Invokamet XR 150-1000mg Tablets
WARNING: Rarely, metformin may cause too much lactic acid in the blood (lactic acidosis). The risk is higher in people who have kidney problems, liver problems, heart failure, use alcohol, or take certain other drugs, including topiramate. The risk is also higher in people who are 65 or older and in people who are having surgery, an exam or test with contrast, or other procedures. If lactic acidosis happens, it can lead to other health problems and can be deadly. Kidney tests may be done while taking this drug.Do not take this drug if you have a very bad infection, low oxygen, or a lot of fluid loss (dehydration).Call your doctor right away if you have signs of too much lactic acid in the blood (lactic acidosis) like confusion; fast breathing; fast or slow heartbeat; a heartbeat that does not feel normal; very bad stomach pain, upset stomach, or throwing up; feeling very sleepy; shortness of breath; feeling very tired or weak; very bad dizziness; feeling cold; or muscle pain or cramps. @ COMMON USES: It is used to help control blood sugar in people with type 2 diabetes.It is used to lower the chance of heart attack, stroke, new or worse kidney problems, having to go to the hospital for heart failure, and death in some people.It may be given to you for other reasons. Talk with the doctor.
Drug Class
Antidiabetic, Oral
Pharmacologic Class
Sodium-glucose co-transporter 2 (SGLT2) inhibitor; Biguanide
Pregnancy Category
Not available
FDA Approved
May 2016
DEA Schedule
Not Controlled
Overview
What is this medicine?
Invokamet XR is a medication used to help manage type 2 diabetes. It contains two active ingredients: canagliflozin and metformin. Canagliflozin works by helping your kidneys remove more sugar from your body through your urine. Metformin works by reducing the amount of sugar your liver makes and helping your body use insulin more effectively. Together, they help lower your blood sugar levels.
How to Use This Medicine
Taking Your Medication Correctly
To get the most benefit from your medication, follow your doctor's instructions carefully. Read all the information provided with your prescription and follow the instructions closely. Take your medication with breakfast to help your body absorb it properly. Swallow the tablet whole - do not chew, break, or crush it.
It's common to see what looks like the tablet in your stool after taking your medication. This is a normal occurrence and is not a cause for concern. If you have any questions or concerns, be sure to discuss them with your doctor.
To stay hydrated, drink plenty of non-caffeinated liquids, unless your doctor has advised you to limit your fluid intake. Continue taking your medication as directed by your doctor or healthcare provider, even if you're feeling well.
Storing and Disposing of Your Medication
Keep your medication in its original container at room temperature, in a dry place. Avoid storing it in a bathroom. If you need to store your medication outside of its original container, be sure to discard any unused portion after 30 days.
What to Do If You Miss a Dose
If you miss a dose, take it as soon as you remember. However, if it's close to the time for your next scheduled dose, skip the missed dose and resume your regular dosing schedule. Do not take two doses at the same time or take extra doses to make up for a missed one.
To get the most benefit from your medication, follow your doctor's instructions carefully. Read all the information provided with your prescription and follow the instructions closely. Take your medication with breakfast to help your body absorb it properly. Swallow the tablet whole - do not chew, break, or crush it.
It's common to see what looks like the tablet in your stool after taking your medication. This is a normal occurrence and is not a cause for concern. If you have any questions or concerns, be sure to discuss them with your doctor.
To stay hydrated, drink plenty of non-caffeinated liquids, unless your doctor has advised you to limit your fluid intake. Continue taking your medication as directed by your doctor or healthcare provider, even if you're feeling well.
Storing and Disposing of Your Medication
Keep your medication in its original container at room temperature, in a dry place. Avoid storing it in a bathroom. If you need to store your medication outside of its original container, be sure to discard any unused portion after 30 days.
What to Do If You Miss a Dose
If you miss a dose, take it as soon as you remember. However, if it's close to the time for your next scheduled dose, skip the missed dose and resume your regular dosing schedule. Do not take two doses at the same time or take extra doses to make up for a missed one.
Lifestyle & Tips
- Take Invokamet XR once daily in the morning with food to reduce stomach upset and improve absorption of metformin XR.
- Maintain a healthy diet as recommended by your doctor or dietitian.
- Engage in regular physical activity as advised by your healthcare provider.
- Stay well-hydrated, especially when exercising or in hot weather, to reduce the risk of dehydration.
- Limit or avoid alcohol consumption, as it can increase the risk of a serious side effect called lactic acidosis.
- Monitor your blood sugar levels regularly as instructed by your doctor.
Dosing & Administration
Adult Dosing
Standard Dose:
Individualized based on efficacy and tolerability, not exceeding 300 mg canagliflozin and 2000 mg metformin extended-release daily. The 150-1000mg strength is taken as one tablet once daily in the morning with food.
Dose Range:
50 - 2000 mg
Condition-Specific Dosing:
initialTherapy:
Initial dose is typically 50 mg canagliflozin/500 mg metformin XR once daily. For patients already on metformin, the dose of metformin XR should be maintained, and canagliflozin 50 mg or 150 mg added. For patients already on canagliflozin, the dose of canagliflozin should be maintained, and metformin XR 500 mg or 1000 mg added.
maintenance:
Titrate based on glycemic control and tolerability. Maximum daily dose is 300 mg canagliflozin and 2000 mg metformin XR.
Pediatric Dosing
Neonatal:
Not established
Infant:
Not established
Child:
Not established
Adolescent:
Not established
Dose Adjustments
Renal Impairment:
Mild:
eGFR 60 to <90 mL/min/1.73m2: No dose adjustment needed. Monitor renal function.
Moderate:
eGFR 45 to <60 mL/min/1.73m2: Initiation of Invokamet XR is not recommended. If eGFR falls to this range while on therapy, limit canagliflozin to 100 mg daily and consider reducing metformin dose by 50% (e.g., max 1000 mg/day). Monitor renal function closely.
eGFR 30 to <45 mL/min/1.73m2: Initiation of Invokamet XR is not recommended. If eGFR falls to this range while on therapy, limit canagliflozin to 100 mg daily and reduce metformin dose by 50% (e.g., max 1000 mg/day). Monitor renal function closely.
Severe:
eGFR <30 mL/min/1.73m2: Contraindicated.
Dialysis:
Contraindicated in patients on dialysis.
Hepatic Impairment:
Mild:
Canagliflozin: No dose adjustment needed. Metformin: Use with caution.
Moderate:
Canagliflozin: No dose adjustment needed. Metformin: Use with caution.
Severe:
Canagliflozin: No dose adjustment needed. Metformin: Contraindicated due to increased risk of lactic acidosis.
Pharmacology
Mechanism of Action
Invokamet XR combines two antihyperglycemic agents with different mechanisms of action: canagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, and metformin hydrochloride, a biguanide.
Canagliflozin: Inhibits SGLT2 in the renal proximal tubules, reducing glucose reabsorption and increasing urinary glucose excretion, thereby lowering plasma glucose concentrations.
Metformin: Decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.
Canagliflozin: Inhibits SGLT2 in the renal proximal tubules, reducing glucose reabsorption and increasing urinary glucose excretion, thereby lowering plasma glucose concentrations.
Metformin: Decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.
Pharmacokinetics
Absorption:
Bioavailability:
Canagliflozin: Approximately 65%; Metformin: 50-60% (oral, immediate release), extended-release formulation has slower and more prolonged absorption.
Tmax:
Canagliflozin: 1-2 hours; Metformin XR: 4-8 hours.
FoodEffect:
Canagliflozin: High-fat meal delays Tmax by 1 hour and decreases Cmax by 17%, but does not affect AUC. Metformin XR: Food increases absorption (AUC and Cmax) by approximately 50% and 25% respectively, and prolongs Tmax by 2.5 hours. Invokamet XR should be taken with food.
Distribution:
Vd:
Canagliflozin: 83.4 L; Metformin: 654 Âą 358 L.
ProteinBinding:
Canagliflozin: >99% (primarily to albumin); Metformin: Negligible.
CnssPenetration:
Canagliflozin: Limited; Metformin: Limited.
Elimination:
HalfLife:
Canagliflozin: 10.6-13.1 hours; Metformin: Plasma elimination half-life is approximately 6.2 hours, blood half-life is approximately 17.6 hours.
Clearance:
Canagliflozin: Renal clearance is 1.30 mL/min/kg; Metformin: Renal clearance is approximately 3.5 times greater than creatinine clearance.
ExcretionRoute:
Canagliflozin: Fecal (63%), Renal (33%); Metformin: Renal (primarily unchanged).
Unchanged:
Canagliflozin: Approximately 33% (renal); Metformin: Approximately 90% (renal).
Pharmacodynamics
OnsetOfAction:
Canagliflozin: Within hours; Metformin: Within days.
PeakEffect:
Canagliflozin: Within 4-6 hours; Metformin: 4-8 hours (XR).
DurationOfAction:
Canagliflozin: 24 hours; Metformin: 24 hours (XR).
Safety & Warnings
BLACK BOX WARNING
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), and an increased lactate/pyruvate ratio; metformin plasma levels generally >5 mcg/mL. If acidosis is suspected, discontinue Invokamet XR and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended. Risk factors include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors), age 65 years or greater, radiological studies with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment.
Side Effects
Urgent Side Effects: Seek Medical Help Right Away
Although rare, some people may experience severe and potentially life-threatening side effects while taking this medication. If you notice any of the following symptoms, contact your doctor or seek medical attention immediately:
Signs of an allergic reaction: rash, hives, itching, red, swollen, blistered, or peeling skin (with or without fever), wheezing, tightness in the chest or throat, trouble breathing, swallowing, or talking, unusual hoarseness, or swelling of the mouth, face, lips, tongue, or throat.
Signs of fluid and electrolyte problems: mood changes, confusion, muscle pain or weakness, fast or abnormal heartbeat, severe dizziness or fainting, increased thirst, seizures, feeling extremely tired or weak, decreased appetite, inability to pass urine or changes in urine output, dry mouth, dry eyes, or severe stomach upset or vomiting.
Signs of a urinary tract infection (UTI): blood in the urine, burning or pain while urinating, frequent or urgent need to urinate, fever, lower abdominal pain, or pelvic pain.
Signs of kidney problems: inability to pass urine, changes in urine output, blood in the urine, or sudden weight gain.
Vaginal yeast infection: report itching, unpleasant odor, or discharge.
Yeast infection of the penis: report pain, swelling, rash, or discharge.
Bone pain.
Low blood sugar: this may occur, especially when taking this medication with other diabetes medications. Signs include dizziness, headache, feeling sleepy or weak, shaking, fast heartbeat, confusion, hunger, or sweating. If you experience any of these symptoms, contact your doctor immediately and follow their instructions for managing low blood sugar, which may include taking glucose tablets, liquid glucose, or certain fruit juices.
Common Side Effects
When starting this medication, it's common to experience stomach problems like upset stomach, vomiting, or diarrhea. However, if you develop stomach problems later during treatment, contact your doctor right away, as this could be a sign of a condition called lactic acidosis.
Rare but Serious Side Effects
A rare but potentially life-threatening infection has been reported with medications like this one. Seek medical help immediately if you experience tenderness, redness, or swelling in the genital area or between the genitals and rectum, accompanied by fever or feeling unwell.
This medication may also increase the risk of lower limb amputations, particularly toe and foot amputations. To minimize this risk, talk to your doctor about proper foot care. If you have a history of amputation, blood vessel disease, nerve disease, or foot ulcers due to diabetes, inform your doctor. Contact your doctor right away if you experience new pain or tenderness, sores or ulcers, or infections in your legs or feet.
Other Side Effects
Like all medications, this drug can cause side effects, although many people may not experience any or may only have mild side effects. If you're bothered by any of the following side effects or if they persist, contact your doctor:
Frequent urination
Gas
Stomach pain or heartburn
Diarrhea, upset stomach, or vomiting
Headache
Feeling tired or weak
This is not an exhaustive list of possible side effects. If you have questions or concerns about side effects, contact your doctor. You can also report side effects to the FDA at 1-800-332-1088 or online at https://www.fda.gov/medwatch.
Although rare, some people may experience severe and potentially life-threatening side effects while taking this medication. If you notice any of the following symptoms, contact your doctor or seek medical attention immediately:
Signs of an allergic reaction: rash, hives, itching, red, swollen, blistered, or peeling skin (with or without fever), wheezing, tightness in the chest or throat, trouble breathing, swallowing, or talking, unusual hoarseness, or swelling of the mouth, face, lips, tongue, or throat.
Signs of fluid and electrolyte problems: mood changes, confusion, muscle pain or weakness, fast or abnormal heartbeat, severe dizziness or fainting, increased thirst, seizures, feeling extremely tired or weak, decreased appetite, inability to pass urine or changes in urine output, dry mouth, dry eyes, or severe stomach upset or vomiting.
Signs of a urinary tract infection (UTI): blood in the urine, burning or pain while urinating, frequent or urgent need to urinate, fever, lower abdominal pain, or pelvic pain.
Signs of kidney problems: inability to pass urine, changes in urine output, blood in the urine, or sudden weight gain.
Vaginal yeast infection: report itching, unpleasant odor, or discharge.
Yeast infection of the penis: report pain, swelling, rash, or discharge.
Bone pain.
Low blood sugar: this may occur, especially when taking this medication with other diabetes medications. Signs include dizziness, headache, feeling sleepy or weak, shaking, fast heartbeat, confusion, hunger, or sweating. If you experience any of these symptoms, contact your doctor immediately and follow their instructions for managing low blood sugar, which may include taking glucose tablets, liquid glucose, or certain fruit juices.
Common Side Effects
When starting this medication, it's common to experience stomach problems like upset stomach, vomiting, or diarrhea. However, if you develop stomach problems later during treatment, contact your doctor right away, as this could be a sign of a condition called lactic acidosis.
Rare but Serious Side Effects
A rare but potentially life-threatening infection has been reported with medications like this one. Seek medical help immediately if you experience tenderness, redness, or swelling in the genital area or between the genitals and rectum, accompanied by fever or feeling unwell.
This medication may also increase the risk of lower limb amputations, particularly toe and foot amputations. To minimize this risk, talk to your doctor about proper foot care. If you have a history of amputation, blood vessel disease, nerve disease, or foot ulcers due to diabetes, inform your doctor. Contact your doctor right away if you experience new pain or tenderness, sores or ulcers, or infections in your legs or feet.
Other Side Effects
Like all medications, this drug can cause side effects, although many people may not experience any or may only have mild side effects. If you're bothered by any of the following side effects or if they persist, contact your doctor:
Frequent urination
Gas
Stomach pain or heartburn
Diarrhea, upset stomach, or vomiting
Headache
Feeling tired or weak
This is not an exhaustive list of possible side effects. If you have questions or concerns about side effects, contact your doctor. You can also report side effects to the FDA at 1-800-332-1088 or online at https://www.fda.gov/medwatch.
Seek Immediate Medical Attention If You Experience:
- **Lactic Acidosis (serious, rare):** Unusual muscle pain, trouble breathing, stomach pain, dizziness, lightheadedness, feeling cold, very tired or weak. Seek immediate medical attention.
- **Diabetic Ketoacidosis (DKA):** Nausea, vomiting, stomach pain, excessive thirst, frequent urination, unusual tiredness, fruity-smelling breath. Seek immediate medical attention.
- **Dehydration/Low Blood Pressure:** Dizziness, lightheadedness, fainting, especially when standing up. Drink plenty of fluids.
- **Kidney Problems:** Changes in urination, swelling in legs or feet.
- **Urinary Tract Infections (UTIs):** Burning sensation when urinating, frequent urination, urgency, pain in the lower abdomen or back, fever.
- **Genital Yeast Infections:** Itching, redness, swelling, or discharge in the genital area.
- **Lower Limb Amputation:** New pain, tenderness, sores, ulcers, or infections in the leg or foot. Report any new foot problems to your doctor immediately.
- **Fournier's Gangrene (serious, rare):** Severe pain, tenderness, redness, or swelling in the genital or anal area, accompanied by fever or feeling unwell. Seek immediate medical attention.
Before Using This Medicine
Before Taking This Medication: Important Information to Share with Your Doctor
It is essential to inform your doctor about the following conditions to ensure safe treatment:
Any allergies you have, including allergies to this medication, its components, or other substances. Be sure to describe the allergic reaction you experienced.
Certain health conditions, such as:
+ Acidic blood problems
+ Kidney disease
+ Liver disease
+ Type 1 diabetes
Recent heart attack or stroke
Inability to eat or drink normally, including situations before procedures or surgery
Upcoming or recent exams or tests using contrast media (within the past 48 hours)
Additionally, inform your doctor if you are:
Pregnant or think you might be pregnant. Do not take this medication during the second or third trimester of pregnancy.
* Breastfeeding. You should not breastfeed while taking this medication.
This list is not exhaustive, and it is crucial to discuss all your medications (prescription, over-the-counter, natural products, and vitamins) and health problems with your doctor and pharmacist. They will help determine if it is safe to take this medication with your other treatments and health conditions. Never start, stop, or change the dose of any medication without consulting your doctor first.
It is essential to inform your doctor about the following conditions to ensure safe treatment:
Any allergies you have, including allergies to this medication, its components, or other substances. Be sure to describe the allergic reaction you experienced.
Certain health conditions, such as:
+ Acidic blood problems
+ Kidney disease
+ Liver disease
+ Type 1 diabetes
Recent heart attack or stroke
Inability to eat or drink normally, including situations before procedures or surgery
Upcoming or recent exams or tests using contrast media (within the past 48 hours)
Additionally, inform your doctor if you are:
Pregnant or think you might be pregnant. Do not take this medication during the second or third trimester of pregnancy.
* Breastfeeding. You should not breastfeed while taking this medication.
This list is not exhaustive, and it is crucial to discuss all your medications (prescription, over-the-counter, natural products, and vitamins) and health problems with your doctor and pharmacist. They will help determine if it is safe to take this medication with your other treatments and health conditions. Never start, stop, or change the dose of any medication without consulting your doctor first.
Precautions & Cautions
Important Warnings and Cautions
It is essential to inform all your healthcare providers, including doctors, nurses, pharmacists, and dentists, that you are taking this medication. Your doctor may need to stop this medication before certain surgical procedures, and will advise you when to resume taking it after the surgery or procedure.
Driving and Blood Sugar Levels
Do not drive if your blood sugar levels are low, as this increases the risk of accidents. To minimize the risk of dizziness or fainting, rise slowly from a sitting or lying position, and exercise caution when climbing stairs.
Diet, Exercise, and Lab Tests
Follow the diet and exercise plan recommended by your doctor. If you are on a low-salt or salt-free diet, consult with your doctor. Regularly check your blood sugar levels and have your blood work and other lab tests done as directed by your doctor. Discuss with your doctor which glucose tests are suitable for you to use.
Interactions and Precautions
This medication may affect certain lab tests, so inform all your healthcare providers and lab workers that you are taking this medication. Consult with your doctor before consuming alcohol. Be aware that high cholesterol has been associated with this medication, and discuss any concerns with your doctor.
Dehydration and Heat-Related Illness
In hot weather or during physical activity, drink plenty of fluids to prevent dehydration. If you are unable to drink liquids or experience persistent stomach upset, vomiting, or diarrhea, contact your doctor to avoid dehydration, which can lead to low blood pressure or worsen kidney problems.
Blood Sugar Control and Stress
Stressful events, such as fever, infection, injury, or surgery, can make it more challenging to control blood sugar levels. Changes in physical activity, exercise, or diet can also impact blood sugar control.
Long-Term Treatment and Vitamin B-12 Levels
Prolonged treatment with metformin may lead to low vitamin B-12 levels. If you have a history of low vitamin B-12 levels, discuss this with your doctor.
Ketoacidosis
This medication can increase the risk of ketoacidosis, a potentially life-threatening condition. This risk is higher in people with diabetes, pancreas problems, or those who are sick, dehydrated, or have skipped meals. Check your ketone levels as directed by your doctor, and consult with your doctor if you have any questions or concerns.
Bone Health and Kidney Problems
This medication may increase the risk of broken bones and kidney problems, including severe urinary tract infections. In some cases, these conditions may require hospitalization or dialysis.
Age-Related Precautions
If you are 65 or older, use this medication with caution, as you may be more susceptible to side effects.
Pregnancy and Birth Control
This medication may increase the risk of pregnancy in women of childbearing age who have not been ovulating. If you wish to avoid pregnancy, use birth control while taking this medication. If you become pregnant or are planning to become pregnant, inform your doctor immediately, as this medication may harm the unborn baby.
It is essential to inform all your healthcare providers, including doctors, nurses, pharmacists, and dentists, that you are taking this medication. Your doctor may need to stop this medication before certain surgical procedures, and will advise you when to resume taking it after the surgery or procedure.
Driving and Blood Sugar Levels
Do not drive if your blood sugar levels are low, as this increases the risk of accidents. To minimize the risk of dizziness or fainting, rise slowly from a sitting or lying position, and exercise caution when climbing stairs.
Diet, Exercise, and Lab Tests
Follow the diet and exercise plan recommended by your doctor. If you are on a low-salt or salt-free diet, consult with your doctor. Regularly check your blood sugar levels and have your blood work and other lab tests done as directed by your doctor. Discuss with your doctor which glucose tests are suitable for you to use.
Interactions and Precautions
This medication may affect certain lab tests, so inform all your healthcare providers and lab workers that you are taking this medication. Consult with your doctor before consuming alcohol. Be aware that high cholesterol has been associated with this medication, and discuss any concerns with your doctor.
Dehydration and Heat-Related Illness
In hot weather or during physical activity, drink plenty of fluids to prevent dehydration. If you are unable to drink liquids or experience persistent stomach upset, vomiting, or diarrhea, contact your doctor to avoid dehydration, which can lead to low blood pressure or worsen kidney problems.
Blood Sugar Control and Stress
Stressful events, such as fever, infection, injury, or surgery, can make it more challenging to control blood sugar levels. Changes in physical activity, exercise, or diet can also impact blood sugar control.
Long-Term Treatment and Vitamin B-12 Levels
Prolonged treatment with metformin may lead to low vitamin B-12 levels. If you have a history of low vitamin B-12 levels, discuss this with your doctor.
Ketoacidosis
This medication can increase the risk of ketoacidosis, a potentially life-threatening condition. This risk is higher in people with diabetes, pancreas problems, or those who are sick, dehydrated, or have skipped meals. Check your ketone levels as directed by your doctor, and consult with your doctor if you have any questions or concerns.
Bone Health and Kidney Problems
This medication may increase the risk of broken bones and kidney problems, including severe urinary tract infections. In some cases, these conditions may require hospitalization or dialysis.
Age-Related Precautions
If you are 65 or older, use this medication with caution, as you may be more susceptible to side effects.
Pregnancy and Birth Control
This medication may increase the risk of pregnancy in women of childbearing age who have not been ovulating. If you wish to avoid pregnancy, use birth control while taking this medication. If you become pregnant or are planning to become pregnant, inform your doctor immediately, as this medication may harm the unborn baby.
Overdose Information
Overdose Symptoms:
- Lactic acidosis (most serious concern with metformin overdose)
- Hypoglycemia (if co-administered with insulin or sulfonylureas)
- Severe dehydration
- Hypotension
- Renal failure
What to Do:
In case of overdose, contact a poison control center immediately (1-800-222-1222). Seek emergency medical attention. Management is supportive. Hemodialysis can be used to remove metformin and canagliflozin from the body.
Drug Interactions
Contraindicated Interactions
- Iodinated contrast media (temporarily discontinue Invokamet XR at the time of or prior to the procedure in patients with an eGFR between 30 and 60 mL/min/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. Re-evaluate eGFR 48 hours after the procedure; restart Invokamet XR only if renal function is stable.)
Major Interactions
- UGT enzyme inducers (e.g., rifampin, phenytoin, phenobarbital, ritonavir): May decrease canagliflozin exposure and efficacy. Consider increasing canagliflozin dose if appropriate.
- Digoxin: Canagliflozin may increase digoxin exposure. Monitor digoxin levels.
- Diuretics (loop or thiazide): Increased risk of volume depletion and symptomatic hypotension.
- Carbonic anhydrase inhibitors (e.g., topiramate, zonisamide, acetazolamide, dichlorphenamide): May increase risk of lactic acidosis with metformin.
- Alcohol: Potentiates the effect of metformin on lactate metabolism, increasing the risk of lactic acidosis.
Moderate Interactions
- Insulin and insulin secretagogues (e.g., sulfonylureas): Increased risk of hypoglycemia when co-administered with canagliflozin. Dose reduction of insulin or secretagogue may be required.
- Cimetidine: May increase metformin exposure (AUC and Cmax) by inhibiting renal tubular secretion of metformin.
- Drugs that affect renal tubular secretion of metformin (e.g., ranolazine, vandetanib, dolutegravir, cimetidine): May increase metformin systemic exposure.
Monitoring
Baseline Monitoring
Renal function (eGFR)
Rationale: To assess kidney function and determine appropriate dosing, as both components are renally cleared and contraindicated in severe renal impairment.
Timing: Prior to initiation of therapy.
Glycated Hemoglobin (A1C)
Rationale: To establish baseline glycemic control.
Timing: Prior to initiation of therapy.
Fasting Plasma Glucose (FPG)
Rationale: To establish baseline glycemic control.
Timing: Prior to initiation of therapy.
Volume status/Blood pressure
Rationale: To assess risk of hypotension, especially in patients on diuretics or with pre-existing low blood pressure.
Timing: Prior to initiation of therapy.
Vitamin B12 levels
Rationale: Metformin can decrease vitamin B12 levels.
Timing: Consider at baseline, especially in patients at risk for deficiency.
Routine Monitoring
Renal function (eGFR)
Frequency: At least annually; more frequently (2-4 times per year) in elderly, patients with impaired renal function, or those on concomitant medications affecting renal function.
Target: >60 mL/min/1.73m2 for full dose; >45 mL/min/1.73m2 for continued use with caution; >30 mL/min/1.73m2 for continued use with dose adjustment.
Action Threshold: If eGFR falls below 45 mL/min/1.73m2, adjust dose. If eGFR falls below 30 mL/min/1.73m2, discontinue.
Glycated Hemoglobin (A1C)
Frequency: Every 3-6 months.
Target: Individualized, typically <7% for most adults.
Action Threshold: If A1C remains above target, consider dose titration or addition of other agents.
Fasting Plasma Glucose (FPG)
Frequency: Periodically, or as needed for glycemic control assessment.
Target: Individualized, typically 80-130 mg/dL.
Action Threshold: If FPG consistently outside target, adjust dose or therapy.
Signs and symptoms of volume depletion
Frequency: Regularly, especially during initial therapy or dose increases.
Target: N/A
Action Threshold: If symptoms (dizziness, orthostatic hypotension) occur, assess hydration status and consider dose adjustment of Invokamet XR or diuretics.
Vitamin B12 levels
Frequency: Periodically (e.g., every 1-2 years) in patients on long-term metformin therapy.
Target: Normal range
Action Threshold: If levels are low, consider supplementation.
Symptom Monitoring
- Signs and symptoms of lactic acidosis (malaise, myalgia, respiratory distress, somnolence, abdominal pain, hypothermia, hypotension, resistant bradyarrhythmias)
- Signs and symptoms of diabetic ketoacidosis (nausea, vomiting, abdominal pain, rapid weight loss, thirst, polyuria, fatigue, difficulty breathing)
- Signs and symptoms of urinary tract infection (dysuria, frequent urination, urgency, fever, flank pain)
- Signs and symptoms of genital mycotic infections (itching, redness, discharge)
- Signs and symptoms of volume depletion/dehydration (dizziness, lightheadedness, orthostatic hypotension, dry mouth, excessive thirst)
- New pain, tenderness, sores, ulcers, or infections in the leg or foot (due to risk of lower limb amputation)
- Signs and symptoms of Fournier's gangrene (pain, tenderness, erythema, or swelling in the genital or perineal area, accompanied by fever or malaise)
Special Patient Groups
Pregnancy
Not recommended during the second and third trimesters of pregnancy due to potential adverse effects on renal development in the fetus (canagliflozin). Limited data on metformin use in pregnancy suggest low risk, but combination product is generally avoided.
Trimester-Specific Risks:
First Trimester:
Canagliflozin: Limited human data. Metformin: Generally considered low risk, often continued if benefits outweigh risks.
Second Trimester:
Canagliflozin: Not recommended due to potential for adverse renal effects on the developing fetus. Metformin: Generally considered low risk.
Third Trimester:
Canagliflozin: Not recommended due to potential for adverse renal effects on the developing fetus. Metformin: Generally considered low risk.
Lactation
Not recommended during breastfeeding. Both canagliflozin and metformin are excreted into human milk. Due to the potential for serious adverse reactions in a breastfed infant (e.g., renal dysfunction, hypoglycemia), a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
Infant Risk:
Canagliflozin: Potential for renal dysfunction and hypoglycemia. Metformin: Low risk of adverse effects, but insufficient data on long-term effects.
Pediatric Use
Safety and effectiveness have not been established in pediatric patients. Not recommended for use in patients younger than 18 years of age.
Geriatric Use
Elderly patients (âĨ65 years of age) are at increased risk for volume depletion, hypotension, and renal impairment. More frequent monitoring of renal function is recommended. The risk of lactic acidosis with metformin also increases with advancing age. Initiate therapy at the lower end of the dosing range and titrate slowly. Assess volume status and renal function more frequently.
Clinical Information
Clinical Pearls
- Educate patients on the signs and symptoms of lactic acidosis and DKA, emphasizing the need for immediate medical attention.
- Advise patients to maintain adequate hydration to minimize the risk of volume depletion and hypotension, especially during illness, exercise, or in hot weather.
- Counsel patients on the importance of foot care and to report any new pain, tenderness, sores, ulcers, or infections in the lower limbs immediately due to the risk of amputation associated with canagliflozin.
- Temporarily discontinue Invokamet XR before any surgical procedures or radiological studies involving iodinated contrast media.
- Monitor renal function closely, especially in elderly patients or those with pre-existing renal impairment, as dose adjustments or discontinuation may be necessary.
- Be aware of the potential for euglycemic DKA (DKA with normal or only mildly elevated blood glucose levels) with SGLT2 inhibitors. Consider DKA in patients presenting with symptoms even if blood glucose is not markedly elevated.
- Consider periodic vitamin B12 level monitoring in patients on long-term metformin therapy, especially those with risk factors for deficiency.
Alternative Therapies
- Other SGLT2 inhibitors (e.g., Invokana, Jardiance, Farxiga)
- Other biguanides (e.g., Metformin IR)
- DPP-4 inhibitors (e.g., Januvia, Tradjenta)
- GLP-1 receptor agonists (e.g., Ozempic, Trulicity)
- Sulfonylureas (e.g., Glipizide, Glyburide)
- Thiazolidinediones (e.g., Pioglitazone)
- Insulin
Cost & Coverage
Average Cost:
Varies widely, typically $500-$700 per 30 tablets
Insurance Coverage:
Tier 2 or 3 (Preferred or Non-Preferred Brand)
General Drug Facts
If your symptoms or health issues persist or worsen, it's essential to contact your doctor for further guidance. To ensure your safety, never share your medication with others or take someone else's medication.
This medication is accompanied by a Medication Guide, which provides crucial information about its use. Please read this guide carefully and review it again whenever you receive a refill. If you have any questions or concerns about this medication, don't hesitate to discuss them with your doctor, pharmacist, or other healthcare provider.
In the event of a suspected overdose, immediately call your local poison control center or seek emergency medical attention. When reporting the incident, be prepared to provide details about the medication taken, the amount, and the time it occurred.
This medication is accompanied by a Medication Guide, which provides crucial information about its use. Please read this guide carefully and review it again whenever you receive a refill. If you have any questions or concerns about this medication, don't hesitate to discuss them with your doctor, pharmacist, or other healthcare provider.
In the event of a suspected overdose, immediately call your local poison control center or seek emergency medical attention. When reporting the incident, be prepared to provide details about the medication taken, the amount, and the time it occurred.