Canagliflozin-Metformin

Canagliflozin-Metformin is a prescription medication used as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (T2DM) who are not adequately controlled on a regimen containing metformin or canagliflozin, or in patients who are already treated with both canagliflozin and metformin. Canagliflozin is also indicated to reduce the risk of end-stage renal disease (ESRD), doubling of serum creatinine, cardiovascular (CV) death, and hospitalization for heart failure in adults with T2DM and diabetic nephropathy with albuminuria greater than 300 mg/day.

• Canagliflozin-Metformin is available under the following different brand names: Invokamet, Invokamet-XR.

Common side effects of Canagliflozin-Metformin include:

• yeast infections (in both women and men)
• urinary tract infection (UTI)
• changes in urination (including an urgent need to urinate, more often, in larger amounts, or at night)
• dehydration
• kidney problems
• high potassium in the blood (hyperkalemia)
• increase in cholesterol
• increased thirst
• constipation
• nausea
• abdominal pain
• vaginal itching

Serious side effects of Canagliflozin-Metformin include:

• hives
• difficulty breathing
• swelling of the face, lips, tongue, or throat
• burning, itching, odor, discharge, pain, tenderness, redness, or swelling of the genital or rectal area
• fever
• feeling unwell
• unusual muscle pain
• stomach pain
• vomiting
• irregular heart rate
• dizziness
• feeling cold
• weakness
• tiredness
• new pain, tenderness, sores, ulcers, or infections in the legs or feet
• little or no urination
• lightheadedness
• nausea
• tingly feeling
• chest pain
• muscle weakness
• confusion
• unusual drowsiness
• pain or burning while urinating
• urine that looks cloudy
• pain in the pelvis or back

Rare side effects of Canagliflozin-Metformin include:

• lactic acidosis

Seek medical care or call 911 at once if you have the following serious side effects:

• Severe headache, confusion, slurred speech, arm or leg weakness, trouble walking, coordination loss, unsteady, very stiff muscles, high fever, profuse sweating, or tremors.
• Serious eye symptoms such as sudden vision loss, blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights.
• Serious heart symptoms include fast, irregular, or pounding heartbeats; fluttering in the chest; shortness of breath; sudden dizziness, lightheadedness, or passing out.

This is not a complete list of side effects and other serious side effects or health problems that may occur because of the use of this drug. Call your doctor for medical advice about serious side effects or adverse reactions. You may report side effects or health problems to FDA at 1-800-FDA-1088.

Adult dosage

Canagliflozin-Metformin

• Tablet
  • 50 mg/500 mg
  • 50 mg/1000 mg
  • 150 mg/500 mg
  • 150 mg/1000 mg
• Tablet, extended-release
  • 50 mg/500 mg
  • 50 mg/1000 mg
  • 150 mg/500 mg
  • 150 mg/1000 mg

Type 2 Diabetes Mellitus

Adult dosage

Dosage overview

• Gradually escalate the metformin dose to reduce gastrointestinal side effects while not exceeding a metformin total daily dose (TDD) of 2000 mg
• Adjust dose based on effectiveness and tolerability; not to exceed TDD of 300 mg/2000 mg
• Starting dose based on the current patient regimen
• Not treated with either canagliflozin or metformin
• Invokamet: 50 mg/500 mg orally two times a day
• Invokamet XR: 2 tablets (50 mg/500 mg) orally once a day

Patients on metformin

• Invokamet:1 tablet orally two times a day where the TDD contains canagliflozin 100 mg and the same, or nearest appropriate, daily dose of metformin
• Invokamet XR: 2 tablets orally once a day where the TDD contains canagliflozin 100 mg and the same, or nearest appropriate, daily dose of metformin

Patients on canagliflozin

• Invokamet: 1 tablet orally two times a day where the TDD contains the same daily dose of canagliflozin and metformin 1000 mg
• Invokamet XR: 2 tablets orally once a day where the TDD contains the same daily dose of canagliflozin and metformin 1000 mg

Patients on canagliflozin and metformin

• Invokamet: 1 tablet orally two times a day where the TDD contains the same daily dose of canagliflozin and the same, or nearest appropriate, daily dose of metformin
• Invokamet XR: 2 tablets orally once a day where the TDD contains the same daily dose of canagliflozin and the same, or nearest appropriate, daily dose of metformin

Patients requiring additional glycemic control

• For patients with eGFR more than 60 mL/min/1.73 m2
  • Invokamet: For patients tolerating canagliflozin 50 mg two times a day, increase canagliflozin dose to 150 mg two times a day, with gradual metformin dose escalation based on tolerability
  • Invokamet XR: For patients tolerating canagliflozin 100 mg once a day, increase the canagliflozin dose to 300 mg once a day, with gradual metformin dose escalation based on tolerability
• Patients on an evening dose of metformin extended-release
  • Skip the last evening dose before starting Canagliflozin-Metformin (regular or XR) the following morning

Dosage Considerations – Should be Given as Follows: 

• See “Dosages”

If your medical doctor is using this medicine to treat your pain, your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor, health care provider, or pharmacist first.

• Canagliflozin-Metformin has severe interactions with no other drugs
• Canagliflozin-Metformin has serious interactions with the following drugs:
  • contrast media (iodinated)
  • ethanol
  • ioversol
  • methylene blue
  • pacritinib
  • ranolazine
  • risdiplam
  • selegiline
  • selegiline transdermal
  • tafenoquine
  • tedizolid
  • tranylcypromine
  • trilaciclib
• Canagliflozin-Metformin has moderate interactions with at least 231 other drugs
• Canagliflozin-Metformin has minor interactions with at least 63 other drugs

This information does not contain all possible interactions or adverse effects. Visit the RxList Drug Interaction Checker for any drug interactions. Therefore, before using this product, tell your doctor or pharmacist about all the products you use. Keep a list of all your medications with you and share this information with your doctor and pharmacist. Check with your healthcare professional or doctor for additional medical advice, health questions, or concerns.

Contraindications

• Moderate renal impairment (eGFR less than 30 mL/min/1.73 m²), which may also result from conditions such as shock, acute myocardial infarction (MI), and septicemia; 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

Effects of drug abuse

• None

Short-Term Effects

• See “What Are Side Effects Associated with Using Canagliflozin-Metformin?”

Long-Term Effects

• See “What Are Side Effects Associated with Using Canagliflozin-Metformin?”

Cautions

• 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 therapy
• Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension, and renal impairment; therapy should be temporarily discontinued while patients have restricted food and fluid intake
• Before initiating therapy, obtain an estimated glomerular filtration rate (eGFR) and obtain an eGFR at least annually; assess more frequently in patients at increased risk for development of renal impairment
• Consider temporarily discontinuing in settings of reduced oral intake or fluid losses; if acute kidney injury occurs, discontinue and promptly treat; monitor renal function during therapy
• Hyperkalemia reported with canagliflozin; monitor potassium levels in patients with impaired renal function and patients predisposed to hyperkalemia
• Canagliflozin increases the risk for genital mycotic infections; treat if indicated
• Increases risk of urinary tract infections (UTIs), including life-threatening urosepsis and pyelonephritis that started as UTIs; evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated
• Metformin may lower vitamin B12 levels without manifestations; monitor hematologic parameters annually
• Increased risk of bone fracture, occurring as early as 12 weeks after treatment initiation, reported; consider factors that contribute to fracture risk before initiating therapy
• Hypersensitivity reactions, including angioedema and anaphylaxis, reported with canagliflozin; these reactions generally occurred within hours to days after initiating canagliflozin; if hypersensitivity reactions occur, discontinue therapy; treat and monitor until signs and symptoms resolve
• Several of the postmarketing cases of metformin-associated lactic acidosis occurred in settings 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 therapy
• Lower limb amputation
  • Increased risk of lower limb amputations associated with canagliflozin use was observed in 2 large, randomized, placebo-controlled trials (CANVAS AND CANVAS-R) 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 (eg, history of prior amputation, peripheral vascular disease, neuropathy, diabetic foot ulcers)
  • Monitor for infection, new pain or tenderness, and sores or ulcers involving the lower limbs; discontinue if these complications occur
  • Counsel patients about the importance of routine preventative foot care
• Ketoacidosis
  • The risk of ketoacidosis may be greater with higher doses; fatal cases of ketoacidosis have been reported in patients taking canagliflozin; therapy is not indicated for the treatment of patients with type 1diabetes mellitus
  • Fatal ketoacidosis associated with Sodium-Glucose Transport Protein2 (SGLT2) inhibitors
  • Monitor for signs of ketoacidosis and advise patients to seek immediate medical attention for symptoms (eg, difficulty breathing, nausea, vomiting, abdominal pain, confusion, unusual fatigue, or sleepiness)
  • Assess patients who present with signs and symptoms of metabolic acidosis or ketoacidosis, regardless of blood glucose level
  • Consider risk factors for ketoacidosis before initiating therapy; consider factors in patient history that may predispose to ketoacidosis including pancreatic insulin deficiency from any cause, caloric restriction, and alcohol abuse; patients may require temporary discontinuation of therapy in clinical situations that may predispose to ketoacidosis
• Diabetic ketoacidosis in patients with type 1 diabetes mellitus
  • In patients with type 1 diabetes mellitus, this drug significantly increases the risk of diabetic ketoacidosis, a life-threatening event, beyond the background rate; this risk may be greater with higher doses of the drug; this therapy is not indicated for glycemic control in patients with type 1 diabetes mellitus
  • Type 2 diabetes mellitus and pancreatic disorders (eg, history of pancreatitis or pancreatic surgery) are also risk factors for ketoacidosis; there have been postmarketing reports of fatal events of ketoacidosis in patients with type 2 diabetes mellitus using SGLT2 inhibitors, including this medication
  • Precipitating conditions for diabetic ketoacidosis or other ketoacidosis include acute febrile illness, reduced caloric intake, ketogenic diet, surgery, volume depletion, under-insulinization due to insulin dose reduction or missed insulin doses, and alcohol abuse
  • Signs and symptoms are consistent with dehydration and severe metabolic acidosis and include nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath; blood glucose levels at presentation may be below those typically expected for diabetic ketoacidosis (eg, less than 250 mg/dL)
  • Ketoacidosis and glucosuria may persist longer than typically expected; urinary glucose excretion persists for 3 days after discontinuing therapy; however, there have been postmarketing reports of ketoacidosis and glucosuria lasting greater than 6 days and some up to 2 weeks after discontinuation of SGLT2 inhibitors
  • Consider ketone monitoring in patients at risk for ketoacidosis if indicated by the clinical situation; assess for ketoacidosis regardless of presenting blood glucose levels in patients who present with signs and symptoms consistent with severe metabolic acidosis
  • If ketoacidosis is suspected, discontinue therapy, promptly evaluate, and treat ketoacidosis, if confirmed; monitor patients for resolution of ketoacidosis before restarting therapy
  • Withhold therapy, if possible, in temporary clinical situations that could predispose patients to ketoacidosis; resume therapy when the patient is clinically stable and has resumed oral intake
  • Educate all patients on signs and symptoms of ketoacidosis and instruct patients to discontinue therapy and seek medical attention immediately if signs and symptoms occur
• Necrotizing fascitis
  • Necrotizing fasciitis of the perineum (Fournier gangrene) reported with SGLT2 inhibitors
  • Signs and symptoms include tenderness, redness, or swelling of the genitals or the area from the genitals back to the rectum and a fever greater than 100.4 F or a general feeling of being unwell
  • If suspected, discontinue the SGLT2 inhibitor and start treatment immediately with broad-spectrum antibiotics and surgical debridement if necessary
• Renal impairment
  • The therapy causes intravascular volume contraction and can cause renal impairment; acute kidney injury, some requiring hospitalization and dialysis reported
  • Before initiating therapy, 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 therapy in any setting of reduced oral intake (such as acute illness or fasting) or fluid losses (such as gastrointestinal illness or excessive heat exposure)
  • Canagliflozin increases serum creatinine and decreases eGFR; ensure normal renal function before initiating and at least annually thereafter
• Lactic acidosis
  • Risk increases with the degree of renal dysfunction and age 
  • Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk
  • Metformin-associated lactic acidosis cases are associated primarily with significant renal impairment; the risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment; metformin substantially excreted by the kidney
  • Metformin-associated lactic acidosis has resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias
  • Onset is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain
  • If suspected, discontinue therapy immediately and institute general supportive measures in a hospital setting; prompt hemodialysis is recommended
  • Metformin use in patients with impaired hepatic function has been associated with cases of lactic acidosis; this may be due to impaired lactate clearance resulting in higher lactate blood levels; avoid use of this drug in patients with clinical or laboratory evidence of hepatic disease
  • Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue therapy and report symptoms to a healthcare provider
• Iodinated contrast imaging procedures
  • Discontinue metformin at the time of or before an iodinated contrast imaging procedure in patients with an eGFR between 45-60 mL/minute/1.73 m²; in patients with a history of liver disease, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast
  • Reevaluate eGFR 48 hours after the imaging procedure; restart metformin if renal function is stable
• Hypoglycemia
  • Canagliflozin can increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue; a lower dose of insulin or insulin secretagogue may be required
  • 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 (eg, sulfonylureas, insulin) or ethanol
• Hypotension
  • Canagliflozin causes intravascular volume contraction
  • Symptomatic hypotension can occur after initiating, particularly with eGFR less than 60 mL/min/1.73 m², elderly patients, coadministration with diuretics or medications that interfere with the renin-angiotensin-aldosterone system (eg, ACE inhibitors, angiotensin receptor blockers), or patients with low systolic blood pressure
  • Assess volume status and correct hypovolemia in patients with renal impairment, the elderly, in patients with low systolic blood pressure, or on diuretics, ACE inhibitors, or ARB; monitor for signs and symptoms during therapy

Pregnancy and Lactation

• Canagliflozin
  • Based on animal data showing adverse renal effects, not recommended during the second and third trimesters of pregnancy
  • Data are limited in pregnant women and are not sufficient to determine a drug-associated risk for major birth defects or miscarriage
• Metformin
  • Metformin was not teratogenic in rats and rabbits at doses up to 600 mg/kg/day; determination of fetal concentrations demonstrated a partial placental barrier to metformin
• Clinical considerations
  • Poorly controlled diabetes in pregnancy increases maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, stillbirth, and delivery complications
  • Poorly controlled diabetes increases fetal risk for major birth defects, stillbirth, and macrosomia-related morbidity
• Lactation
  • Breastfeeding not recommended
  • Canagliflozin
    • No information regarding the distribution of human milk or its effects on the breastfed infant or on milk production
    • Present in milk of lactating rats
    • Since human kidney maturation occurs in utero and during the first 2 years of life when lactational exposure may occur, there may be a risk to the developing human kidney
  • Metformin
    • Excreted into milk in rats and reaches levels comparable to those in plasma; breastfeeding is not recommended