Canagliflozin Invokana is an SGLT-2 inhibitor that inhibits the reabsorption of glucose from the kidney tubules. This results in the excretion of glucose in the urine. Excess glucose loss in the urine causes less utilization of glucose by the cells resulting in weight loss. Excess glucose and sodium loss in the urine causes volume loss resulting in improvement in the symptoms of heart failure.

It is used to enhance glycemic control and lower the risk of major cardiovascular events (cardiovascular mortality, myocardial infarction, and nonfatal stroke) in adults with type 2 diabetes and established cardiovascular disease as a monotherapy or as an add-on therapy.

The credence trial showed a delay in the progression to end-stage renal disease by 30% along with a reduction in cardiovascular deaths.

Canagliflozin Dose in Adults

Note: If present, correct volume depletion prior to initiation.

Dose in the treatment of type 2 Diabetes mellitus:

• • 100 mg orally once a day before the first meal of the day initially to a maximum of 300 mg once a day.

• Dosing adjustment in patients on UGT inducers like rifampin, phenobarbital, phenytoin, and ritonavir:

  • The usual dose is 100 mg once daily.
  • Some patients may be advised 300 mg once daily if they are tolerating the 100 mg dose and they are not achieving their glycemic targets.
  • Patients receiving UGT inducers and have an eGFR of less than 60 ml/min may be advised an alternative drug.

Dose in Children:

Not recommended.

Pregnancy Risk Factor: C

• Animal studies have shown that adverse fetal outcomes were common, especially in the second and third trimesters.
• You should also consider other recommended treatments, such as insulin, during pregnancy.

Canagliflozin invokana use during breastfeeding:

• It is not recommended for use during breastfeeding as excretion into the breastmilk is not known.

Canagliflozin Dose in Renal Disease:

• eGFR of more than 60 mL/minute/1.73 m²:
  • Adjustment in the dose is not required.

• eGFR 45 to less than 60 mL/minute/1.73 m²:

  • Maximum daily intake should not exceed 100mg
  • Therapy should not be initiated for patients on UGT enzyme inducers such as rifampin and ritonavir.

• eGFR 30 to 45 mL/minute/1.73 m²:

  • Treatment should not be initiated in these patients especially patients with a persistently low eGFR.

• eGFR of less than 30 mL/minute/1.73 m², end-stage renal disease, and patients on hemodialysis:

  • Use is contraindicated.

Canagliflozin Dose in Liver Disease:

• Mild-to-moderate hepatic impairment (Child-Pugh class A and B):
  • Adjustment in the dose is not required.
• Severe renal impairment (Child-Pugh class C):
  • Avoid its use as it has not been studied.

Common Side Effects of Canagliflozin invokana:

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

Less Common Side Effects of Canagliflozin:

• 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

Contraindications to Canagliflozin Invokana:

• Severe allergic reactions to canagliflozin and any component of this formulation
• Severe renal impairment, i.e. An eGFR below 30 mL/minute/1.73m2, end-stage kidney disease, or patients on dialysis.

Warnings & Precautions

• Bone fractures:
  • The CANVAS trial found that canagliflozin was associated with a higher risk of fractures.
  • Patients who have had a history of fractures in the past, patients with existing cardiovascular disease, elderly people, and those with reduced ejection fraction are at greater risk for developing fractures.
  • Fractures can occur up to three months after therapy has begun.
• Genital mycotic infections:
  • Use of it increases the risk of developing genital fungal infections such as vaginal candidiasis and vulvovaginitis.
  • Patients who have had fungal vaginal infection in the past and uncircumscribed males are at particular risk.
• Hypersensitivity reactions:
  • Within hours or days of starting treatment, severe allergic reactions such as angioedema or anaphylaxis can occur.
  • The treatment may be stopped and the patient treated immediately.
• Hypotension:
  • It can lead to volume loss, which could cause hypotension.
  • Before initiating therapy, patients should be evaluated for hypotension symptoms and treated.
  • Patients with renal impairment, the elderly, patients taking antihypertensives such as diuretics or ACE inhibitors and patients with low systolic pressure are all at-risk.
• Hyperkalemia:
  • Patients at high risk for hyperkalemia should have their serum potassium monitored.
  • Patients who are on potassium-sparing diuretics or ACE inhibitors, ARBS or have kidney dysfunction should be monitored regularly for hyperkalemia.
• Ketoacidosis:
  • Diabetic ketoacidosis can be fatal in type 1 and 2 diabetics with normal or elevated plasma glucose levels.
  • Before initiating therapy, it is important to identify any risk factors that could lead to ketoacidosis. Risk factors include insulin deficiency and caloric restriction, exercise excessively, alcohol abuse, stroke, myocardial injury, surgery, severe infections, discontinuation of insulin or reduction in insulin dose.
  • AACE and ACE recommend that you withhold therapy for 24 hours before an event that could lead to diabetic ketoacidosis. 
  • Others recommend that there be a delay of between 3 and 5 days.
  • Diabetic ketoacidosis patients should be closely monitored for signs and symptoms such as nausea, vomiting, abdominal pains, shortness or breathlessness, altered mental state, and abdominal pains.
  • It is important to stop using the drug and get prompt treatment.
• Lipid abnormality:
  • It has been linked to dyslipidemia.
  • LDL-c levels should be checked and treated as appropriate.
• Lower limb amputation: [US Boxed Warning]:
  • Canagliflozin has been linked to a 2-fold increase in the risk of lower-limb amputations.
  • The studies report that amputations occurred in the toe, middlefoot, and less often the leg.
  • Infections, gangrene and foot ulcers are all risk factors for lower-limb amputation.
  • Foot care should be taught to patients.
  • If the patient has osteomyelitis symptoms, tenderness or new pain, and ulcers in the lower limbs, it is best to stop treatment.
• Necrotizing fasciitis:
  • Use of SGLT2 inhibitors, including canagliflozin, has been linked to rare and serious infections of the perineum.
  • Patients with fever, genital or perineal pains, tenderness, erythema or swelling should stop receiving treatment.
• Renal effects:
  • Before initiating treatment, assess the patient for signs and symptoms that could indicate renal failure. 
  • These include heart disease, chronic kidney disease, hypovolemia, heart failure, hypovolemia, and use of concomitant medications such as diuretics, ACE inhibitors or NSAIDs.
  • If the patient experiences acute kidney injury due to volume loss or dehydration, treatment may be stopped temporarily.
  • Before starting therapy, monitor your renal function and correct any volume loss.
• Urinary tract infection:
  • It may result in glucosuria. There have been reports of urinary tract infections such pyelonephritis and urosepsis.
  • Sometimes, serious infections may need hospitalization.
• Hepatic impairment:
  • It is not advised for usage in severe hepatic impairment because it has not been researched in this population.
• Renal impairment:
  • Patients with end-stage renal disease and CrCl levels less than 30 ml/min are to stay away from it.
  • Adjustment is required for those with an eGFR below 60 ml/minute.
  • Monitoring of renal functions at baseline and regularly thereafter is recommended.
  • Patients suffering from renal impairment have a decreased glycemic efficacy.

Monitor:

• Blood glucose
• Glycated hemoglobin at least twice yearly in patients who have achieved target HbA1C and every three months in patients who have not achieved the target HbA1C.
• Renal function
• Volume status
• Serum potassium in patients predisposed to hyperkalemia like those with renal failure
• Serum magnesium levels
• Serum Phosphate levels
• LDL-C
• Genital infections and urinary tract infections
• Monitor for allergic reactions
• Check the pulses and monitor for lower limb and feet ulcers
• Monitor for ketoacidosis in patients who are symptomatic like those with nausea and vomiting, abdominal pain, malaise, and shortness of breath.

How to administer Canagliflozin invokana?

• It may be administered without regards to meals.
• it should be preferably taken before the first meal of the day as it results in post-prandial hyperglycemia.

Mechanism of action ofCanagliflozin:

• It inhibits the sodium–glucose cotransporter 2 (SGLT2) in the proximal kidney tubules. It prevents glucose from being reabsorbed by the kidneys. 
• Osmotic diuresis is when excess glucose is eliminated via the kidneys.
• This may prove beneficial for hypertensive patients, those suffering from cardiac disease or fluid overload. 
• It can also lead to recurrent infections of the urinary tract, volume depletion and dehydration.

The onset of action: It works for 24 hours, the maximum effect on glucose-lowering is seen at 300 mg.

Absorption: The effects of the drug are not affected. However, the delayed gastrointestinal glucose absorption results in postprandial hyperglycemia being reduced by administration of the drug together with the first meal. 99 percent of the drug is bound to albumin. It is Metabolized by UGT1A9, UGT2B4 via O-glucuronidation to inactive metabolites Orally, 65% of the drug is bioavailable. After the administration of 100 or 300 mg doses, it has a half life of 10.6 to 13.1 hour. It reaches the Peak plasma concentration in 1 - 2 Hours 41.5% is the drug is metabolized, the rest is excreted through urine as metabolites.

Canagliflozin international brands:

• Canaflo
• Canaglif
• Canaglu
• Invocana
• Invokana
• Sulicent

Canagliflozin Brands in Pakistan:

No brands available in Pakistan