discontinue immediately if a reaction occurs and seek emergency care.
  6. Elevated Cholesterol
    • Who is this pertinent to? Patients with pre-existing dyslipidemia or cardiovascular risk factors.
    • Why does this occur? Canagliflozin promotes fat oxidation and shifts energy metabolism, which may transiently increase circulating LDL cholesterol levels.
    • How likely is it? Modest, dose-dependent increases have been observed in clinical trials.
    • Precautions:
      • Monitor lipid profiles regularly.
      • Consider statin therapy or other lipid-lowering interventions if indicated.
      • Encourage a heart-healthy diet and regular exercise.
  7. Hepatic Impairment
    • Who is this pertinent to? Patients with pre-existing liver disease or those taking other hepatotoxic medications.
    • How likely is it? Very rare but clinically significant.
    • Precautions:
      • Monitor liver function tests (LFTs) periodically during treatment.
      • Educate patients on symptoms of liver dysfunction, such as jaundice, fatigue, or dark urine.
      • Avoid in patients with severe hepatic impairment.
    • Management: Discontinue immediately if a reaction occurs and seek emergency care.
  8. Hypersensitivity Reactions
    • Who is this pertinent to? Patients with a history of drug allergies or known hypersensitivity to SGLT-2 inhibitors.
    • Why does this occur? Canagliflozin may trigger immune-mediated reactions, such as angioedema or anaphylaxis, in susceptible individuals.
    • How likely is it? Rare but potentially severe.
    • Precautions:
      • Educate patients on symptoms: rash, swelling, difficulty breathing.
      • Discontinue immediately if a reaction occurs and seek emergency care.
      • Avoid use in patients with a history of severe hypersensitivity to similar medications.
    • Management: Discontinue immediately if a reaction occurs and seek emergency care.

Rare Side Effects

  1. Pancreatitis:
    • Who is this pertinent to? Patients with a history of pancreatitis, gallstones, alcohol misuse, or high triglyceride levels are at increased risk.
    • Symptoms include severe abdominal pain radiating to the back.
    • Management:
      • Discontinue Canagliflozin immediately if pancreatitis is suspected.
  2. Photosensitivity Reactions:
    • Who is this pertinent to? Patients with frequent sun exposure, a history of photosensitivity reactions, or those who engage in prolonged outdoor activities.
    • Why does this occur? Canagliflozin may increase skin sensitivity to ultraviolet (UV) light, though the exact mechanism remains unknown. This can result in sunburn-like reactions or skin irritation.
    • How likely is it? Very rare but reported in post-marketing data.
    • Precautions:
      • Advise patients to use broad-spectrum sunscreen (SPF 30+), wear protective clothing, and limit prolonged sun exposure.
      • Educate patients to report any skin rashes or burns promptly.
    • Management:
      • For mild symptoms: Recommend cool compresses, moisturizers, and over-the-counter anti-inflammatory creams.
      • For severe reactions: Discontinue Canagliflozin and evaluate for alternative therapies.
      • Refer to a dermatologist if symptoms persist or worsen.
  3. Impairment in Renal Function:
    • Who is this pertinent to? Patients with chronic kidney disease (CKD), elderly individuals, or those on diuretics, ACE inhibitors, ARBs, or nephrotoxic medications.
    • Why does this occur? Canagliflozin increases glucose and water excretion through the kidneys, which may transiently reduce kidney function, particularly in those with pre-existing renal impairment, dehydration, or volume depletion.
    • How likely is it? Rare but more likely in patients with compromised kidney function. Transient increases in serum creatinine and decreases in eGFR have been observed, particularly after initiation.
    • Precautions:
      • Assess renal function (serum creatinine and eGFR) before initiating therapy and monitor periodically during treatment.
      • Ensure patients are adequately hydrated to reduce stress on kidney function.
    • Management:
      • If a mild decline in renal function occurs:
        • Encourage hydration and reassess kidney function in 1–2 weeks.
      • For significant or worsening renal impairment:
        • Discontinue Canagliflozin and refer for further evaluation.
        • Assess for contributing factors such as volume depletion or concurrent nephrotoxic medications.