canagliflozin 300 MG Oral Tablet [Invokana]

INDICATIONS AND USAGE INVOKAMET and INVOKAMET XR are a combination of canagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, and metformin hydrochloride (HCl), a biguanide, indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus ( 1 ). Canagliflozin Canagliflozin, when used as a component of INVOKAMET or INVOKAMET XR is indicated in adults with type 2 diabetes mellitus to reduce the risk of: Major adverse cardiovascular events in adults with type 2 diabetes mellitus and established cardiovascular disease ( 1 ). End-stage kidney disease, doubling of serum creatinine, cardiovascular death, and hospitalization for heart failure in adults with type 2 diabetes mellitus and diabetic nephropathy with albuminuria ( 1 ). Limitations of Use: Not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus ( 1 ). INVOKAMET INVOKAMET is a combination of canagliflozin and metformin HCl immediate-release indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus. INVOKAMET XR INVOKAMET XR is a combination of canagliflozin and metformin HCl extended-release indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus. Canagliflozin Canagliflozin, when used as a component of INVOKAMET or INVOKAMET XR, is indicated in adults with type 2 diabetes mellitus to reduce the risk of: Major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction and nonfatal stroke) in adults with type 2 diabetes mellitus and established cardiovascular disease (CVD). End-stage kidney disease (ESKD), doubling of serum creatinine, cardiovascular (CV) death, and hospitalization for heart failure in adults with type 2 diabetes mellitus and diabetic nephropathy with albuminuria greater than 300 mg/day. Limitations of Use INVOKAMET or INVOKAMET XR are not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus [see Warnings and Precautions (5.2) ] .

DOSAGE AND ADMINISTRATION Assess renal function before initiating and as clinically indicated. Assess volume status and correct volume depletion before initiating ( 2.1 ). Individualize starting dose based on the patient's current regimen and renal function. See Table 1 in the full prescribing information for recommended starting dosages based on the current regimen ( 2.2 , 2.3 ). The maximum recommended total daily dosage is 300 mg of canagliflozin and 2,000 mg of metformin HCl ( 2.2 ). Initiation of INVOKAMET or INVOKAMET XR is not recommended in patients with an eGFR less than 45 mL/min/1.73 m 2 , due to the metformin HCl component ( 2.3 ). INVOKAMET: take one tablet orally twice daily with meals ( 2.2 ). INVOKAMET XR: take two tablets orally once daily with the morning meal. Swallow whole. Never crush, cut, or chew ( 2.2 ). Gradually escalate the dosage of metformin HCl in INVOKAMET or INVOKAMET XR to reduce the risk of gastrointestinal adverse reactions with metformin HCl ( 2.2 ). Dose adjustment for patients with renal impairment may be required ( 2.3 ). See full prescribing information for INVOKAMET and INVOKAMET XR dosage modifications due to drug interactions ( 2.4 ). May need to be discontinued at time of, or prior to, iodinated contrast imaging procedures ( 2.5 ). Withhold INVOKAMET or INVOKAMET XR at least 3 days, if possible, prior to surgery or procedures associated with prolonged fasting ( 2.6 ). 2.1 Prior to Initiation of INVOKAMET or INVOKAMET XR Assess renal function before initiating INVOKAMET or INVOKAMET XR and as clinically indicated [see Dosage and Administration (2.3) , Contraindications (4) , and Warnings and Precautions (5.1 , 5.4) ]. In patients with volume depletion, correct this condition before initiating INVOKAMET or INVOKAMET XR [see Warnings and Precautions (5.4) and Use in Specific Populations (8.5 , 8.6) ] . 2.2 Recommended Dosage and Administration INVOKAMET and INVOKAMET XR INVOKAMET and INVOKAMET XR contain canagliflozin and metformin HCl. For the available strengths of the canagliflozin and metformin HCl components in INVOKAMET and INVOKAMET XR, see Dosage Forms and Strengths (3) . Individualize the starting dosage of INVOKAMET or INVOKAMET XR based on the patient's current regimen as presented in Table 1 and based on renal function as presented in Table 2 [see Dosage and Administration (2.3 ] . INVOKAMET Take one tablet of INVOKAMET orally twice daily with meals. INVOKAMET XR Take two tablets of INVOKAMET XR orally once daily with the morning meal. Swallow each tablet whole and never crush, cut, or chew. Table 1 presents the recommended starting dosage of INVOKAMET and INVOKAMET XR based on the patient's current regimen. Table 1: Recommended Starting Dosage Based on the Current Regimen Current Regimen INVOKAMET Recommended Dosage INVOKAMET XR Recommended Dosage Not treated with either canagliflozin or metformin HCl Total daily dosage is canagliflozin 100 mg and metformin HCl 1,000 mg Metformin HCl For patients taking an evening dosage of metformin HCl extended-release tablets, skip the last dose before starting INVOKAMET or INVOKAMET XR the following morning. Total daily dosage is canagliflozin 100 mg and the nearest appropriate total daily dosage of metformin HCl Canagliflozin The same total daily dosage of canagliflozin and a total daily dosage of metformin HCl 1,000 mg Canagliflozin and metformin HCl The same total daily dosage of canagliflozin and the nearest appropriate total daily dosage of metformin HCl Recommended Dosage for Additional Glycemic Control in Adults and Pediatric Patients Aged 10 Years and Older INVOKAMET The dosage of canagliflozin in INVOKAMET may be increased to the maximum total daily dosage of 300 mg (150 mg orally twice daily) in patients tolerating a dosage of 100 mg (50 mg twice daily) of canagliflozin. The dosage of metformin HCl in INVOKAMET may be increased to the maximum total daily dosage of 2,000 mg (1,000 mg orally twice daily), with gradual escalation to reduce the risk of gastrointestinal adverse reactions with metformin HCl [see Adverse Reactions (6.1) ]. INVOKAMET XR The dosage of canagliflozin in INVOKAMET XR may be increased to the maximum total daily dosage of 300 mg orally once daily in patients tolerating a 100 mg once daily dosage of canagliflozin. The dosage of metformin HCl in INVOKAMET XR may be increased to the maximum total daily dosage of 2,000 mg once daily, with gradual escalation to reduce the risk of gastrointestinal adverse reactions with metformin HCl [see Adverse Reactions (6.1) ]. 2.3 Recommended Dosage in Adults and Pediatric Patients Aged 10 Years and Older with Renal Impairment Initiation of INVOKAMET or INVOKAMET XR is not recommended in adults or pediatric patients aged 10 years and older with an eGFR less than 45 mL/min/1.73 m 2 , due to the metformin component. Table 2 provides dosage recommendations for adults and pediatric patients aged 10 years and older with renal impairment, based on eGFR [see Use in Specific Populations (8.6) and Clinical Studies (14.4) ]. Table 2: Recommended Dosage in Adults and Pediatric Patients Aged 10 Years and Older with Renal Impairment Estimated Glomerular Filtration Rate [eGFR (mL/min/1.73 m 2 )] Recommended Dosage of INVOKAMET or INVOKAMET XR For the dosing frequency of INVOKAMET and INVOKAMET XR, see Dosage and Administration (2.2). eGFR 45 to less than 60 The maximum total daily dosage of canagliflozin is 100 mg. eGFR 30 to less than 45 Assess the benefit risk of continuing INVOKAMET or INVOKAMET XR. The maximum total daily dosage of canagliflozin is 100 mg. eGFR less than 30 Contraindicated. If eGFR falls below 30 during treatment; discontinue INVOKAMET or INVOKAMET XR [see Contraindications (4) ] . 2.4 Concomitant Use with UDP-Glucuronosyltransferase (UGT) Enzyme Inducers When co-administering INVOKAMET or INVOKAMET XR with an inducer of UGT (e.g., rifampin, phenytoin, phenobarbital, ritonavir), increase the total daily dosage of canagliflozin based on renal function [see Drug Interactions (7) ] : In patients with eGFR 60 mL/min/1.73 m 2 or greater, increase the total daily dosage of canagliflozin to 200 mg in patients currently tolerating a total daily dosage of canagliflozin 100 mg. The maximum total daily dosage of canagliflozin is 300 mg. In patients with eGFR less than 60 mL/min/1.73 m 2 , increase the total daily dosage of canagliflozin to a maximum of 200 mg in patients currently tolerating a total daily dosage of canagliflozin 100 mg. 2.5 Discontinuation for Iodinated Contrast Imaging Procedures Discontinue INVOKAMET or INVOKAMET XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR of less than 60 mL/min/1.73 m 2 ; in patients with a history of liver disease, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart INVOKAMET or INVOKAMET XR if renal function is stable [see Warnings and Precautions (5.1) ] . 2.6 Temporary Interruption for Surgery Withhold INVOKAMET or INVOKAMET XR at least 3 days, if possible, prior to surgery or procedures associated with prolonged fasting. Resume INVOKAMET or INVOKAMET XR when the patient is clinically stable and has resumed oral intake [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.2) ].

WARNINGS AND PRECAUTIONS Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis : Consider ketone monitoring in patients at risk for ketoacidosis, as indicated. Assess for ketoacidosis regardless of presenting blood glucose levels and discontinue INVOKANA if ketoacidosis is suspected. Monitor patients for resolution of ketoacidosis before restarting ( 5.1 ) Lower Limb Amputation : Consider factors that may increase the risk of amputation before initiating INVOKANA. Monitor patients for infection or ulcers of lower limb and discontinue if these occur ( 5.2 ) Volume Depletion : May result in acute kidney injury. Before initiating INVOKANA, assess and correct volume status in patients with renal impairment, elderly patients, or patients on loop diuretics. Monitor for signs and symptoms during therapy ( 5.3 ) Urosepsis and pyelonephritis : Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated ( 5.4 ) Hypoglycemia : Consider a lower dose of insulin or the insulin secretagogue to reduce the risk of hypoglycemia when used in combination with INVOKANA ( 5.5 ) Necrotizing fasciitis of the perineum (Fournier's gangrene) : Serious, life-threatening cases have occurred in both females and males. Assess patients presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise. If suspected, institute prompt treatment ( 5.6 ) Genital mycotic infections : Monitor and treat if indicated ( 5.7 ) Hypersensitivity reactions : Discontinue INVOKANA and monitor until signs and symptoms resolve ( 5.8 ) Bone fracture : Consider factors that contribute to fracture risk before initiating INVOKANA ( 5.9 ) 5.1 Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis In patients with type 1 diabetes mellitus, INVOKANA significantly increases the risk of diabetic ketoacidosis, a life-threatening event, beyond the background rate. In placebo-controlled trials of patients with type 1 diabetes mellitus, the risk of ketoacidosis was markedly increased in patients who received sodium glucose transporter 2 (SGLT2) inhibitors compared to patients who received placebo; this risk may be greater with higher doses of INVOKANA. INVOKANA is not indicated for glycemic control in patients with type 1 diabetes mellitus. Type 2 diabetes mellitus and pancreatic disorders (e.g., history of pancreatitis or pancreatic surgery) are also risk factors for ketoacidosis. There have been postmarketing reports of fatal events of ketoacidosis in patients with type 2 diabetes mellitus using SGLT2 inhibitors, including INVOKANA. Precipitating conditions for diabetic ketoacidosis or other ketoacidosis include acute febrile illness, reduced caloric intake, ketogenic diet, surgery, insulin dose reduction, volume depletion, and alcohol abuse. Signs and symptoms are consistent with dehydration and severe metabolic acidosis and include nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. Blood glucose levels at presentation may be below those typically expected for diabetic ketoacidosis (e.g., less than 250 mg/dL). Ketoacidosis and glucosuria may persist longer than typically expected. Urinary glucose excretion persists for 3 days after discontinuing INVOKANA [see Clinical Pharmacology (12.2) ]; however, there have been postmarketing reports of ketoacidosis and glucosuria lasting greater than 6 days and some up to 2 weeks after discontinuation of SGLT2 inhibitors. Consider ketone monitoring in patients at risk for ketoacidosis if indicated by the clinical situation. Assess for ketoacidosis regardless of presenting blood glucose levels in patients who present with signs and symptoms consistent with severe metabolic acidosis. If ketoacidosis is suspected, discontinue INVOKANA, promptly evaluate, and treat ketoacidosis, if confirmed. Monitor patients for resolution of ketoacidosis before restarting INVOKANA. Withhold INVOKANA, if possible, in temporary clinical situations that could predispose patients to ketoacidosis. Resume INVOKANA when the patient is clinically stable and has resumed oral intake [see Dosage and Administration (2.5) ] . Educate all patients on the signs and symptoms of ketoacidosis and instruct patients to discontinue INVOKANA and seek medical attention immediately if signs and symptoms occur. 5.2 Lower Limb Amputation An increased risk of lower limb amputations associated with INVOKANA use versus placebo was observed in CANVAS (5.9 vs 2.8 events per 1000 patient-years) and CANVAS-R (7.5 vs 4.2 events per 1000 patient-years), two randomized, placebo-controlled trials evaluating patients with type 2 diabetes mellitus who had either established cardiovascular disease or were at risk for cardiovascular disease. The risk of lower limb amputations was observed at both the 100 mg and 300 mg once daily dosage regimens. The amputation data for CANVAS and CANVAS-R are shown in Tables 3 and 4, respectively [see Adverse Reactions (6.1) ]. Amputations of the toe and midfoot (99 out of 140 patients with amputations receiving INVOKANA in the two trials) were the most frequent; however, amputations involving the leg, below and above the knee, were also observed (41 out of 140 patients with amputations receiving INVOKANA in the two trials). Some patients had multiple amputations, some involving both lower limbs. Lower limb infections, gangrene, and diabetic foot ulcers were the most common precipitating medical events leading to the need for an amputation. The risk of amputation was highest in patients with a baseline history of prior amputation, peripheral vascular disease, and neuropathy. Before initiating INVOKANA, consider factors in the patient history that may predispose to the need for amputations, such as a history of prior amputation, peripheral vascular disease, neuropathy and diabetic foot ulcers. Counsel patients about the importance of routine preventative foot care. Monitor patients receiving INVOKANA for signs and symptoms of infection (including osteomyelitis), new pain or tenderness, sores or ulcers involving the lower limbs, and discontinue INVOKANA if these complications occur. 5.3 Volume Depletion INVOKANA can cause intravascular volume contraction which may sometimes manifest as symptomatic hypotension or acute transient changes in creatinine [see Adverse Reactions (6.1) ] . There have been post-marketing reports of acute kidney injury which are likely related to volume depletion, some requiring hospitalizations and dialysis, in patients with type 2 diabetes mellitus receiving SGLT2 inhibitors, including INVOKANA. Patients with impaired renal function (eGFR less than 60 mL/min/1.73 m 2 ), elderly patients, or patients on loop diuretics may be at increased risk for volume depletion or hypotension. Before initiating INVOKANA in patients with one or more of these characteristics, assess and correct volume status. Monitor for signs and symptoms of volume depletion after initiating therapy. 5.4 Urosepsis and Pyelonephritis There have been postmarketing reports of serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalization in patients receiving INVOKANA. Treatment with INVOKANA increases the risk for urinary tract infections. Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated [see Adverse Reactions (6) ] . 5.5 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues Insulin and insulin secretagogues are known to cause hypoglycemia. INVOKANA may increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue [see Adverse Reactions (6.1) ] . Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with INVOKANA. 5.6 Necrotizing Fasciitis of the Perineum (Fournier's Gangrene) Reports of necrotizing fasciitis

CONTRAINDICATIONS INVOKAMET or INVOKAMET XR is contraindicated in patients with: Severe renal impairment (eGFR less than 30 mL/min/1.73 m 2 ) [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6) ] . Acute or chronic metabolic acidosis, including diabetic ketoacidosis [see Warnings and Precautions (5.2) ] . Serious hypersensitivity reaction to canagliflozin or metformin HCl, such as anaphylaxis or angioedema [see Warnings and Precautions (5.9) and Adverse Reactions (6) ] . Severe renal impairment (eGFR less than 30 mL/min/1.73 m 2 ) ( 4 ) Metabolic acidosis, including diabetic ketoacidosis ( 4 ) Serious hypersensitivity reaction to canagliflozin or metformin HCl ( 4 )

Mechanism of Action Canagliflozin SGLT2, expressed in the proximal renal tubules, is responsible for the majority of the reabsorption of filtered glucose from the tubular lumen. Canagliflozin is an inhibitor of SGLT2. By inhibiting SGLT2, canagliflozin reduces reabsorption of filtered glucose and lowers the renal threshold for glucose (RT G ), and thereby increases urinary glucose excretion (UGE). Canagliflozin increases the delivery of sodium to the distal tubule by blocking SGLT2-dependent glucose and sodium reabsorption. This is believed to increase tubuloglomerular feedback and reduce intraglomerular pressure. Metformin HCl Metformin HCl is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Metformin HCl decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may decrease.