Invokamet XR 150mg-500mg Tabets
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
Jul 2016
DEA Schedule
Not Controlled
Overview
What is this medicine?
Invokamet XR is a combination medicine used to help control high blood sugar in adults with type 2 diabetes. It contains two drugs: 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. This combination helps 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. You may notice what appears to be the tablet in your stool after taking it, but this is a normal occurrence and not a cause for concern. If you have any questions or concerns, be sure to discuss them with your doctor.
It's also important to stay hydrated by drinking plenty of non-caffeinated liquids, unless your doctor advises you to limit your fluid intake. Continue taking your medication as directed by your doctor or healthcare provider, even if you start to feel better.
Storing and Disposing of Your Medication
To maintain the effectiveness and safety of your medication, store it 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. You may notice what appears to be the tablet in your stool after taking it, but this is a normal occurrence and not a cause for concern. If you have any questions or concerns, be sure to discuss them with your doctor.
It's also important to stay hydrated by drinking plenty of non-caffeinated liquids, unless your doctor advises you to limit your fluid intake. Continue taking your medication as directed by your doctor or healthcare provider, even if you start to feel better.
Storing and Disposing of Your Medication
To maintain the effectiveness and safety of your medication, store it 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 tolerability.
- Swallow the extended-release tablets whole; do not crush, chew, or break them.
- 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 and kidney problems.
- Limit alcohol intake, as it can increase the risk of lactic acidosis with metformin.
- Monitor your blood sugar levels regularly as instructed by your doctor.
- Inform your doctor if you are scheduled for any surgery or medical procedures, especially those involving iodinated contrast dye, as you may need to temporarily stop this medication.
Dosing & Administration
Adult Dosing
Standard Dose:
Initial dose is typically Canagliflozin 50 mg/Metformin 500 mg XR or 50 mg/1000 mg XR once daily in the morning. Doses can be titrated based on efficacy and tolerability. The maximum recommended dose is Canagliflozin 300 mg/Metformin 2000 mg XR once daily. The 150mg/500mg strength is one of the available dosage forms for maintenance therapy.
Dose Range:
50 - 300 mg
Condition-Specific Dosing:
type2DiabetesMellitus:
Individualize dosing based on efficacy and tolerability, not exceeding maximum recommended doses for each component.
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/1.73 m²: No dose adjustment needed for either component. Monitor renal function.
Moderate:
eGFR 45 to <60 mL/min/1.73 m²: Max canagliflozin dose is 300 mg daily. Continue metformin if already on it, but do not initiate if eGFR is in this range. Monitor renal function every 3-6 months.
eGFR 30 to <45 mL/min/1.73 m²: Max canagliflozin dose is 100 mg daily. Do not initiate metformin. If already on metformin, consider discontinuing. Monitor renal function every 3 months.
Severe:
eGFR <30 mL/min/1.73 m²: Contraindicated due to metformin component. Discontinue Invokamet XR.
Dialysis:
Contraindicated due to metformin component.
Hepatic Impairment:
Mild:
No dose adjustment needed for canagliflozin. Metformin: Use with caution, monitor for lactic acidosis.
Moderate:
No dose adjustment needed for canagliflozin. Metformin: Use with caution, monitor for lactic acidosis.
Severe:
Metformin is generally contraindicated in severe hepatic impairment due to increased risk of lactic acidosis. Canagliflozin: No specific dose adjustment, but use with caution due to limited experience.
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, a biguanide.
Canagliflozin: Inhibits SGLT2 in the renal proximal tubules, reducing glucose reabsorption and increasing urinary glucose excretion (glucosuria), 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. It does not produce hypoglycemia in patients with type 2 diabetes when used alone.
Canagliflozin: Inhibits SGLT2 in the renal proximal tubules, reducing glucose reabsorption and increasing urinary glucose excretion (glucosuria), 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. It does not produce hypoglycemia in patients with type 2 diabetes when used alone.
Pharmacokinetics
Absorption:
Bioavailability:
Canagliflozin: ~65%; Metformin: 50-60% (oral)
Tmax:
Canagliflozin: 1-2 hours; Metformin XR: 4-8 hours
FoodEffect:
Canagliflozin: No clinically meaningful effect on AUC or Cmax. Metformin XR: Food may slightly decrease Cmax and extend Tmax, but overall absorption is not significantly affected.
Distribution:
Vd:
Canagliflozin: 119 L; Metformin: 654 ± 358 L
ProteinBinding:
Canagliflozin: ~99% (primarily to albumin); Metformin: Negligible
CnssPenetration:
Limited for both
Elimination:
HalfLife:
Canagliflozin: 10.6 hours (100 mg), 13.1 hours (300 mg); Metformin: ~6.2 hours (plasma), ~17.6 hours (blood)
Clearance:
Canagliflozin: Renal and metabolic; Metformin: Primarily renal
ExcretionRoute:
Canagliflozin: Feces (~52% as unchanged drug, ~33% as metabolites), Urine (~33% as unchanged drug, ~1% as metabolites); Metformin: Urine (primarily unchanged drug)
Unchanged:
Canagliflozin: ~33% (urine), ~52% (feces); Metformin: >90% (urine)
Pharmacodynamics
OnsetOfAction:
Canagliflozin: Within hours (glucosuria); Metformin: Days to weeks for full glucose-lowering effect
PeakEffect:
Canagliflozin: Within 24 hours; Metformin: 2-3 weeks
DurationOfAction:
Canagliflozin: 24 hours; Metformin: 24 hours (XR formulation)
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 non-specific abdominal distress. 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 lactic 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, having a radiological study 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 Attention Immediately
Although rare, some people may experience severe and potentially life-threatening side effects while taking this medication. If you experience any of the following symptoms, contact your doctor or seek medical help right away:
Allergic reactions: 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.
Fluid and electrolyte problems: Mood changes, confusion, muscle pain or weakness, fast or abnormal heartbeat, severe dizziness or passing out, increased thirst, seizures, feeling very tired or weak, decreased appetite, unable to pass urine or change in the amount of urine produced, dry mouth, dry eyes, or severe upset stomach or vomiting.
Urinary tract infection (UTI): Blood in the urine, burning or pain when passing urine, feeling the need to pass urine often or right away, fever, lower stomach pain, or pelvic pain.
Kidney problems: Unable to pass urine, change in how much urine is passed, blood in the urine, or a significant weight gain.
Vaginal yeast infection: Itching, bad odor, or discharge.
Yeast infection of the penis: Pain, swelling, rash, or discharge.
Low blood sugar: Dizziness, headache, feeling sleepy or weak, shaking, fast heartbeat, confusion, hunger, or sweating. If you experience any of these symptoms, follow your doctor's instructions for managing low blood sugar, which may include taking glucose tablets, liquid glucose, or some fruit juices.
Stomach problems: If you experience stomach problems later during treatment, such as upset stomach, vomiting, or diarrhea, contact your doctor right away, as this may be a sign of lactic acidosis, a serious condition.
Rare but serious infection: If your genitals or the area between your genitals and rectum becomes tender, red, or swollen, and you have a fever or do not feel well, seek medical help immediately.
Increased risk of lower limb amputations: Toe and foot amputations have occurred most often. Talk to your doctor about how to take care of your feet, especially if you have a history of amputation, blood vessel disease, nerve disease, or a foot ulcer caused by diabetes. Contact your doctor right away if you experience new pain or tenderness, sores or ulcers, or infections in your legs or feet.
Other Possible Side Effects
While many people may not experience any side effects or only minor ones, it's essential to be aware of the following possible side effects:
Passing urine more often
Gas
Stomach pain or heartburn
Diarrhea, upset stomach, or vomiting
Headache
Feeling tired or weak
If any of these side effects bother you or do not go away, contact your doctor or seek medical help. This is not an exhaustive list of possible side effects. If you have questions or concerns about side effects, contact your doctor.
Reporting Side Effects
You can 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 experience any of the following symptoms, contact your doctor or seek medical help right away:
Allergic reactions: 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.
Fluid and electrolyte problems: Mood changes, confusion, muscle pain or weakness, fast or abnormal heartbeat, severe dizziness or passing out, increased thirst, seizures, feeling very tired or weak, decreased appetite, unable to pass urine or change in the amount of urine produced, dry mouth, dry eyes, or severe upset stomach or vomiting.
Urinary tract infection (UTI): Blood in the urine, burning or pain when passing urine, feeling the need to pass urine often or right away, fever, lower stomach pain, or pelvic pain.
Kidney problems: Unable to pass urine, change in how much urine is passed, blood in the urine, or a significant weight gain.
Vaginal yeast infection: Itching, bad odor, or discharge.
Yeast infection of the penis: Pain, swelling, rash, or discharge.
Low blood sugar: Dizziness, headache, feeling sleepy or weak, shaking, fast heartbeat, confusion, hunger, or sweating. If you experience any of these symptoms, follow your doctor's instructions for managing low blood sugar, which may include taking glucose tablets, liquid glucose, or some fruit juices.
Stomach problems: If you experience stomach problems later during treatment, such as upset stomach, vomiting, or diarrhea, contact your doctor right away, as this may be a sign of lactic acidosis, a serious condition.
Rare but serious infection: If your genitals or the area between your genitals and rectum becomes tender, red, or swollen, and you have a fever or do not feel well, seek medical help immediately.
Increased risk of lower limb amputations: Toe and foot amputations have occurred most often. Talk to your doctor about how to take care of your feet, especially if you have a history of amputation, blood vessel disease, nerve disease, or a foot ulcer caused by diabetes. Contact your doctor right away if you experience new pain or tenderness, sores or ulcers, or infections in your legs or feet.
Other Possible Side Effects
While many people may not experience any side effects or only minor ones, it's essential to be aware of the following possible side effects:
Passing urine more often
Gas
Stomach pain or heartburn
Diarrhea, upset stomach, or vomiting
Headache
Feeling tired or weak
If any of these side effects bother you or do not go away, contact your doctor or seek medical help. This is not an exhaustive list of possible side effects. If you have questions or concerns about side effects, contact your doctor.
Reporting Side Effects
You can 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:
- Signs of lactic acidosis: unusual muscle pain, trouble breathing, stomach pain, dizziness, lightheadedness, feeling cold, or a very slow or irregular heartbeat. Seek emergency medical attention immediately.
- Signs of diabetic ketoacidosis (DKA): nausea, vomiting, stomach pain, excessive thirst, frequent urination, unusual tiredness, or fruity-smelling breath. Seek emergency medical attention immediately.
- Signs of dehydration: dizziness, lightheadedness, feeling faint, especially when standing up.
- Signs of urinary tract infection (UTI): burning sensation when urinating, frequent urination, urgent need to urinate, pain in the lower abdomen or back, fever.
- Signs of genital yeast infection: itching, redness, swelling, or discharge in the genital area.
- Signs of Fournier's gangrene (a serious infection of the genital or perineal area): pain, tenderness, redness, or swelling in the genital or anal area, accompanied by fever or feeling unwell. Seek emergency medical attention immediately.
- Symptoms of hypoglycemia (low blood sugar): sweating, shaking, fast heartbeat, hunger, confusion, dizziness, or irritability. Carry a source of sugar (e.g., glucose tablets, juice) to treat mild hypoglycemia.
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:
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
Any difficulties with eating or drinking, including situations where you may need to fast before a procedure or surgery
Upcoming or recent exams or tests that involve contrast agents (within the past 48 hours)
Additionally, if you are:
Pregnant or think you may be pregnant, note that this medication should not be taken during the second or third trimester
* Breast-feeding, as you should not breast-feed 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 issues with your doctor and pharmacist. They will help determine if it is safe to take this medication with your other drugs and health conditions. Never start, stop, or adjust the dosage of any medication without first consulting your doctor.
It is essential to inform your doctor about the following:
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
Any difficulties with eating or drinking, including situations where you may need to fast before a procedure or surgery
Upcoming or recent exams or tests that involve contrast agents (within the past 48 hours)
Additionally, if you are:
Pregnant or think you may be pregnant, note that this medication should not be taken during the second or third trimester
* Breast-feeding, as you should not breast-feed 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 issues with your doctor and pharmacist. They will help determine if it is safe to take this medication with your other drugs and health conditions. Never start, stop, or adjust the dosage of any medication without first consulting your doctor.
Precautions & Cautions
Important Warnings and Cautions
Inform all your healthcare providers, including doctors, nurses, pharmacists, and dentists, that you are taking this medication. Your doctor may instruct you to stop taking this drug before certain surgical procedures. If you need to stop taking this medication, your doctor will advise you on when to resume taking it after your surgery or procedure.
Driving and Blood Sugar Control
Do not drive if you have experienced low blood sugar, as this increases your risk of being involved in an accident. To minimize the risk of dizziness or fainting, get up slowly from a sitting or lying down position. Be cautious when climbing stairs. Follow the diet and exercise plan recommended by your doctor.
Dietary Considerations
If you are on a low-salt or salt-free diet, consult with your doctor. Have your blood work and other laboratory tests done as scheduled by your doctor. Monitor your blood sugar levels as instructed by your doctor. Discuss with your doctor which glucose tests are suitable for you to use.
Interactions with Lab Tests and Alcohol
This medication may affect certain laboratory test results. Inform all your healthcare providers and laboratory personnel that you are taking this drug. Consult with your doctor before consuming alcohol.
Potential Side Effects
High cholesterol has been reported in patients taking this medication. If you have concerns, discuss them with your doctor. Be cautious in hot weather or during physical activity, and drink plenty of fluids to avoid dehydration. If you are unable to drink fluids or experience persistent vomiting, diarrhea, or stomach upset, contact your doctor to prevent dehydration, which can lead to low blood pressure or worsen kidney problems.
Blood Sugar Control During Stressful Situations
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.
Risk of Ketoacidosis
This medication can increase the risk of ketoacidosis, a potentially life-threatening condition characterized by excessive acid in the blood or urine. This risk is higher in patients with diabetes, pancreas problems, or those who are sick, dehydrated, or have a history of skipping meals. The risk is also increased in patients on a ketogenic diet, undergoing surgery, or taking insulin. Monitor your ketone levels as instructed by your doctor, and consult with your doctor if you have any questions.
Bone Health and Kidney Problems
This medication may increase the risk of fractures. Discuss this with your doctor. Kidney problems and severe urinary tract infections (UTIs) have been reported, and in some cases, hospitalization may be necessary. Kidney problems may require dialysis.
Special Considerations
If you are 65 or older, use this medication with caution, as you may be more susceptible to side effects. Women of childbearing age who have not been ovulating may be at risk of pregnancy. If you wish to avoid pregnancy, use birth control while taking this medication. If you become pregnant or suspect you are pregnant while taking this medication, contact your doctor immediately, as this medication may harm the unborn baby.
Inform all your healthcare providers, including doctors, nurses, pharmacists, and dentists, that you are taking this medication. Your doctor may instruct you to stop taking this drug before certain surgical procedures. If you need to stop taking this medication, your doctor will advise you on when to resume taking it after your surgery or procedure.
Driving and Blood Sugar Control
Do not drive if you have experienced low blood sugar, as this increases your risk of being involved in an accident. To minimize the risk of dizziness or fainting, get up slowly from a sitting or lying down position. Be cautious when climbing stairs. Follow the diet and exercise plan recommended by your doctor.
Dietary Considerations
If you are on a low-salt or salt-free diet, consult with your doctor. Have your blood work and other laboratory tests done as scheduled by your doctor. Monitor your blood sugar levels as instructed by your doctor. Discuss with your doctor which glucose tests are suitable for you to use.
Interactions with Lab Tests and Alcohol
This medication may affect certain laboratory test results. Inform all your healthcare providers and laboratory personnel that you are taking this drug. Consult with your doctor before consuming alcohol.
Potential Side Effects
High cholesterol has been reported in patients taking this medication. If you have concerns, discuss them with your doctor. Be cautious in hot weather or during physical activity, and drink plenty of fluids to avoid dehydration. If you are unable to drink fluids or experience persistent vomiting, diarrhea, or stomach upset, contact your doctor to prevent dehydration, which can lead to low blood pressure or worsen kidney problems.
Blood Sugar Control During Stressful Situations
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.
Risk of Ketoacidosis
This medication can increase the risk of ketoacidosis, a potentially life-threatening condition characterized by excessive acid in the blood or urine. This risk is higher in patients with diabetes, pancreas problems, or those who are sick, dehydrated, or have a history of skipping meals. The risk is also increased in patients on a ketogenic diet, undergoing surgery, or taking insulin. Monitor your ketone levels as instructed by your doctor, and consult with your doctor if you have any questions.
Bone Health and Kidney Problems
This medication may increase the risk of fractures. Discuss this with your doctor. Kidney problems and severe urinary tract infections (UTIs) have been reported, and in some cases, hospitalization may be necessary. Kidney problems may require dialysis.
Special Considerations
If you are 65 or older, use this medication with caution, as you may be more susceptible to side effects. Women of childbearing age who have not been ovulating may be at risk of pregnancy. If you wish to avoid pregnancy, use birth control while taking this medication. If you become pregnant or suspect you are pregnant while taking this medication, contact your doctor immediately, as this medication may harm the unborn baby.
Overdose Information
Overdose Symptoms:
- Lactic acidosis (severe metabolic acidosis, hypothermia, hypotension, resistant bradyarrhythmias)
- Hypoglycemia (if taken with insulin or sulfonylureas)
- Volume depletion/dehydration
- Electrolyte imbalances
What to Do:
Call 911 or Poison Control (1-800-222-1222) immediately. Treatment is symptomatic and supportive. Hemodialysis is effective for removing metformin and canagliflozin from the body.
Drug Interactions
Contraindicated Interactions
- Iodinated contrast media (for metformin component, temporarily discontinue before or at the time of procedure and for 48 hours after, re-evaluate renal function before restarting)
- Drugs that increase risk of lactic acidosis (e.g., topiramate, zonisamide, acetazolamide, dichlorphenamide, alcohol abuse)
Major Interactions
- Loop diuretics (increased risk of volume depletion and hypotension with canagliflozin)
- Insulin and insulin secretagogues (sulfonylureas) (increased risk of hypoglycemia, may require dose reduction of insulin/sulfonylurea)
- UGT enzyme inducers (e.g., rifampin, phenytoin, phenobarbital, ritonavir) (may decrease canagliflozin exposure, consider increasing canagliflozin dose)
- Drugs that affect renal function or metformin disposition (e.g., cimetidine, ranolazine, dolutegravir, trimethoprim, vandetanib, isavuconazole, cimetidine, amiloride, digoxin, morphine, procainamide, quinidine, quinine, triamterene, verapamil) (may increase metformin levels, monitor)
Moderate Interactions
- ACE inhibitors/ARBs (increased risk of hypotension and renal impairment with canagliflozin)
- Digoxin (canagliflozin may increase digoxin exposure, monitor digoxin levels)
- Lithium (canagliflozin may decrease lithium exposure, monitor lithium levels)
- Corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, isoniazid (may produce hyperglycemia, requiring dose adjustment of Invokamet XR)
Minor Interactions
- Not specifically listed as minor, but general caution with drugs affecting glucose levels.
Monitoring
Baseline Monitoring
Renal function (eGFR)
Rationale: To determine appropriate dosing and assess contraindications for both components.
Timing: Prior to initiation
HbA1c and Fasting Plasma Glucose
Rationale: To establish baseline glycemic control.
Timing: Prior to initiation
Vitamin B12 levels
Rationale: Metformin can decrease B12 absorption.
Timing: Prior to initiation (consider, especially in at-risk patients)
Volume status/Blood pressure
Rationale: To assess risk of hypotension/volume depletion with canagliflozin.
Timing: Prior to initiation
Routine Monitoring
Renal function (eGFR)
Frequency: At least annually; more frequently (e.g., every 3-6 months) in patients with eGFR <60 mL/min/1.73 m² or elderly patients.
Target: >30 mL/min/1.73 m² for continued use
Action Threshold: Discontinue if eGFR falls persistently below 30 mL/min/1.73 m².
HbA1c
Frequency: Every 3-6 months
Target: Individualized, typically <7%
Action Threshold: Adjust therapy if target not met.
Fasting Plasma Glucose
Frequency: Regularly (e.g., daily self-monitoring or as directed by physician)
Target: Individualized
Action Threshold: Adjust therapy if target not met or if hypoglycemia/hyperglycemia occurs.
Signs/symptoms of lactic acidosis
Frequency: Ongoing
Target: N/A
Action Threshold: Promptly evaluate if suspected; discontinue drug immediately.
Signs/symptoms of urinary tract infection (UTI) or genital mycotic infection
Frequency: Ongoing
Target: N/A
Action Threshold: Treat promptly if suspected; consider drug discontinuation if severe or recurrent.
Volume status/Blood pressure
Frequency: Regularly, especially in patients prone to hypotension
Target: Normal BP
Action Threshold: Manage volume depletion; consider dose adjustment or discontinuation if symptomatic hypotension occurs.
Vitamin B12 levels
Frequency: Every 2-3 years, or if megaloblastic anemia or neuropathy is suspected.
Target: Normal range
Action Threshold: Supplement B12 if deficient.
Symptom Monitoring
- Symptoms of lactic acidosis (malaise, myalgia, respiratory distress, somnolence, abdominal distress)
- Symptoms of dehydration/volume depletion (dizziness, lightheadedness, orthostatic hypotension)
- Symptoms of urinary tract infection (dysuria, frequency, urgency, fever, flank pain)
- Symptoms of genital mycotic infection (itching, redness, discharge)
- Symptoms of diabetic ketoacidosis (nausea, vomiting, abdominal pain, rapid breathing, unusual thirst, confusion, fruity breath odor)
- Symptoms of Fournier's gangrene (pain, tenderness, erythema, swelling in genital/perineal area, fever, malaise)
- Symptoms of hypoglycemia (sweating, tremor, confusion, hunger, dizziness, rapid heartbeat)
Special Patient Groups
Pregnancy
Not recommended during the second and third trimesters of pregnancy due to potential adverse renal effects on the developing fetus (canagliflozin). Limited data on metformin use in pregnancy, but generally considered safer than canagliflozin. Discuss risks and benefits with a healthcare provider. Insulin is generally preferred for glycemic control during pregnancy.
Trimester-Specific Risks:
First Trimester:
Limited human data for canagliflozin. Metformin: Data from observational studies and meta-analyses have not shown an increased risk of major birth defects or miscarriage. However, metformin crosses the placenta.
Second Trimester:
Canagliflozin: Not recommended. Animal studies show adverse renal effects (renal pelvic and tubule dilatations) in offspring when exposed during periods of renal development, which correspond to the second and third trimesters of human pregnancy. Metformin: Generally considered acceptable, but insulin is often preferred.
Third Trimester:
Canagliflozin: Not recommended due to potential for adverse renal effects on the fetus. Metformin: Generally considered acceptable, but insulin is often preferred.
Lactation
Not recommended during breastfeeding. Canagliflozin is present in rat milk, and it is unknown if it is present in human milk. Metformin is excreted into human milk in small amounts. Due to the potential for serious adverse reactions in a breastfed infant (e.g., hypoglycemia, lactic acidosis, renal effects), a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Infant Risk:
Risk of hypoglycemia, lactic acidosis (metformin), and potential renal effects (canagliflozin) in the infant. Unknown effects on infant glucose homeostasis.
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
No dose adjustment is required based on age alone. However, older patients are more likely to have decreased renal function, and renal function should be assessed more frequently. They may also be at increased risk for volume depletion and hypotension with canagliflozin. Use with caution and monitor closely.
Clinical Information
Clinical Pearls
- Invokamet XR should be taken once daily in the morning with food to minimize gastrointestinal side effects of metformin and improve tolerability.
- Patients should be well-hydrated before and during treatment to minimize the risk of volume depletion and acute kidney injury, especially in patients with impaired renal function, elderly patients, or those on diuretics.
- Educate patients on the signs and symptoms of lactic acidosis, DKA, UTIs, genital mycotic infections, and Fournier's gangrene, and advise them to seek immediate medical attention if these occur.
- Temporarily discontinue Invokamet XR before or at the time of an iodinated contrast imaging procedure, surgery, or other procedures that may lead to volume depletion, hypoxia, or a significant reduction in renal function. Re-evaluate renal function 48 hours after the procedure before restarting.
- Monitor Vitamin B12 levels periodically in patients on long-term metformin therapy, especially if neuropathy or anemia is suspected.
- The 150mg/500mg strength refers to 150mg of canagliflozin and 500mg of metformin extended-release. Dosing should be individualized based on the patient's current glycemic control, renal function, and tolerability to each component.
Alternative Therapies
- Other SGLT2 inhibitors (e.g., empagliflozin, dapagliflozin, ertugliflozin)
- Other biguanides (Metformin IR)
- DPP-4 inhibitors (e.g., sitagliptin, saxagliptin, linagliptin)
- GLP-1 receptor agonists (e.g., liraglutide, semaglutide, dulaglutide)
- Sulfonylureas (e.g., glipizide, glyburide, glimepiride)
- Thiazolidinediones (e.g., pioglitazone, rosiglitazone)
- Insulin therapy
Cost & Coverage
Average Cost:
$500 - $700 per 30 tablets
Insurance Coverage:
Tier 2 or 3 (Brand-name drug, often requires prior authorization or step therapy)
General Drug Facts
If your symptoms or health issues persist or worsen, it is essential to contact your doctor promptly. To ensure safe use, never share your medication with others or take someone else's medication. This medication is accompanied by a Medication Guide, which provides crucial information for patients. It is vital to read this guide carefully and review it again each time your prescription is refilled. If you have any questions or concerns about this medication, consult your doctor, pharmacist, or other healthcare provider. In the event of a suspected overdose, immediately call the poison control center or seek emergency medical attention. When reporting the incident, be prepared to provide details about the medication taken, the quantity, and the time it occurred.