WARNING: LACTIC ACIDOSIS AND LOWER-LIMB AMPUTATION
- Postmarketing 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/L); anion gap acidosis (without evidence of ketonuria or ketonemia); an increased lactate:pyruvate ratio; and metformin plasma levels generally >5 mcg/mL.
- Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (eg, carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (eg, acute congestive heart failure), 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.
- If metformin-associated lactic acidosis is suspected, immediately discontinue INVOKAMET®/ INVOKAMET® XR and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.
Risk of Lower-Limb Amputation
- An approximately 2-fold increased risk of lower-limb amputations associated with canagliflozin, a component of INVOKAMET®/INVOKAMET® XR, was observed in CANVAS and CANVAS-R, two large, randomized, placebo-controlled trials in patients with type 2 diabetes who had established cardiovascular disease (CVD) or were at risk for CVD.
- Amputations of the toe and midfoot were most frequent; however, amputations involving the leg were also observed. Some patients had multiple amputations, some involving both limbs.
- Before initiating, consider factors that may increase the risk of amputation, such as a history of prior amputation, peripheral vascular disease, neuropathy, and diabetic foot ulcers.
Monitor patients receiving INVOKAMET®/INVOKAMET® XR for infection, new pain or tenderness, sores, or ulcers involving the lower limbs, and discontinue if these complications occur.
- Moderate to severe renal impairment (eGFR below 45 mL/min/1.73 m2), end stage renal disease (ESRD), or patients on dialysis
- Acute or chronic metabolic acidosis, including diabetic ketoacidosis
- History of a serious hypersensitivity reaction to canagliflozin or metformin, such as anaphylaxis or angioedema
WARNINGS and PRECAUTIONS
Lactic Acidosis: Postmarketing cases of metformin-associated lactic acidosis, including fatal cases, were reported. 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/L), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate:pyruvate ratio; and 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. In INVOKAMET®/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. Hemodialysis has often resulted in reversal of symptoms and recovery.
Educate patients and their families about the symptoms of lactic acidosis and if symptoms occur instruct them to discontinue INVOKAMET®/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: 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. Obtain an eGFR before initiation and at least annually thereafter, and more frequently in patients at increased risk of renal impairment.
Drug Interactions: The concomitant use of INVOKAMET®/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 (eg, cationic drugs). Consider more frequent monitoring of patients.
Age 65 or Greater: The risk of metformin-associated lactic acidosis increases with the patient’s age due to a greater likelihood of hepatic, renal, or cardiac impairment. Assess renal function more frequently in elderly patients.
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®/INVOKAMET® XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR of 45 to 60 mL/min/1.73 m2; 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®/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®/INVOKAMET® XR should be temporarily discontinued while patients have restricted food and fluid intake.
Hypoxic States: Several postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure. 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®/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®/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. Avoid use of INVOKAMET®/INVOKAMET® XR in patients with clinical or laboratory evidence of hepatic disease.
Lower-Limb Amputation: An approximately 2-fold increased risk of lower-limb amputations associated with canagliflozin, a component of INVOKAMET®/INVOKAMET® XR, was observed in CANVAS and CANVAS-R, two large, randomized, placebo-controlled trials evaluating patients with type 2 diabetes who had either established cardiovascular disease or were at risk for cardiovascular disease. In CANVAS, canagliflozin-treated patients and placebo-treated patients had 5.9 and 2.8 amputations per 1000 patients per year, respectively. In CANVAS-R, canagliflozin-treated patients and placebo-treated patients had 7.5 and 4.2 amputations per 1000 patients per year, respectively. The risk of lower-limb amputations was observed at both the 100-mg and 300-mg once-daily dosage regimens.
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.
Before initiating, 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 for signs and symptoms of infection (including osteomyelitis), new pain or tenderness, sores, or ulcers involving the lower limbs, and discontinue if these complications occur.
- Hypotension: Canagliflozin causes intravascular volume contraction. Symptomatic hypotension can occur after initiating INVOKAMET®/INVOKAMET® XR, particularly in patients with an eGFR <60 mL/min/1.73 m2, elderly patients, patients on either diuretics or medications that interfere with the renin-angiotensin-aldosterone system, or patients with low systolic blood pressure. Before initiating INVOKAMET®/INVOKAMET® XR in patients with ≥1 of these characteristics who were not already on canagliflozin, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy.
- Ketoacidosis: Reports of ketoacidosis, a serious life-threatening condition requiring urgent hospitalization, have been identified in patients with type 1 and 2 diabetes mellitus receiving SGLT2 inhibitors, including canagliflozin. Fatal cases of ketoacidosis have been reported in patients taking canagliflozin. Before initiating INVOKAMET®/INVOKAMET® XR, consider factors in patient history that may predispose to ketoacidosis, including pancreatic insulin deficiency, caloric restriction disorders, and alcohol abuse. In patients treated with INVOKAMET®/INVOKAMET® XR, consider monitoring for ketoacidosis and temporarily discontinuing in clinical situations known to predispose to ketoacidosis (eg, prolonged fasting due to acute illness or surgery).
Acute Kidney Injury and Impairment in Renal Function: Canagliflozin causes intravascular volume contraction and can cause renal impairment. Postmarketing reports of acute kidney injury, some requiring hospitalization and dialysis, were reported; some reports involved patients younger than 65 years of age. Before initiation, consider factors that may predispose patients to acute kidney injury including hypovolemia, chronic renal insufficiency, congestive heart failure, and concomitant medications. Consider temporarily discontinuing INVOKAMET®/INVOKAMET® XR in any setting of reduced oral intake or fluid losses; monitor patients for signs and symptoms of acute kidney injury. If acute kidney injury occurs, discontinue promptly and institute treatment.
Canagliflozin increases serum creatinine and decreases eGFR. Patients with hypovolemia may be more susceptible to these changes. Renal function abnormalities can occur after initiation. Renal function should be evaluated prior to initiation and periodically thereafter. Dose adjustment and more frequent renal function monitoring are recommended in patients with an eGFR <60 mL/min/1.73 m2.
Hyperkalemia: Canagliflozin can lead to hyperkalemia. Patients with moderate renal impairment who are taking medications that interfere with potassium excretion, such as potassium-sparing diuretics, or medications that interfere with the renin-angiotensin-aldosterone system are at an increased risk of developing hyperkalemia.
Monitor serum potassium levels periodically after initiating INVOKAMET®/INVOKAMET® XR in patients with impaired renal function and in patients predisposed to hyperkalemia due to medications or other medical conditions.
- Urosepsis and Pyelonephritis: There have been postmarketing reports of serious urinary tract infections, including urosepsis and pyelonephritis, requiring hospitalization in patients receiving SGLT2 inhibitors, including canagliflozin. Treatment with SGLT2 inhibitors increases the risk for urinary tract infections. Evaluate patients for signs and symptoms and treat promptly.
Use With Medications Known to Cause Hypoglycemia
Canagliflozin can increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue. A lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with INVOKAMET®/INVOKAMET® XR.
Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or when used concomitantly with other glucose-lowering agents (such as sulfonylureas or insulin) or ethanol. Elderly, debilitated, or malnourished patients, and those with adrenal or pituitary insufficiency or alcohol intoxication, are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly and in people who are taking beta-adrenergic blocking drugs. Monitor for a need to lower the dose of INVOKAMET®/INVOKAMET® XR to minimize the risk of hypoglycemia in these patients.
- Genital Mycotic Infections: Canagliflozin increases risk of genital mycotic infections. Patients with a history of these infections and uncircumcised males were more likely to develop these infections. Monitor and treat appropriately.
- Hypersensitivity Reactions: Hypersensitivity reactions, including angioedema and anaphylaxis, were reported with canagliflozin; these reactions generally occurred within hours to days after initiation. If reactions occur, discontinue INVOKAMET®/INVOKAMET® XR; treat and monitor until signs and symptoms resolve.
- Bone Fracture: Increased risk of bone fracture, occurring as early as 12 weeks after treatment initiation, was observed in patients using canagliflozin. Consider factors that contribute to fracture risk prior to initiating INVOKAMET®/INVOKAMET® XR.
- Vitamin B12 Levels: In clinical trials of metformin, a decrease to subnormal levels of previously normal serum vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of metformin-treated patients. The decrease in vitamin B12 levels appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation. Measure hematologic parameters on an annual basis in patients on INVOKAMET®/INVOKAMET® XR and investigate and treat if abnormalities occur. Patients with inadequate vitamin B12 or calcium intake or absorption may be predisposed to develop subnormal vitamin B12 levels.
- Increases in Low-Density Lipoprotein (LDL-C): Dose-related increases in LDL-C can occur with canagliflozin. Monitor LDL-C and treat if appropriate after initiating INVOKAMET®/INVOKAMET® XR.
- Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with canagliflozin or metformin.
Drug Interactions With Metformin
Carbonic Anhydrase Inhibitors
Topiramate or other carbonic anhydrase inhibitors (eg, zonisamide, acetazolamide, or dichlorphenamide) frequently decrease serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs may induce metabolic acidosis. Use these drugs with caution in patients treated with metformin, as the risk of lactic acidosis may increase.
Drugs That Reduce Metformin Clearance
Drugs that are eliminated by renal tubular secretion (eg, cationic drugs such as cimetidine) may increase accumulation of metformin and risk for lactic acidosis.
Alcohol is known to potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake while receiving INVOKAMET®/INVOKAMET® XR.
Drugs Affecting Glycemic Control
Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid. When such drugs are administered to a patient receiving INVOKAMET®/INVOKAMET® XR, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from a patient receiving INVOKAMET®/INVOKAMET® XR, the patient should be observed closely for hypoglycemia.
Drug Interactions With Canagliflozin
UGT Enzyme Inducers
Rifampin: Rifampin lowered canagliflozin exposure, which may reduce the efficacy of INVOKAMET®/INVOKAMET® XR. If an inducer of UGT enzymes must be co-administered with INVOKAMET®/INVOKAMET® XR, consider increasing the total daily dose of canagliflozin to 300 mg if patients are currently tolerating a total daily dose of 100 mg canagliflozin, have an eGFR >60 mL/min/1.73 m2, and require additional glycemic control.
Canagliflozin increased digoxin exposure. Digoxin, as a cationic drug, also has the potential to compete with metformin for common renal tubular transport systems. Monitor patients taking INVOKAMET®/INVOKAMET® XR with concomitant digoxin for a need to adjust dose of either drug.
Drug/Laboratory Test Interference
Positive Urine Glucose Test
Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors as SGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose test results. Use alternative methods to monitor glycemic control.
Interference With 1,5-Anhydroglucitol (1,5-AG) Assay
Monitoring glycemic control with 1,5-AG assay is not recommended as measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control.
USE IN SPECIFIC POPULATIONS
- Pregnancy: Based on animal data showing adverse renal effects, INVOKAMET®/INVOKAMET® XR is not recommended during the second and third trimesters of pregnancy. A clear association of major birth defect or miscarriage risk with metformin or canagliflozin use during pregnancy has not been determined. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy.
- Nursing Mothers: 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. There is insufficient information on the effects of metformin on the breastfed infant and no available information on the effects on milk production. Because of the potential for serious adverse reactions in a breastfed infant, INVOKAMET®/INVOKAMET® XR is not recommended while breastfeeding.
- Females and Males of Reproductive Potential: Discuss the potential for unintended pregnancy with premenopausal women as therapy with metformin may result in ovulation in some anovulatory women.
- Pediatric Use: Safety and effectiveness of INVOKAMET®/INVOKAMET® XR in patients <18 years of age have not been established.
Geriatric Use: 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, frequently monitor renal function after initiating INVOKAMET®/INVOKAMET® XR in elderly patients and adjust dose based on renal function.
2034 patients ≥65 years and 345 patients ≥75 years were exposed to canagliflozin in 9 clinical studies. Patients ≥65 years had a higher incidence of adverse reactions related to reduced intravascular volume (eg, hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration), particularly with the 300-mg dose, compared to younger patients; more prominent increase in the incidence was seen in patients who were ≥75 years. Smaller reductions in HbA1c relative to placebo were seen in patients ≥65 years (-0.61% with canagliflozin 100 mg and -0.74% with canagliflozin 300 mg) compared to younger patients (-0.72% with canagliflozin 100 mg and -0.87% with canagliflozin 300 mg).
Controlled clinical studies of metformin 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 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.
- Renal Impairment: INVOKAMET®/INVOKAMET® XR should not be used in patients with severe renal impairment (eGFR <45 mL/min/1.73 m2), with end-stage renal disease, or receiving dialysis.
- Hepatic Impairment: Metformin use in patients with hepatic impairment has been associated with some cases of lactic acidosis. INVOKAMET®/INVOKAMET® XR is not recommended in patients with hepatic impairment.
In the event of an overdose with INVOKAMET®/INVOKAMET® XR, contact the Poison Control Center. Employ the usual supportive measures (eg, remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive treatment) as needed.
There were no reports of overdose during the clinical development program of canagliflozin.
Overdose of metformin hydrochloride has occurred, including ingestion of amounts >50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin hydrochloride has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases.
- The most common (≥5%) adverse reactions with canagliflozin were female genital mycotic infections, urinary tract infections, and increased urination.
- The most common adverse reactions due to initiation of metformin are diarrhea, nausea/vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache.