Canagliflozin - Uses, Mechanism of Action, Precautions, and Contraindications

How Does Canagliflozin Work?

Canagliflozin works by inhibiting the SGLT2 (sodium-glucose co-transporter 2) found in the kidney tubules, thus hampering the reabsorption of the filtered glucose from the kidney tubules. This inhibition decreases the reabsorption of filtered glucose into the body, further reducing the renal threshold for glucose and leading to increased glucose excretion through the urine.

Uses of Canagliflozin:

Canagliflozin treats type 2 diabetes mellitus along with diet and proper exercise.

Limitations:

Canagliflozin is not recommended for treating individuals with type 1 diabetes mellitus and diabetic ketoacidosis.

Dosage Restrictions:

1. Route of Administration - Oral.

2. Dosage Strengths

• 100 mg.

• 300 mg.

3. Dosage Forms

• 100 mg tablets are yellow, capsule-shaped, with 'CFZ' embossed and '100' on the other.

• 300 mg tablets are white, capsule-shaped, with 'CFZ' embossed and '300' on the other.

Special Considerations:

Warnings and Contraindications

Canagliflozin is contraindicated in the following:

• Severe renal impairment.

• End-stage kidney disease.

• Individuals on dialysis.

• Individuals who are allergic or sensitive to the drug.

Warnings and Precautions:

• Amputation of the Lower Limb: Increased risk of lower limb amputations has been associated with Canagliflozin in patients with type 2 diabetes who either had an underlying cardiovascular disease or were at risk for developing one. The common causes leading to amputations are infections of the lower limb, gangrene, and diabetic foot ulcers.

• Low Blood Pressure: Canagliflozin has been associated with intravascular volume contraction. Hypotension or low blood pressure can occur in individuals with impaired kidney function, the elderly, individuals on diuretics or medications, or ones with low blood pressure.

• Diabetic Ketoacidosis: Diabetic ketoacidosis, a severe life-threatening condition, has been found to occur in patients taking Canagliflozin.

• Acute Kidney Injury: Canagliflozin causes acute kidney injury by the contraction of the intravascular volume. Canagliflozin increases serum creatinine and decreases the glomerular filtration rate. Hypovolemic individuals taking Canagliflozin are more prone to kidney injury.

• Hyperkalemia: Canagliflozin can lead to hyperkalemia. Individuals with underlying kidney impairment and are under medications that interfere with the excretion of potassium, such as potassium-sparing diuretics or medications interfering with the renin-angiotensin-aldosterone system, are prone to develop hyperkalemia.

• Pyelonephritis and Urosepsis: Canagliflozin is associated with urinary tract infections like urosepsis and pyelonephritis.

• Hypoglycemia: Canagliflozin increases the risk of developing hypoglycemia when combined with insulin.

• Fungal Infections of the Genitals: Canagliflozin increases the risk of mycotic infections of the genital area of individuals with a previous history of genital mycotic infections.

• Hypersensitivity: Canagliflozin has been associated with hypersensitivity reactions like angioedema and anaphylaxis.

• Fracture: Increased fracture risk has been associated with Canagliflozin treatment occurring 12 weeks after the treatment.

For Patients:

What Is Type 2 Diabetes?

Type 2 diabetes is a condition leading to excess sugar in the bloodstream. Type 2 diabetes occurs because either the pancreas does not produce enough insulin or the cells of the body do not utilize the insulin properly, leading to an increased blood sugar level.

Why Is Canagliflozin Prescribed for Type 2 Diabetes?

Canagliflozin is a drug used to lower blood sugar levels in people with type 2 diabetes along with diet and exercise. Canagliflozin can also decrease the risk of stroke, heart attack, or death in people with type 2 diabetes with heart and blood vessel disease. Canagliflozin belongs to a class of medications called sodium-glucose co-transporter 2 (SGLT2) inhibitors. It lowers blood sugar levels by making the kidneys excrete more glucose in the urine.

Facts One Should Know About Canagliflozin:

How Should One Take Canagliflozin?

• Canagliflozin is taken orally.

• It is taken once a day before the first meal of the day.

• It should be taken around the same time of the day.

• Do not take less or more of the drug.

• It should be taken as prescribed by the doctor.

What Should One Discuss With the Doctor Before Beginning Canagliflozin?

Before beginning the treatment with Canagliflozin, the doctor should be informed about the following:

• In case the person is allergic to Canagliflozin or any other medications.

• Suppose the person takes other prescription and nonprescription medications, vitamins, and supplements. Medications like angiotensin-converting enzyme (ACE) inhibitors such as Benazepril, Captopril, Enalapril, Fosinopril, Lisinopril, Moexipril, Perindopril, Quinapril, Ramipril, and Trandolapril; angiotensin receptor blockers such as Azilsartan, Candesartan, Eprosartan, Irbesartan, Losartan, Olmesartan, Telmisartan, and Valsartan; Digoxin; diuretics; insulin; other medications for diabetes; Phenobarbital; Phenytoin; Rifampin, and Ritonavir, should be informed.

• The doctor should be informed if one is on dialysis.

• The doctor should be informed if one drinks alcohol or is on a low-sodium diet.

• The doctor should be informed if one had an amputation, heart disease, peripheral vascular disease, neuropathy, foot ulcers or sores, low blood pressure, urinary tract infections, urinary problems, pancreatic disease like pancreatitis (swelling of the pancreas), surgery of the pancreas, yeast infections in the genital area, osteoporosis, kidney or liver disease.

• The doctor should be informed if one is eating less due to a specific illness, surgery, or a diet change. Also, if one often gets dehydrated while being in the sun.

• The doctor should be informed if one is pregnant, planning to conceive, or breastfeeding.

• Inform the doctor in case of surgery, including dental surgery.

Is Canagliflozin Safe?

Canagliflozin is a safe drug when used as prescribed.

Is Canagliflozin Effective?

Canagliflozin controls type 2 diabetes but does not cure it completely.

What Side Effects Can One Expect With Canagliflozin?

The side effects associated with Canagliflozin include:

1. Excess urination, especially at night.

2. Increase in thirst.

3. Constipation.

4. Dry mouth.

5. Pain or burning while passing urine.

6. Reduced urination.

7. Cloudy, reddish, pinkish, or brownish urine.

8. Strongly smelling urine.

9. Pain in the pelvic area.

10. Whitish or yellowish vaginal discharge with a foul odor.

11. Redness, itching, and swelling of the penis with foul-smelling discharge.

12. Fatigue with fever, tenderness, and swelling of the genitals.

13. Anaphylaxis or Allergic Reactions:

    • Rash.

    • Hives.

    • Hoarseness of voice.

    • Difficulty in swallowing.

    • Swelling of the face, tongue, throat, mouth, or eyes.

    • Itching.

Can One Stop Taking Canagliflozin Without the Doctor's Approval?

Of course, one should not stop taking Canagliflozin without the doctor's consent.

Are There Any Dietary Restrictions to Consider When Taking Canagliflozin?

It is essential to eat a healthy balanced diet as per the doctor's or dietician's recommendation and exercise regularly. In addition, drink plenty of fluids while on the medication throughout the day.

How Should One Store Canagliflozin?

Store the medication in a tightly closed container, out of the kids' reach. Store it at room temperature, away from sunlight, heat, and moisture. In order to keep the medication away from kids, always lock the safety caps.

How Should One Dispose of Canagliflozin?

Unused and expired medications should be disposed of in ways so that pets, kids, and other people cannot ingest them. But, it should not be flushed down the toilet. Instead, the medicines should be disposed of through a medicine take-back program.

What To Do in Case of Overdose?

In the case of an overdose, the poison control team should be immediately informed. Likewise, if the person has collapsed, had a seizure, is unconscious, or has difficulty breathing, the emergency services should be promptly informed.

For Doctors:

Indications:

Type 2 Diabetes Mellitus

Canagliflozin controls type 2 diabetes mellitus along with diet and exercise. It also reduces the risk of developing cardiovascular disorders in type 2 diabetic individuals with an underlying cardiovascular disease. It also decreases the risk of end-stage kidney disease.

What Is the Pharmacology of Canagliflozin?

Description:

Canagliflozin inhibits sodium-glucose co-transporter 2, which is responsible for reabsorbing most of the glucose filtered by the kidneys. Canagliflozin is chemically (1S)-1,5-anhydrous-1-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol hemihydrate, with a formula C24H25FO5S.1/2 H2O, and a weight of 453.53.

Components:

1. Active Ingredients

• Canagliflozin.

2. Inactive Ingredients

• Croscarmellose sodium.

• Hydroxypropyl cellulose.

• Lactose anhydrous.

• Magnesium stearate.

• Microcrystalline cellulose.

Clinical Pharmacology:

Mechanism of Action

The sodium-glucose co-transporter 2 (SGLT2) is present in the proximal renal tubules and is responsible for most of the reabsorption of the glucose filtered from the tubular lumen. Canagliflozin works by inhibiting SGLT2, thus decreasing the reabsorption of the filtered glucose and lowering the renal threshold for glucose (RTG), which in turn increases urinary glucose excretion (UGE).

Pharmacodynamics

Canagliflozin increases the excretion of glucose and decreases the renal threshold for glucose (RTG) in a dose-dependent way. Thus, Canagliflozin administration leads to an increase in glucose excretion and less absorption of glucose by the kidneys, thereby decreasing the glucose level in the bloodstream and improving glycemic control in type 2 diabetic individuals.

Pharmacokinetics

• Mean Cmax- Cmax is dose-dependent.

• Median Tmax- One to two hours after the dose.

[Cmax- Maximum concentration achieved by a drug in the blood, cerebrospinal fluid, or target organ after administration of a dose]

[Tmax- It is the time taken for a drug to reach its maximum concentration after administration of a dose]

Pharmacokinetic Changes

• Canagliflozin does not show time-dependent pharmacokinetics, and 36 % of it accumulates in the plasma after several 100 mg and 300 mg doses.

A. Distribution

• Steady-state Plasma Levels - 36 %.

• Time to Approach Steady-state Levels - Four to five days of daily dosage with 100 to 300 mg of Canagliflozin.

• Binding to Plasma Proteins - 99 %.

B. Metabolism-

O-glucuronidation metabolizes Canagliflozin. It is mainly glucuronidated by the enzymes UGT1A9 and UGT2B4 into two inactive O-glucuronide metabolites. The oxidative metabolism of Canagliflozin by CYP3A4, the hepatic cytochrome enzyme, is around seven percent.

C. Excretion

Recovery of Canagliflozin

• In Feces: 41.5 % of Canagliflozin, 7 % hydroxylated metabolite, and 3.2 % O-glucuronide metabolite.

• In Urine: 33 % of Canagliflozin is excreted, primarily as O-glucuronide metabolites 30.5 %, and less than one percent is removed unchanged.

D. Elimination

• The half-life of Canagliflozin is 10.6 hr (100 mg dose) and 13.1 hr (300 mg dose).

• The total body clearance is 192 mL/minute.

Special Considerations:

• Kidney Impairment: The pharmacodynamics of Canagliflozin decreases with increasing severity of kidney impairment. Therefore, Canagliflozin removal by hemodialysis is negligible.

• Hepatic Impairment: No dose adjustment is required for individuals with mild to moderate hepatic impairment.

• Age, Body Mass Index (BMI), Weight, Gender, and Race: Age, body mass index (BMI), weight, gender, and race do not affect Canagliflozin's pharmacokinetics.

Drug Interactions

• Aceclofenac: Canagliflozin might increase Aceclofenac's excretion rate, resulting in a lower serum level and reduced efficacy.

• Acetaminophen: Canagliflozin increases the excretion rate of Acetaminophen, resulting in a reduced serum level and efficacy.

• Baclofen: The efficiency of Canagliflozin can be decreased when used with Baclofen.

What Have Clinical Trials Shown About Canagliflozin?

Several studies and trials have been conducted on Canagliflozin. One of those is:

Canagliflozin Cardiovascular Assessment Study (CANVAS)

The CANVAS program consisted of two double-blind, randomized trials evaluating Canagliflozin's effect versus the placebo in participants with type 2 diabetes mellitus, with a high risk of cardiovascular events, carried out in 30 countries. Type 2 diabetic people under 30 years of age and an HbA1c of 7·0 to 10·5 % had a history of symptomatic atherosclerotic vascular disease, or individuals 50 years of age and had at least two cardiovascular risk factors were made to participate. The participants were randomly given 300 mg and 100 mg of Canagliflozin or matching placebo once a day.

Results

It was found that treatment with Canagliflozin was associated with a reduced risk of loss of kidney function, reduced drop in the eGFR, and decreased albuminuria, thus signifying a kidney protective effect of the drug in people with type 2 diabetes mellitus.

Patient Counseling Information:

Administration Instructions

• The patient should be instructed to review the medication guide before beginning Canagliflozin therapy.

• Canagliflozin should be administered orally, with a starting dose of 100 mg once daily before the day's first meal.

• The patient should be informed about Canagliflozin's potential risks and benefits.

• The patients should be enlightened about the importance of following particular dietary instructions, regular physical activity, periodic blood glucose monitoring, and HbA1C testing, proper management of hypoglycemia and hyperglycemia, and routine evaluation for diabetes complications.

• The patients should be advised to get prompt medical attention in case of fever, trauma, infection, or surgery.

• The patient should be instructed to take Canagliflozin only as prescribed. In case of a missed dosage, the individual should take it soon on remembering unless it is time for the next dose, wherein the patients should skip the missed dose and take medicine at the scheduled time. The patients should be instructed not to double the dose of Canagliflozin simultaneously. The patient should be informed about the drug's common side effects, such as genital mycotic infection, urinary tract infection, and increased urination.

• Female patients should be advised to use the drug during pregnancy only if the advantage justifies the potential risk it might cause the fetus.

• Pregnant patients should inform the doctor about the pregnancy as soon as possible. The nursing mothers should be advised to discontinue Canagliflozin or breastfeeding, subject to the importance of the drug to the mother.

Complications or Side Effects

The side effects of Canagliflozin include:

• Genital mycotic infections.

• Urinary tract infections.

• Increased frequency of urination.

• Increased thirst.

• Constipation.

• Nausea.

• Ketoacidosis.

• Urosepsis.

• Anaphylaxis.

• Pyelonephritis.

• Angioedema.

• Acute kidney injury.

• Fournier's gangrene.