INVOKAMET (canagliflozin and metformin hydrochloride) tablet, film coated
Janssen Pharmaceuticals, Inc.
WARNING: LACTIC ACIDOSIS
- Post-marketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (> 5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL [see Warnings and Precautions (5.1)] .
- 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 [see Warnings and Precautions (5.1)] .
- Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the full prescribing information [see Dosage and Administration (2.2, 2.3), Contraindications (4), Warnings and Precautions (5.1), Drug Interactions (7), and Use in Specific Populations (8.6, 8.7)] .
- If metformin-associated lactic acidosis is suspected, immediately discontinue INVOKAMET or INVOKAMET XR and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended [see Warnings and Precautions (5.1)] .
WARNING: LACTIC ACIDOSIS
See full prescribing information for complete boxed warning.
- Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. Symptoms included malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Laboratory abnormalities included elevated blood lactate levels, anion gap acidosis, increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL. ( 5.1)
- Risk factors include renal impairment, concomitant use of certain drugs, age >65 years old, radiological studies with contrast, surgery and other procedures, hypoxic states, excessive alcohol intake, and hepatic impairment. Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the Full Prescribing Information. ( 5.1)
- If lactic acidosis is suspected, discontinue INVOKAMET or INVOKAMET XR and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended. ( 5.1)
1 INDICATIONS AND USAGE
INVOKAMET and INVOKAMET XR are a combination of canagliflozin and metformin HCl indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
Canagliflozin is indicated 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).
Canagliflozin is indicated to reduce the risk of 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.
INVOKAMET and INVOKAMET XR are a combination of canagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, and metformin HCl, a biguanide, indicated:
- As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus ( 1)
- Canagliflozin is indicated to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes mellitus and established cardiovascular disease ( 1)
- Canagliflozin is indicated to reduce the risk of 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)
Limitations of Use
INVOKAMET or INVOKAMET XR is not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus [see Warnings and Precautions (5.2)] .
2 DOSAGE AND ADMINISTRATION
- Individualize starting dose based on the patient's current regimen and renal function ( 2.2, 2.3, 2.4)
- 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 component ( 2.4)
- INVOKAMET: one tablet, twice daily with meals, recommended starting dose of canagliflozin is 50 mg twice daily and metformin HCl 500 mg twice daily ( 2.2)
- INVOKAMET XR: two tablets, once daily with the morning meal. Swallow whole. Never crush, cut, or chew ( 2.2)
- Canagliflozin dose can be increased to a total daily dose of 300 mg in patients tolerating 100 mg who have an eGFR of 60 mL/min/1.73 m 2or greater and require additional glycemic control. Do not exceed a total daily canagliflozin dose of 300 mg ( 2.2)
- Gradually escalate metformin HCl dose to reduce the gastrointestinal side effects while not exceeding a total daily dose of 2,000 mg ( 2.3)
- Assess renal function before initiating and as clinically indicated ( 2.1, 2.3)
- Dose adjustment for patients with renal impairment may be required ( 2.4)
- See full prescribing information for INVOKAMET and INVOKAMET XR dosage modifications due to drug interactions. ( 2.5)
- May need to be discontinued at time of, or prior to, iodinated contrast imaging procedures ( 2.6)
- Withhold INVOKAMET or INVOKAMET XR at least 3 days, if possible, prior to surgery or procedures associated with prolonged fasting ( 2.7)
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 (2.4)and Warnings and Precautions (5.1, 5.4), Contraindications (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 Dosage Overview
INVOKAMET
Take one tablet of INVOKAMET orally twice daily with meals [see Dosage and Administration (2.3)] .
INVOKAMET XR
Take two tablets of INVOKAMET XR orally once daily with the morning meal [see Dosage and Administration (2.3)] . Swallow each tablet whole and never crush, cut, or chew.
2.3 Recommended Dosage and Administration
Individualize the starting dose of INVOKAMET or INVOKAMET XR based on the patient's current regimen and renal function [see Dosage and Administration (2.4)] . Table 1 presents the recommended starting dosage of INVOKAMET and INVOKAMET XR based on the patient's current regimen. For the available strengths of the canagliflozin and metformin components in INVOKAMET and INVOKAMET XR, see Dosage Forms and Strengths (3) .
Current Regimen | INVOKAMET
Recommended Dosage Administered as one tablet, orally, twice daily with meals |
INVOKAMET XR
Recommended Dosage Administered as two tablets, orally, once daily with the morning meal |
---|---|---|
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
INVOKAMET
Canagliflozin may be increased to the maximum recommended dosage of 150 mg twice daily in patients tolerating 50 mg twice daily and metformin may be increased to the maximum recommended dosage of 1,000 mg twice daily, with gradual escalation to reduce gastrointestinal adverse reactions with metformin [see Adverse Reactions (6.1)].
INVOKAMET XR
Canagliflozin may be increased to the maximum recommended dosage of 300 mg once daily in patients tolerating 100 mg once daily and metformin may be increased to the maximum recommended dosage of 2,000 mg once daily, with gradual escalation to reduce gastrointestinal adverse reactions with metformin [see Adverse Reactions (6.1)].
2.4 Recommended Dosage for Patients with Renal Impairment
- 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 component.
- Table 2 provides dosage recommendations for patients with renal impairment, based on eGFR [see Use in Specific Populations (8.6)and Clinical Studies (14.3)].
Estimated Glomerular Filtration Rate
[eGFR (mL/min/1.73 m 2)] |
Recommended Dosage |
---|---|
eGFR 45 to less than 60 | The maximum recommended dosage of canagliflozin is 100 mg daily. |
eGFR 30 to less than 45 | Assess the benefit risk of continuing INVOKAMET or INVOKAMET XR. The maximum recommended dosage of canagliflozin is 100 mg daily. |
eGFR less than 30 | Contraindicated. If eGFR falls below 30 during treatment; discontinue INVOKAMET or INVOKAMET XR [see Contraindications (4)] . |
2.5 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 2or 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 recommended dosage of canagliflozin is 300 mg daily.
- 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.
2.6 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)] .
2.7 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)].
3 DOSAGE FORMS AND STRENGTHS
INVOKAMET (canagliflozin and metformin HCl) tablets are available as follows:
Canagliflozin Strength | Metformin HCl Strength | Color/Shape | Tablet Identifiers Embossing appears on both sides of tablet. |
---|---|---|---|
50 mg | 500 mg | white/capsule-shaped | CM 155 |
50 mg | 1,000 mg | beige/capsule-shaped | CM 551 |
150 mg | 500 mg | yellow/capsule-shaped | CM 215 |
150 mg | 1,000 mg | purple/capsule-shaped | CM 611 |
INVOKAMET XR (canagliflozin and metformin HCl) extended-release tablets are available as follows:
Canagliflozin Strength | Metformin HCl Strength | Color/Shape | Tablet Identifiers Embossing appears on one side only of tablet. |
---|---|---|---|
50 mg | 500 mg | almost white to light orange/oblong, biconvex | CM1 |
50 mg | 1,000 mg | pink/oblong, biconvex | CM3 |
150 mg | 500 mg | orange/oblong, biconvex | CM2 |
150 mg | 1,000 mg | reddish brown/oblong, biconvex | CM4 |
4 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)] .
- With acute or chronic metabolic acidosis, including diabetic ketoacidosis [see Warnings and Precautions (5.2)] .
- With serious hypersensitivity reaction to canagliflozin or metformin HCl, such as anaphylaxis or angioedema [see Warnings and Precautions (5.9)and Adverse Reactions (6)] .
5 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 INVOKAMET or INVOKAMET XR if ketoacidosis is suspected. Monitor patients for resolution of ketoacidosis before restarting ( 5.2)
- Lower Limb Amputation: Monitor patients for infection or ulcers of lower limb and discontinue if these occur ( 5.3)
- Volume Depletion: May result in acute kidney injury. Before initiating, assess and correct volume status in patients with renal impairment, elderly patients, or patients on loop diuretics. Monitor for signs and symptoms during therapy ( 5.4)
- Urosepsis and Pyelonephritis: Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated ( 5.5)
- Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues: Consider a lower dose of insulin or insulin secretagogue to reduce the risk of hypoglycemia when used in combination ( 5.6)
- 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 ( 5.7)
- Genital Mycotic Infections: Monitor and treat if indicated ( 5.8)
- Hypersensitivity Reactions: Discontinue and monitor until signs and symptoms resolve ( 5.9)
- Bone Fracture: Consider factors that contribute to fracture risk before initiating INVOKAMET or INVOKAMET XR ( 5.10)
- Vitamin B 12Deficiency : Metformin HCl may lower vitamin B 12levels. Measure hematological parameters annually and vitamin B 12at 2- to 3-year intervals and manage any abnormalities ( 5.11)
5.1 Lactic Acidosis
There have been post-marketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate:pyruvate ratio; metformin plasma levels generally >5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk.
If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of INVOKAMET or INVOKAMET XR. In INVOKAMET or INVOKAMET XR-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin is dialyzable, with a clearance of up to 170 mL/min under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery.
Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue INVOKAMET or INVOKAMET XR and report these symptoms to their healthcare provider.
For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below:
Renal Impairment:The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patient's renal function include [see Dosage and Administration (2.4)and Clinical Pharmacology (12.3)].
- Before initiating INVOKAMET or INVOKAMET XR, obtain an estimated glomerular filtration rate (eGFR).
- INVOKAMET or INVOKAMET XR is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m 2 [see Contraindications (4)] .
- Obtain an eGFR at least annually in all patients taking INVOKAMET or INVOKAMET XR. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.
Drug Interactions:The concomitant use of INVOKAMET or INVOKAMET XR with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation (e.g. cationic drugs) [see Drug Interactions (7)]. Therefore, consider more frequent monitoring of patients.
Age 65 or Greater:The risk of metformin-associated lactic acidosis increases with the patient's age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients [ see Use in Specific Populations (8.5)].
Radiological Studies with Contrast:Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop INVOKAMET or INVOKAMET XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR less than 60 mL/min/1.73 m 2; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart INVOKAMET or INVOKAMET XR if renal function is stable.
Surgery and Other Procedures:Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension and renal impairment.
INVOKAMET or INVOKAMET XR should be temporarily discontinued while patients have restricted food and fluid intake.
Hypoxic States:Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause pre-renal azotemia. When such events occur, discontinue INVOKAMET or INVOKAMET XR.
Excessive Alcohol Intake:Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving INVOKAMET or INVOKAMET XR.
Hepatic Impairment:Patients with hepatic impairment have developed metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of INVOKAMET or INVOKAMET XR in patients with clinical or laboratory evidence of hepatic disease.
5.2 Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis
In patients with type 1 diabetes mellitus, INVOKAMET or INVOKAMET XR 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 INVOKAMET or INVOKAMET XR. INVOKAMET or INVOKAMET XR 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 INVOKAMET or INVOKAMET XR.
Precipitating conditions for diabetic ketoacidosis or other ketoacidosis include under-insulinization due to insulin dose reduction or missed insulin doses, acute febrile illness, reduced caloric intake, ketogenic diet, surgery, 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 INVOKAMET or INVOKAMET XR [see Clinical Pharmacology (12.2)] ; however, there have been postmarketing reports of ketoacidosis and/or 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 INVOKAMET or INVOKAMET XR, promptly evaluate, and treat ketoacidosis, if confirmed. Monitor patients for resolution of ketoacidosis before restarting INVOKAMET or INVOKAMET XR.
Withhold INVOKAMET or INVOKAMET XR, if possible, in temporary clinical situations that could predispose patients to ketoacidosis. Resume INVOKAMET or INVOKAMET XR when the patient is clinically stable and has resumed oral intake [see Dosage and Administration (2.7)] .
Educate all patients on the signs and symptoms of ketoacidosis and instruct patients to discontinue INVOKAMET or INVOKAMET XR and seek medical attention immediately if signs and symptoms occur.
5.3 Lower Limb Amputation
An increased risk of lower limb amputations associated with canagliflozin, a component of INVOKAMET or INVOKAMET XR, versus placebo was observed in CANVAS (5.9 vs 2.8 events per 1,000 patient-years) and CANVAS-R (7.5 vs 4.2 events per 1,000 patient-years), two randomized, placebo-controlled trials evaluating patients with type 2 diabetes 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 4 and 5, respectively [see Adverse Reactions (6.1)] .
Amputations of the toe and midfoot (99 out of 140 patients with amputations receiving canagliflozin 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 canagliflozin 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.
Counsel patients about the importance of routine preventative foot care. Monitor patients receiving INVOKAMET or INVOKAMET XR for signs and symptoms of infection (including osteomyelitis), new pain or tenderness, sores or ulcers involving the lower limbs, and discontinue INVOKAMET or INVOKAMET XR if these complications occur.
5.4 Volume Depletion
Canagliflozin 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 canagliflozin. 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 INVOKAMET or INVOKAMET XR 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.
5.5 Urosepsis and Pyelonephritis
There have been postmarketing reports of serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalization in patients receiving canagliflozin. Treatment with INVOKAMET or INVOKAMET XR 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)] .
5.6 Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues
Insulin and insulin secretagogues are known to cause hypoglycemia. INVOKAMET or INVOKAMET XR may increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue [see Adverse Reactions (6.1)] . The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylurea (or other concomitantly administered insulin secretagogues) or insulin. Inform patients using these concomitant medications of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia.
5.7 Necrotizing Fasciitis of the Perineum (Fournier's Gangrene)
Reports of necrotizing fasciitis of the perineum (Fournier's gangrene), a rare but serious and life-threatening necrotizing infection requiring urgent surgical intervention, have been identified in postmarketing surveillance in patients with diabetes mellitus receiving SGLT2 inhibitors, including canagliflozin. Cases have been reported in both females and males. Serious outcomes have included hospitalization, multiple surgeries, and death.
Patients treated with INVOKAMET or INVOKAMET XR presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise, should be assessed for necrotizing fasciitis. If suspected, start treatment immediately with broad-spectrum antibiotics and, if necessary, surgical debridement. Discontinue INVOKAMET or INVOKAMET XR, closely monitor blood glucose levels, and provide appropriate alternative therapy for glycemic control.
5.8 Genital Mycotic Infections
Canagliflozin increases the risk of genital mycotic infections. Patients with a history of genital mycotic infections and uncircumcised males were more likely to develop genital mycotic infections [see Adverse Reactions (6.1)] . Monitor and treat appropriately.
5.9 Hypersensitivity Reactions
Hypersensitivity reactions, including angioedema and anaphylaxis, have been reported with canagliflozin. These reactions generally occurred within hours to days after initiating canagliflozin. If hypersensitivity reactions occur, discontinue use of INVOKAMET or INVOKAMET XR; treat and monitor until signs and symptoms resolve [see Contraindications (4)and Adverse Reactions (6.1, 6.2)] .
5.10 Bone Fracture
An increased risk of bone fracture, occurring as early as 12 weeks after treatment initiation, was observed in patients using canagliflozin in the CANVAS trial [see Clinical Studies (14.2)] . Consider factors that contribute to fracture risk prior to initiating INVOKAMET or INVOKAMET XR [see Adverse Reactions (6.1)] .
5.11 Vitamin B 12Levels
In metformin HCl clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B 12levels was observed in approximately 7% of patients. Such decrease, possibly due to interference with B 12absorption from the B 12-intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin HCl or vitamin B 12supplementation. Certain individuals (those with inadequate vitamin B 12or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B 12levels. Measure hematologic parameters on an annual basis and vitamin B 12at 2- to 3-year intervals in patients on INVOKAMET or INVOKAMET XR and manage any abnormalities [see Adverse Reactions (6.1)].
6 ADVERSE REACTIONS
The following important adverse reactions are also discussed elsewhere in the labeling:
- Lactic Acidosis [see Boxed Warningand Warnings and Precautions (5.1, 5.4)]
- Diabetic Ketoacidosis in Patients with Type 1 Diabetes and Other Ketoacidosis [see Warnings and Precautions (5.2)]
- Lower Limb Amputation [see Warnings and Precautions (5.3)]
- Volume Depletion [see Warnings and Precautions (5.4)]
- Urosepsis and Pyelonephritis [see Warnings and Precautions (5.5)]
- Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues [see Warnings and Precautions (5.6)]
- Necrotizing Fasciitis of the Perineum (Fournier's gangrene) [see Warnings and Precautions (5.7)]
- Genital Mycotic Infections [see Warnings and Precautions (5.8)]
- Hypersensitivity Reactions [see Warnings and Precautions (5.9)]
- Bone Fracture [see Warnings and Precautions (5.10)]
- Vitamin B 12Deficiency [see Warnings and Precautions (5.11)]
- Most common adverse reactions associated with canagliflozin (5% or greater incidence): female genital mycotic infections, urinary tract infection, and increased urination ( 6.1)
- Most common adverse reactions associated with metformin HCl (5% or greater incidence) are diarrhea, nausea, vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache ( 6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Janssen Pharmaceuticals, Inc. at 1-800-526-7736 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
6.1 Clinical Studies Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
Pool of Placebo-Controlled Trials for Glycemic Control
Canagliflozin
The data in Table 3 is derived from four 26-week placebo-controlled trials where canagliflozin was used as monotherapy in one trial and as add-on therapy in three trials. These data reflect exposure of 1,667 patients to canagliflozin and a mean duration of exposure to canagliflozin of 24 weeks with 1,275 patients exposed to a combination of canagliflozin and metformin HCl. Patients received canagliflozin 100 mg (N=833), canagliflozin 300 mg (N=834) or placebo (N=646) once daily. The mean daily dose of metformin HCl was 2,138 mg (SD 337.3) for the 1,275 patients in the three placebo-controlled metformin HCl add-on trials. The mean age of the population was 56 years and 2% were older than 75 years of age. Fifty percent (50%) of the population was male and 72% were White, 12% were Asian, and 5% were Black or African American. At baseline the population had diabetes for an average of 7.3 years, had a mean HbA 1Cof 8.0% and 20% had established microvascular complications of diabetes. Baseline renal function was normal or mildly impaired (mean eGFR 88 mL/min/1.73 m 2).
Table 3 shows common adverse reactions associated with the use of canagliflozin. These adverse reactions were not present at baseline, occurred more commonly on canagliflozin than on placebo, and occurred in at least 2% of patients treated with either canagliflozin 100 mg or canagliflozin 300 mg.
Adverse Reaction | Placebo
N=646 |
Canagliflozin
100 mg N=833 |
Canagliflozin
300 mg N=834 |
---|---|---|---|
Note: Percentages were weighted by studies. Study weights were proportional to the harmonic mean of the three treatment sample sizes. | |||
Urinary tract infections Urinary tract infections include the following adverse reactions: Urinary tract infection, Cystitis, Kidney infection, and Urosepsis. | 3.8% | 5.9% | 4.4% |
Increased urination Increased urination includes the following adverse reactions: Polyuria, Pollakiuria, Urine output increased, Micturition urgency, and Nocturia. | 0.7% | 5.1% | 4.6% |
Thirst Thirst includes the following adverse reactions: Thirst, Dry mouth, and Polydipsia. | 0.1% | 2.8% | 2.4% |
Constipation | 0.9% | 1.8% | 2.4% |
Nausea | 1.6% | 2.1% | 2.3% |
N=312 | N=425 | N=430 | |
Female genital mycotic infections Female genital mycotic infections include the following adverse reactions: Vulvovaginal candidiasis, Vulvovaginal mycotic infection, Vulvovaginitis, Vaginal infection, Vulvitis, and Genital infection fungal. | 2.8% | 10.6% | 11.6% |
Vulvovaginal pruritus | 0.0% | 1.6% | 3.2% |
N=334 | N=408 | N=404 | |
Male genital mycotic infections Male genital mycotic infections include the following adverse reactions: Balanitis or Balanoposthitis, Balanitis candida, and Genital infection fungal. | 0.7% | 4.2% | 3.8% |
Abdominal pain was also more commonly reported in patients taking canagliflozin 100 mg (1.8%), 300 mg (1.7%) than in patients taking placebo (0.8%).
Canagliflozin and Metformin HCl
The incidence and type of adverse reactions in the three 26-week placebo-controlled metformin HCl tablets add-on trials, representing a majority of data from the four 26-week placebo-controlled trials, was similar to the adverse reactions described in Table 3. There were no additional adverse reactions identified in the pooling of these three placebo-controlled trials that included metformin HCl tablets relative to the four placebo-controlled trials.
In a trial with canagliflozin as initial combination therapy with metformin HCl [see Clinical Studies (14.1)] , an increased incidence of diarrhea was observed in the canagliflozin and metformin HCl combination groups (4.2%) compared to canagliflozin or metformin HCl monotherapy groups (1.7%).
Placebo-Controlled Trial in Diabetic Nephropathy
The occurrence of adverse reactions for canagliflozin was evaluated in patients participating in CREDENCE, a study in patients with type 2 diabetes mellitus and diabetic nephropathy with albuminuria ˃ 300 mg/day [see Clinical Studies (14.3)] . These data reflect exposure of 2,201 patients to canagliflozin and a mean duration of exposure to canagliflozin of 137 weeks.
The rate of lower limb amputations associated with the use of canagliflozin 100 mg relative to placebo was 12.3 vs 11.2 events per 1,000 patient-years, respectively, with 2.6 years mean duration of follow-up.
The incidence of hypotension was 2.8% and 1.5% on canagliflozin 100 mg and placebo, respectively.
Pool of Placebo- and Active-Controlled Trials for Glycemic Control and Cardiovascular Outcomes
The occurrence of adverse reactions for canagliflozin was evaluated in patients participating in placebo- and active-controlled trials and in an integrated analysis of two cardiovascular trials, CANVAS and CANVAS-R.
The types and frequency of common adverse reactions observed in the pool of eight clinical trials (which reflect an exposure of 6,177 patients to canagliflozin) were consistent with those listed in Table 3. Percentages were weighted by studies. Study weights were proportional to the harmonic mean of the three treatment sample sizes. In this pool, canagliflozin was also associated with the adverse reactions of fatigue (1.8%, 2.2%, and 2.0% with comparator, canagliflozin 100 mg, and canagliflozin 300 mg, respectively) and loss of strength or energy (i.e., asthenia) (0.6%, 0.7%, and 1.1% with comparator, canagliflozin 100 mg, and canagliflozin 300 mg, respectively).
In the pool of eight clinical trials, the incidence rate of pancreatitis (acute or chronic) was 0.1%, 0.2%, and 0.1% receiving comparator, canagliflozin 100 mg, and canagliflozin 300 mg, respectively.
In the pool of eight clinical trials, hypersensitivity-related adverse reactions (including erythema, rash, pruritus, urticaria, and angioedema) was 3.0%, 3.8%, and 4.2% of patients receiving comparator, canagliflozin 100 mg, and canagliflozin 300 mg, respectively. Five patients experienced serious adverse reactions of hypersensitivity with canagliflozin, which included 4 patients with urticaria and 1 patient with a diffuse rash and urticaria occurring within hours of exposure to canagliflozin. Among these patients, 2 patients discontinued canagliflozin. One patient with urticaria had recurrence when canagliflozin was re-initiated.
Photosensitivity-related adverse reactions (including photosensitivity reaction, polymorphic light eruption, and sunburn) occurred in 0.1%, 0.2%, and 0.2% of patients receiving comparator, canagliflozin 100 mg, and canagliflozin 300 mg, respectively.
Other adverse reactions occurring more frequently on canagliflozin than on comparator were:
Lower Limb Amputation
An increased risk of lower limb amputations associated with canagliflozin was observed in CANVAS (5.9 vs 2.8 events per 1,000 patient-years) and CANVAS-R (7.5 vs 4.2 events per 1,000 patient-years), two randomized, placebo-controlled trials evaluating patients with type 2 diabetes who had either established cardiovascular disease or were at risk for cardiovascular disease. Patients in CANVAS and CANVAS-R were followed for an average of 5.7 and 2.1 years, respectively [see Clinical Studies (14.2)] . The amputation data for CANVAS and CANVAS-R are shown in Tables 4 and 5, respectively .
Placebo
N=1,441 |
Canagliflozin
100 mg N=1,445 |
Canagliflozin
300 mg N=1,441 |
Canagliflozin
(Pooled) N=2,886 |
|
---|---|---|---|---|
Note: Incidence is based on the number of patients with at least one amputation, and not the total number of amputation events. A patient's follow-up is calculated from Day 1 to the first amputation event date. Some patients had more than one amputation. | ||||
Patients with an amputation, n (%) | 22 (1.5) | 50 (3.5) | 45 (3.1) | 95 (3.3) |
Total amputations | 33 | 83 | 79 | 162 |
Amputation incidence rate
(per 1,000 patient-years) |
2.8 | 6.2 | 5.5 | 5.9 |
Hazard Ratio (95% CI) | -- | 2.24 (1.36, 3.69) | 2.01 (1.20, 3.34) | 2.12 (1.34, 3.38) |
Placebo
N=2,903 |
Canagliflozin
100 mg (with up-titration to 300 mg) N=2,904 |
|
---|---|---|
Note: Incidence is based on the number of patients with at least one amputation, and not the total number of amputation events. A patient's follow-up is calculated from Day 1 to the first amputation event date. Some patients had more than one amputation. | ||
Patients with an amputation, n (%) | 25 (0.9) | 45 (1.5) |
Total amputations | 36 | 59 |
Amputation incidence rate
(per 1,000 patient-years) |
4.2 | 7.5 |
Hazard Ratio (95% CI) | -- | 1.80 (1.10, 2.93) |
Renal Cell Carcinoma
In the CANVAS trial (mean duration of follow-up of 5.7 years) [see Clinical Studies (14.2)] , the incidence of renal cell carcinoma was 0.15% (2/1,331) and 0.29% (8/2,716) for placebo and canagliflozin, respectively, excluding patients with less than 6 months of follow-up, less than 90 days of treatment, or a history of renal cell carcinoma. A causal relationship to canagliflozin could not be established due to the limited number of cases.
Volume Depletion-Related Adverse Reactions
Canagliflozin results in an osmotic diuresis, which may lead to reductions in intravascular volume. In clinical trials for glycemic control, treatment with canagliflozin was associated with a dose-dependent increase in the incidence of volume depletion-related adverse reactions (e.g., hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration). An increased incidence was observed in patients on the 300 mg dose. The three factors associated with the largest increase in volume depletion-related adverse reactions in these trials were the use of loop diuretics, moderate renal impairment (eGFR 30 to less than 60 mL/min/1.73 m 2), and age 75 years and older (Table 6) [see Use in Specific Populations (8.5and 8.6)] .
Baseline Characteristic | Comparator Group
Includes placebo and active-comparator groups
% |
Canagliflozin 100 mg
% |
Canagliflozin 300 mg
% |
---|---|---|---|
Overall population | 1.5% | 2.3% | 3.4% |
75 years of age and older Patients could have more than 1 of the listed risk factors | 2.6% | 4.9% | 8.7% |
eGFR less than 60 mL/min/1.73 m 2 | 2.5% | 4.7% | 8.1% |
Use of loop diuretic | 4.7% | 3.2% | 8.8% |
Falls
In a pool of nine clinical trials with mean duration of exposure to canagliflozin of 85 weeks, the proportion of patients who experienced falls was 1.3%, 1.5%, and 2.1% with comparator, canagliflozin 100 mg, and canagliflozin 300 mg, respectively. The higher risk of falls for patients treated with canagliflozin was observed within the first few weeks of treatment.
Genital Mycotic Infections
In the pool of four placebo-controlled clinical trials for glycemic control, female genital mycotic infections (e.g., vulvovaginal mycotic infection, vulvovaginal candidiasis, and vulvovaginitis) occurred in 2.8%, 10.6%, and 11.6% of females treated with placebo, canagliflozin 100 mg, and canagliflozin 300 mg, respectively. Patients with a history of genital mycotic infections were more likely to develop genital mycotic infections on canagliflozin. Female patients who developed genital mycotic infections on canagliflozin were more likely to experience recurrence and require treatment with oral or topical antifungal agents and anti-microbial agents. In females, discontinuation due to genital mycotic infections occurred in 0% and 0.7% of patients treated with placebo and canagliflozin, respectively.
In the pool of four placebo-controlled clinical trials, male genital mycotic infections (e.g., candidal balanitis, balanoposthitis) occurred in 0.7%, 4.2%, and 3.8% of males treated with placebo, canagliflozin 100 mg, and canagliflozin 300 mg, respectively. Male genital mycotic infections occurred more commonly in uncircumcised males and in males with a prior history of balanitis or balanoposthitis. Male patients who developed genital mycotic infections on canagliflozin were more likely to experience recurrent infections (22% on canagliflozin versus none on placebo) and require treatment with oral or topical antifungal agents and anti-microbial agents than patients on comparators. In males, discontinuations due to genital mycotic infections occurred in 0% and 0.5% of patients treated with placebo and canagliflozin, respectively.
In the pooled analysis of 8 randomized trials evaluating glycemic control, phimosis was reported in 0.3% of uncircumcised male patients treated with canagliflozin and 0.2% required circumcision to treat the phimosis.
Hypoglycemia
In canagliflozin glycemic control trials, hypoglycemia was defined as any event regardless of symptoms, where biochemical hypoglycemia was documented (any glucose value below or equal to 70 mg/dL). Severe hypoglycemia was defined as an event consistent with hypoglycemia where the patient required the assistance of another person to recover, lost consciousness, or experienced a seizure (regardless of whether biochemical documentation of a low glucose value was obtained). In individual clinical trials of glycemic control [see Clinical Studies (14.1)] , episodes of hypoglycemia occurred at a higher rate when canagliflozin was co-administered with insulin or sulfonylureas (Table 7).
Monotherapy
(26 weeks) |
Placebo
(N=192) |
Canagliflozin 100 mg
(N=195) |
Canagliflozin 300 mg
(N=197) |
Overall [N (%)] | 5 (2.6) | 7 (3.6) | 6 (3.0) |
In Combination with Metformin HCl
(26 weeks) |
Placebo + Metformin HCl
(N=183) |
Canagliflozin 100 mg + Metformin HCl
(N=368) |
Canagliflozin 300 mg + Metformin HCl
(N=367) |
Overall [N (%)] | 3 (1.6) | 16 (4.3) | 17 (4.6) |
Severe [N (%)] Severe episodes of hypoglycemia were defined as those where the patient required the assistance of another person to recover, lost consciousness, or experienced a seizure (regardless of whether biochemical documentation of a low glucose value was obtained) | 0 (0) | 1 (0.3) | 1 (0.3) |
In Combination with Metformin HCl
(18 weeks) Phase 2 clinical study with twice daily dosing (50 mg or 150 mg twice daily in combination with metformin HCl) |
Placebo
(N=93) |
Canagliflozin 100 mg
(N=93) |
Canagliflozin 300 mg
(N=93) |
Overall [N (%)] | 3 (3.2) | 4 (4.3) | 3 (3.2) |
In Combination with Metformin HCl + Sulfonylurea
(26 weeks) |
Placebo + Metformin HCl + Sulfonylurea
(N=156) |
Canagliflozin 100 mg + Metformin HCl + Sulfonylurea
(N=157) |
Canagliflozin 300 mg + Metformin HCl + Sulfonylurea
(N=156) |
Overall [N (%)] | 24 (15.4) | 43 (27.4) | 47 (30.1) |
Severe [N (%)] | 1 (0.6) | 1 (0.6) | 0 |
In Combination with Metformin HCl + Pioglitazone
(26 weeks) |
Placebo + Metformin HCl + Pioglitazone
(N=115) |
Canagliflozin 100 mg + Metformin HCl + Pioglitazone
(N=113) |
Canagliflozin 300 mg + Metformin HCl + Pioglitazone
(N=114) |
Overall [N (%)] | 3 (2.6) | 3 (2.7) | 6 (5.3) |
In Combination with Insulin
(18 weeks) |
Placebo
(N=565) |
Canagliflozin 100 mg
(N=566) |
Canagliflozin 300 mg
(N=587) |
Overall [N (%)] | 208 (36.8) | 279 (49.3) | 285 (48.6) |
Severe [N (%)] | 14 (2.5) | 10 (1.8) | 16 (2.7) |
In Combination with Insulin and Metformin HCl (18 weeks) Subgroup of patients (N=287) from insulin substudy on canagliflozin in combination with metformin HCl and insulin (with or without other antiglycemic agents) |
Placebo
(N=145) |
Canagliflozin 100 mg
(N=139) |
Canagliflozin 300 mg
(N=148) |
Overall [N (%)] | 66 (45.5) | 58 (41.7) | 70 (47.3) |
Severe [N (%)] | 4 (2.8) | 1 (0.7) | 3 (2.0) |
Bone Fracture
In the CANVAS trial [see Clinical Studies (14.2)] , the incidence rates of all adjudicated bone fracture were 1.09, 1.59, and 1.79 events per 100 patient-years of follow-up to placebo, canagliflozin 100 mg, and canagliflozin 300 mg, respectively. The fracture imbalance was observed within the first 26 weeks of therapy and remained through the end of the trial. Fractures were more likely to be low trauma (e.g., fall from no more than standing height), and affect the distal portion of upper and lower extremities.
Metformin HCl
The most common adverse reactions (5% or greater incidence) due to initiation of metformin HCl are diarrhea, nausea, vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache.
In metformin clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B 12levels was observed in approximately 7% of patients.
Laboratory and Imaging Tests
Increases in Serum Creatinine and Decreases in eGFR
Initiation of canagliflozin causes an increase in serum creatinine and decrease in estimated GFR. In patients with moderate renal impairment, the increase in serum creatinine generally does not exceed 0.2 mg/dL, occurs within the first 6 weeks of starting therapy, and then stabilizes. Increases that do not fit this pattern should prompt further evaluation to exclude the possibility of acute kidney injury [see Clinical Pharmacology (12.1)] . The acute effect on eGFR reverses after treatment discontinuation suggesting acute hemodynamic changes may play a role in the renal function changes observed with canagliflozin.
Increases in Serum Potassium
In a pooled population of patients (N=723) in glycemic control trials with moderate renal impairment (eGFR 45 to less than 60 mL/min/1.73 m 2), increases in serum potassium to greater than 5.4 mEq/L and 15% above occurred in 5.3%, 5.0%, and 8.8% of patients treated with placebo, canagliflozin 100 mg, and canagliflozin 300 mg, respectively. Severe elevations (greater than or equal to 6.5 mEq/L) occurred in 0.4% of patients treated with placebo, no patients treated with canagliflozin 100 mg, and 1.3% of patients treated with canagliflozin 300 mg.
In these patients, increases in potassium were more commonly seen in those with elevated potassium at baseline. Among patients with moderate renal impairment, approximately 84% were taking medications that interfere with potassium excretion, such as potassium-sparing diuretics, angiotensin-converting-enzyme inhibitors, and angiotensin-receptor blockers [see Use in Specific Populations (8.6)].
In CREDENCE, no difference in serum potassium, no increase in adverse events of hyperkalemia, and no increase in absolute (> 6.5 mEq/L) or relative (> upper limit of normal and > 15% increase from baseline) increases in serum potassium were observed with canagliflozin 100 mg relative to placebo.
Increases in Low-Density Lipoprotein Cholesterol (LDL-C) and non-High-Density Lipoprotein Cholesterol (non-HDL-C)
In the pool of four glycemic control placebo-controlled trials, dose-related increases in LDL-C with canagliflozin were observed. Mean changes (percent changes) from baseline in LDL-C relative to placebo were 4.4 mg/dL (4.5%) and 8.2 mg/dL (8.0%) with canagliflozin 100 mg and canagliflozin 300 mg, respectively. The mean baseline LDL-C levels were 104 to 110 mg/dL across treatment groups.
Dose-related increases in non-HDL-C with canagliflozin were observed. Mean changes (percent changes) from baseline in non-HDL-C relative to placebo were 2.1 mg/dL (1.5%) and 5.1 mg/dL (3.6%) with canagliflozin 100 mg and 300 mg, respectively. The mean baseline non-HDL-C levels were 140 to 147 mg/dL across treatment groups.
Increases in Hemoglobin
In the pool of four placebo-controlled trials of glycemic control, mean changes (percent changes) from baseline in hemoglobin were -0.18 g/dL (-1.1%) with placebo, 0.47 g/dL (3.5%) with canagliflozin 100 mg, and 0.51 g/dL (3.8%) with canagliflozin 300 mg. The mean baseline hemoglobin value was approximately 14.1 g/dL across treatment groups. At the end of treatment, 0.8%, 4.0%, and 2.7% of patients treated with placebo, canagliflozin 100 mg, and canagliflozin 300 mg, respectively, had hemoglobin above the upper limit of normal.
Decreases in Bone Mineral Density
Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry in a clinical trial of 714 older adults (mean age 64 years) [see Clinical Studies (14.1)] . At 2 years, patients randomized to canagliflozin 100 mg and canagliflozin 300 mg had placebo-corrected declines in BMD at the total hip of 0.9% and 1.2%, respectively, and at the lumbar spine of 0.3% and 0.7%, respectively. Additionally, placebo-adjusted BMD declines were 0.1% at the femoral neck for both canagliflozin doses and 0.4% at the distal forearm for patients randomized to canagliflozin 300 mg. The placebo-adjusted change at the distal forearm for patients randomized to canagliflozin 100 mg was 0%.
6.2 Postmarketing Experience
Additional adverse reactions have been identified during post-approval use of canagliflozin and/or metformin. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Canagliflozin
Ketoacidosis
Acute Kidney Injury
Anaphylaxis, Angioedema
Urosepsis and Pyelonephritis
Necrotizing Fasciitis of the Perineum (Fournier's gangrene)
Metformin HCl
Cholestatic, hepatocellular, and mixed hepatocellular liver injury
7 DRUG INTERACTIONS
Carbonic Anhydrase Inhibitors | |
Clinical Impact: | Carbonic anhydrase inhibitors frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with INVOKAMET or INVOKAMET XR may increase the risk for lactic acidosis. |
Intervention: | Consider more frequent monitoring of these patients. |
Examples: | Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) |
Drugs That Reduce Metformin Clearance | |
Clinical Impact: | Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2] / multidrug and toxin extrusion [MATE] inhibitors could increase systemic exposure to metformin and may increase the risk for lactic acidosis [see Clinical Pharmacology (12.3)]. |
Intervention: | Consider the benefits and risks of concomitant use. |
Examples: | Ranolazine, vandetanib, dolutegravir, and cimetidine |
Alcohol | |
Clinical Impact: | Alcohol is known to potentiate the effect of metformin HCl on lactate metabolism. |
Intervention: | Warn patients against excessive alcohol intake while receiving INVOKAMET or INVOKAMET XR. |
UGT Enzyme Inducers | |
Clinical Impact: | UGT enzyme inducers decrease canagliflozin exposure which may reduce the effectiveness of INVOKAMET or NVOKAMET XR. |
Intervention: | For patients with eGFR 60 mL/min/1.73 m
2or greater, if an inducer of UGTs is co-administered with INVOKAMET or INVOKAMET XR, increase the total daily dose of canagliflozin to 200 mg in patients currently tolerating INVOKAMET or INVOKAMET XR with a total daily dose of canagliflozin 100 mg. The total daily dose of canagliflozin may be increased to 300 mg in patients currently tolerating canagliflozin 200 mg and who require additional glycemic control.
For patients with eGFR less than 60 mL/min/1.73 m 2, if an inducer of UGTs is co-administered with INVOKAMET or INVOKAMET XR, increase the total daily dose of canagliflozin to 200 mg in patients currently tolerating canagliflozin 100 mg [see Dosage and Administration (2.5)and Clinical Pharmacology (12.3)] . |
Examples: | Rifampin, phenytoin, phenobarbital, ritonavir |
Insulin or Insulin Secretagogues | |
Clinical Impact: | The risk of hypoglycemia is increased when INVOKAMET or INVOKAMET XR is used concomitantly with insulin secretagogues (e.g., sulfonylurea) or insulin. |
Intervention: | Concomitant use may require a lower dosage of the insulin secretagogue or insulin to reduce the risk of hypoglycemia. |
Drugs Affecting Glycemic Control | |
Clinical Impact: | Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. |
Intervention: | When such drugs are administered to a patient receiving INVOKAMET or INVOKAMET XR, monitor for loss of blood glucose control. When such drugs are withdrawn from a patient receiving INVOKAMET or INVOKAMET XR, monitor for hypoglycemia. |
Examples: | Thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid. |
Digoxin | |
Clinical Impact: | Canagliflozin increases digoxin exposure [see Clinical Pharmacology (12.3)] . |
Intervention: | Monitor patients taking INVOKAMET or INVOKAMET XR with concomitant digoxin for a need to adjust the dosage of digoxin. |
Lithium | |
Clinical Impact: | Concomitant use of an SGLT2 inhibitor with lithium may decrease serum lithium concentrations. |
Intervention: | Monitor serum lithium concentration more frequently during INVOKAMET or INVOKAMET XR initiation and dosage changes. |
Drug/Laboratory Test Interference | |
Positive Urine Glucose Test | |
Clinical Impact: | SGLT2 inhibitors increase urinary glucose excretion which will lead to positive urine glucose tests. |
Intervention: | Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control. |
Interference with 1,5-anhydroglucitol (1,5-AG) Assay | |
Clinical Impact: | Measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors. |
Intervention: | Monitoring glycemic control with 1,5-AG assay is not recommended in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control. |
- Carbonic Anhydrase Inhibitors:May increase risk of lactic acidosis. Consider more frequent monitoring ( 7)
- Drugs that Reduce Metformin Clearance:May increase risk of lactic acidosis. Consider benefits and risks of concomitant use ( 7)
- See full prescribing information for additional drug interactions and information on interference of INVOKAMET and INVOKAMET XR with laboratory tests. ( 7)
8 USE IN SPECIFIC POPULATIONS
- Pregnancy: Advise females of the potential risk to a fetus especially during the second and third trimesters ( 8.1)
- Lactation: Not recommended when breastfeeding ( 8.2)
- Females and Males of Reproductive Potential: Advise premenopausal females of the potential for an unintended pregnancy ( 8.3)
- Geriatrics: Higher incidence of adverse reactions related to reduced intravascular volume. Assess renal function more frequently ( 6.1, 8.5)
- Renal Impairment: Higher incidence of adverse reactions related to hypotension and renal function ( 8.6)
- Hepatic Impairment: Avoid use in patients with hepatic impairment ( 8.7)
8.1 Pregnancy
Risk Summary
Based on juvenile animal data showing adverse renal effects from canagliflozin, INVOKAMET or INVOKAMET XR is not recommended during the second and third trimesters of pregnancy.
Limited data with INVOKAMET, INVOKAMET XR or canagliflozin in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. Published studies with metformin HCl use during pregnancy have not reported a clear association with metformin HCl and major birth defect or miscarriage risk [see Data]. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy [see Clinical Considerations].
In juvenile animal studies, adverse renal pelvic and tubule dilatations that were not reversible were observed in rats when canagliflozin was administered during a period of renal development corresponding to the late second and third trimesters of human pregnancy, at an exposure 0.5-times the 300 mg clinical dose, based on AUC. No adverse developmental effects were observed when metformin HCl was administered to pregnant Sprague Dawley rats and rabbits during the period of organogenesis at doses up to 2- and 6-times, respectively, a 2,000 mg clinical dose, based on body surface area [see Data] .
The estimated background risk of major birth defects is 6–10% in women with pre-gestational diabetes with a HbA 1C>7 and has been reported to be as high as 20–25% in women with a HbA 1C>10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.
Clinical Considerations
Disease-associated Maternal and/or Embryo/Fetal Risk
Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity.
Data
Human Data
Published data from post-marketing studies have not reported a clear association with metformin HCl and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin HCl was used during pregnancy. However, these studies cannot definitely establish the absence of any metformin-associated risk because of methodological limitations, including small sample size and inconsistent comparator groups.
Animal Data
Canagliflozin
Canagliflozin dosed directly to juvenile rats from postnatal day (PND) 21 until PND 90 at doses of 4, 20, 65, or 100 mg/kg increased kidney weights and dose dependently increased the incidence and severity of renal pelvic and tubular dilatation at all doses tested. Exposure at the lowest dose was greater than or equal to 0.5-times the 300 mg clinical dose, based on AUC. These outcomes occurred with drug exposure during periods of renal development in rats that correspond to the late second and third trimester of human renal development. The renal pelvic dilatations observed in juvenile animals did not fully reverse within a 1-month recovery period.
In embryo-fetal development studies in rats and rabbits, canagliflozin was administered for intervals coinciding with the first trimester period of organogenesis in humans. No developmental toxicities independent of maternal toxicity were observed when canagliflozin was administered at doses up to 100 mg/kg in pregnant rats and 160 mg/kg in pregnant rabbits during embryonic organogenesis or during a study in which maternal rats were dosed from gestation day (GD) 6 through PND 21, yielding exposures up to approximately 19-times the 300 mg clinical dose, based on AUC.
Metformin HCl
Metformin HCl did not cause adverse developmental effects when administered to pregnant Sprague Dawley rats and rabbits up to 600 mg/kg/day during the period of organogenesis. This represents an exposure of about 2- and 6-times a 2,000 mg clinical dose based on body surface area (mg/m 2) for rats and rabbits, respectively.
Canagliflozin and Metformin HCl
No adverse developmental effects were observed when canagliflozin and metformin HCl were co-administered to pregnant rats during the period of organogenesis at exposures up to 11 and 13 times, respectively, the 300 mg and 2,000 mg clinical doses of canagliflozin and metformin HCl based on AUC.
8.2 Lactation
Risk Summary
There is no information regarding the presence of INVOKAMET, INVOKAMET XR or canagliflozin in human milk, the effects on the breastfed infant, or the effects on milk production. Limited published studies report that metformin is present in human milk [see Data] . However, there is insufficient information on the effects of metformin HCl on the breastfed infant and no available information on the effects of metformin HCl on milk production. Canagliflozin is present in the milk of lactating rats [see Data] . Since human kidney maturation occurs in uteroand during the first 2 years of life when lactational exposure may occur, there may be risk to the developing human kidney.
Because of the potential for serious adverse reactions in a breastfed infant, advise women that use of INVOKAMET or INVOKAMET XR is not recommended while breastfeeding.
Data
Published clinical lactation studies report that metformin is present in human milk which resulted in infant doses approximately 0.11% to 1% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 0.13 and 1. However, the studies were not designed to definitely establish the risk of use of metformin HCl during lactation because of small sample size and limited adverse event data collected in infants.
Radiolabeled canagliflozin administered to lactating rats on day 13 post-partum was present at a milk/plasma ratio of 1.40, indicating that canagliflozin and its metabolites are transferred into milk at a concentration comparable to that in plasma. Juvenile rats directly exposed to canagliflozin showed a risk to the developing kidney (renal pelvic and tubular dilatations) during maturation.
8.3 Females and Males of Reproductive Potential
Discuss the potential for unintended pregnancy with premenopausal women as therapy with metformin HCl may result in ovulation in some anovulatory women.
8.4 Pediatric Use
Safety and effectiveness of INVOKAMET or INVOKAMET XR in pediatric patients under 18 years of age have not been established.
8.5 Geriatric Use
INVOKAMET and INVOKAMET XR
Because renal function abnormalities can occur after initiating canagliflozin, metformin is substantially excreted by the kidney, and aging can be associated with reduced renal function, monitor renal function more frequently after initiating INVOKAMET or INVOKAMET XR in the elderly and then adjust dose based on renal function [see Dosage and Administration (2.4)and Warnings and Precautions (5.1, 5.4)] .
Canagliflozin
In 13 clinical trials of canagliflozin, 2,294 patients 65 years and older, and 351 patients 75 years and older were exposed to canagliflozin. Of these patients, 1,534 patients 65 years and older and 196 patients 75 years and older were exposed to the combination of canagliflozin and metformin HCl [see Clinical Studies (14.1)] . 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), particularly with the 300 mg daily dose, compared to younger patients; a more prominent increase in the incidence was seen in patients who were 75 years and older [see Dosage and Administration (2.1)and Adverse Reactions (6.1)]. Smaller reductions in HbA 1Cwith canagliflozin relative to placebo were seen in older (65 years and older; -0.61% with canagliflozin 100 mg and -0.74% with canagliflozin 300 mg relative to placebo) compared to younger patients (-0.72% with canagliflozin 100 mg and -0.87% with canagliflozin 300 mg relative to placebo).
Metformin HCl
Controlled clinical trials of metformin HCl did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients, although other reported clinical experience has not identified differences in responses between the elderly and younger patients. The initial and maintenance dosing of metformin HCl should be conservative in patients with advanced age due to the potential for decreased renal function in this population. Any dose adjustment should be based on a careful assessment of renal function [see Contraindications (4), Warnings and Precautions (5.4), and Clinical Pharmacology (12.3)] .
8.6 Renal Impairment
Canagliflozin
The efficacy and safety of canagliflozin for glycemic control were evaluated in a trial that included patients with moderate renal impairment (eGFR 30 to less than 50 mL/min/1.73 m 2). These patients had less overall glycemic efficacy, and patients treated with canagliflozin 300 mg per day had increases in serum potassium, which were transient and similar by the end of study. Patients with renal impairment using canagliflozin for glycemic control may also be more likely to experience hypotension and may be at higher risk for acute kidney injury [see Warnings and Precautions (5.4)] .
Efficacy and safety studies with canagliflozin did not enroll patients with ESKD on dialysis or patients with an eGFR less than 30 mL/min/1.73 m 2 [see Clinical Pharmacology (12.3)] .
Metformin HCl
Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. INVOKAMET or INVOKAMET XR is contraindicated in severe renal impairment (eGFR less than 30 mL/min/1.73 m 2) or in patients on dialysis [see Dosage and Administration (2.4), Contraindications (4), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)].
8.7 Hepatic Impairment
Use of metformin HCl in patients with hepatic impairment has been associated with some cases of lactic acidosis. INVOKAMET or INVOKAMET XR is not recommended in patients with hepatic impairment [see Warnings and Precautions (5.1)].
10 OVERDOSAGE
Overdose of metformin HCl has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin HCl use has been established. Lactic acidosis has been reported in approximately 32% of metformin HCl overdose cases [see Warnings and Precautions (5.1)] .
In the event of an overdose with INVOKAMET or INVOKAMET XR, contact the Poison Control Center. Employ the usual supportive measures (e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive treatment) as dictated by the patient's clinical status. Canagliflozin was negligibly removed during a 4-hour hemodialysis session. Canagliflozin is not expected to be dialyzable by peritoneal dialysis. Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful partly for removal of accumulated metformin from patients in whom INVOKAMET or INVOKAMET XR overdosage is suspected.
11 DESCRIPTION
INVOKAMET ® (canagliflozin and metformin HCl immediate-release tablets) and INVOKAMET ® XR (canagliflozin and metformin HCl extended-release tablets) contain canagliflozin and metformin HCl.
Canagliflozin
Canagliflozin is an inhibitor of SGLT2, the transporter responsible for reabsorbing the majority of glucose filtered by the kidney. Canagliflozin is chemically known as (1 S)-1,5-anhydro-1-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol hemihydrate and its molecular formula and weight are C 24H 25FO 5S∙1/2 H 2O and 453.53, respectively. The structural formula for canagliflozin is:
Canagliflozin is practically insoluble in aqueous media from pH 1.1 to 12.9.
Metformin HCl
Metformin HCl is a biguanide chemically known as 1,1-Dimethylbiguanide HCl and its molecular formula and weight are C 4H 11N 5∙ HCl and 165.62, respectively. The structural formula for metformin HCl is:
INVOKAMET and INVOKAMET XR
INVOKAMET or INVOKAMET XR are supplied as film-coated tablets for oral administration. Each 50 mg/500 mg tablet and 50 mg/1,000 mg tablet contains 51 mg of canagliflozin equivalent to 50 mg canagliflozin (anhydrous) and 500 mg or 1,000 mg metformin HCl (equivalent to metformin 389.93 mg and 779.86 mg, respectively).
Each 150 mg/500 mg tablet and 150 mg/1,000 mg tablet contains 153 mg of canagliflozin equivalent to 150 mg canagliflozin (anhydrous) and 500 mg or 1,000 mg metformin HCl (equivalent to metformin 389.93 mg and 779.86 mg, respectively).
INVOKAMET contains the following inactive ingredients: croscarmellose sodium, hypromellose, magnesium stearate, and microcrystalline cellulose. The magnesium stearate is vegetable-sourced. The tablets are finished with a commercially available film-coating consisting of the following inactive ingredients: macrogol/PEG3350, polyvinyl alcohol (partially hydrolyzed), talc, titanium dioxide, iron oxide yellow (50 mg/1,000 mg and 150 mg/500 mg tablets only), iron oxide red (50 mg/1,000 mg, 150 mg/500 mg and 150 mg/1,000 mg tablets only), and iron oxide black (150 mg/1,000 mg tablets only).
INVOKAMET XR contains the following inactive ingredients: croscarmellose sodium, hydroxypropyl cellulose, hypromellose, lactose anhydrous, magnesium stearate (vegetable-sourced), microcrystalline cellulose, polyethylene oxide, and silicified microcrystalline cellulose (50 mg/500 mg and 50 mg/1,000 mg tablets only). The tablets are finished with a commercially available film-coating consisting of the following inactive ingredients: macrogol/PEG3350, polyvinyl alcohol (partially hydrolyzed), talc, titanium dioxide, iron oxide red, iron oxide yellow, and iron oxide black (50 mg/1,000 mg and 150 mg/1,000 mg tablets only).
INVOKAMET XR tablets provide canagliflozin for immediate-release and metformin HCl for extended-release. Each bilayer tablet is compressed from two separate granulates, one for each active ingredient of the tablet, and finished with a film-coating. The metformin HCl extended-release layer is based on a polymer matrix which controls the drug release by passive diffusion through the swollen matrix in combination with tablet erosion.
12 CLINICAL PHARMACOLOGY
12.1 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.
12.2 Pharmacodynamics
Canagliflozin
Following single and multiple oral doses of canagliflozin in patients with type 2 diabetes, dose-dependent decreases in RT Gand increases in urinary glucose excretion were observed. From a starting RT Gvalue of approximately 240 mg/dL, canagliflozin at 100 mg and 300 mg once daily suppressed RT Gthroughout the 24-hour period. Data from single oral doses of canagliflozin in healthy volunteers indicate that, on average, the elevation in urinary glucose excretion approaches baseline by about 3 days for doses up to 300 mg once daily. Maximal suppression of mean RT Gover the 24-hour period was seen with the 300 mg daily dose to approximately 70 to 90 mg/dL in patients with type 2 diabetes in Phase 1 trials. The reductions in RT Gled to increases in mean UGE of approximately 100 g/day in patients with type 2 diabetes treated with either 100 mg or 300 mg of canagliflozin. The 24-h mean RT Gat steady state was similar following once daily and twice daily dosing regimens at the same total daily dose of 100 mg or 300 mg. In patients with type 2 diabetes given 100 to 300 mg once daily over a 16-day dosing period, reductions in RT Gand increases in urinary glucose excretion were observed over the dosing period. In this trial, plasma glucose declined in a dose-dependent fashion within the first day of dosing.
Cardiac Electrophysiology
In a randomized, double-blind, placebo-controlled, active-comparator, 4-way crossover trial, 60 healthy subjects were administered a single oral dose of canagliflozin 300 mg, canagliflozin 1,200 mg (4 times the maximum recommended dose), moxifloxacin, and placebo. No meaningful changes in QTc interval were observed with either the recommended dose of 300 mg or the 1,200 mg dose.
12.3 Pharmacokinetics
INVOKAMET
Administration of INVOKAMET 150 mg/1,000 mg fixed-dose combination with food resulted in no change in overall exposure of canagliflozin. There was no change in metformin AUC; however, the mean peak plasma concentration of metformin was decreased by 16% when administered with food. A delayed time to peak plasma concentration was observed for both components (a delay of 2 hours for canagliflozin and 1 hour for metformin) under fed conditions. These changes are not likely to be clinically meaningful.
INVOKAMET XR
After administration of INVOKAMET XR tablets with a high-fat breakfast, the peak (C max) and total (AUC) exposure of canagliflozin were not altered relative to dosing in the fasted state. However, the AUC of metformin increased by approximately 61% and C maxincreased by approximately 13%.
Canagliflozin
The pharmacokinetics of canagliflozin is essentially similar in healthy subjects and patients with type 2 diabetes. Following single-dose oral administration of 100 mg and 300 mg of canagliflozin, peak plasma concentrations (median T max) of canagliflozin occurs within 1 to 2 hours post-dose. Plasma C maxand AUC of canagliflozin increased in a dose-proportional manner from 50 mg to 300 mg. The apparent terminal half-life (t 1/2) was 10.6 hours and 13.1 hours for the 100 mg and 300 mg doses, respectively. Steady-state was reached after 4 to 5 days of once-daily dosing with canagliflozin 100 mg to 300 mg. Canagliflozin does not exhibit time-dependent pharmacokinetics and accumulated in plasma up to 36% following multiple doses of 100 mg and 300 mg. The mean systemic exposure (AUC) at steady state was similar following once daily and twice daily dosing regimens at the same total daily dose of 100 mg or 300 mg.
Absorption
Canagliflozin
The mean absolute oral bioavailability of canagliflozin is approximately 65%.
Metformin
The absolute bioavailability of a metformin HCl 500 mg tablet given under fasting conditions is approximately 50% to 60%. Trials using single oral doses of metformin HCl 500 to 1,500 mg, and 850 to 2,550 mg, indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination.
Following a single oral dose of 1,000 mg metformin HCl extended-release tablets (two 500 mg tablets) after a meal, the time to reach maximum plasma metformin concentration (T max) is achieved at approximately 7–8 hours. In both single and multiple-dose trials in healthy subjects, once daily 1,000 mg (two 500 mg tablets) dosing results in up to 35% higher C max, of metformin relative to the immediate-release given as 500 mg twice daily without any change in overall systemic exposure, as measured by AUC.
Distribution
Canagliflozin
The mean steady-state volume of distribution of canagliflozin following a single intravenous infusion in healthy subjects was 83.5 L, suggesting extensive tissue distribution. Canagliflozin is extensively bound to proteins in plasma (99%), mainly to albumin. Protein binding is independent of canagliflozin plasma concentrations. Plasma protein binding is not meaningfully altered in patients with renal or hepatic impairment.
Metformin
The apparent volume of distribution (V/F) of metformin following single oral doses of metformin HCl 850 mg immediate-release tablets averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins, in contrast to sulfonylureas, which are more than 90% protein bound. Metformin partitions into erythrocytes, most likely as a function of time.
Metabolism
Canagliflozin
O-glucuronidation is the major metabolic elimination pathway for canagliflozin, which is mainly glucuronidated by UGT1A9 and UGT2B4 to two inactive O-glucuronide metabolites. CYP3A4-mediated (oxidative) metabolism of canagliflozin is minimal (approximately 7%) in humans.
Metformin
Intravenous single-dose trials in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) or biliary excretion.
Excretion
Canagliflozin
Following administration of a single oral [ 14C] canagliflozin dose to healthy subjects, 41.5%, 7.0%, and 3.2% of the administered radioactive dose was recovered in feces as canagliflozin, a hydroxylated metabolite, and an O-glucuronide metabolite, respectively. Enterohepatic circulation of canagliflozin was negligible.
Approximately 33% of the administered radioactive dose was excreted in urine, mainly as O-glucuronide metabolites (30.5%). Less than 1% of the dose was excreted as unchanged canagliflozin in urine. Renal clearance of canagliflozin 100 mg and 300 mg doses ranged from 1.30 to 1.55 mL/min.
Mean systemic clearance of canagliflozin was approximately 192 mL/min in healthy subjects following intravenous administration.
Metformin
Renal clearance is approximately 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, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.
Specific Populations
Trials characterizing the pharmacokinetics of canagliflozin and metformin after administration of INVOKAMET or INVOKAMET XR were not conducted in patients with renal and hepatic impairment. Descriptions of the individual components in this patient population are described below.
Patients with Renal Impairment
Canagliflozin
A single-dose, open-label trial evaluated the pharmacokinetics of canagliflozin 200 mg in subjects with varying degrees of renal impairment (classified using the MDRD-eGFR formula) compared to healthy subjects.
Renal impairment did not affect the C maxof canagliflozin. Compared to healthy subjects (N=3; eGFR greater than or equal to 90 mL/min/1.73 m 2), plasma AUC of canagliflozin was increased by approximately 15%, 29%, and 53% in subjects with mild (N=10), moderate (N=9), and severe (N=10) renal impairment, respectively, (eGFR 60 to less than 90, 30 to less than 60, and 15 to less than 30 mL/min/1.73 m 2, respectively), but was similar for ESKD (N=8) subjects and healthy subjects. Increases in canagliflozin AUC of this magnitude are not considered clinically relevant. The glucose lowering pharmacodynamic response to canagliflozin declines with increasing severity of renal impairment [see Contraindications (4)and Warnings and Precautions (5.4)].
Canagliflozin was negligibly removed by hemodialysis.
Metformin
In patients with decreased renal function, the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased [see Contraindications (4)and Warnings and Precautions (5.1)] .
Following a single dose administration of metformin HCl extended-release tablets 500 mg in patients with mild and moderate renal failure (based on measured creatinine clearance), the oral and renal clearance of metformin were decreased by 33% and 50% and 16% and 53%, respectively [see Warnings and Precautions (5.4)] . Metformin peak and systemic exposure was 27% and 61% greater, respectively in mild renal impaired and 74% and 2.36-fold greater in moderate renal impaired patients as compared to healthy subjects [see Contraindications (4)and Warnings and Precautions (5.1)] .
Patients with Hepatic Impairment
Canagliflozin
Relative to subjects with normal hepatic function, the geometric mean ratios for C maxand AUC ∞of canagliflozin were 107% and 110%, respectively, in subjects with Child-Pugh class A (mild hepatic impairment) and 96% and 111%, respectively, in subjects with Child-Pugh class B (moderate hepatic impairment) following administration of a single 300 mg dose of canagliflozin.
These differences are not considered to be clinically meaningful. There is no clinical experience in patients with Child-Pugh class C (severe) hepatic impairment [see Warnings and Precautions (5.1)] .
Metformin
No pharmacokinetic trials of metformin HCl tablets have been conducted in patients with hepatic insufficiency [see Warnings and Precautions (5.1)] .
Pharmacokinetic Effects of Age, Body Mass Index (BMI)/Weight, Gender and Race
Canagliflozin
Based on the population PK analysis with data collected from 1,526 subjects, age, body mass index (BMI)/weight, gender, and race do not have a clinically meaningful effect on the pharmacokinetics of canagliflozin [see Use in Specific Populations (8.5)] .
Metformin
Metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 2 diabetes when analyzed according to gender.
No trials of metformin pharmacokinetic parameters according to race have been performed.
Canagliflozin
Age had no clinically meaningful effect on the pharmacokinetics of canagliflozin based on a population pharmacokinetic analysis [see Adverse Reactions (6.1)and Use in Specific Populations (8.5)] .
Metformin
Limited data from controlled pharmacokinetic trials of metformin HCl tablets in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged, and C maxis increased, compared with healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function [see Warnings and Precautions (5.1, 5.4)and Use in Specific Populations (8.5)] .
Drug Interaction Studies
INVOKAMET and INVOKAMET XR
Pharmacokinetic drug interaction trials with INVOKAMET or INVOKAMET XR have not been performed; however, such trials have been conducted with the individual components canagliflozin and metformin HCl.
Co-administration of multiple doses of canagliflozin (300 mg) and metformin HCl (2,000 mg) given once daily did not meaningfully alter the pharmacokinetics of either canagliflozin or metformin in healthy subjects.
Canagliflozin
In VitroAssessment of Drug Interactions
Canagliflozin did not induce CYP450 enzyme expression (3A4, 2C9, 2C19, 2B6, and 1A2) in cultured human hepatocytes. Canagliflozin did not inhibit the CYP450 isoenzymes (1A2, 2A6, 2C19, 2D6, or 2E1) and weakly inhibited CYP2B6, CYP2C8, CYP2C9, and CYP3A4 based on in vitrostudies with human hepatic microsomes. Canagliflozin is a weak inhibitor of P-gp.
Canagliflozin is also a substrate of drug transporters P-glycoprotein (P-gp) and MRP2.
In VivoAssessment of Drug Interactions
Co-Administered Drug | Dose of Co-Administered Drug Single dose unless otherwise noted | Dose of Canagliflozin | Geometric Mean Ratio
(Ratio With/Without Co-Administered Drug) No Effect = 1.0 |
|
---|---|---|---|---|
AUC
AUC
inf for drugs given as a single dose and AUC
24h for drugs given as multiple doses
(90% CI) |
C
max
(90% CI) |
|||
QD = once daily; BID = twice daily | ||||
See Drug Interactions (7) for the clinical relevance of the following: | ||||
Rifampin | 600 mg QD for 8 days | 300 mg | 0.49
(0.44; 0.54) |
0.72
(0.61; 0.84) |
No dose adjustments of canagliflozin required for the following: | ||||
Cyclosporine | 400 mg | 300 mg QD for 8 days | 1.23
(1.19; 1.27) |
1.01
(0.91; 1.11) |
Ethinyl estradiol and levonorgestrel | 0.03 mg ethinyl estradiol and 0.15 mg levonorgestrel | 200 mg QD for 6 days | 0.91
(0.88; 0.94) |
0.92
(0.84; 0.99) |
Hydrochlorothiazide | 25 mg QD for 35 days | 300 mg QD for 7 days | 1.12
(1.08; 1.17) |
1.15
(1.06; 1.25) |
Metformin HCl | 2,000 mg | 300 mg QD for 8 days | 1.10
(1.05; 1.15) |
1.05
(0.96; 1.16) |
Probenecid | 500 mg BID for 3 days | 300 mg QD for 17 days | 1.21
(1.16; 1.25) |
1.13
(1.00; 1.28) |
Co-Administered Drug | Dose of Co-Administered Drug Single dose unless otherwise noted | Dose of Canagliflozin | Geometric Mean Ratio
(Ratio With/Without Co-Administered Drug) No Effect = 1.0 |
||
---|---|---|---|---|---|
AUC
AUC
inf for drugs given as a single dose and AUC
24h for drugs given as multiple doses
(90% CI) |
C
max
(90% CI) |
||||
QD = once daily; BID = twice daily; INR = International Normalized Ratio | |||||
See Drug Interactions (7) for the clinical relevance of the following: | |||||
Digoxin | 0.5 mg QD first day followed by 0.25 mg QD for 6 days | 300 mg QD for 7 days | Digoxin | 1.20
(1.12; 1.28) |
1.36
(1.21; 1.53) |
No dose adjustments of co-administered drug required for the following: | |||||
Acetaminophen | 1,000 mg | 300 mg BID for 25 days | Acetaminophen | 1.06
AUC
0–12h
(0.98; 1.14) |
1.00
(0.92; 1.09) |
Ethinyl estradiol and levonorgestrel | 0.03 mg ethinyl estradiol and 0.15 mg levonorgestrel | 200 mg QD for 6 days | ethinyl estradiol | 1.07
(0.99; 1.15) |
1.22
(1.10; 1.35) |
Levonorgestrel | 1.06
(1.00; 1.13) |
1.22
(1.11; 1.35) |
|||
Glyburide | 1.25 mg | 200 mg QD for 6 days | Glyburide | 1.02
(0.98; 1.07) |
0.93
(0.85; 1.01) |
3-cis-hydroxy-glyburide | 1.01
(0.96; 1.07) |
0.99
(0.91; 1.08) |
|||
4-trans-hydroxy-glyburide | 1.03
(0.97; 1.09) |
0.96
(0.88; 1.04) |
|||