Pronunciation:

kan-a-gli-FLOE-zin, met-FOR-min hye-droe-KLOR-ide

Brand Names:

• Invokamet
• Invokamet XR

Dosage Forms:

• Tablet, Extended Release
• Tablet

Warnings:

Lactic Acidosis:Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (greater than 5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally greater than 5 mcg/mL.Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (eg, carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (eg, acute congestive heart failure), excessive alcohol intake, and hepatic impairment. Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the full prescribing information.If metformin-associated lactic acidosis is suspected, immediately discontinue canagliflozin/metformin hydrochloride and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.

Classifications:

Therapeutic—

Hypoglycemic

Pharmacologic—

Sodium Glucose Co-Transporter 2 Inhibitor

Chemical—

Metformin

Uses of This Medicine:

Canagliflozin and metformin combination is used together with proper diet and exercise to treat type 2 diabetes. This medicine is also used to lower the risk of heart attack, stroke, or death in patients with type 2 diabetes and heart or blood vessel disease. This medicine is also used to lower the risk of end stage kidney disease, worsening of kidney function, and hospitalization for heart failure in patients with type 2 diabetes and diabetic kidney disease with a certain amount of protein in the urine.

Canagliflozin works in the kidneys to prevent absorption of glucose (blood sugar). This helps lower the blood sugar level. Metformin reduces the absorption of sugar from the stomach, reduces the release of stored sugar from the liver, and helps your body use sugar better. It does not help patients who have insulin-dependent or type 1 diabetes. Type 1 diabetic patients must use insulin injections.

This medicine is available only with your doctor's prescription.

Before Using This Medicine:

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies—

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Children—

Appropriate studies have not been performed on the relationship of age to the effects of canagliflozin and metformin combination in the pediatric population. Safety and efficacy have not been established.

Older adults—

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of canagliflozin and metformin combination in the elderly. However, elderly patients are more likely to have kidney, liver, or heart problems, which may require caution and an adjustment in the dose for patients receiving canagliflozin and metformin combination.

Breast-feeding—

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Other medicines—

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Abiraterone Acetate
• Acetazolamide
• Alogliptin
• Aspirin
• Bexagliflozin
• Bictegravir
• Brinzolamide
• Bupropion
• Capmatinib
• Chloroquine
• Chlorothiazide
• Chlorpropamide
• Chlorthalidone
• Cimetidine
• Ciprofloxacin
• Cyclosporine
• Dasabuvir
• Delafloxacin
• Diatrizoate
• Dichlorphenamide
• Digoxin
• Dofetilide
• Dolutegravir
• Dorzolamide
• Enoxacin
• Ethiodized Oil
• Fedratinib
• Fexinidazole
• Furosemide
• Gatifloxacin
• Gemifloxacin
• Glimepiride
• Glipizide
• Glyburide
• Grepafloxacin
• Hydrochlorothiazide
• Hydroflumethiazide
• Hydroxychloroquine
• Indapamide
• Insulin
• Insulin Aspart, Recombinant
• Insulin Bovine
• Insulin Degludec
• Insulin Detemir
• Insulin Glargine, Recombinant
• Insulin Glulisine
• Insulin Lispro, Recombinant
• Iodipamide
• Iodixanol
• Iohexol
• Iopamidol
• Iopanoic Acid
• Iopromide
• Iothalamate
• Iotrolan
• Ioversol
• Ioxaglate
• Ipodate
• Isavuconazole
• Lanreotide Acetate
• Levofloxacin
• Levoketoconazole
• Liraglutide
• Lithium
• Lomefloxacin
• Methazolamide
• Metolazone
• Metrizamide
• Moxifloxacin
• Nateglinide
• Norfloxacin
• Octreotide Acetate
• Ofloxacin
• Ombitasvir
• Paritaprevir
• Pasireotide Diaspartate
• Pioglitazone
• Polythiazide
• Pramlintide
• Ranolazine
• Repaglinide
• Repotrectinib
• Semaglutide
• Sitagliptin
• Somatrogon-ghla
• Sotagliflozin
• Sparfloxacin
• Tafenoquine
• Thioctic Acid
• Tolazamide
• Tolbutamide
• Topiramate
• Triamterene
• Trovafloxacin
• Vandetanib
• Zonisamide

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Acebutolol
• Atenolol
• Betaxolol
• Bisoprolol
• Bitter Melon
• Carteolol
• Carvedilol
• Celiprolol
• Colesevelam
• Esmolol
• Fenugreek
• Glecaprevir
• Glucomannan
• Goldenseal
• Guar Gum
• Hydrastis
• Isocarboxazid
• Labetalol
• Levobunolol
• Linezolid
• Methylene Blue
• Metipranolol
• Metoprolol
• Nadolol
• Nebivolol
• Oxprenolol
• Ozanimod
• Patiromer
• Penbutolol
• Phenelzine
• Pibrentasvir
• Pindolol
• Practolol
• Procarbazine
• Propranolol
• Psyllium
• Rasagiline
• Rifampin
• Safinamide
• Selegiline
• Sotalol
• Timolol
• Tirzepatide
• Tranylcypromine
• Verapamil

Other interactions—

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Other medical problems—

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Adrenal gland problem (underactive) or
• Alcohol use disorder, history of or
• Congestive heart failure or
• Dehydration, severe or
• Hypovolemia (low blood volume) or
• Pancreatic insulin deficiency or pancreatic disorder (eg, pancreatitis, pancreatic surgery), history of or
• Pituitary gland problem (underactive) or
• Poorly nourished condition or
• Sepsis (severe infection) or
• Weakened physical condition—Use with caution. May cause side effects to become worse.

• Anemia (low red blood cells) or
• Dehydration or
• Genital yeast (fungus) infection (eg, balanitis, balanoposthitis, vulvovaginitis), history of or
• Hyperkalemia (high potassium in the blood) or
• Hypotension (low blood pressure) or
• Kidney disease or
• Urinary tract infection (eg, pyelonephritis, urosepsis), history of or
• Vitamin B12 deficiency—Use with caution. May make these conditions worse.

• Blood vessel disease or
• Diabetic foot ulcer or
• Leg amputation (leg removal surgery), history of or
• Neuropathy (nerve problem) of the leg—May increase the risk of leg amputations.

• Diabetic ketoacidosis (high ketones and acid in the blood) or
• Kidney disease, severe or
• Liver disease or
• Metabolic acidosis (acid in the blood) or
• Type I diabetes—Should not be used in patients with these conditions.

• Fever or
• Infection or
• Surgery or
• Trauma—Use with caution. These conditions may cause problems with blood sugar control.

• Hypoxia (low oxygen in the blood) or
• Kidney damage or
• Liver damage or
• Radiologic procedures (eg, X-rays, CT scans, MRIs) that require dyes to be injected into your vein—May increase your risk for lactic acidosis (too much acid in the blood).

Proper Use of This Medicine:

Take this medicine only as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered.

This medicine should come with a Medication Guide. Read and follow these instructions carefully. Ask your doctor if you have any questions.

The tablets should be taken with meals to help reduce unwanted stomach effects that may occur during the first few weeks.

Swallow the extended-release tablet whole. Do not crush, break, or chew it. It should be taken with the morning meal.

A part of the extended-release tablet may pass into your stool. This is normal and is nothing to worry about.

Tell your doctor if you are on a low-salt or sodium diet.

If you are taking an evening dose of metformin extended-release tablets, you should skip the last dose before starting treatment with this medicine the following morning.

Carefully follow the special meal plan your doctor gave you. This is the most important part of controlling your diabetes, and will help the medicine work properly. Exercise regularly and test for sugar in your blood or urine as directed.

Dosing—

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For type 2 diabetes:
  • For oral dosage form (extended-release tablets):
    • For patients not on canagliflozin or metformin treatment:
      • Adults—2 tablets once a day. Each tablet contains canagliflozin 50 milligrams (mg) and metformin 500 mg. Your doctor may adjust your dose as needed.
      • Children—Use and dose must be determined by your doctor.
    • For patients on metformin treatment:
      • Adults—2 tablets once a day. This is equivalent to canagliflozin 100 milligrams (mg) plus the total daily dose of metformin already being taken. Your doctor may adjust your dose as needed. However, the dose is usually not more than metformin 2000 mg and canagliflozin 300 mg per day.
      • Children—Use and dose must be determined by your doctor.
    • For patients on canagliflozin treatment:
      • Adults—2 tablets once a day. This is equivalent to metformin 1000 milligrams (mg) plus the total daily dose of canagliflozin already being taken. Your doctor may adjust your dose as needed. However, the dose is usually not more than metformin 2000 mg and canagliflozin 300 mg per day.
      • Children—Use and dose must be determined by your doctor.
    • For patients previously treated with canagliflozin and metformin:
      • Adults—2 tablets once a day. The total daily dose is the same as the dose you are already taking. Your doctor may adjust your dose as needed. However, the dose is usually not more than metformin 2000 mg and canagliflozin 300 mg per day.
      • Children—Use and dose must be determined by your doctor.
  • For oral dosage form (tablets):
    • For patients not on canagliflozin or metformin treatment:
      • Adults—One tablet 2 times a day. Each tablet contains canagliflozin 50 milligrams (mg) and metformin 500 mg. Your doctor may adjust your dose as needed.
      • Children—Use and dose must be determined by your doctor.
    • For patients on metformin treatment:
      • Adults—One tablet 2 times a day. This is equivalent to canagliflozin 100 milligrams (mg) plus the daily dose of metformin already being taken, divided into two doses. Your doctor may adjust your dose as needed. However, the dose is usually not more than metformin 2000 mg and canagliflozin 300 mg per day.
      • Children—Use and dose must be determined by your doctor.
    • For patients on canagliflozin treatment:
      • Adults—One tablet 2 times a day. This is equivalent to metformin 1000 milligrams (mg) plus the total daily dose of canagliflozin already being taken, divided into two doses. Your doctor may adjust your dose as needed. However, the dose is usually not more than metformin 2000 mg and canagliflozin 300 mg per day.
      • Children—Use and dose must be determined by your doctor.
    • For patients previously treated with canagliflozin and metformin:
      • Adults—One tablet 2 times a day. The total daily dose is the same as the dose you are already taking. Your doctor may adjust your dose as needed. However, the dose is usually not more than metformin 2000 mg and canagliflozin 300 mg per day.
      • Children—Use and dose must be determined by your doctor.

Missed dose—

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage—

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep the tablets in its original container to protect them from moisture. You may also store the tablets in a pill box or pill organizer for up to 30 days only.

Precautions While Using This Medicine:

It is very important that your doctor check your progress at regular visits, especially during the first few weeks that you take this medicine. Blood and urine tests may be needed to check for unwanted effects.

Using this medicine during the second and third part of your pregnancy can harm your unborn baby. If you think you have become pregnant while using this medicine, tell your doctor right away.

This medicine may cause ovulation in people who do not have regular monthly periods. This can increase the chance of pregnancy. If you are female and of childbearing potential, you should discuss birth control options with your doctor.

It is very important to follow carefully any instructions from your doctor about:

• Alcohol—Drinking alcohol may cause severe low blood sugar. Discuss this with your doctor.
• Other medicines—Do not take other medicines unless they have been discussed with your doctor. This especially includes nonprescription medicines such as aspirin, and medicines for appetite control, asthma, colds, cough, hay fever, or sinus problems.
• Counseling—Other family members need to learn how to prevent side effects or help with side effects if they occur. Also, patients with diabetes may need special counseling about the changes in the dosing of their diabetes medicine that might occur because of lifestyle changes, such as changes in exercise and diet. Furthermore, counseling on contraception and pregnancy may be needed because of the problems that can occur in patients with diabetes during pregnancy.
• Travel—Keep a recent prescription and your medical history with you. Be prepared for an emergency as you would normally. Make allowances for changing time zones and keep your meal times as close as possible to your usual meal times.
• In case of emergency—There may be a time when you need emergency help for a problem caused by your diabetes. You need to be prepared for these emergencies. It is a good idea to wear a medical identification (ID) bracelet or neck chain at all times. Also, carry an ID card in your wallet or purse that says that you have diabetes and a list of all of your medicines.

Under certain conditions, too much metformin can cause a serious condition, called lactic acidosis. The symptoms of lactic acidosis are severe and appear quickly. Lactic acidosis usually occurs when other serious health problems are present, such as a heart attack or kidney failure. The symptoms of lactic acidosis include: stomach discomfort, decreased appetite, diarrhea, fast or shallow breathing, a general feeling of discomfort, muscle pain or cramping, and unusual sleepiness, tiredness, or weakness. If you have more than one of these symptoms together, you should get emergency medical help right away.

This medicine may increase your risk of having leg, toe, or midfoot amputation (leg removal surgery). Check with your doctor right away if you have pain, tenderness, sores or ulcers, or infections on your leg or foot.

Dizziness, lightheadedness, or fainting may occur with this medicine. This is more common if you have kidney disease, low blood pressure, or if you are taking a diuretic (water pill). Taking plenty of fluids each day may help. Drink plenty of water during exercise or in hot weather. Check with your doctor if you have severe nausea, vomiting, or diarrhea that does not stop. This may cause you to lose too much water.

Ketoacidosis (high ketones and acid in the blood) may occur while you are using this medicine. This can be life-threatening and requires immediate medical attention. Your doctor may give you insulin, fluid, and carbohydrate replacement to treat this condition. Tell your doctor right away if you have nausea, vomiting, trouble breathing, increased thirst or urination.

Check with your doctor right away if you have bloody urine, decrease in how much or how often you urinate, an increase in blood pressure, increased thirst, loss of appetite, lower back or side pain, nausea, swelling of the face, fingers, or lower legs, trouble breathing, unusual tiredness or weakness, vomiting, or weight gain. These could be symptoms of a serious kidney problem.

This medicine may cause vaginal yeast infections in women and yeast infections of the penis in men. This is more common in patients who have a history of genital yeast infections or in men who are not circumcised. Women may have a vaginal discharge, itching, or odor. Men may have redness, itching, swelling, or pain around the penis, or a discharge with a strong odor from the penis. Check with your doctor right away if you have any of these symptoms.

This medicine may increase risk of having urinary tract infections, including pyelonephritis or urosepsis. Check with your doctor right away if you have bladder pain, bloody or cloudy urine, difficult, burning, or painful urination, or lower back or side pain.

This medicine may cause serious allergic reactions, including anaphylaxis or angioedema. These reactions can be life-threatening and require immediate medical attention. Call your doctor right away if you have a rash, itching, blistering, peeling, or loosening of the skin, fever or chills, trouble breathing or swallowing, or any swelling of your hands, face, mouth, or throat while you are using this medicine.

This medicine may cause a rare but serious bacterial infection, called necrotizing fasciitis of the perineum or Fournier's gangrene, which can cause damage to the tissue under the skin in the area between and around the anus and genitals (perineum). Fournier's gangrene may lead to hospitalization, multiple surgeries, or death. Check with your doctor right away if you have fever, unusual tiredness or weakness, or pain, tenderness, redness, or swelling of the area between and around your anus and genitals.

Do not drink a lot of alcohol while you are using this medicine. Heavy alcohol use can increase your risk for lactic acidosis.

This medicine may increase the risk of bone fractures. Ask your doctor about ways to keep your bones strong to help prevent fractures.

This medicine may cause hypoglycemia (low blood sugar). This is more common when this medicine is taken together with other diabetes medicines (eg, insulin, glipizide, or glyburide). Low blood sugar must be treated before it causes you to faint or lose consciousness. People feel different symptoms of low blood sugar. It is important that you learn which symptoms you usually have so you can treat it quickly. Talk to your doctor about the best way to treat low blood sugar.

Hyperglycemia (high blood sugar) may occur if you do not take enough or skip a dose of your diabetes medicine, overeat, or do not follow your diet plan, have a fever or infection, or do not exercise as much as usual. Some symptoms of high blood sugar include: blurred vision, drowsiness, dry mouth, flushed and dry skin, a fruit-like breath odor, increased frequency and amount of urination, ketones in the urine, loss of appetite, nausea or vomiting, rapid and deep breathing, tiredness, or unusual thirst. If symptoms of high blood sugar occur, check your blood sugar level and call your doctor for instructions.

Let your doctor or dentist know you are taking this medicine. Your doctor may advise you to stop taking this medicine before you have major surgery or diagnostic tests, especially tests with contrast dye.

Make sure any doctor or dentist who treats you knows that you are using this medicine. This medicine may affect the results of certain medical tests (eg, urine glucose tests may not be accurate).

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

Side Effects of This Medicine:

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

More common

Bladder pain

bloody or cloudy urine

decreased appetite

diarrhea

difficult, burning, or painful urination

fast, shallow breathing

frequent urge to urinate

frequent urination

general feeling of discomfort

increased urge to urinate during the night

increased volume of pale, dilute urine

itching of the vagina or genitals

itching, stinging, or redness of the vaginal area

lower back or side pain

muscle pain or cramping

nausea

sleepiness

stomach discomfort

thick, white vaginal discharge with mild or no odor

unusual tiredness or weakness

waking to urinate at night

Less common

Dry mouth

increased thirst

Incidence not known

Anxiety

blurred vision

chills

clay-colored stools

cold sweats

confusion

cool, pale skin

depression

difficulty with swallowing

dizziness

dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position

fast heartbeat

fever

flushing, redness of the skin

headache

hives, itching, skin rash

increased hunger

irregular heartbeat

large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or genitals

loss of appetite

loss of consciousness

nightmares

numbness or tingling in the hands, feet, or lips

pain in the skin around the penis

pain, tenderness, redness, or swelling of the area between the anus and genitals

reddening of the skin, especially around the ears

redness, itching, or swelling of the penis

seizures

shakiness

slurred speech

stomach pain or tenderness

sweating

swelling of the eyes, face, or inside of the nose

swelling of the feet or lower legs

unpleasant breath odor

vomiting

vomiting of blood

weakness or heaviness of the legs

yellow eyes or skin

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

Bloated

excess air or gas in the stomach or bowels

full feeling

indigestion

passing gas

Less common

Constipation

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.