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Invokamet®
Invokamet® XR logo
Invokana®
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Important Safety Information For:
INVOKAMET® and INVOKAMET® XR Professional Indication Statement & ISI

INVOKANA® (canagliflozin) is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

INVOKANA® is not recommended in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

INVOKAMET® and INVOKAMET® XR are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both canagliflozin and metformin is appropriate.

INVOKAMET® and INVOKAMET® XR are not recommended in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

IMPORTANT SAFETY INFORMATION for INVOKAMET® and INVOKAMET® XR For INVOKAMET®

WARNING: LACTIC ACIDOSIS AND LOWER-LIMB AMPUTATION

Lactic Acidosis

  • 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.
     

CONTRAINDICATIONS

  • 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
    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.
    Metformin
    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

  • 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
    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.
    Digoxin
    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.
    Canagliflozin
    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).
    Metformin
    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.

OVERDOSAGE

  • 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.
    Canagliflozin
    There were no reports of overdose during the clinical development program of canagliflozin.
    Metformin
    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.

ADVERSE REACTIONS

  • 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.

Please see full Prescribing Informationincluding Boxed WARNINGS, and Medication Guide for INVOKAMET® XR.

Please see full Prescribing Informationincluding Boxed WARNINGS, and Medication Guide for INVOKAMET®.

Please see full Prescribing Information, including Boxed WARNING, and Medication Guide for INVOKANA®.

 

076193-170713

INVOKAMET® and INVOKAMET® XR Professional Indication Statement & ISI

INVOKANA® (canagliflozin) is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

INVOKANA® is not recommended in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

INVOKAMET® and INVOKAMET® XR are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both canagliflozin and metformin is appropriate.

INVOKAMET® and INVOKAMET® XR are not recommended in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

IMPORTANT SAFETY INFORMATION for INVOKAMET® and INVOKAMET® XR For INVOKAMET® XR

WARNING: LACTIC ACIDOSIS AND LOWER-LIMB AMPUTATION

Lactic Acidosis

  • 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.
     

CONTRAINDICATIONS

  • 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
    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.
    Metformin
    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

  • 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
    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.
    Digoxin
    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.
    Canagliflozin
    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).
    Metformin
    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.

OVERDOSAGE

  • 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.
    Canagliflozin
    There were no reports of overdose during the clinical development program of canagliflozin.
    Metformin
    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.

ADVERSE REACTIONS

  • 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.

Please see full Prescribing Informationincluding Boxed WARNINGS, and Medication Guide for INVOKAMET® XR.

Please see full Prescribing Informationincluding Boxed WARNINGS, and Medication Guide for INVOKAMET®.

Please see full Prescribing Information, including Boxed WARNING, and Medication Guide for INVOKANA®.

 

076193-170713

INDICATION AND USAGE

INVOKANA® (canagliflozin) is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

INVOKANA® is not recommended in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

Important Safety Information For INVOKANA®

IMPORTANT SAFETY INFORMATION

WARNING: LOWER-LIMB AMPUTATION

  • An approximately 2-fold increased risk of lower-limb amputations associated with INVOKANA® use 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 INVOKANA® for infection, new pain or tenderness, sores, or ulcers involving the lower limbs, and discontinue if these complications occur.


CONTRAINDICATIONS

  • History of a serious hypersensitivity reaction to INVOKANA®, such as anaphylaxis or angioedema
  • Severe renal impairment (eGFR <30 mL/min/1.73 m2), end-stage renal disease, or patients on dialysis

WARNINGS and PRECAUTIONS

  • Lower-Limb Amputation: An approximately 2-fold increased risk of lower-limb amputations associated with INVOKANA® use 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, INVOKANA®-treated patients and placebo-treated patients had 5.9 and 2.8 amputations per 1000 patients per year, respectively. In CANVAS-R, INVOKANA®-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 INVOKANA® in the two trials) were the most frequent; however, amputations involving the leg, below and above the knee, were also observed (41 out of 140 patients with amputations receiving INVOKANA® in the two trials). Some patients had multiple amputations, some involving both lower limbs.

    Lower-limb infections, gangrene, and diabetic foot ulcers were the most common precipitating medical events leading to the need for an amputation. The risk of amputation was highest in patients with a baseline history of prior amputation, peripheral vascular disease, and neuropathy.

    Before initiating, 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: INVOKANA® causes intravascular volume contraction. Symptomatic hypotension can occur after initiating INVOKANA®, particularly in patients with impaired renal function (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 in patients with ≥1 of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating.
  • 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 INVOKANA®. Fatal cases of ketoacidosis have been reported in patients taking INVOKANA®. Before initiating INVOKANA®, consider factors in patient history that may predispose to ketoacidosis, including pancreatic insulin deficiency, caloric restriction disorders, and alcohol abuse. In patients treated with INVOKANA®, 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: INVOKANA® 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 INVOKANA® 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.

    INVOKANA® 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: INVOKANA® can lead to hyperkalemia. Patients with moderate renal impairment who are taking medications that interfere with potassium excretion or medications that interfere with the renin-angiotensin-aldosterone system are more likely to develop hyperkalemia. Monitor serum potassium levels periodically 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 reports of serious urinary tract infections, including urosepsis and pyelonephritis, requiring hospitalization in patients receiving SGLT2 inhibitors, including INVOKANA®. Treatment with SGLT2 inhibitors increases this risk. Evaluate patients for signs and symptoms and treat promptly.
  • Hypoglycemia With Concomitant Use With Insulin and Insulin Secretagogues: INVOKANA® 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 INVOKANA®.
  • Genital Mycotic Infections: INVOKANA® increases risk of genital mycotic infections. Patients with 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 INVOKANA®; these reactions generally occurred within hours to days after initiation. If reactions occur, discontinue INVOKANA®, treat per standard of care, 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 INVOKANA®. Consider factors that contribute to fracture risk prior to initiating INVOKANA®.
  • Increases in Low-Density Lipoprotein (LDL-C): Dose-related increases in LDL-C can occur with INVOKANA®. Monitor LDL-C and treat per standard of care after initiating.
  • Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with INVOKANA®.

DRUG INTERACTIONS

  • UGT Enzyme Inducers: Rifampin: Co-administration of INVOKANA® with rifampin decreased INVOKANA® area under the curve (AUC) by 51% and therefore may decrease efficacy. If an inducer of UGT enzymes must be co-administered with INVOKANA®, consider increasing the dose to 300 mg once daily if patients are currently tolerating INVOKANA® 100 mg once daily, have an eGFR ≥60 mL/min/1.73 m2, and require additional glycemic control. Consider other antihyperglycemic therapy in patients with an eGFR <60 mL/min/1.73 m2 who require additional glycemic control.
  • Digoxin: There was an increase in the AUC and mean peak drug concentration of digoxin (20% and 36%, respectively) when co-administered with INVOKANA® 300 mg. Monitor appropriately.
  • 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, INVOKANA® is not recommended during the second and third trimesters of pregnancy. Limited data with INVOKANA® in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. There are risks to mother and fetus associated with poorly controlled diabetes in pregnancy.
  • Nursing Mothers: There is no information regarding the presence of INVOKANA® in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed infant, advise women that use of INVOKANA® is not recommended while breastfeeding.
  • Pediatric Use: Safety and effectiveness in patients <18 years of age have not been established.
  • Geriatric Use: 2034 patients ≥65 years and 345 patients ≥75 years were exposed to INVOKANA® 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 INVOKANA® 100 mg and -0.74% with INVOKANA® 300 mg) compared to younger patients (-0.72% with INVOKANA® 100 mg and -0.87% with INVOKANA® 300 mg).
  • Renal Impairment: Efficacy and safety were evaluated in a study that included patients with moderate renal impairment (eGFR 30 to <50 mL/min/1.73 m2). These patients had less overall glycemic efficacy and a higher occurrence of adverse reactions related to reduced intravascular volume, renal-related adverse reactions, and decreases in eGFR compared to patients with mild renal impairment or normal renal function (eGFR ≥60 mL/min/1.73 m2); patients treated with 300 mg were more likely to experience increases in potassium. INVOKANA® is not recommended in patients with severe renal impairment (eGFR <30 mL/min/1.73 m2), with end-stage renal disease, or receiving dialysis.
  • Hepatic Impairment: INVOKANA® has not been studied in patients with severe hepatic impairment and is not recommended in this population.

OVERDOSAGE

  • In the event of an overdose, contact the Poison Control Center and employ the usual supportive measures, eg, remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive treatment as needed.

ADVERSE REACTIONS

  • The most common adverse reactions associated with INVOKANA® (5% or greater incidence) were female genital mycotic infections, urinary tract infections, and increased urination.

Please see full Prescribing Information, including Boxed WARNING, and Medication Guide.

076189-170713

Indications

XARELTO® is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (AF).

There are limited data on the relative effectiveness of XARELTO® and warfarin in reducing the risk of stroke and systemic embolism when warfarin therapy is well controlled.

XARELTO® is indicated for the treatment of deep vein thrombosis (DVT). XARELTO® is indicated for the treatment of pulmonary embolism (PE). XARELTO® is indicated for the reduction in the risk of recurrence of DVT and of PE following initial 6 months treatment for DVT and/or PE.

XARELTO® is indicated for the prophylaxis of DVT, which may lead to PE in patients undergoing knee or hip replacement surgery.

Important Safety Information For XARELTO®

WARNING: (A) PREMATURE DISCONTINUATION OF XARELTO® INCREASES THE RISK OF THROMBOTIC EVENTS,
(B) SPINAL/EPIDURAL HEMATOMA

A. Premature discontinuation of XARELTO® increases the risk of thrombotic events

Premature discontinuation of any oral anticoagulant, including XARELTO®, increases the risk of thrombotic events. If anticoagulation with XARELTO® is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant.

B. Spinal/epidural hematoma

Epidural or spinal hematomas have occurred in patients treated with XARELTO® who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include:

  • Use of indwelling epidural catheters
  • Concomitant use of other drugs that affect hemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants, see Drug Interactions
  • A history of traumatic or repeated epidural or spinal punctures
  • A history of spinal deformity or spinal surgery
  • Optimal timing between the administration of XARELTO® and neuraxial procedures is not known

Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary.

Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis.

CONTRAINDICATIONS

  • Active pathological bleeding
  • Severe hypersensitivity reaction to XARELTO® (eg, anaphylactic reactions)

WARNINGS AND PRECAUTIONS

  • Increased Risk of Thrombotic Events After Premature Discontinuation: Premature discontinuation of any oral anticoagulant, including XARELTO®, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from XARELTO® to warfarin in clinical trials in atrial fibrillation patients. If XARELTO® is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant.
  • Risk of Bleeding: XARELTO® increases the risk of bleeding and can cause serious or fatal bleeding. Promptly evaluate any signs or symptoms of blood loss and consider the need for blood replacement. Discontinue XARELTO® in patients with active pathological hemorrhage.
    • A specific antidote for rivaroxaban is not available. Because of high plasma protein binding, rivaroxaban is not expected to be dialyzable.
    • Concomitant use of other drugs that impair hemostasis increases the risk of bleeding. These include aspirin, P2Y12 platelet inhibitors, other antithrombotic agents, fibrinolytic therapy, NSAIDs, selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs).
  • Spinal/Epidural Anesthesia or Puncture: When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulant agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma, which can result in long-term or permanent paralysis. To reduce the potential risk of bleeding associated with the concurrent use of rivaroxaban and epidural or spinal anesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of rivaroxaban. Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of rivaroxaban is low; however, the exact timing to reach a sufficiently low anticoagulant effect in each patient is not known. An indwelling epidural or intrathecal catheter should not be removed before at least 2 half-lives have elapsed (ie, 18 hours in young patients aged 20 to 45 years and 26 hours in elderly patients aged 60 to 76 years), after the last administration of XARELTO®. The next XARELTO® dose should not be administered earlier than 6 hours after the removal of the catheter. If traumatic puncture occurs, delay the administration of XARELTO® for 24 hours. Should the physician decide to administer anticoagulation in the context of epidural or spinal anesthesia/analgesia or lumbar puncture, monitor frequently to detect any signs or symptoms of neurological impairment, such as midline back pain, sensory and motor deficits (numbness, tingling, or weakness in lower limbs), or bowel and/or bladder dysfunction. Instruct patients to immediately report if they experience any of the above signs or symptoms. If signs or symptoms of spinal hematoma are suspected, initiate urgent diagnosis and treatment including consideration for spinal cord decompression even though such treatment may not prevent or reverse neurological sequelae.
  • Use in Patients With Renal Impairment:
    • Nonvalvular Atrial Fibrillation: Periodically assess renal function as clinically indicated (ie, more frequently in situations in which renal function may decline) and adjust therapy accordingly. Consider dose adjustment or discontinuation of XARELTO® in patients who develop acute renal failure while on XARELTO®.
    • Treatment of Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), and Reduction in the Risk of Recurrence of DVT and of PE: Avoid the use of XARELTO® in patients with CrCl <30 mL/min due to an expected increase in rivaroxaban exposure and pharmacodynamic effects in this patient population.
    • Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery: Avoid the use of XARELTO® in patients with CrCl <30 mL/min due to an expected increase in rivaroxaban exposure and pharmacodynamic effects in this patient population. Observe closely and promptly evaluate any signs or symptoms of blood loss in patients with CrCl 30 to 50 mL/min. Patients who develop acute renal failure while on XARELTO® should discontinue the treatment.
  • Use in Patients With Hepatic Impairment: No clinical data are available for patients with severe hepatic impairment. Avoid use of XARELTO® in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy, since drug exposure and bleeding risk may be increased.
  • Use With P-gp and Strong CYP3A4 Inhibitors or Inducers: Avoid concomitant use of XARELTO® with known combined P-gp and strong CYP3A4 inhibitors. Avoid concomitant use of XARELTO® with drugs that are known combined P-gp and strong CYP3A4 inducers.
  • Risk of Pregnancy-Related Hemorrhage: In pregnant women, XARELTO® should be used only if the potential benefit justifies the potential risk to the mother and fetus. XARELTO® dosing in pregnancy has not been studied. The anticoagulant effect of XARELTO® cannot be monitored with standard laboratory testing and is not readily reversed. Promptly evaluate any signs or symptoms suggesting blood loss (eg, a drop in hemoglobin and/or hematocrit, hypotension, or fetal distress).
  • Patients With Prosthetic Heart Valves: The safety and efficacy of XARELTO® have not been studied in patients with prosthetic heart valves. Therefore, use of XARELTO® is not recommended in these patients.
  • Acute PE in Hemodynamically Unstable Patients/Patients Who Require Thrombolysis or Pulmonary Embolectomy: Initiation of XARELTO® is not recommended acutely as an alternative to unfractionated heparin in patients with pulmonary embolism who present with hemodynamic instability or who may receive thrombolysis or pulmonary embolectomy.

DRUG INTERACTIONS

  • Combined P-gp and strong CYP3A4 inhibitors increase exposure to rivaroxaban and may increase the risk of bleeding.
  • Combined P-gp and strong CYP3A4 inducers decrease exposure to rivaroxaban and may increase the risk of thromboembolic events.
  • XARELTO® should not be used in patients with CrCl 15 to <80 mL/min who are receiving concomitant combined P-gp and moderate CYP3A4 inhibitors (eg, erythromycin) unless the potential benefit justifies the potential risk.
  • Coadministration of enoxaparin, warfarin, aspirin, clopidogrel, and chronic NSAID use may increase the risk of bleeding.
  • Avoid concurrent use of XARELTO® with other anticoagulants due to increased bleeding risk, unless benefit outweighs risk. Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with aspirin, other platelet aggregation inhibitors, or NSAIDs.

USE IN SPECIFIC POPULATIONS

  • Pregnancy Category C: XARELTO® should be used during pregnancy only if the potential benefit justifies the potential risk to mother and fetus. There are no adequate or well-controlled studies of XARELTO® in pregnant women, and dosing for pregnant women has not been established. Use XARELTO® with caution in pregnant patients because of the potential for pregnancy-related hemorrhage and/or emergent delivery with an anticoagulant that is not readily reversible. The anticoagulant effect of XARELTO® cannot be reliably monitored with standard laboratory testing.
  • Labor and Delivery: Safety and effectiveness of XARELTO® during labor and delivery have not been studied in clinical trials.
  • Nursing Mothers: It is not known if rivaroxaban is excreted in human milk.
  • Pediatric Use: Safety and effectiveness in pediatric patients have not been established.
  • Females of Reproductive Potential: Females of reproductive potential requiring anticoagulation should discuss pregnancy planning with their physician.

OVERDOSAGE

  • Discontinue XARELTO® and initiate appropriate therapy if bleeding complications associated with overdosage occur. A specific antidote for rivaroxaban is not available. The use of activated charcoal to reduce absorption in case of XARELTO® overdose may be considered. Due to the high plasma protein binding, rivaroxaban is not dialyzable.

ADVERSE REACTIONS IN CLINICAL STUDIES

  • The most common adverse reactions with XARELTO® were bleeding complications.

Please see full Prescribing Information, including Boxed WARNINGS.

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