Canagliflozin
Medicine Type :
Allopathy
Allopathy
Prescription Type:
Prescription Required
Prescription Required
Approval :
DCGI (Drugs Controller General of India)
DCGI (Drugs Controller General of India)
Schedule
Schedule H
Schedule H
Pharmacological Class:
Sodium-glucose cotransporter-2 (SGLT2) inhibitors, Therapy Class:
Antidiabetic Agent, Approved Countries
India, the United States, Canada, the United Kingdom, France, Japan, Germany and Australia.
Canagliflozin is an anti-diabetic Agent belonging to the pharmacological class of Sodium-glucose cotransporter-2 (SGLT2) Inhibitors.
Canagliflozin is approved to treat type 2 diabetes by lowering the blood sugar levels by inhibiting glucose reabsorption in the kidneys and increasing glucose excretion in urine.
Canagliflozin absorbs quickly when taken orally. It is mainly found in the extracellular fluid and binds to plasma proteins very little. There is minimal metabolism, and most medication is eliminated unaltered in the urine. Canagliflozin has a half-life of roughly 10.6 hours and is mainly excreted by the kidneys.
Canagliflozin's most common side effects include fungal infection of the vagina, urinary tract infection, and frequent urge to urinate.
Canagliflozin is available in the form of oral tablets.
The molecule is available in India, the United States, Canada, the United Kingdom, France, Japan, Germany and Australia.
Canagliflozin is an anti-diabetic agent belonging to the pharmacological class of Sodium-glucose cotransporter-2 (SGLT2) Inhibitors.
The kidney's proximal tubules contain the sodium-glucose co-transporter 2 (SGLT2), which reabsorbs filtered glucose from the renal tubular lumen. SGLT2 co-transporter inhibition is caused by canagliflozin. Because of this inhibition, the body absorbs filtered glucose less readily, and the renal threshold for glucose (RTG) is lowered, which increases the amount of glucose excreted in the urine.
Data duration of Canagliflozin action typically lasts up to 24 hours after oral administration.
The Data of Tmax of Canagliflozin is approximately 1-2 hours after oral administration.
The Data of Cmax of Canagliflozin is approximately 2 hours following oral administration.
Canagliflozin is available in the form of Oral Tablets.
Tablets: To be swallowed whole with water/liquid. Do not chew, crush or break it.
As the physician recommends, take the medication orally once daily, generally with or without a meal.
Canagliflozin can be used in the following health conditions:
- To treat type 2 diabetes mellitus by helping to lower blood sugar levels.
- Controlling hypertension in individuals diagnosed with type 2 diabetes.
- Lowering the risk of strokes and heart attack in individuals with type 2 diabetes who already have cardiovascular disease.
In Treatment of Type 2 diabetes mellitus
Canagliflozin aids in managing elevated blood glucose (sugar) levels by facilitating the removal of excess glucose through urine. Lowering blood glucose levels is a vital component of diabetes management.
To effectively manage diabetes, the blood glucose levels must be reduced. Controlling blood sugar levels will lower the likelihood of any of the severe complications of diabetes, including kidney damage, eye damage, nerve problems, and amputation of limbs. The risk of cardiac disease and stroke can be decreased with proper diabetes management. Individuals can live longer if they take this medication consistently and follow a healthy diet and exercise routine.
Canagliflozin is indicated as follows:
- As an adjunct to diet and exercise to help people with type 2 diabetes manage their blood sugar levels (T2DM).
- Also indicated to lower adult T2DM patients' risk of significant adverse cardiovascular events, such as stroke, nonfatal MI, and cardiovascular mortality.
- For people with type 2 diabetes (T2DM) and diabetic nephropathy, albuminuria <300 mg/day can reduce the risk of end-stage kidney disease (ESKD), serum creatinine doubling, cardiovascular (CV) death, and heart failure hospitalization.
Limitation of Use:
It is not recommended for type 1 diabetes mellitus or diabetic ketoacidosis.
Orally: Canagliflozin can be taken with or without food. Canagliflozin can be taken with or without food, as a high-fat meal has no significant impact on its pharmacokinetics. However, to maximize effectiveness, it's recommended to take it before the first meal. Adequate fluid intake is essential to reduce the risk of hypotension. If a dose is missed, it should be taken promptly, but doubling the following amount is not advised.
The dosage and duration of treatment should be as per the treating physician's clinical judgment.
Tablets: 100mg, 300 mg.
Canagliflozin is available in the form of oral tablets.
Dose Adjustment in Adult Patients:
Diabetes Mellitus Type 2
Primary: Take 100 mg PO qDay before the day's first meal.
If individuals with eGFR ≥60 mL/min/1.73 m² tolerate 100 mg/day, the dose may be increased to 300 mg qDay if more glycemic control is needed.
Dosing Considerations
It is not advised to treat diabetic ketoacidosis or type 1 diabetes.
Before the primary treatment
Appropriate volume decrease
Evaluate renal function and subsequently regularly.
Canagliflozin should be used in treating Type 2 Diabetes Mellitus, along with appropriate nutritional limits.
While taking Canagliflozin, avoid large meals and maintain regular meals with balanced macronutrient content to help stabilize blood sugar levels.
Excessive consumption of alcohol can increase the risk of dehydration and may affect blood sugar levels.
Maintaining an appropriate fluid intake is essential to avoiding dehydration and its associated adverse effects, particularly in water.
It is advised to stay hydrated, maintain a rich, balanced diet with appropriate carbohydrate intake, and consume plenty of vegetables, whole grains, fruits, and lean proteins to help manage your overall health and blood sugar levels effectively.
The dietary restriction should be individualized as per patient requirements.
Canagliflozin may be contraindicated in the following conditions:-
- Severe hypersensitivity to Canagliflozin, such as angioedema or anaphylaxis.
- Patients undergoing dialysis.
- Hypotension: Low systolic blood pressure, elderly patients, patients with renal impairment, patients taking diuretics, ACE inhibitors, or patients taking ARBs should all have their volume status evaluated and hypovolemia corrected before starting Canagliflozin. While receiving therapy, monitor for any indications or symptoms.
- Ketoacidosis: Regardless of blood glucose level, evaluate individuals for ketoacidosis if they show signs and symptoms of metabolic acidosis. When suspected, stop taking canagliflozin, get checked out, and start treatment right away. Examine your risk of ketoacidosis before starting on canagliflozin. In clinical situations, when there is a recognized risk of ketoacidosis, patients may need to be closely monitored and have their therapy temporarily stopped.
- Impairment in renal function: Monitor renal function while receiving treatment. Patients with an eGFR less than 60 mL/min/1.73 m2 should have more regular monitoring.
- Hyperkalemia: Individuals at risk for hyperkalemia and those with reduced renal function should have their potassium levels checked. Pyelonephritis and Urosepsis: Assess patients for urinary tract infection symptoms and signs and treat them as soon as necessary.
- Hypoglycemia: When taking Canagliflozin with insulin, consider reducing the insulin dose or using an insulin secretagogue to lessen the risk of Hypoglycemia.
- Infections with genital mycotics: Monitor and treat if necessary.
- Hypersensitivity reactions: Stop taking canagliflozin and monitor until symptoms are gone completely.
- Bone fracture: Before starting Canagliflozin, consider the variables that increase the fracture risk.
- Elevated LDL-C: Maintain a close watch on it and seek treatment if necessary.
Alcohol Warning
It is unsafe to consume Canagliflozin with Alcohol.
Breast Feeding Warning
It is most likely not safe to use canagliflozin during breastfeeding. The medication might harm the unborn child if it enters the breastmilk, according to limited human data.
Pregnancy Warning
Safe to use during pregnancy only if the possible benefit outweighs the potential risk to the foetus. Use caution.
Food Warning
Limit Alcohol and avoid fatty or high-calorie meals.
The adverse reactions related to Canagliflozin can be categorized as:
- Common Adverse Effects: Female genital mycotic infections
- Less Common Adverse Effects: Urinary tract infections, increased urination, male genital mycotic infections, thirst, constipation, nausea and volume depletion.
- Rare Adverse Effects: Ketoacidosis, hypersensitivity Reactions, impaired Renal and Hepatic function.
Reports on Post-marketing
Ketoacidosis
Acute kidney injury
Hypersensitivity
Fournier's gangrene, or necrotizing fasciitis of the perineum
Angioedema
Urosepsis
Pyelonephritis
The clinically relevant drug interactions of Canagliflozin are briefly summarized here.
- UGT Enzyme Inducers: UGT1A9, UGT2B4, and other nonselective enzyme inducers, such as rifampin, decreased canagliflozin exposure (AUC) by 51%. This could make canagliflozin less effective. If patients require further glycemic control, tolerate 100 mg of canagliflozin daily, and have an eGFR more significant than 60 mL/min/1.73 m2, you may want to explore raising the dose to 300 mg daily while co-administering an inducer of these UGTs with INVOKANA (canagliflozin). Individuals who require extra glycemic control and have an eGFR of 45 to less than 60 mL/min/1.73 m2 and are on concurrent UGT inducer therapy may want to consider other antihyperglycemic treatments.
- Digoxin: When digoxin and canagliflozin 300 mg were given together, there was a rise in the AUC and Cmax of digoxin (20% and 36%, respectively). Patients who are concurrently taking digoxin and Icanagliflozin need to be well monitored.
- Positive Urine Glucose Test: It is not advised for patients taking SGLT2 inhibitors to use urine glucose tests to monitor their glycemic control because these drugs increase the excretion of urine glucose and can cause positive results on these tests. Change up how you keep an eye on your glycemic control.
- Interference with 1,5-anhydroglucitol (1,5-AG) Assay: It is not advised to use the 1,5-AG assay to monitor glycemic control in patients using SGLT2 inhibitors because the results of this test are not consistently accurate. To keep an eye on glycemic management, try using several techniques.
- Diuretics: Concomitant use of diuretics, especially loop diuretics, can increase the risk of dehydration and volume depletion when combined with renal function.
The most common side effects of Canagliflozin include:
- Nausea
- Constipation
- Increased thirst
- Rash
- Polyuria
- Urinary tract infection
- Genital fungal infection
- Pregnancy
Pregnancy Category C. Use with caution if the benefits outweigh the risks.
Based on animal evidence suggesting harmful kidney consequences, not advised during the second and third trimesters of pregnancy
Pregnancy-related data are scarce and insufficient to establish if drugs increase the incidence of severe birth abnormalities or miscarriages.
Clinical considerations
Pregnancy-related poorly managed diabetes raises the risk of diabetic ketoacidosis, preeclampsia, spontaneous abortions, premature birth, stillbirth, and problems during delivery for the mother.
Severe hyperglycemia increases the chance of serious birth abnormalities, stillbirth, and morbidity associated with macrosomia in neonates.
- Nursing mothers:
There is no data available on the distribution of Canagliflozin in human breast milk or its impact on breastfeeding infants or milk production. However, it has been detected in the milk of lactating rats. Kidney maturation in humans happens in utero, during the first two years of life, and lactational exposure might coincide with this critical development. There could be potential risks to the developing human kidney. Therefore, it is advised to counsel women not to breastfeed while using Canagliflozin.
- Pediatric Use:
As per FDA, safety and effectiveness in the pediatric population have yet to be established.
- Geriatric Use:
Canagliflozin has well-established safety and effectiveness characteristics in the elderly population. Blood glucose management with canagliflozin benefits the elderly, but close monitoring is necessary because of changes in kidney function caused by ageing and other potential medical disorders.
Dosage adjustment in geriatric patients:
Individuals over 65 years of age experienced a greater frequency of adverse reactions associated with decreased intravascular volume (such as hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration), especially when using the 300 mg daily dose, in comparison to younger patients; a more pronounced increase in the frequency was observed in patients over 75 years of age.
Elderly patients (≥65 years) experienced lower reductions in HbA1C when compared to placebo (-0.61% with a 100-mg dose and -0.74% with a 300-mg amount).
Dose Adjustment in Kidney Impairment Patients:
If eGFR is ≥60 mL/min/1.73 m2, there is no need to modify the dosage.
If your eGFR is between 30 and <60 mL/min/1.73 m2, as well as have albuminuria more significant than 300 mg/day, one should take 100 mg once daily to lower the risk of end-stage renal disease, increasing the level of serum creatinine, cardiovascular mortality, and heart failure hospitalization.
eGFR <30 mL/min/1.73 m2: It is not advised to start.
When on dialysis: Not recommended.
Dose Adjustment in Hepatic Impairment Patients:
Mild-to-moderate: No dosage modification is required
Severe: This has not been researched and is not advised.
Signs and Symptoms
The physician should be vigilant about the knowledge pertaining to the identification and treatment of overdosage of Canagliflozin.
Overconsumption of Canagliflozin may lead to dehydration, increased urination, low blood pressure, and electrolyte imbalances. Severe cases may result in renal impairment.
Management
There is no specific antidote or treatment for excessive intake of Canagliflozin. However, immediate medical attention is essential. Canagliflozin should be terminated immediately when an overdose is In cases of overdose, close medical attention is crucial. Canagliflozin should be discontinued if an overdose is suspected or if unusual symptoms occur after ingestion. The primary intervention is supportive care, which may involve monitoring vital signs, providing fluids and electrolytes if necessary, and addressing symptoms such as nausea or vomiting. In severe cases of overdose, hemodialysis may be considered, particularly in instances of acute kidney injury or overdose with canagliflozin. It is vital for healthcare professionals to closely manage and support the patient until their condition stabilizes, with specific attention to maintaining adequate hydration and managing any metabolic disturbances.
Pharmacodynamics:
This medication lowers the renal threshold for glucose (RTG) and increases urine glucose excretion dose-dependently. What is known as the renal threshold is the lowest blood glucose level at which measurable glucose appears in the urine. After taking canagliflozin, there is a reduction in renal absorption of glucose and a rise in urine excretion of glucose, which lowers blood glucose levels and improves glycemic control.
Note on type 2 diabetes and cardiovascular disease.
Diabetes damages blood vessels and neurons in the cardiovascular system, increasing the risk of cardiovascular events in those with type 2 diabetes. Specifically, hyperglycemia has been shown to induce pro-atherogenic (plaque-forming) lesions in blood arteries, which can result in several deadly and nonfatal events, such as myocardial infarction and stroke. In patients with type 2 diabetes, long-term glycemic management is beneficial in preventing cardiovascular events like myocardial infarction and stroke.
Pharmacokinetics:
Absorption
Canagliflozin has an absolute oral bioavailability of, on average, 65%. After 4 to 5 days of daily dosage administration, steady-state concentrations between 100 and 300 mg are achieved.
Bioavailability: 65%
Peak plasma time: 1-2 hr
Distribution
Canagliflozin exhibits extensive distribution within the body, with an average volume of distribution of 83.5 litres at a steady state following intravenous administration in healthy individuals. It is highly bound to albumin in the plasma, with a binding rate of 99%.
Protein-bound: 99% (predominantly to albumin)
Vd: 119 L
Metabolism
O-glucuronidation is the main metabolic pathway for canagliflozin. The UGT1A9 and UGT2B4 enzymes mostly glucuronidate it to produce two inactive O-glucuronide metabolites.
In humans, hepatic cytochrome enzyme CYP3A4 has a minimal (about 7%) role in the oxidative metabolism of canagliflozin.
Elimination
Following a single oral radiolabeled dose of canagliflozin to healthy subjects, approximately 41.5% of the unchanged radiolabeled drug, 7.0% as a hydroxylated metabolite, and 3.2% as an O-glucuronide metabolite were excreted in faeces. In urine, around 33% of the ingested radiolabeled dose was excreted, primarily as O-glucuronide metabolites, with less than 1% as an unchanged drug.
Half-life: 10.6 hr (100 mg dose); 13.1 hr (300 mg dose)
Total body clearance: 192 mL/min
- Perkovic V, et al. Canagliflozin and renal outcomes in type 2 diabetes: results from the CANVAS Program randomized clinical trials. Lancet Diabetes Endocrinol. 2018 Sep;6(9):691-704. doi: 10.1016/S2213-8587(18)30141-4. Epub 2018 Jun 21. PMID: 29937267.
- Tian L, et al. Canagliflozin for Prevention of Cardiovascular and Renal Outcomes in type 2 Diabetes: A Systematic Review and Meta-analysis of a Randomized Controlled Trials. Front Pharmacol. 2021 Jul 19;12:691878. Doi: 10.3389/fphar.2021.691878. PMID: 34349651; PMCID: PMC8327383.
- Mahaffey KW, et al. Canagliflozin and Cardiovascular and Renal Outcomes in Type 2 Diabetes Mellitus and Chronic Kidney Disease in the Primary and Secondary Cardiovascular Prevention Groups. Circulation. 2019 Aug 27;140(9):739-750. doi: 10.1161/CIRCULATIONAHA.119.042007. Epub 2019 Jul 11. PMID: 31291786; PMCID: PMC6727954.
- Jardine MJ, et al; CREDENCE Study Investigators. Renal, Cardiovascular, and the Safety Outcomes of Canagliflozin by Baseline Kidney Function: A Secondary Analysis of the CREDENCE Randomized Trial. J Am Soc Nephrol. 2020 May;31(5):1128-1139. doi: 10.1681/ASN.2019111168. PMID: 32354987; PMCID: PMC7217416.
- Gupta V, Willis M, Johansen P, Nilsson A, Shah M, Mane A, Neslusan C. Long-Term Clinical Benefits of Canagliflozin 100 mg Versus Sulfonylurea in the Patients With Type 2 Diabetes Mellitus Inadequately Controlled With Metformin in India. Value Health Reg Issues. 2019 May;18:65-73. doi: 10.1016/j.vhri.2018.06.002. Epub 2018 Nov 28. PMID: 30502662.
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- https://dailymed.nlm.nih.gov/dailymed/drugInfo.
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3859282/
- https://www.ema.europa.eu/en/medicines/human/EPAR/invokana
Published on: 6 Nov 2023 5:53 AM GMT