Canaglif

Uses

Canaglif is used for an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus.

Canaglif is also used to associated treatment for these conditions: Cardiovascular Events, Cardiovascular Mortality, End Stage Renal Disease (ESRD), Type 2 Diabetes Mellitus, Hospitalization due to cardiac failure, Increased serum creatinine, Glycemic Control

How Canaglif works

The sodium-glucose co-transporter2 (SGLT2), is found in the proximal tubules of the kidney, and reabsorbs filtered glucose from the renal tubular lumen. Canaglif inhibits the SGLT2 co-transporter. This inhibition leads to lower reabsorption of filtered glucose into the body and decreases the renal threshold for glucose (RTG), leading to increased glucose excretion in the urine .

Dosage

Canaglif dosage

The recommended starting dose of Canaglif is 100 mg once daily, taken before the first meal of the day. Dose can be increased to 300 mg once daily in patients tolerating Canaglif 100 mg once daily who have an eGFR of 60 ml/min/1.73 m2 or greater and require additional glycemic control. If the eGFR of Patients is 45 to 60 ml/min/1.73 m2,the dose of Canaglif should be 100 mg once daily.

Side Effects

Dehydration, Vaginal yeast infection, Yeast infection of the penis (balanitis or balanoposthitis)

Toxicity

Overdose information

If an overdose occurs, contact the Poison Control Center. Normal supportive measures should be taken, including the removal unabsorbed drug from the gastrointestinal tract, initiating clinical monitoring of the patient, and providing supportive treatment as deemed necessary. Canaglif has been removed in very small quantities after a 4-hour hemodialysis session. This drug is likely not dialyzable by peritoneal dialysis .

Pregnancy and lactation

Animal data has demonstrated that canagliflozin may cause adverse renal effects in a growing fetus. Data are insufficient at this time in determining a potential canagliflozin related risk for major birth defects or possible miscarriage in humans . There are known risks, however, of uncontrolled diabetes in pregnancy . Inform female patients taking canagliflozin of the potential risk, which is increased during the second and third trimesters. This drug is not recommended during nursing .

Mutagenesis and carcinogenicity

Canaglif was not found to be mutagenic in both metabolically activated and inactivated states in the Ames assay. Canaglif showed mutagenicity in laboratory mouse lymphoma assay, but only in the activated state. Canaglif was not found to be mutagenic in several in vivo assays performed on rats .

The carcinogenic risk of canagliflozin was assessed in 2-year studies completed in both CD1 mice and Sprague-Dawley rats. Canaglif was not shown to increase tumor incidence in mouse models given doses less than or equal to 14 times the exposure from a typical 300 mg dose in humans. Despite these negative findings in mice, the incidence of several tumors increased in mice, including Leydig cell tumors, renal tubular adenomas, and adrenal pheochromocytomas .

Precaution

Hypotension: Before initiating Canaglif, assess volume status and correct hypovolemia in patients with renal impairment, the elderly, in patients with low systolic blood pressure, or if on diuretics, ACEi, or ARB. Monitor for signs and symptoms during therapy.

Impairment in Renal Function: Monitor renal function during therapy. More frequent monitoring is recommended in patients with eGFR below 60 mL/min/1.73 m2. Do not initiate Canaglif if eGFR is below 45 mL/min/1.73 m2.

Hyperkalemia: Monitor potassium levels in patients with impaired renal function and in patients predisposed to hyperkalemia.

Hypoglycemia: Consider a lower dose of insulin or the insulin secretagogue to reduce the risk of hypoglycemia when used in combination with Canaglif.

Interaction

UGT enzyme inducers: The efficacy of Canaglif may be reduced when Co-administered with UGT enzyme inducers (e.g., with rifampin, phenytoin,phenobarbital, ritonavir).There was an increase in the area AUC and mean peak drug concentration (Cmax) of digoxin (20% and 36%, respectively) when co-administered with Canaglif.

Food Interaction

• Avoid alcohol. Excess alcohol intake may promote ketoacidosis.
• Drink plenty of fluids.
• Take before a meal. It is recommended to take this drug before the first meal of the day.

[Moderate] GENERALLY AVOID: Alcohol may cause hypoglycemia or hyperglycemia in patients with diabetes.

Hypoglycemia most frequently occurs during acute consumption of alcohol.

Even modest amounts can lower blood sugar significantly, especially when the alcohol is ingested on an empty stomach or following exercise.

The mechanism involves inhibition of both gluconeogenesis as well as the counter-regulatory response to hypoglycemia.

Episodes of hypoglycemia may last for 8 to 12 hours after ethanol ingestion.

By contrast, chronic alcohol abuse can cause impaired glucose tolerance and hyperglycemia.

Moderate alcohol consumption generally does not affect blood glucose levels in patients with well controlled diabetes.

A disulfiram-like reaction (e.g., flushing, headache, and nausea) to alcohol has been reported frequently with the use of chlorpropamide and very rarely with other sulfonylureas.

MANAGEMENT: Patients with diabetes should avoid consuming alcohol if their blood glucose is not well controlled, or if they have hypertriglyceridemia, neuropathy, or pancreatitis.

Patients with well controlled diabetes should limit their alcohol intake to one drink daily for women and two drinks daily for men (1 drink = 5 oz wine, 12 oz beer, or 1.5 oz distilled spirits) in conjunction with their normal meal plan.

Alcohol should not be consumed on an empty stomach or following exercise.

Canaglif Drug Interaction

Moderate: glipizide, insulin glargine, metoprololUnknown: aspirin, aspirin, dutasteride, sulfamethoxazole / trimethoprim, ubiquinone, copper gluconate, rosuvastatin, glycerin, metformin / sitagliptin, sitagliptin, empagliflozin, pregabalin, acetaminophen, bifidobacterium infantis / lactobacillus acidophilus, bioflavonoids, cyanocobalamin, cholecalciferol

Canaglif Disease Interaction

Major: liver dysfunction, renal dysfunctionModerate: hypotension, infections

Volume of Distribution

This drug is extensively distributed throughout the body. On average, the volume of distribution of canagliflozin at steady state following a single intravenous dose in healthy patients was measured to be 83.5 L .

Elimination Route

Bioavailability and steady-state

The absolute oral bioavailability of canagliflozin, on average, is approximately 65% . Steady-state concentrations are achieved after 4 to 5 days of daily dose administration between the range of 100mg to 300mg .

Effect of food on absorption

Co-administration of a high-fat meal with canagliflozin exerted no appreciable effect on the pharmacokinetic parameters of canagliflozin. This drug may be administered without regard to food. Despite this, because of the potential of canagliflozin to decrease postprandial plasma glucose excretion due to prolonged intestinal glucose absorption, it is advisable to take this drug before the first meal of the day .

Half Life

In a clinical study, the terminal half-life of canagliflozin was 10.6 hours for the 100mg dose and 13.1 hours for the 300 mg dose .

Clearance

In healthy subjects, canagliflozin clearance was approximately 192 mL/min after intravenous (IV) administration .

The renal clearance of 100 mg and 300 mg doses of canagliflozin was measured to be in the range of 1.30 - 1.55 mL/min .

Elimination Route

After a single oral radiolabeled dose canagliflozin dose to healthy subjects, the following ratios of canagliflozin or metabolites were measured in the feces and urine :

Feces

41.5% as the unchanged radiolabeled drug

7.0% as a hydroxylated metabolite

3.2% as an O-glucuronide metabolite

Urine

About 33% of the ingested radiolabled dose was measured in the urine, generally in the form of O-glucuronide metabolites. Less than 1% of the dose was found excreted as unchanged drug in urine.

Pregnancy & Breastfeeding use

Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. Canaglif should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. It is not known if Canaglif passes into breast milk. Discontinue drug or nursing

Contraindication

History of a serious hypersensitivity reaction to Canaglif, Severe renal impairment (eGFR less than 30 mL/min/1.73 m2), end stage renal disease or patients on dialysis.

Special Warning

Pediatric Uses: Safety and effectiveness of Canaglif in pediatric patients under 18 years of age have not been established.

Geriatric Uses: Patients 65 years and older had a higher incidence of adverse reactions related to reduced intravascular volume with Canaglif (such as hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration).

Storage Condition

Protect from light and moisture. Store below 30°C. Keep medicine out of the reach of children.

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