Invokamet

Medications can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of Invokamet, there are no specific foods that you must exclude from your diet when receiving this medication.

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

Invokamet falls into category C. No studies have been done in animals, and no well-controlled studies have been done in pregnant women. Invokamet should be given to a pregnant woman only if clearly needed.

Tell your doctor if you are breastfeeding or plan to breastfeed.

Metformin has been detected in human breast milk, but canagliflozin is not known if it crosses into human breast milk. Because of the possibility for adverse reactions in nursing infants from Invokamet, a choice should be made whether to stop nursing or to stop use of this medication. The importance of the drug to the mother should be considered.

You should not use this medicine if you have moderate to severe kidney disease, diabetic ketoacidosis, or if you are on dialysis.

This medicine may cause a serious condition called lactic acidosis. Get emergency medical help if you have: muscle pain or weakness, numb or cold feeling in your arms and legs, trouble breathing, stomach pain, nausea with vomiting, slow or uneven heart rate, dizziness, or feeling very weak or tired.

• Store in the original container at room temperature.
• Store in a dry place. Do not store in a bathroom.
• If stored outside of the original container, throw away any part not used after 30 days.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

Lactic Acidosis

There have been post-marketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate:pyruvate ratio; metformin plasma levels generally >5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk.

If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of Invokamet. In Invokamet-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin hydrochloride is dialyzable, with a clearance of up to 170 mL/minute under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery.

Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue Invokamet and report these symptoms to their healthcare provider.

For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below:

Renal Impairment: The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patient's renal function include [see Dosage and Administration (2.2), Clinical Pharmacology (12.3)].

• Before initiating Invokamet, obtain an estimated glomerular filtration rate (eGFR).
• Invokamet is contraindicated in patients with an eGFR less than 45 mL/minute/1.73 m2 [see Contraindications (4)].
• Obtain an eGFR at least annually in all patients taking Invokamet. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.

Drug Interactions: The concomitant use of Invokamet with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation (e.g. cationic drugs) [see Drug Interactions (7)]. Therefore, consider more frequent monitoring of patients.

Age 65 or Greater: The risk of metformin-associated lactic acidosis increases with the patient's age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients [see Use in Specific Populations (8.5)].

Radiological Studies with Contrast: Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop Invokamet at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 45 and 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 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 should be temporarily discontinued while patients have restricted food and fluid intake.

Hypoxic States: Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause pre-renal azotemia. When such events occur, discontinue Invokamet.

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.

Hepatic Impairment: Patients with hepatic impairment have developed metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of Invokamet 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, 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. The amputation data for CANVAS and CANVAS-R are shown in Tables 2 and 3, respectively [see Adverse Reactions (6.1)].

Amputations of the toe and midfoot (99 out of 140 patients with amputations receiving canagliflozin in the two trials) were the most frequent; however, amputations involving the leg, below and above the knee, were also observed (41 out of 140 patients with amputations receiving canagliflozin in the two trials). Some patients had multiple amputations, some involving both lower limbs.

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

Before initiating Invokamet, consider factors in the patient history that may predispose to the need for amputations, such as a history of prior amputation, peripheral vascular disease, neuropathy and diabetic foot ulcers. Counsel patients about the importance of routine preventative foot care. Monitor patients receiving Invokamet for signs and symptoms of infection (including osteomyelitis), new pain or tenderness, sores or ulcers involving the lower limbs, and discontinue Invokamet if these complications occur.

Hypotension

Canagliflozin causes intravascular volume contraction. Symptomatic hypotension can occur after initiating Invokamet [see Adverse Reactions (6.1)] particularly in patients with eGFR less than 60 mL/min/1.73 m2, elderly patients, patients on either diuretics or medications that interfere with the renin-angiotensin-aldosterone system (e.g., angiotensin-converting-enzyme [ACE] inhibitors, angiotensin receptor blockers [ARBs]), or patients with low systolic blood pressure. Before initiating Invokamet in patients with one or more 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 postmarketing surveillance in patients with type 1 and type 2 diabetes mellitus receiving sodium glucose co-transporter-2 (SGLT2) inhibitors, including canagliflozin. Fatal cases of ketoacidosis have been reported in patients taking canagliflozin. Invokamet is not indicated for the treatment of patients with type 1 diabetes mellitus [see Indications and Usage (1)].

Patients treated with Invokamet who present with signs and symptoms consistent with severe metabolic acidosis should be assessed for ketoacidosis regardless of presenting blood glucose levels, as ketoacidosis associated with Invokamet may be present even if blood glucose levels are less than 250 mg/dL. If ketoacidosis is suspected, Invokamet should be discontinued, patient should be evaluated, and prompt treatment should be instituted. Treatment of ketoacidosis may require insulin, fluid and carbohydrate replacement.

In many of the postmarketing reports, and particularly in patients with type 1 diabetes, the presence of ketoacidosis was not immediately recognized and institution of treatment was delayed because presenting blood glucose levels were below those typically expected for diabetic ketoacidosis (often less than 250 mg/dL). Signs and symptoms at presentation were consistent with dehydration and severe metabolic acidosis and included nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. In some but not all cases, factors predisposing to ketoacidosis such as insulin dose reduction, acute febrile illness, reduced caloric intake due to illness or surgery, pancreatic disorders suggesting insulin deficiency (e.g., type 1 diabetes, history of pancreatitis or pancreatic surgery), and alcohol abuse were identified.

Before initiating Invokamet consider factors in the patient history that may predispose to ketoacidosis including pancreatic insulin deficiency from any cause, caloric restriction, and alcohol abuse. In patients treated with Invokamet consider monitoring for ketoacidosis and temporarily discontinuing Invokamet in clinical situations known to predispose to ketoacidosis (e.g., prolonged fasting due to acute illness or surgery).

Acute Kidney Injury and Impairment in Renal Function

Canagliflozin causes intravascular volume contraction [see Warnings and Precautions (5.3)] and can cause renal impairment [see Adverse Reactions (6.1)]. There have been postmarketing reports of acute kidney injury, some requiring hospitalization and dialysis, in patients receiving canagliflozin; some reports involved patients younger than 65 years of age.

Before initiating Invokamet, consider factors that may predispose patients to acute kidney injury including hypovolemia, chronic renal insufficiency, congestive heart failure, and concomitant medications (diuretics, ACE inhibitors, ARBs, NSAIDs). Consider temporarily discontinuing Invokamet in any setting of reduced oral intake (such as acute illness or fasting) or fluid losses (such as gastrointestinal illness or excessive heat exposure); monitor patients for signs and symptoms of acute kidney injury. If acute kidney injury occurs, discontinue Invokamet 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 initiating Invokamet [see Adverse Reactions (6.1)]. Renal function should be evaluated prior to initiation of Invokamet and monitored periodically thereafter. Dosage adjustment and more frequent renal function monitoring are recommended in patients with an eGFR below 60 mL/min/1.73 m2. Invokamet is contraindicated in patients with an eGFR below 45 mL/min/1.73 m2 [see Dosage and Administration (2.2), Contraindications (4), Warnings and Precautions (5.1) and Use in Specific Populations (8.6)].

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 [see Dosage and Administration (2.2) and Adverse Reactions (6.1)].

Monitor serum potassium levels periodically after initiating Invokamet 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 of urinary tract infections and treat promptly, if indicated [see Adverse Reactions (6)].

Hypoglycemia with Concomitant Use of Sulfonylurea or Insulin

Canagliflozin

Insulin and insulin secretagogues are known to cause hypoglycemia. Canagliflozin can increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue [see Adverse Reactions (6.1)]. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with Invokamet.

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 during concomitant use with other glucose-lowering agents (such as sulfonylureas and 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 to minimize the risk of hypoglycemia in these patients.

Genital Mycotic Infections

Canagliflozin increases the risk of genital mycotic infections. Patients with a history of genital mycotic infections and uncircumcised males were more likely to develop genital mycotic infections [see Adverse Reactions (6.1)]. Monitor and treat appropriately.

Hypersensitivity Reactions

Hypersensitivity reactions, including angioedema and anaphylaxis, have been reported with canagliflozin. These reactions generally occurred within hours to days after initiating canagliflozin. If hypersensitivity reactions occur, discontinue use of Invokamet; treat and monitor until signs and symptoms resolve [see Contraindications (4) and Adverse Reactions (6.1, 6.2)].

Bone Fracture

An 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 [see Adverse Reactions (6.1)].

Vitamin B12 Levels

In controlled, 29-week 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. Such decreases, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, is, however, very rarely associated with anemia or neurologic manifestations due to the short duration (less than 1 year) of the clinical trials. This risk may be more relevant to patients receiving long-term treatment with metformin and adverse hematologic and neurologic reactions have been reported postmarketing. 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 and investigate and treat if abnormalities occur. Patients with inadequate vitamin B12 or calcium intake or absorption may be predisposed to developing subnormal vitamin B12 levels, and routine serum vitamin B12 measurement at 2- to 3-year intervals is recommended in these patients.

Increases in Low-Density Lipoprotein (LDL-C)

Dose-related increases in LDL-C occur with canagliflozin [see Adverse Reactions (6.1)]. Monitor LDL-C and treat if appropriate after initiating Invokamet.

Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Invokamet [see Adverse Reactions (6.1)].

Pregnancy

Risk Summary

Based on animal data showing adverse renal effects, Invokamet is not recommended during the second and third trimesters of pregnancy.

Limited data with Invokamet or canagliflozin in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. Published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage risk [see Data]. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy [see Clinical Considerations].

In animal studies, adverse renal pelvic and tubule dilatations that were not reversible were observed in rats when canagliflozin was administered at an exposure 0.5-times the 300 mg clinical dose, based on AUC during a period of renal development corresponding to the late second and third trimesters of human pregnancy. No adverse developmental effects were observed when metformin was administered to pregnant Sprague Dawley rats and rabbits during the period of organogenesis at doses up to 2- and 6-times, respectively, a 2000 mg clinical dose, based on body surface area [see Data].

The estimated background risk of major birth defects is 6–10% in women with pre-gestational diabetes with an HbA1C >7 and has been reported to be as high as 20–25% in women with a HbA1C >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, stillbirth and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity.

Data

Human Data

Published data from post-marketing studies have not reported a clear association with metformin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin was used during pregnancy. However, these studies cannot definitely establish the absence of any metformin-associated risk because of methodological limitations, including small sample size and inconsistent comparator groups.

Animal Data

Canagliflozin

Canagliflozin dosed directly to juvenile rats from postnatal day (PND) 21 until PND 90 at doses of 4, 20, 65, or 100 mg/kg increased kidney weights and dose dependently increased the incidence and severity of renal pelvic and tubular dilatation at all doses tested. Exposure at the lowest dose was greater than or equal to 0.5-times the 300 mg clinical dose, based on AUC. These outcomes occurred with drug exposure during periods of renal development in rats that correspond to the late second and third trimester of human renal development. The renal pelvic dilatations observed in juvenile animals did not fully reverse within a 1 month recovery period.

In embryo-fetal development studies in rats and rabbits, canagliflozin was administered for intervals coinciding with the first trimester period of organogenesis in humans. No developmental toxicities independent of maternal toxicity were observed when canagliflozin was administered at doses up to 100 mg/kg in pregnant rats and 160 mg/kg in pregnant rabbits during embryonic organogenesis or during a study in which maternal rats were dosed from gestation day (GD) 6 through PND 21, yielding exposures up to approximately 19-times the 300 mg clinical dose, based on AUC.

Metformin Hydrochloride

Metformin hydrochloride did not cause adverse developmental effects when administered to pregnant Sprague Dawley rats and rabbits up to 600 mg/kg/day during the period of organogenesis. This represents an exposure of about 2- and 6-times a 2000 mg clinical dose based on body surface area (mg/m2) for rats and rabbits, respectively.

Canagliflozin and Metformin

No adverse developmental effects were observed when canagliflozin and metformin were co-administered to pregnant rats during the period of organogenesis at exposures up to 11 and 13 times, respectively, the 300 mg and 2000 mg clinical doses of canagliflozin and metformin based on AUC.

Lactation

Risk Summary

There is no information regarding the presence of Invokamet or canagliflozin in human milk, the effects on the breastfed infant, or the effects on milk production. Limited published studies report that metformin is present in human milk [see Data]. However, there is insufficient information on the effects of metformin on the breastfed infant and no available information on the effects of metformin on milk production. Canagliflozin is present in the milk of lactating rats [see Data]. Since human kidney maturation occurs in utero and during the first 2 years of life when lactational exposure may occur, there may be risk to the developing human kidney.

Because of the potential for serious adverse reactions in a breastfed infant, advise women that use of Invokamet is not recommended while breastfeeding.

Data

Human Data

Published clinical lactation studies report that metformin is present in human milk which resulted in infant doses approximately 0.11% to 1% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 0.13 and 1. However, the studies were not designed to definitely establish the risk of use of metformin during lactation because of small sample size and limited adverse event data collected in infants.

Animal Data

Radiolabeled canagliflozin administered to lactating rats on day 13 post-partum was present at a milk/plasma ratio of 1.40, indicating that canagliflozin and its metabolites are transferred into milk at a concentration comparable to that in plasma. Juvenile rats directly exposed to canagliflozin showed a risk to the developing kidney (renal pelvic and tubular dilatations) during maturation.

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 in pediatric patients under 18 years of age have not been established.

Geriatric Use

Invokamet

Because renal function abnormalities can occur after initiating canagliflozin, metformin is substantially excreted by the kidney, and aging can be associated with reduced renal function, monitor renal function more frequently after initiating Invokamet in the elderly and then adjust dose based on renal function [see Dosage and Administration (2.2) and Warnings and Precautions (5.1, 5.5)].

Canagliflozin

Two thousand thirty-four (2034) patients 65 years and older, and 345 patients 75 years and older were exposed to canagliflozin in nine clinical studies of canagliflozin. Of these patients, 1334 patients 65 years and older and 181 patients 75 years and older were exposed to the combination of canagliflozin and metformin [see Clinical Studies (14)]. Patients 65 years and older had a higher incidence of adverse reactions related to reduced intravascular volume with canagliflozin (such as hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration), particularly with the 300 mg daily dose, compared to younger patients; a more prominent increase in the incidence was seen in patients who were 75 years and older [see Dosage and Administration (2.1) and Adverse Reactions (6.1)]. Smaller reductions in HbA1C with canagliflozin relative to placebo were seen in older (65 years and older; -0.61% with canagliflozin 100 mg and -0.74% with canagliflozin 300 mg relative to placebo) compared to younger patients (-0.72% with canagliflozin 100 mg and -0.87% with canagliflozin 300 mg relative to placebo).

Metformin

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 [see Contraindications (4), Warnings and Precautions (5.5), and Clinical Pharmacology (12.3)].

Renal Impairment

Canagliflozin

The efficacy and safety of canagliflozin were evaluated in a study that included patients with moderate renal impairment (eGFR 30 to less than 50 mL/min/1.73 m2). These patients had less overall glycemic efficacy and had 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 greater than or equal to 60 mL/min/1.73 m2). Dose-related, transient mean increases in serum potassium were observed early after initiation of canagliflozin (i.e., within 3 weeks) in this trial. Increases in serum potassium of greater than 5.4 mEq/L and 15% above baseline occurred in 16.1%, 12.4%, and 27.0% of patients treated with placebo, canagliflozin 100 mg, and canagliflozin 300 mg, respectively. Severe elevations (greater than or equal to 6.5 mEq/L) occurred in 1.1%, 2.2%, and 2.2% of patients treated with placebo, canagliflozin 100 mg, and canagliflozin 300 mg, respectively [see Dosage and Administration (2.2), Contraindications (4), Warnings and Precautions (5.1, 5.4, 5.5), and Adverse Reactions (6.1)].

The efficacy and safety of canagliflozin have not been established in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m2), with ESRD, or receiving dialysis. Canagliflozin is not expected to be effective in these patient populations [see Contraindications (4) and Clinical Pharmacology (12.3)].

Hepatic Impairment

Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. Invokamet is not recommended in patients with hepatic impairment. [see Warnings and Precautions (5.1)]

In the event of an overdose with Invokamet, contact the Poison Control Center. Employ the usual supportive measures (e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive treatment) as dictated by the patient's clinical status. Canagliflozin was negligibly removed during a 4-hour hemodialysis session. Canagliflozin is not expected to be dialyzable by peritoneal dialysis. Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful partly for removal of accumulated metformin from patients in whom Invokamet overdosage is suspected.

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 greater than 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 [see Warnings and Precautions (5.1)].

NDC 50458-540-60
60 tablets

Invokamet®
(canagliflozin and
metformin HCl)
Tablets 50 mg/500 mg

Dispense with Medication Guide

Store and Dispense in the original container.
May be stored in a pill box for up to 30 days.

Rx only
janssen

Avoid drinking alcohol. It lowers blood sugar and may increase your risk of lactic acidosis while taking Invokamet.

Get emergency medical help if you have signs of an allergic reaction to Invokamet: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Early symptoms of lactic acidosis may get worse over time and this condition can be fatal. Get emergency medical help if you have even mild symptoms: muscle pain or weakness, numb or cold feeling in your arms and legs, trouble breathing, stomach pain, nausea with vomiting, slow or uneven heart rate, dizziness, or feeling very weak or tired.

Call your doctor at once if you have:

• new pain, tenderness, sores, ulcers, or infections in your legs or feet;

• a light-headed feeling, like you might pass out;

• high potassium - slow heart rate, weak pulse, muscle weakness, tingly feeling;

• ketoacidosis (too much acid in the blood) - nausea, vomiting, stomach pain, confusion, unusual drowsiness, or trouble breathing;

• signs of a kidney problem - little or no urination, painful or difficult urination, swelling in your feet or ankles, feeling tired or short of breath;

• signs of a bladder infection - pain or burning when you urinate, urine that looks cloudy, pain in pelvis or back; or

• signs of a genital infection (penis or vagina) - pain, burning, itching, rash, redness, odor, or discharge.

You may be more likely to have bone fractures (even after only a minor impact trauma) while you are taking medicine that contains canagliflozin. Talk with your doctor about how to avoid the risk of fractures.

Older adults may be more likely to have kidney problems while taking this medicine.

Common Invokamet side effects may include:

• urinating more than usual;

• headache, weakness;

• gas, stomach pain, indigestion;

• nausea, vomiting; or

• diarrhea.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.