Canagliflozin + Metformin

Canagliflozin+ Metformin is an Anti-diabetic Agent belonging to the pharmacological class of Sodium-glucose transport protein 2 (SGLT2) Inhibitors and biguanides.

Combining Canagliflozin and metformin is approved for treating type 2 diabetes mellitus to improve the glycemic control. It helps lower blood sugar levels through different mechanisms, enhancing the management of this metabolic disorder.

Canagliflozin is absorbed in the gastrointestinal tract, extensively distributed throughout the body, and mainly bound to albumin in the bloodstream. It is primarily metabolized in the liver and eliminated in the urine. Metformin is absorbed in the small intestine, has limited distribution, is not protein-bound, is not significantly metabolized, or excreted unchanged in the urine.

The common side effects of Canagliflozin+ Metformin are genital infection, urinary tract infection, abnormal urination, diarrhoea, nausea, vomiting, flatulence, weakness, indigestion, and headache.

Canagliflozin+ Metformin is available as a tablet for convenient administration.

Canagliflozin+ Metformin is available in the United States, Canada, the United Kingdom, Germany, France and Australia.

Canagliflozin+ Metformin is an Anti-diabetic Agent belonging to the pharmacological class of Sodium-glucose transport protein 2 (SGLT2) Inhibitors and biguanides.

Canagliflozin: 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.

Metformin: Metformin decreases hepatic glucose production, reduces glucose absorption in the intestine and improves insulin sensitivity (increases peripheral glucose uptake and utilization).

Synergistic Benefits: Canagliflozin helps lower blood sugar levels by encouraging the elimination of extra glucose in the urine, which also helps with weight loss. Metformin reduces the liver's synthesis of glucose and increases insulin sensitivity. When combined, they provide improved glycemic control, which enhances blood glucose regulation and may have beneficial implications for cardiovascular health. For the treatment of type 2 diabetes, this combination can be highly effective.

Data Onset of action of Canagliflozin+ Metformin typically occurs within a few hours after administration.

Data duration of action of Canagliflozin+ Metformin effects generally lasts throughout the day.

The Data of Tmax (time to peak concentration) of Canagliflozin+ Metformin generally reached within 1-3 hours (immediate-release) and 2-4 hours (extended-release) after oral administration.

The Data of Cmax of Canagliflozin+ Metformin is achieved within 1-3 hours (immediate-release) and 2-4 hours (extended-release) after oral administration.

Canagliflozin+ Metformin is available in 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 or twice daily, generally with a meal.

Canagliflozin+ Metformin can be used in the following health conditions:

Canagliflozin: 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.

Metformin: Metformin improves glucose tolerance by lowering basal and postprandial plasma glucose. It exerts its effect by decreasing hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis, delaying intestinal glucose absorption, and increasing insulin sensitivity by increasing peripheral glucose uptake and utilization.

For treating type 2 diabetes, the canagliflozin + metformin combination provides many benefits. Through increased glucose excretion and decreased absorption, it helps maintain blood sugar levels and promote weight management. Combining these benefits can help people with diabetes improve long-term glucose regulation, possibly lead to weight loss, and improve cardiovascular health. It also reduces the risk of hypoglycemia, supports heart health, and helps lower overall glycated haemoglobin levels.

Orally: Canagliflozin+ Metformin is a tablet that can be taken orally.

For regular tablets, the recommended dose is to be taken twice daily with morning and evening meals. If you're using the extended-release version, it should be taken once daily in the morning with food. Ensure you swallow the extended-release tablet whole and do not crush, cut, or chew it.

The dosage and duration of treatment should be as per the treating physician's clinical judgment.

Canagliflozin+ Metformin has various strengths, such as 50 mg+500 mg, 50mg+1000mg, 150 mg+ 500mg, 150 mg+1000 mg.

Canagliflozin+ Metformin is available in the form of Oral tablets.

Determine the patient's existing regimen before determining the Canagliflozin+ Metformin starting dose:

Individuals taking metformin should switch to Canagliflozin+ Metformin, which contains 50 mg of canagliflozin with a comparable daily dose of metformin;

Those taking canagliflozin should switch to Canagliflozin+ Metformin, which contains 500 mg of metformin with a comparable daily dose of canagliflozin and

Patients receiving canagliflozin and metformin should switch to Canagliflozin+ Metformin, which contains the same total daily doses of each component.

UDP-glucuronosyl transferase (UGT) enzyme inducers

GFR < 60 mL/min/1.73 m²

Taking 100 mg of canagliflozin daily may raise the dosage to 200 mg daily.

If canagliflozin 200 mg/day is tolerated, the dose may be increased to 300 mg qDay if eGFR is less than 60 mL/min/1.73 m2.

If taking 100 mg of canagliflozin daily, you may raise the dosage to 200 mg daily.

If a patient needs more glycemic control, add another antihyperglycemic medication.

Assess renal function before initiating and periodically after that

Evaluation of renal function before initiation and regularly after that

Before starting treatment, patients who have not previously received canagliflozin should correct volume depletion.

Not for the management of diabetic ketoacidosis or type 1 diabetes

It could be necessary to stop therapy immediately before or at the time of iodinated contrast imaging examinations.

Canagliflozin + Metformin should be used in treating type 2 diabetes mellitus, along with appropriate dietary restrictions.

While taking Canagliflozin + Metformin, maintain an appropriate diet, primarily focusing on regulating carbohydrate intake and consuming a balanced and healthy meal plan. Patients should avoid excessive alcohol consumption to reduce the risk of hypoglycemia and dehydration. Adequate fluid intake is essential to mitigate the potential for decreased blood pressure.

While taking this combination, it is advised to stay hydrated, consume a rich-balanced diet low in saturated fats and cholesterol—and drink plenty of vegetables, whole grains, fruits, and lean proteins in meals.

The dietary restriction should be individualized as per patient requirements.

Canagliflozin+ Metformin may be contraindicated in the following conditions:-

The adverse reactions related to Canagliflozin+ Metformin can be categorized as:-

Acute oedema

Acute renal damage and impaired renal function

Decreased renal function and critical kidney damage.

Hepatocellular, mixed hepatocellular, and cholestatic liver damage

Allergic reactions

Pyelonephritis and Urosepsis

The clinically relevant drug interactions of Canagliflozin+ Metformin are briefly summarized here:

The most common side effects of Canagliflozin+ Metformin include:

Genital infection

Diarrhea

Nausea

Indigestion

Headache

Vomiting

Flatulence

Weakness

Urinary tract infection

Abnormal urination

Canagliflozin+ Metformin should be prudent in the following group of special populations.

Pregnancy Category C: Use with caution if the benefits outweigh the risks.

Not advised during the second and third trimesters of pregnancy due to animal research demonstrating detrimental effects on the kidneys.

Pregnancy-related data are scarce and insufficient to establish if drugs increase the incidence of severe birth abnormalities or miscarriages.

In rats and rabbits, metformin at dosages up to 600 mg/kg/day did not cause teratogenic effects; analysis of fetal concentrations suggested a partial placental barrier to metformin.

Maternal risk factors for poorly managed diabetes during pregnancy include preeclampsia, spontaneous abortions, preterm birth, stillbirth, and problems during delivery.

Uncontrolled diabetes raises the chance of severe birth abnormalities, stillbirth, and morbidity associated with macrosomia in the fetus.

Breastfeeding not recommended

No information is available about the distribution of human milk, the effects on nursing infants, or milk production.

Present in nursing rats' milk.

There may be a risk to the developing human kidney since human kidney maturation occurs in utero and throughout the first two years of life, when lactational exposure may occur.

Excreted into milk in rats, reaching levels similar to plasma; not advised for nursing mothers.

As per FDA, safety and effectiveness in the pediatric population have yet to be established.

Measure eGFR before beginning metformin and then on a recurrent basis if eGFR is ≥60 mL/min/1.73 m2. No dosage modification is necessary.

eGFR between 45 and <60 mL/min/1.73 m2: Canagliflozin TDD dosage limit: 100 mg

30 to <45 mL/min/1.73 m2 eGFR: Limit canagliflozin TDD at 100 mg; evaluate the risk/benefit of continuing medication.

If eGFR is less than 45 mL/min/1.73 m2 or dialysis is being used, Not recommended.

Metformin use in hepatic impairment patients has been linked to lactic acidosis in certain circumstances. Patients with hepatic impairment should not use Canagliflozin + Metformin.

The physician should be vigilant about the knowledge pertaining to the identification and treatment of overdosage of Canagliflozin + Metformin.

Overconsumption of Canagliflozin+ Metformin could lead to severe hypoglycemia, dehydration, kidney dysfunction, electrolyte imbalances, and gastrointestinal distress such as nausea and vomiting.

There is no specific antidote or treatment for excessive intake of Canagliflozin + Metformin. However, immediate medical attention is essential. Canagliflozin + Metformin should be terminated immediately when an overdose is In cases of overdose, close medical attention is crucial. Canagliflozin + Metformin should be discontinued if an overdose is suspected or if unusual symptoms occur after ingestion. Activated charcoal or gastric lavage may also be considered if the overdose is detected shortly after ingestion to reduce absorption.

Patients may require supportive care to address the overdose's various effects. This may include providing fluids and electrolytes to correct dehydration and electrolyte imbalances. For severe hypoglycemia, treatment with glucose or other appropriate interventions may be needed.

In severe overdoses, mainly if acute kidney injury is present, hemodialysis may be considered to remove excess Metformin from the bloodstream

Canagliflozin: This medication lowers the renal threshold for glucose (RTG) and increases urine glucose excretion dose independently. 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.

Metformin: Metformin is an antihyperglycemic medication that lowers basal and postprandial plasma glucose levels in people with type 2 diabetes, improving their glucose tolerance. Its pharmacologic modes of action are distinct from those of other oral antihyperglycemic medication groups. Metformin increases peripheral glucose uptake and utilization, which lowers intestinal glucose absorption, reduces hepatic glucose synthesis, and enhances insulin sensitivity. Metformin, unlike sulfonylureas, does not result in hyperinsulinemia or hypoglycemia in either type 2 diabetes patients or healthy persons. Metformin medication does not alter insulin secretion, although it may reduce the plasma insulin response throughout the day and insulin levels while fasting.

Canagliflozin: 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.

Metformin: Slowly and incompletely absorbed from the gastrointestinal tract. Food slightly delays and decreases the extent of absorption. Absolute bioavailability: 50-60%. Time to peak plasma concentration: 2-3 hours (immediate-release); 7 hours, range: 4-8 hours (extended-release).

Bioavailability: 50-60% (Metformin [fasted])

Canagliflozin: Canagliflozin exhibits extensive distribution within the body, with an average 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%.

Metformin: Concentrates in the liver, kidney and gastrointestinal tract. It crosses the placenta and then enters breast milk (small amounts). Volume of distribution: 654 ± 358 L.

Protein-bound: Negligible (Metformin)

Canagliflozin: 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.

Metformin: Excreted unchanged in the urine and did not undergo specific hepatic metabolism (no metabolites have been found in humans) or biliary excretion.

Canagliflozin: 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.

Metformin: With a plasma elimination half-life of roughly 6.2 hours, 90% of the absorbed medication is excreted via the renal pathway during the first 24 hours following oral administration. The elimination half-life of blood is roughly 17.6 hours, indicating that the erythrocyte bulk could constitute a distribution compartment.

Canagliflozin increases the amount of glucose excreted in the urine by decreasing renal glucose reabsorption. Metformin enhances insulin sensitivity and reduces the synthesis of glucose in the liver. Combined, they provide more effective glycemic control by lowering blood sugar levels.

Canagliflozin has been linked to weight loss because it increases the excretion of glucose in the urine, which reduces calories. By increasing insulin sensitivity, metformin may also help with weight management. Patients who need to maintain or decrease weight may benefit from this combination.

For those with type 2 diabetes, canagliflozin + metformin may offer significant cardiovascular benefits.