Invokamet

Uses

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

Metformin Hydrochloride, as monotherapy, is used for an adjunct to diet to lower blood glucose especially in overweight patients with non-insulin-dependent diabetes mellitus (NIDDM) or type 2 diabetes mellitus whose hyperglycemia cannot be satisfactorily managed on diet alone. Metformin Hydrochloride may be used concomitantly with a sulfonylurea when diet and metformin hydrochloride or sulfonylureas alone do not result in adequate glycemic control.

Invokamet 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 ControlPolycystic Ovaries Syndrome, Type 2 Diabetes Mellitus, Glycemic Control

How Invokamet 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. Canagliflozin 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 .

Metformin's mechanisms of action are unique from other classes of oral antihyperglycemic drugs. Metformin decreases blood glucose levels by decreasing hepatic glucose production (gluconeogenesis), decreasing the intestinal absorption of glucose, and increasing insulin sensitivity by increasing peripheral glucose uptake and utilization . It is well established that metformin inhibits mitochondrial complex I activity, and it has since been generally postulated that its potent antidiabetic effects occur through this mechanism . The above processes lead to a decrease in blood glucose, managing type II diabetes and exerting positive effects on glycemic control.

After ingestion, the organic cation transporter-1 (OCT1) is responsible for the uptake of metformin into hepatocytes (liver cells). As this drug is positively charged, it accumulates in cells and in the mitochondria because of the membrane potentials across the plasma membrane as well as the mitochondrial inner membrane. Metformin inhibits mitochondrial complex I, preventing the production of mitochondrial ATP leading to increased cytoplasmic ADP:ATP and AMP:ATP ratios . These changes activate AMP-activated protein kinase (AMPK), an enzyme that plays an important role in the regulation of glucose metabolism . Aside from this mechanism, AMPK can be activated by a lysosomal mechanism involving other activators. Following this process, increases in AMP:ATP ratio also inhibit fructose-1,6-bisphosphatase enzyme, resulting in the inhibition of gluconeogenesis, while also inhibiting adenylate cyclase and decreasing the production of cyclic adenosine monophosphate (cAMP) , a derivative of ATP used for cell signaling . Activated AMPK phosphorylates two isoforms of acetyl-CoA carboxylase enzyme, thereby inhibiting fat synthesis and leading to fat oxidation, reducing hepatic lipid stores and increasing liver sensitivity to insulin .

In the intestines, metformin increases anaerobic glucose metabolism in enterocytes (intestinal cells), leading to reduced net glucose uptake and increased delivery of lactate to the liver. Recent studies have also implicated the gut as a primary site of action of metformin and suggest that the liver may not be as important for metformin action in patients with type 2 diabetes. Some of the ways metformin may play a role on the intestines is by promoting the metabolism of glucose by increasing glucagon-like peptide I (GLP-1) as well as increasing gut utilization of glucose .

In addition to the above pathway, the mechanism of action of metformin may be explained by other ways, and its exact mechanism of action has been under extensive study in recent years .

Dosage

Invokamet dosage

The recommended starting dose of Canagliflozin 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 Canagliflozin 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 Canagliflozin should be 100 mg once daily.

Adult-

Metformin 500 mg tablet: Initial dosage is 500 mg tablet 2-3 times daily with or after meals, gradually increased if necessary to 2 to 3 gm daily.

Metformin 850 mg tablet: Initial dosage is 850 mg tablet once or twice daily with or after meals, gradually increased if necessary to 2 to 3 gm daily.

Metformin extended release orlong acting tablet: The usual starting dose of Metformin extended release tabletis 500 mg once daily with the evening meal. Dosage increases should be made in increments of 500 mg weekly, up to a maximum of 2000 mg once daily with the evening meal. If glycemic control is not achieved on Metformin extended release tablet 2000 mg once daily, a trial of Metformin extended release tablet 1000 mg twice daily should be considered. The maximum recommended dose of metformin is 3 gm daily.

Transfer from other antidiabetic therapy: When transferring patients from standard oral hypoglycemic agents other than Chlorpropamide to Metformin HCl, no transition period generally is necessary. When transferring patients fromChlorpropamide, care should be exercised during the first two weeks because of the prolonged retention of Chlorpropamide in the body, leading to overlapping drug effects and possible hypoglycemia.

Children and adolescents-

Monotherapy and combination with insulin

• Metformin tablets can be used in children from 10 years of age and adolescents.
• The usual starting dose is one tablet of 500 mg or 850 mg once daily, given during meals or after meals.

After 10 to 15 days the should be adjusted on the basis of blood glucose measurements. A slow increase of dose may improve gastrointestinal tolerability. The maximum recommended dose of metformin is 2 g daily, taken as 2 or 3 divided doses.

Elderly-

Due to the potential for decreased renal function in elderly subjects, the metformin dosage should be adjusted based on renal function. Regular assessment of renal function is necessary.

Side Effects

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

Metformin may cause gastro-intestinal adverse effects like diarrhoea, anorexia, nausea & vomiting. Lactic acidosis and malabsorption of vitamin B12 may be occurred. Patients may experience a metallic taste and there may be weight loss, which in some diabetics could be an advantage.

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. Canagliflozin 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

Canagliflozin was not found to be mutagenic in both metabolically activated and inactivated states in the Ames assay. Canagliflozin showed mutagenicity in laboratory mouse lymphoma assay, but only in the activated state. Canagliflozin 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. Canagliflozin 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 .

Metformin (hydrochloride) toxicity data:

Oral LD50 (rat): 1 g/kg; Intraperitoneal LD50 (rat): 500 mg/kg; Subcutaneous LD50 (rat): 300 mg/kg; Oral LD50 (mouse): 1450 mg/kg; Intraperitoneal LD50 (mouse): 420 mg/kg; Subcutaneous LD50 (mouse): 225 mg/kg .

A note on lactic acidosis

Metformin decreases liver uptake of lactate, thereby increasing lactate blood levels which may increase the risk of lactic acidosis . There have been reported postmarketing cases of metformin-associated lactic acidosis, including some fatal cases. Such cases had a subtle onset and were accompanied by nonspecific symptoms including malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence. In certain cases, hypotension and resistant bradyarrhythmias have occurred with severe lactic acidosis . Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), as well as an increased lactate:pyruvate ratio; metformin plasma levels were generally >5 mcg/mL.

Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g. carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment .

A note on renal function

In patients with decreased renal function, the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased .

Metformin should be avoided in those with severely compromised renal function (creatinine clearance < 30 ml/min), acute/decompensated heart failure, severe liver disease and for 48 hours after the use of iodinated contrast dyes due to the risk of lactic acidosis . Lower doses should be used in the elderly and those with decreased renal function. Metformin decreases fasting plasma glucose, postprandial blood glucose and glycosolated hemoglobin (HbA1c) levels, which are reflective of the last 8-10 weeks of glucose control. Metformin may also have a positive effect on lipid levels.

A note on hypoglycemia

When used alone, metformin does not cause hypoglycemia, however, it may potentiate the hypoglycemic effects of sulfonylureas and insulin when they are used together .

Use in pregnancy

Available data from post-marketing studies have not indicated a clear association of metformin with major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin was ingested during pregnancy. Despite this, the abovementioned studies cannot definitively establish the absence of any metformin-associated risk due to methodological limitations, including small sample size and inconsistent study groups .

Use in nursing

A limited number of published studies indicate that metformin is present in human milk. There is insufficient information to confirm the effects of metformin on the nursing infant and no available data on the effects of metformin on the production of milk. The developmental and health benefits of breastfeeding should be considered as well as the mother’s clinical need for metformin and any possible adverse effects on the nursing child .

Precaution

Hypotension: Before initiating Canagliflozin, 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 Canagliflozin 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 Canagliflozin.

Lactic acidosis is a rare, but serious (high mortality in the absence of prompt treatment), metabolic complication that can occur due to metformin accumulation. Reported cases of lactic acidosis in patients on metformin have occurred primarily in diabetic patients with significant renal failure. The incidence of lactic acidosis can and should be reduced by assessing also other associated risk factors such as poorly controlled diabetes, ketosis, prolonged fasting, excessive alcohol intake, hepatic insufficiency and any condition associated with hypoxia. Lactic acidosis is characterized by acidotic dyspnea, abdominal pain and hypothermia followed by coma. Diagnostic laboratory findings are decreased blood pH, plasma lactate levels above 5 mmol/L, and an increased anion gap and lactate/pyruvate ratio. If metabolic acidosis is suspected, metformin should be discontinued and the patient should be hospitalized immediately.

Renal function: As metformin is excreted by the kidney, serum creatinine levels should be determined before initiating treatment and regularly thereafter: at least annually in patients with normal renal function, at least two to four times a year in patients with serum creatinine levels at the upper limit of normal and in elderly subjects. Decreased renal function in elderly subjects is frequent and asymptomatic. Special caution should be exercised in situations where renal function may become impaired, for example when initiating antihypertensive therapy or diuretic therapy and when starting therapy with an NSAID.

Administration of iodinated contrast agent: As the intravascular administration of iodinated contrast materials in radiologic studies can lead to renal failure, metformin should be discontinued prior to, or at the time of the test and not reinstituted until 48 hours afterwards, and only after renal function has been re-evaluated and found to be normal.

Surgery: Metformin hydrochloride should be discontinued 48 hours before elective surgery with general anesthesia and should not be usually resumed earlier than 48 hours afterwards.

Children and adolescents: The diagnosis of type 2 diabetes mellitus should be confirmed before treatment with metformin is initiated. No effect of metformin on growth and puberty has been detected during controlled clinical studies of one-year duration but no long-term data on these specific points are available. Therefore, a careful follow-up of the effect of metformin on these parameters in metformin-treated children, especially pre-pubescent children, is recommended.

Children aged between 10 and 12 years: Only 15 subjects aged between 10 and 12 years were included in the controlled clinical studies conducted in children and adolescents. Although metformin efficacy and safety in children below 12 did not differ from efficacy and safety in older children, particular caution is recommended when prescribing to children aged between 10 and 12 years.

Other precautions: All patients should continue their diet with a regular distribution of carbohydrate intake during the day. Overweight patients should continue their energy-restricted diet. The usual laboratory tests for diabetes monitoring should be performed regularly. Metformin alone never causes hypoglycemia, although caution is advised when it is used in combination with insulin or sulphonylureas.

Interaction

UGT enzyme inducers: The efficacy of Canagliflozin 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 Canagliflozin.

Concomitant use not recommended-

Alcohol: Increased risk of lactic acidosis in acute alcohol intoxication, particularly in case of: fasting or malnutrition, hepatic insufficiency. Avoid consumption of alcohol and alcohol-containing medications.

Iodinated contrast agents: Intravascular administration of iodinated contrast agents may lead to renal failure, resulting in metformin accumulation and a risk of lactic acidosis. Metformin should be discontinued prior to, or at the time of the test and not reinstituted until 48 hours afterwards, and only after renal function has been re-evaluated and found to be normal.

Combinations requiring precautions for use-

Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include thiazide and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. When such drugs are administered to a patient receiving Metformin HCl, the patient should be closely observed to maintain adequate glycemic control. Inform the patient and perform more frequent blood glucose monitoring, especially at the beginning of treatment. If necessary, adjust the dosage of the antidiabetic drug during therapy with the other drug and upon its discontinuation.

Nifedipine appears to enhance the absorption of Metformin. Metformin has minimal effects on nifedipine. ACE-inhibitors may decrease the blood glucose levels. If necessary, adjust the dosage of the antidiabetic drug during therapy with the other drug and upon its discontinuation.

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 .

The apparent volume of distribution (V/F) of metformin after one oral dose of metformin 850 mg averaged at 654 ± 358 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 .

Regular tablet absorption

The absolute bioavailability of a metformin 500 mg tablet administered in the fasting state is about 50%-60%. Single-dose clinical studies using oral doses of metformin 500 to 1500 mg and 850 to 2550 mg show that there is a lack of dose proportionality with an increase in metformin dose, attributed to decreased absorption rather than changes in elimination .

At usual clinical doses and dosing schedules of metformin, steady-state plasma concentrations of metformin are achieved within 24-48 hours and are normally measured at Label.

Extended-release tablet absorption

After a single oral dose of metformin extended-release, Cmax is reached with a median value of 7 hours and a range of between 4 and 8 hours. Peak plasma levels are measured to be about 20% lower compared to the same dose of regular metformin, however, the extent of absorption of both forms (as measured by area under the curve - AUC), are similar .

Effect of food

Food reduces the absorption of metformin, as demonstrated by about a 40% lower mean peak plasma concentration (Cmax), a 25% lower area under the plasma concentration versus time curve (AUC), and a 35-minute increase in time to peak plasma concentration (Tmax) after ingestion of an 850 mg tablet of metformin taken with food, compared to the same dose administered during fasting .

Though the extent of metformin absorption (measured by the area under the curve - AUC) from the metformin extended-release tablet is increased by about 50% when given with food, no effect of food on Cmax and Tmax of metformin is observed. High and low-fat meals exert similar effects on the pharmacokinetics of extended-release metformin .

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 .

Approximately 6.2 hours in the plasma and in the blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution .

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 .

Renal clearance is about 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours .

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.

This drug is substantially excreted by the kidney .

Renal clearance of metformin is about 3.5 times higher than creatinine clearance, which shows that renal tubular secretion is the major route of metformin elimination. After oral administration, about 90% of absorbed metformin is eliminated by the kidneys within the first 24 hours post-ingestion .

Pregnancy & Breastfeeding use

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

Pregnancy Category B. Animal studies do not indicate harmful effects with respect to pregnancy, embryonic or fetal development, parturition or postnatal development. There are no adequate and well-controlled studies in pregnant women. Can be used in pregnancy for both preexisting and gestational diabetes. Women with gestational diabetes should discontinue treatment after giving birth.

Lactation: Metformin is excreted into milk in lactating rats. Similar data is not available in humans and a decision should be made whether to discontinue nursing or to discontinue metformin, taking into account the importance of the drug to the mother. May be used during breast-feeding in women with pre existing diabetes.

Contraindication

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

• Hypersensitivity to metformin hydrochloride or to any of the excipients of the medication.
• Diabetic ketoacidosis, diabetic pre-coma
• Renal failure or renal dysfunction (creatinine clearance < 60 mL/min)
• Acute conditions with the potential to alter renal function such as: dehydration, severe infection, shock, intravascular
• administration of iodinated contrast agents.
• Acute or chronic disease which may cause tissue hypoxia such as: cardiac or respiratory failure, recent myocardial
• infarction, shock
• Hepatic insufficiency, acute alcohol intoxication, alcoholism
• Lactation

Special Warning

Pediatric Uses: Safety and effectiveness of Canagliflozin 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 Canagliflozin (such as hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration).

Renal Impairment: Metformin is contraindicated in patients with an eGFR < 30 mL/minute/1.73 m2 . Starting metformin in patients with an eGFR between 30-45 mL/minute/1.73 m2 is not recommended. In patients taking metformin whose eGFR later falls below 45 mL/minute/1.73 m2 , assess the benefits and risks of continuing treatment. Discontinue metformin if the patient’s eGFR later falls below 30 mL/minute/1.73 m2 .

Acute Overdose

Hypoglycemia has not been seen with metformin doses up to 85g, although lactic acidosis has occurred in such circumstances. High overdose or concomitant risks of metformin may lead to lactic acidosis. Lactic acidosis is a medical emergency and must be treated in hospital. The most effective method to remove lactate and metformin is hemodialysis.

Storage Condition

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

Keep out of the reach of children. Do not store above 25°C. Keep in the original package in a cool & dry place in order to protect from light and moisture.

Innovators Monograph

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