SPL MEDGUIDE SECTION.

Medication GuideINVOKAMET(R) (in vok met)(canagliflozin and metformin hydrochloride) tablets, for oral useandINVOKAMET(R) (in vok met) XR(canagliflozin and metformin hydrochloride) extended-release tablets, for oral use This Medication Guide has been approved by the U.S. Food and Drug Administration.Revised 10/2018What is the most important information should know about INVOKAMET and INVOKAMET XRINVOKAMET and INVOKAMET XR can cause serious side effects, including:Lactic Acidosis. Metformin, one of the medicines in INVOKAMET and INVOKAMET XR, can cause rare but serious condition called lactic acidosis (a build-up of lactic acid in the blood) that can cause death. Lactic acidosis is medical emergency and must be treated in the hospital. Call your doctor right away if you have any of the following symptoms, which could be signs of lactic acidosis: you feel cold in your hands or feetyou feel very weak or tiredyou have trouble breathingyou have stomach pains, nausea, or vomitingyou have slow or irregular heartbeatyou have unusual (not normal) muscle painyou have unusual sleepiness or sleep longer than usualyou feel dizzy or lightheadedMost people who have had lactic acidosis had other conditions that, in combination with metformin use, led to the lactic acidosis. Tell your doctor if you have any of the following, because you have higher chance for getting lactic acidosis with INVOKAMET or INVOKAMET XR if you:have severe kidney problems or your kidneys are affected by certain x-ray tests that use injectable dye.have liver problems.drink alcohol very often, or drink lot of alcohol in short-term binge drinking.get dehydrated (lose large amount of body fluids). This can happen if you are sick with fever, vomiting, or diarrhea. Dehydration can also happen when you sweat lot with activity or exercise and do not drink enough fluids.have surgery.have heart attack, severe infection, or stroke.The best way to keep from having problem with lactic acidosis from metformin is to tell your doctor if you have any of the problems in the list above. Your doctor will decide to stop your INVOKAMET or INVOKAMET XR for while if you have any of these things.Amputations. INVOKAMET or INVOKAMET XR may increase your risk of lower limb amputations. Amputations mainly involve removal of the toe or part of the foot, however, amputations involving the leg, below and above the knee, have also occurred. Some people had more than one amputation, some on both sides of the body.You may be at higher risk of lower limb amputation if you:have history of amputation have heart disease or are at risk for heart diseasehave had blocked or narrowed blood vessels, usually in your leghave damage to the nerves (neuropathy) in your leghave had diabetic foot ulcers or soresCall your doctor right away if you have new pain or tenderness, any sores, ulcers, or infections in your leg or foot. Your doctor may decide to stop your INVOKAMET or INVOKAMET XR for while if you have any of these signs or symptoms.Talk to your doctor about proper foot care.INVOKAMET or INVOKAMET XR can have other serious side effects. See What are the possible side effects of INVOKAMET or INVOKAMET XR What is INVOKAMET or INVOKAMET XRINVOKAMET contains prescription medicines called canagliflozin (INVOKANA) and metformin hydrochloride (GLUCOPHAGE). INVOKAMET XR contains prescription medicines called canagliflozin (INVOKANA) and metformin hydrochloride extended-release (GLUMETZA). INVOKAMET or INVOKAMET XR can be used:along with diet and exercise to lower blood sugar (glucose) in adults with type diabetes in adults with type diabetes who have known cardiovascular disease when both canagliflozin and metformin are appropriate and canagliflozin is needed to reduce the risk of major cardiovascular events such as heart attack, stroke, or death.INVOKAMET or INVOKAMET XR is not for people with type diabetes.INVOKAMET or INVOKAMET XR is not for people with diabetic ketoacidosis (increased ketones in blood or urine).It is not known if INVOKAMET or INVOKAMET XR is safe and effective in children under 18 years of age.Who should not take INVOKAMET or INVOKAMET XRDo not take INVOKAMET or INVOKAMET XR if you:have moderate to severe kidney problems or are on dialysis.have condition called metabolic acidosis or diabetic ketoacidosis (increased ketones in the blood or urine).are allergic to canagliflozin, metformin, or any of the ingredients in INVOKAMET or INVOKAMET XR. See the end of this Medication Guide for list of ingredients in INVOKAMET and INVOKAMET XR. Symptoms of allergic reaction to INVOKAMET and INVOKAMET XR may include:rashraised red patches on your skin (hives)swelling of the face, lips, mouth, tongue, and throat that may cause difficulty in breathing or swallowing What should tell my doctor before taking INVOKAMET or INVOKAMET XRBefore you take INVOKAMET or INVOKAMET XR, tell your doctor if you:have history of amputation.have heart disease or are at risk for heart disease.have had blocked or narrowed blood vessels, usually in your leg.have damage to the nerves (neuropathy) in your leg.have had diabetic foot ulcers or sores.have moderate to severe kidney problems.have liver problems.have history of urinary tract infections or problems with urination.are on low sodium (salt) diet. Your doctor may change your diet or your dose of INVOKAMET or INVOKAMET XR.have ever had an allergic reaction to INVOKAMET or INVOKAMET XR.are going to get an injection of dye or contrast agents for an x-ray procedure. INVOKAMET or INVOKAMET XR may need to be stopped for short time. Talk to your doctor about when you should stop INVOKAMET or INVOKAMET XR and when you should start INVOKAMET or INVOKAMET XR again. See What is the most important information should know about INVOKAMET or INVOKAMET XRhave heart problems, including congestive heart failure.are going to have surgery.are eating less due to illness, surgery, or change in your diet.have or have had problems with your pancreas, including pancreatitis or surgery on your pancreas.drink alcohol very often, or drink lot of alcohol in the short-term (binge drinking).have other medical conditions.are pregnant or plan to become pregnant. INVOKAMET or INVOKAMET XR may harm your unborn baby. If you become pregnant while taking INVOKAMET or INVOKAMET XR, tell your doctor as soon as possible. Talk with your doctor about the best way to control your blood sugar while you are pregnant.are premenopausal woman (before the change of life), who does not have periods regularly or at all. INVOKAMET or INVOKAMET XR may increase your chance of becoming pregnant. Talk to your doctor about birth control choices while taking INVOKAMET or INVOKAMET XR, if you are not planning to become pregnant. Tell your doctor right away if you become pregnant while taking INVOKAMET or INVOKAMET XR.are breastfeeding or plan to breastfeed. INVOKAMET or INVOKAMET XR may pass into your breast milk and may harm your baby. Talk with your doctor about the best way to feed your baby if you are taking INVOKAMET or INVOKAMET XR. Do not breastfeed while taking INVOKAMET or INVOKAMET XR.Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.INVOKAMET or INVOKAMET XR may affect the way other medicines work and other medicines may affect how INVOKAMET or INVOKAMET XR works. Especially tell your doctor if you take:diuretics (water pills)phenytoin or phenobarbital (used to control seizures)digoxin (Lanoxin(R)) (used to treat heart problems)rifampin (used to treat or prevent tuberculosis)ritonavir (Norvir(R), Kaletra(R)) (used to treat HIV infection)Ask your doctor or pharmacist for list of these medicines if you are not sure if your medicine is listed above.Know the medicines you take. Keep list of them and show it to your doctor and pharmacist when you get new medicine.How should take INVOKAMET or INVOKAMET XRIf you are prescribed INVOKAMET, take by mouth times each day with meals exactly as your doctor tells you to take it. Taking INVOKAMET with meals may lower your chance of having an upset stomach.If you are prescribed INVOKAMET XR, take by mouth time each day with the morning meal exactly as your doctor tells you to take it. Taking INVOKAMET XR with meal may lower your chance of having an upset stomach.Swallow INVOKAMET XR whole. Do not crush, cut, or chew.You may sometimes pass soft mass in your stools (bowel movement) that looks like INVOKAMET XR tablets. It is normal to see this in your stool.Your doctor will tell you how much INVOKAMET or INVOKAMET XR to take and when to take it. Your doctor may change your dose if needed.Your doctor may tell you to take INVOKAMET or INVOKAMET XR along with other diabetes medicines. Low blood sugar can happen more often when INVOKAMET or INVOKAMET XR is taken with certain other diabetes medicines. See What are the possible side effects of INVOKAMET or INVOKAMET XRIf you miss dose of INVOKAMET, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose and take the medicine at the next regularly scheduled time. Do not take tablets of INVOKAMET at the same time. Talk to your doctor if you have questions about missed dose.If you miss dose of INVOKAMET XR, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose and take the medicine at the next regularly scheduled time. Do not take more than tablets of INVOKAMET XR at the same time. Talk to your doctor if you have questions about missed dose.If you take too much INVOKAMET or INVOKAMET XR, call your doctor or go to the nearest hospital emergency room right away.When your body is under some types of stress, such as fever, trauma (such as car accident), infection, or surgery, the amount of diabetes medicine you need may change. Tell your doctor right away if you have any of these conditions and follow your doctors instructions.Stay on your prescribed diet and exercise program while taking INVOKAMET or INVOKAMET XR.Check your blood sugar as your doctor tells you to.INVOKAMET and INVOKAMET XR will cause your urine to test positive for glucose.Your doctor may do certain blood tests before you start INVOKAMET or INVOKAMET XR and during treatment as needed. Your doctor may change your dose of INVOKAMET or INVOKAMET XR based on the results of your blood tests.Your doctor will check your diabetes with regular blood tests, including your blood sugar levels and your hemoglobin A1C.What should avoid while taking INVOKAMET or INVOKAMET XRAvoid drinking alcohol very often, or drinking lot of alcohol in short period of time (binge drinking). It can increase your chances of getting serious side effects.What are the possible side effects of INVOKAMET or INVOKAMET XRINVOKAMET or INVOKAMET XR may cause serious side effects including:See What is the most important information should know about INVOKAMET or INVOKAMET XRdehydration. INVOKAMET or INVOKAMET XR can cause some people to become dehydrated (the loss of too much body water). Dehydration may cause you to feel dizzy, faint, lightheaded, or weak, especially when you stand up (orthostatic hypotension).You may be at higher risk of dehydration if you:have low blood pressuretake medicines to lower your blood pressure, including diuretics (water pill)are on low sodium (salt) diethave kidney problemsare 65 years of age or olderTalk to your doctor about what you can do to prevent dehydration including how much fluid you should drink on daily basis.ketoacidosis (increased ketones in your blood or urine). Ketoacidosis has happened in people who have type diabetes or type diabetes, during treatment with canagliflozin, one of the medicines in INVOKAMET and INVOKAMET XR. Ketoacidosis is serious condition, which may need to be treated in hospital. Ketoacidosis may lead to death. Ketoacidosis can happen with INVOKAMET or INVOKAMET XR, even if your blood sugar is less than 250 mg/dL. Stop taking INVOKAMET or INVOKAMET XR and call your doctor right away if you get any of the following symptoms: nauseavomitingstomach area (abdominal) paintirednesstrouble breathingIf you get any of these symptoms during treatment with INVOKAMET or INVOKAMET XR, if possible, check for ketones in your urine, even if your blood sugar is less than 250 mg/dL.kidney problems. Sudden kidney injury has happened to people taking INVOKAMET or INVOKAMET XR. Talk to your doctor right away if you:reduce the amount of food or liquid you drink for example, if you are sick or cannot eat oryou start to lose liquids from your body for example, from vomiting, diarrhea or being in the sun too long. serious urinary tract infections. Serious urinary tract infections that may lead to hospitalization have happened in people who are taking canagliflozin, one of the medicines in INVOKAMET and INVOKAMET XR. Tell your doctor if you have any signs or symptoms of urinary tract infection such as burning feeling when passing urine, need to urinate often, the need to urinate right away, pain in the lower part of your stomach (pelvis), or blood in the urine. Sometimes people may also have fever, back pain, nausea, or vomiting.low blood sugar (hypoglycemia). If you take INVOKAMET or INVOKAMET XR with another medicine that can cause low blood sugar, such as sulfonylurea or insulin, your risk of getting low blood sugar is higher. The dose of your sulfonylurea medicine or insulin may need to be lowered while you take INVOKAMET or INVOKAMET XR. Signs and symptoms of low blood sugar may include:headacheirritabilitydrowsinesshungerweaknessfast heartbeatconfusionsweatingdizzinessshaking or feeling jitterya rare but serious bacterial infection that causes damage to the tissue under the skin (necrotizing fasciitis) in the area between and around the anus and genitals (perineum). Necrotizing fasciitis of the perineum has happened in women and men who take canagliflozin, one of the medicines in INVOKAMET and INVOKAMET XR. Necrotizing fasciitis of the perineum may lead to hospitalization, may require multiple surgeries, and may lead to death. Seek medical attention immediately if you have fever or you are feeling very weak, tired or uncomfortable (malaise) and you develop any of the following symptoms in the area between and around your anus and genitals:pain or tendernessswellingredness of the skin (erythema)vaginal yeast infection. Women who take INVOKAMET or INVOKAMET XR may get vaginal yeast infections. Symptoms of vaginal yeast infection include:vaginal odorwhite or yellowish vaginal discharge (discharge may be lumpy or look like cottage cheese)vaginal itching yeast infection of the penis (balanitis or balanoposthitis). Men who take INVOKAMET or INVOKAMET XR may get yeast infection of the skin around the penis. Certain men who are not circumcised may have swelling of the penis that makes it difficult to pull back the skin around the tip of the penis. Other symptoms of yeast infection of the penis include:redness, itching, or swelling of the penisfoul smelling discharge from the penisrash of the penispain in the skin around the penisTalk to your doctor about what to do if you get symptoms of yeast infection of the vagina or penis. Your doctor may suggest you use an over-the-counter antifungal medicine. Talk to your doctor right away if you use an over-the-counter antifungal medication and your symptoms do not go away.serious allergic reaction. If you have any symptoms of serious allergic reaction, stop taking INVOKAMET or INVOKAMET XR and call your doctor right away or go to the nearest hospital emergency room. See Who should not take INVOKAMET or INVOKAMET XR. Your doctor may give you medicine for your allergic reaction and prescribe different medicine for your diabetes.broken bones (fractures). Bone fractures have been seen in patients taking canagliflozin. Talk to your doctor about factors that may increase your risk of bone fracture.low vitamin B12 (vitamin B12 deficiency). Using metformin for long periods of time may cause decrease in the amount of vitamin B12 in your blood, especially if you have had low vitamin B12 blood levels before. Your doctor may do blood tests to check your vitamin B12 levels.Other common side effects of INVOKAMET or INVOKAMET XR include:nausea and vomitinggasdiarrheaupset stomachweaknessindigestionheadachechanges in urination, including urgent need to urinate more often, in larger amounts, or at nightTell your doctor if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of INVOKAMET or INVOKAMET XR. For more information, ask your doctor or pharmacist.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.You may also report side effects to Janssen Pharmaceuticals, Inc. at 1-800-526-7736.How should store INVOKAMET or INVOKAMET XRStore INVOKAMET and INVOKAMET XR at room temperature between 68F to 77F (20C to 25C).Store in the original container to protect from moisture. Storage in pill box or pill organizer is allowed for up to 30 days.Keep INVOKAMET and INVOKAMET XR and all medicines out of the reach of children.General information about the safe and effective use of INVOKAMET and INVOKAMET XR.Medicines are sometimes prescribed for purposes other than those listed in the Medication Guide. Do not use INVOKAMET or INVOKAMET XR for condition for which it was not prescribed. Do not give INVOKAMET or INVOKAMET XR to other people, even if they have the same symptoms you have. It may harm them.This Medication Guide summarizes the most important information about INVOKAMET and INVOKAMET XR. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about INVOKAMET or INVOKAMET XR that is written for healthcare professionals.For more information about INVOKAMET or INVOKAMET XR, call 1-800-526-7736 or visit our websites at www.invokamet.com or www.invokametxr.com.What are the ingredients of INVOKAMETActive ingredients: canagliflozin and metformin hydrochlorideInactive ingredients: The tablet core contains croscarmellose sodium, hypromellose, magnesium stearate, and microcrystalline cellulose. The magnesium stearate is vegetable-sourced. In addition, the tablet coating contains Macrogol/PEG3350, polyvinyl alcohol (partially hydrolyzed), talc, titanium dioxide, iron oxide yellow (50 mg/1,000 mg and 150 mg/500 mg tablets only), iron oxide red (50 mg/1,000 mg, 150 mg/500 mg and 150 mg/1,000 mg tablets only), and iron oxide black (150 mg/1,000 mg tablets only).What are the ingredients of INVOKAMET XRActive ingredients: canagliflozin and metformin hydrochlorideInactive ingredients: The tablet core contains croscarmellose sodium, hydroxypropyl cellulose, hypromellose, lactose anhydrous, magnesium stearate (vegetable-sourced), microcrystalline cellulose, polyethylene oxide, and silicified microcrystalline cellulose (50 mg/500 mg and 50 mg/1,000 mg tablets only). In addition, the tablet coating contains macrogol/PEG3350, polyvinyl alcohol (partially hydrolyzed), talc, titanium dioxide, iron oxide red, iron oxide yellow, and iron oxide black (50 mg/1,000 mg and 150 mg/1,000 mg tablets only).The brands listed are trademarks of their respective owners and are not trademarks of Janssen Pharmaceuticals, Inc.Manufactured for: Janssen Pharmaceuticals, Inc., Titusville, NJ 08560. INVOKAMET manufactured by: Janssen Ortho LLC, Gurabo, PR 00778 or Janssen Cilag SpA, Latina, Italy. INVOKAMET XR manufactured by: Janssen Ortho LLC, Gurabo, PR 00778. Licensed from Mitsubishi Tanabe Pharma Corporation. (C) 2014, 2016 Janssen Pharmaceutical Companies. Lactic Acidosis. Metformin, one of the medicines in INVOKAMET and INVOKAMET XR, can cause rare but serious condition called lactic acidosis (a build-up of lactic acid in the blood) that can cause death. Lactic acidosis is medical emergency and must be treated in the hospital. Call your doctor right away if you have any of the following symptoms, which could be signs of lactic acidosis: you feel cold in your hands or feet. you feel very weak or tired. you have trouble breathing. you have stomach pains, nausea, or vomiting. you have slow or irregular heartbeat. you have unusual (not normal) muscle pain. you have unusual sleepiness or sleep longer than usual. you feel dizzy or lightheaded. have severe kidney problems or your kidneys are affected by certain x-ray tests that use injectable dye.. have liver problems.. drink alcohol very often, or drink lot of alcohol in short-term binge drinking.. get dehydrated (lose large amount of body fluids). This can happen if you are sick with fever, vomiting, or diarrhea. Dehydration can also happen when you sweat lot with activity or exercise and do not drink enough fluids.. have surgery.. have heart attack, severe infection, or stroke.. Amputations. INVOKAMET or INVOKAMET XR may increase your risk of lower limb amputations. Amputations mainly involve removal of the toe or part of the foot, however, amputations involving the leg, below and above the knee, have also occurred. Some people had more than one amputation, some on both sides of the body.You may be at higher risk of lower limb amputation if you:have history of amputation have heart disease or are at risk for heart diseasehave had blocked or narrowed blood vessels, usually in your leghave damage to the nerves (neuropathy) in your leghave had diabetic foot ulcers or sores. have history of amputation have heart disease or are at risk for heart disease. have had blocked or narrowed blood vessels, usually in your leg. have damage to the nerves (neuropathy) in your leg. have had diabetic foot ulcers or sores. INVOKAMET contains prescription medicines called canagliflozin (INVOKANA) and metformin hydrochloride (GLUCOPHAGE). INVOKAMET XR contains prescription medicines called canagliflozin (INVOKANA) and metformin hydrochloride extended-release (GLUMETZA). INVOKAMET or INVOKAMET XR can be used:along with diet and exercise to lower blood sugar (glucose) in adults with type diabetes along with diet and exercise to lower blood sugar (glucose) in adults with type diabetes. in adults with type diabetes who have known cardiovascular disease when both canagliflozin and metformin are appropriate and canagliflozin is needed to reduce the risk of major cardiovascular events such as heart attack, stroke, or death.. INVOKAMET or INVOKAMET XR is not for people with type diabetes.. INVOKAMET or INVOKAMET XR is not for people with diabetic ketoacidosis (increased ketones in blood or urine).. It is not known if INVOKAMET or INVOKAMET XR is safe and effective in children under 18 years of age.. have moderate to severe kidney problems or are on dialysis.. have condition called metabolic acidosis or diabetic ketoacidosis (increased ketones in the blood or urine).. are allergic to canagliflozin, metformin, or any of the ingredients in INVOKAMET or INVOKAMET XR. See the end of this Medication Guide for list of ingredients in INVOKAMET and INVOKAMET XR. Symptoms of allergic reaction to INVOKAMET and INVOKAMET XR may include:rashraised red patches on your skin (hives)swelling of the face, lips, mouth, tongue, and throat that may cause difficulty in breathing or swallowing rash. raised red patches on your skin (hives). swelling of the face, lips, mouth, tongue, and throat that may cause difficulty in breathing or swallowing. have history of amputation.. have heart disease or are at risk for heart disease.. have had blocked or narrowed blood vessels, usually in your leg.. have damage to the nerves (neuropathy) in your leg.. have had diabetic foot ulcers or sores.. have moderate to severe kidney problems.. have liver problems.. have history of urinary tract infections or problems with urination.. are on low sodium (salt) diet. Your doctor may change your diet or your dose of INVOKAMET or INVOKAMET XR.. have ever had an allergic reaction to INVOKAMET or INVOKAMET XR.. are going to get an injection of dye or contrast agents for an x-ray procedure. INVOKAMET or INVOKAMET XR may need to be stopped for short time. Talk to your doctor about when you should stop INVOKAMET or INVOKAMET XR and when you should start INVOKAMET or INVOKAMET XR again. See What is the most important information should know about INVOKAMET or INVOKAMET XR. have heart problems, including congestive heart failure.. are going to have surgery.. are eating less due to illness, surgery, or change in your diet.. have or have had problems with your pancreas, including pancreatitis or surgery on your pancreas.. drink alcohol very often, or drink lot of alcohol in the short-term (binge drinking).. have other medical conditions.. are pregnant or plan to become pregnant. INVOKAMET or INVOKAMET XR may harm your unborn baby. If you become pregnant while taking INVOKAMET or INVOKAMET XR, tell your doctor as soon as possible. Talk with your doctor about the best way to control your blood sugar while you are pregnant.. are premenopausal woman (before the change of life), who does not have periods regularly or at all. INVOKAMET or INVOKAMET XR may increase your chance of becoming pregnant. Talk to your doctor about birth control choices while taking INVOKAMET or INVOKAMET XR, if you are not planning to become pregnant. Tell your doctor right away if you become pregnant while taking INVOKAMET or INVOKAMET XR.. are breastfeeding or plan to breastfeed. INVOKAMET or INVOKAMET XR may pass into your breast milk and may harm your baby. Talk with your doctor about the best way to feed your baby if you are taking INVOKAMET or INVOKAMET XR. Do not breastfeed while taking INVOKAMET or INVOKAMET XR.. diuretics (water pills). phenytoin or phenobarbital (used to control seizures). digoxin (Lanoxin(R)) (used to treat heart problems). rifampin (used to treat or prevent tuberculosis). ritonavir (Norvir(R), Kaletra(R)) (used to treat HIV infection). If you are prescribed INVOKAMET, take by mouth times each day with meals exactly as your doctor tells you to take it. Taking INVOKAMET with meals may lower your chance of having an upset stomach.. If you are prescribed INVOKAMET XR, take by mouth time each day with the morning meal exactly as your doctor tells you to take it. Taking INVOKAMET XR with meal may lower your chance of having an upset stomach.. Swallow INVOKAMET XR whole. Do not crush, cut, or chew.. You may sometimes pass soft mass in your stools (bowel movement) that looks like INVOKAMET XR tablets. It is normal to see this in your stool.. Your doctor will tell you how much INVOKAMET or INVOKAMET XR to take and when to take it. Your doctor may change your dose if needed.. Your doctor may tell you to take INVOKAMET or INVOKAMET XR along with other diabetes medicines. Low blood sugar can happen more often when INVOKAMET or INVOKAMET XR is taken with certain other diabetes medicines. See What are the possible side effects of INVOKAMET or INVOKAMET XR. If you miss dose of INVOKAMET, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose and take the medicine at the next regularly scheduled time. Do not take tablets of INVOKAMET at the same time. Talk to your doctor if you have questions about missed dose.. If you miss dose of INVOKAMET XR, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose and take the medicine at the next regularly scheduled time. Do not take more than tablets of INVOKAMET XR at the same time. Talk to your doctor if you have questions about missed dose.. If you take too much INVOKAMET or INVOKAMET XR, call your doctor or go to the nearest hospital emergency room right away.. When your body is under some types of stress, such as fever, trauma (such as car accident), infection, or surgery, the amount of diabetes medicine you need may change. Tell your doctor right away if you have any of these conditions and follow your doctors instructions.. Stay on your prescribed diet and exercise program while taking INVOKAMET or INVOKAMET XR.. Check your blood sugar as your doctor tells you to.. INVOKAMET and INVOKAMET XR will cause your urine to test positive for glucose.. Your doctor may do certain blood tests before you start INVOKAMET or INVOKAMET XR and during treatment as needed. Your doctor may change your dose of INVOKAMET or INVOKAMET XR based on the results of your blood tests.. Your doctor will check your diabetes with regular blood tests, including your blood sugar levels and your hemoglobin A1C.. Avoid drinking alcohol very often, or drinking lot of alcohol in short period of time (binge drinking). It can increase your chances of getting serious side effects.. See What is the most important information should know about INVOKAMET or INVOKAMET XR. dehydration. INVOKAMET or INVOKAMET XR can cause some people to become dehydrated (the loss of too much body water). Dehydration may cause you to feel dizzy, faint, lightheaded, or weak, especially when you stand up (orthostatic hypotension).. have low blood pressure. take medicines to lower your blood pressure, including diuretics (water pill). are on low sodium (salt) diet. have kidney problems. are 65 years of age or older. ketoacidosis (increased ketones in your blood or urine). Ketoacidosis has happened in people who have type diabetes or type diabetes, during treatment with canagliflozin, one of the medicines in INVOKAMET and INVOKAMET XR. Ketoacidosis is serious condition, which may need to be treated in hospital. Ketoacidosis may lead to death. Ketoacidosis can happen with INVOKAMET or INVOKAMET XR, even if your blood sugar is less than 250 mg/dL. Stop taking INVOKAMET or INVOKAMET XR and call your doctor right away if you get any of the following symptoms: nausea. vomiting. stomach area (abdominal) pain. tiredness. trouble breathing. kidney problems. Sudden kidney injury has happened to people taking INVOKAMET or INVOKAMET XR. Talk to your doctor right away if you:reduce the amount of food or liquid you drink for example, if you are sick or cannot eat oryou start to lose liquids from your body for example, from vomiting, diarrhea or being in the sun too long. reduce the amount of food or liquid you drink for example, if you are sick or cannot eat or. you start to lose liquids from your body for example, from vomiting, diarrhea or being in the sun too long.. serious urinary tract infections. Serious urinary tract infections that may lead to hospitalization have happened in people who are taking canagliflozin, one of the medicines in INVOKAMET and INVOKAMET XR. Tell your doctor if you have any signs or symptoms of urinary tract infection such as burning feeling when passing urine, need to urinate often, the need to urinate right away, pain in the lower part of your stomach (pelvis), or blood in the urine. Sometimes people may also have fever, back pain, nausea, or vomiting.. low blood sugar (hypoglycemia). If you take INVOKAMET or INVOKAMET XR with another medicine that can cause low blood sugar, such as sulfonylurea or insulin, your risk of getting low blood sugar is higher. The dose of your sulfonylurea medicine or insulin may need to be lowered while you take INVOKAMET or INVOKAMET XR. Signs and symptoms of low blood sugar may include:. headache. irritability. drowsiness. hunger. weakness. fast heartbeat. confusion. sweating. dizziness. shaking or feeling jittery. rare but serious bacterial infection that causes damage to the tissue under the skin (necrotizing fasciitis) in the area between and around the anus and genitals (perineum). Necrotizing fasciitis of the perineum has happened in women and men who take canagliflozin, one of the medicines in INVOKAMET and INVOKAMET XR. Necrotizing fasciitis of the perineum may lead to hospitalization, may require multiple surgeries, and may lead to death. Seek medical attention immediately if you have fever or you are feeling very weak, tired or uncomfortable (malaise) and you develop any of the following symptoms in the area between and around your anus and genitals:. pain or tenderness. swelling. redness of the skin (erythema). vaginal yeast infection. Women who take INVOKAMET or INVOKAMET XR may get vaginal yeast infections. Symptoms of vaginal yeast infection include:vaginal odorwhite or yellowish vaginal discharge (discharge may be lumpy or look like cottage cheese)vaginal itching vaginal odor. white or yellowish vaginal discharge (discharge may be lumpy or look like cottage cheese). vaginal itching. yeast infection of the penis (balanitis or balanoposthitis). Men who take INVOKAMET or INVOKAMET XR may get yeast infection of the skin around the penis. Certain men who are not circumcised may have swelling of the penis that makes it difficult to pull back the skin around the tip of the penis. Other symptoms of yeast infection of the penis include:. redness, itching, or swelling of the penis. foul smelling discharge from the penis. rash of the penis. pain in the skin around the penis. serious allergic reaction. If you have any symptoms of serious allergic reaction, stop taking INVOKAMET or INVOKAMET XR and call your doctor right away or go to the nearest hospital emergency room. See Who should not take INVOKAMET or INVOKAMET XR. Your doctor may give you medicine for your allergic reaction and prescribe different medicine for your diabetes.. broken bones (fractures). Bone fractures have been seen in patients taking canagliflozin. Talk to your doctor about factors that may increase your risk of bone fracture.. low vitamin B12 (vitamin B12 deficiency). Using metformin for long periods of time may cause decrease in the amount of vitamin B12 in your blood, especially if you have had low vitamin B12 blood levels before. Your doctor may do blood tests to check your vitamin B12 levels.. nausea and vomiting. gas. diarrhea. upset stomach. weakness. indigestion. headache. changes in urination, including urgent need to urinate more often, in larger amounts, or at night. Store INVOKAMET and INVOKAMET XR at room temperature between 68F to 77F (20C to 25C).. Store in the original container to protect from moisture. Storage in pill box or pill organizer is allowed for up to 30 days.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. INVOKAMETThe results of bioequivalence trial in healthy subjects demonstrated that INVOKAMET 50 mg/500 mg, 50 mg/1,000 mg, 150 mg/500 mg and 150 mg/1,000 mg combination tablets are bioequivalent to co-administration of corresponding doses of canagliflozin and metformin HCl as individual tablets under fed conditions.Administration of INVOKAMET 150 mg/1,000 mg fixed-dose combination with food resulted in no change in overall exposure of canagliflozin. There was no change in metformin AUC; however, the mean peak plasma concentration of metformin was decreased by 16% when administered with food. delayed time to peak plasma concentration was observed for both components (a delay of hours for canagliflozin and hour for metformin) under fed conditions. These changes are not likely to be clinically meaningful.. INVOKAMET XRAfter administration of INVOKAMET XR tablets with high-fat breakfast, the peak (Cmax) and total (AUC) exposure of canagliflozin were not altered relative to dosing in the fasted state. However, the AUC of metformin increased by approximately 61% and Cmax increased by approximately 13%.. CanagliflozinThe pharmacokinetics of canagliflozin is essentially similar in healthy subjects and patients with type diabetes. Following single-dose oral administration of 100 mg and 300 mg of canagliflozin, peak plasma concentrations (median Tmax) of canagliflozin occurs within to hours post-dose. Plasma Cmax and AUC of canagliflozin increased in dose-proportional manner from 50 mg to 300 mg. The apparent terminal half-life (t1/2) was 10.6 hours and 13.1 hours for the 100 mg and 300 mg doses, respectively. Steady-state was reached after to days of once-daily dosing with canagliflozin 100 mg to 300 mg. Canagliflozin does not exhibit time-dependent pharmacokinetics and accumulated in plasma up to 36% following multiple doses of 100 mg and 300 mg. The mean systemic exposure (AUC) at steady state was similar following once daily and twice daily dosing regimens at the same total daily dose of 100 mg or 300 mg.. Absorption. CanagliflozinThe mean absolute oral bioavailability of canagliflozin is approximately 65%.. MetforminThe absolute bioavailability of metformin HCl 500 mg tablet given under fasting conditions is approximately 50% to 60%. Trials using single oral doses of metformin hydrochloride 500 to 1,500 mg, and 850 to 2,550 mg, indicate that there is lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination.Following single oral dose of 1,000 mg (two 500 mg tablets) metformin HCl extended-release after meal, the time to reach maximum plasma metformin concentration (Tmax) is achieved at approximately 7-8 hours. In both single and multiple-dose trials in healthy subjects, once daily 1,000 mg (two 500 mg tablets) dosing results in up to 35% higher Cmax, of metformin relative to the immediate-release given as 500 mg twice daily without any change in overall systemic exposure, as measured by AUC.. Distribution. CanagliflozinThe mean steady-state volume of distribution of canagliflozin following single intravenous infusion in healthy subjects was 83.5 L, suggesting extensive tissue distribution. Canagliflozin is extensively bound to proteins in plasma (99%), mainly to albumin. Protein binding is independent of canagliflozin plasma concentrations. Plasma protein binding is not meaningfully altered in patients with renal or hepatic impairment.. MetforminThe apparent volume of distribution (V/F) of metformin following single oral doses of metformin HCl 850 mg immediate-release tablets averaged 654 +- 358 L. Metformin is negligibly bound to plasma proteins, in contrast to sulfonylureas, which are more than 90% protein bound. Metformin partitions into erythrocytes, most likely as function of time. At usual clinical doses and dosing schedules of metformin HCl tablets, steady-state plasma concentrations of metformin are reached within 24 to 48 hours and are generally less than mcg/mL.. Metabolism. CanagliflozinO-glucuronidation is the major metabolic elimination pathway for canagliflozin, which is mainly glucuronidated by UGT1A9 and UGT2B4 to two inactive O-glucuronide metabolites. CYP3A4-mediated (oxidative) metabolism of canagliflozin is minimal (approximately 7%) in humans.. MetforminIntravenous single-dose trials in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) or biliary excretion. Excretion. CanagliflozinFollowing administration of single oral [14C] canagliflozin dose to healthy subjects, 41.5%, 7.0%, and 3.2% of the administered radioactive dose was recovered in feces as canagliflozin, hydroxylated metabolite, and an O-glucuronide metabolite, respectively. Enterohepatic circulation of canagliflozin was negligible.Approximately 33% of the administered radioactive dose was excreted in urine, mainly as O-glucuronide metabolites (30.5%). Less than 1% of the dose was excreted as unchanged canagliflozin in urine. Renal clearance of canagliflozin 100 mg and 300 mg doses ranged from 1.30 to 1.55 mL/min.Mean systemic clearance of canagliflozin was approximately 192 mL/min in healthy subjects following intravenous administration.. MetforminRenal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be compartment of distribution.. Specific PopulationsTrials characterizing the pharmacokinetics of canagliflozin and metformin after administration of INVOKAMET/INVOKAMET XR were not conducted in patients with renal and hepatic impairment. Descriptions of the individual components in this patient population are described below.. Renal Impairment. CanagliflozinA single-dose, open-label trial evaluated the pharmacokinetics of canagliflozin 200 mg in subjects with varying degrees of renal impairment (classified using the MDRD-eGFR formula) compared to healthy subjects.Renal impairment did not affect the Cmax of canagliflozin. Compared to healthy subjects (N=3; eGFR greater than or equal to 90 mL/min/1.73 m2), plasma AUC of canagliflozin was increased by approximately 15%, 29%, and 53% in subjects with mild (N=10), moderate (N=9), and severe (N=10) renal impairment, respectively, (eGFR 60 to less than 90, 30 to less than 60, and 15 to less than 30 mL/min/1.73 m2, respectively), but was similar for ESRD (N=8) subjects and healthy subjects. Increases in canagliflozin AUC of this magnitude are not considered clinically relevant. The pharmacodynamic response to canagliflozin declines with increasing severity of renal impairment [see Contraindications (4) and Warnings and Precautions (5.5)]. Canagliflozin was negligibly removed by hemodialysis.. MetforminIn patients with decreased renal function, the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased [see Contraindications (4) and Warnings and Precautions (5.1)].Following single dose administration of metformin HCl extended-release 500 mg in patients with mild and moderate renal failure (based on measured creatinine clearance), the oral and renal clearance of metformin were decreased by 33% and 50% and 16% and 53%, respectively [see Warnings and Precautions (5.5)]. Metformin peak and systemic exposure was 27% and 61% greater, respectively in mild renal impaired and 74% and 2.36-fold greater in moderate renal impaired patients as compared to healthy subjects [see Contraindications (4) and Warnings and Precautions (5.1)].. Hepatic Impairment. CanagliflozinRelative to subjects with normal hepatic function, the geometric mean ratios for Cmax and AUC of canagliflozin were 107% and 110%, respectively, in subjects with Child-Pugh class (mild hepatic impairment) and 96% and 111%, respectively, in subjects with Child-Pugh class (moderate hepatic impairment) following administration of single 300 mg dose of canagliflozin.These differences are not considered to be clinically meaningful. There is no clinical experience in patients with Child-Pugh class (severe) hepatic impairment [see Warnings and Precautions (5.1)].. MetforminNo pharmacokinetic trials of metformin have been conducted in patients with hepatic insufficiency [see Warnings and Precautions (5.1)].. Pharmacokinetic Effects of Age, Body Mass Index (BMI)/Weight, Gender and Race. CanagliflozinBased on the population PK analysis with data collected from 1526 subjects, age, body mass index (BMI)/weight, gender, and race do not have clinically meaningful effect on the pharmacokinetics of canagliflozin [see Use in Specific Populations (8.5)].. MetforminMetformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type diabetes when analyzed according to gender.No trials of metformin pharmacokinetic parameters according to race have been performed.. CanagliflozinAge had no clinically meaningful effect on the pharmacokinetics of canagliflozin based on population pharmacokinetic analysis [see Adverse Reactions (6.1) and Use in Specific Populations (8.5)].. MetforminLimited data from controlled pharmacokinetic trials of metformin in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged, and Cmax is increased, compared with healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by change in renal function [see Warnings and Precautions (5.1, 5.5) and Use in Specific Populations (8.5)].. Drug-Drug Interactions. INVOKAMET and INVOKAMET XRPharmacokinetic drug interaction trials with INVOKAMET/INVOKAMET XR have not been performed; however, such trials have been conducted with the individual components canagliflozin and metformin hydrochloride.Co-administration of multiple doses of canagliflozin (300 mg) and metformin (2,000 mg) given once daily did not meaningfully alter the pharmacokinetics of either canagliflozin or metformin in healthy subjects.. Canagliflozin. In Vitro Assessment of Drug InteractionsCanagliflozin did not induce CYP450 enzyme expression (3A4, 2C9, 2C19, 2B6, and 1A2) in cultured human hepatocytes. Canagliflozin did not inhibit the CYP450 isoenzymes (1A2, 2A6, 2C19, 2D6, or 2E1) and weakly inhibited CYP2B6, CYP2C8, CYP2C9, and CYP3A4 based on in vitro studies with human hepatic microsomes. Canagliflozin is weak inhibitor of P-gp.Canagliflozin is also substrate of drug transporters P-glycoprotein (P-gp) and MRP2.. In Vivo Assessment of Drug InteractionsTable 7:Effect of Co-Administered Drugs on Systemic Exposures of CanagliflozinCo-Administered DrugDose of Co-Administered DrugSingle dose unless otherwise noted Dose of Canagliflozin Geometric Mean Ratio(Ratio With/Without Co-Administered Drug)No Effect 1.0AUCAUCinf for drugs given as single dose and AUC24h for drugs given as multiple doses (90% CI)Cmax (90% CI)QD once daily; BID twice dailySee Drug Interactions (7.2) for the clinical relevance of the following:Rifampin600 mg QD for days300 mg0.49(0.44; 0.54)0.72(0.61; 0.84)No dose adjustments of canagliflozin required for the following:Cyclosporine400 mg300 mg QD for days1.23(1.19; 1.27)1.01(0.91; 1.11)Ethinyl estradiol and levonorgestrel0.03 mg ethinyl estradiol and 0.15 mg levonorgestrel200 mg QD for days0.91(0.88; 0.94)0.92(0.84; 0.99)Hydrochlorothiazide25 mg QD for 35 days300 mg QD for days1.12(1.08; 1.17)1.15(1.06; 1.25)Metformin2,000 mg300 mg QD for days1.10(1.05; 1.15)1.05(0.96; 1.16)Probenecid500 mg BID for days300 mg QD for 17 days1.21(1.16; 1.25)1.13(1.00; 1.28)Table 8:Effect of Canagliflozin on Systemic Exposure of Co-Administered DrugsCo-Administered DrugDose of Co-Administered DrugSingle dose unless otherwise noted Dose of Canagliflozin Geometric Mean Ratio(Ratio With/Without Co-Administered Drug)No Effect 1.0AUCAUCinf for drugs given as single dose and AUC24h for drugs given as multiple doses (90% CI)Cmax (90% CI)QD once daily; BID twice daily; INR International Normalized RatioSee Drug Interactions (7.2) for the clinical relevance of the following:Digoxin0.5 mg QD first day followed by 0.25 mg QD for days300 mg QD for daysDigoxin1.20(1.12; 1.28)1.36(1.21; 1.53)No dose adjustments of co-administered drug required for the following:Acetaminophen1,000 mg300 mg BID for 25 daysAcetaminophen1.06AUC0-12h (0.98; 1.14)1.00(0.92; 1.09)Ethinyl estradiol and levonorgestrel0.03 mg ethinyl estradiol and 0.15 mg levonorgestrel200 mg QD for daysethinyl estradiol1.07(0.99; 1.15)1.22(1.10; 1.35)Levonorgestrel1.06(1.00; 1.13)1.22(1.11; 1.35)Glyburide1.25 mg200 mg QD for daysGlyburide1.02(0.98; 1.07)0.93(0.85; 1.01)3-cis-hydroxy-glyburide1.01(0.96; 1.07)0.99(0.91; 1.08)4-trans-hydroxy-glyburide1.03(0.97; 1.09)0.96(0.88; 1.04)Hydrochlorothiazide25 mg QD for 35 days300 mg QD for daysHydrochlorothiazide0.99(0.95; 1.04)0.94(0.87; 1.01)Metformin2,000 mg300 mg QD for daysMetformin1.20(1.08; 1.34)1.06(0.93; 1.20)Simvastatin40 mg300 mg QD for daysSimvastatin1.12(0.94; 1.33)1.09(0.91; 1.31)simvastatin acid1.18(1.03; 1.35)1.26(1.10; 1.45)Warfarin30 mg300 mg QD for 12 days(R)-warfarin1.01(0.96; 1.06)1.03(0.94; 1.13)(S)-warfarin1.06(1.00; 1.12)1.01(0.90; 1.13)INR1.00(0.98; 1.03)1.05(0.99; 1.12). MetforminTable 9:Effect of Co-Administered Drugs on Plasma Metformin Systemic ExposuresCo-Administered DrugDose of Co-Administered DrugSingle dose unless otherwise noted Dose of Metformin HCl Geometric Mean Ratio(Ratio With/Without Co-Administered Drug)No Effect 1.00AUCAUC AUC0- Cmax No dose adjustments required for the following:Glyburide5 mg500 mgMetformin HCl extended-release tablets 500 mg 0.98Ratio of arithmetic means 0.99 Furosemide40 mg850 mg1.09 1.22 Nifedipine10 mg850 mg1.161.21Propranolol40 mg850 mg0.900.94Ibuprofen400 mg850 mg1.05 1.07 Drugs that are eliminated by renal tubular secretion increase the accumulation of metformin [see Warnings and Precautions (5) and Drug Interactions (7)]Cimetidine400 mg850 mg1.401.61Carbonic anhydrase inhibitors may cause metabolic acidosis [see Warnings and Precautions (5) and Drug Interactions (7)]TopiramateHealthy volunteer study at steady state with topiramate 100 mg every 12 hours and metformin 500 mg every 12 hours for days. Study conducted to assess pharmacokinetics only 100 mg500 mg1.25Steady state AUC0-12h. 1.18Table 10:Effect of Metformin on Co-Administered Drug Systemic ExposuresCo-Administered DrugDose of Co-Administered DrugSingle dose unless otherwise noted Dose of Metformin HCl Geometric Mean Ratio(Ratio With/Without Co-Administered Drug)No Effect 1.00AUCAUC AUC0- Cmax No dose adjustments required for the following:Glyburide5 mg500 mgAUC0-24 hr reported 0.78Ratio of arithmetic means, p-value of difference <0.05 0.63 Furosemide40 mg850 mg0.87 0.69 Nifedipine10 mg850 mg1.10 1.08Propranolol40 mg850 mg1.01 0.94Ibuprofen400 mg850 mg0.97Ratio of arithmetic means. 1.01 Cimetidine400 mg850 mg0.95 1.01Metformin is negligibly bound to plasma proteins and is, therefore, less likely to interact with highly protein-bound drugs such as salicylates, sulfonamides, chloramphenicol, and probenecid.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following important adverse reactions are also discussed elsewhere in the labeling:Lactic Acidosis [see Boxed Warning and Warnings and Precautions (5.1, 5.5)] Lower Limb Amputation [see Boxed Warning and Warnings and Precautions (5.2)] Hypotension [see Warnings and Precautions (5.3)] Ketoacidosis [see Warnings and Precautions (5.4)] Acute Kidney Injury [see Warnings and Precautions (5.5)] Urosepsis and Pyelonephritis [see Warnings and Precautions (5.6)] Hypoglycemia with Concomitant Use of Sulfonylurea or Insulin [see Warnings and Precautions (5.7)] Necrotizing Fasciitis of the Perineum (Fourniers gangrene) [see Warnings and Precautions (5.8)] Genital Mycotic Infections [see Warnings and Precautions (5.9)] Hypersensitivity Reactions [see Warnings and Precautions (5.10)] Bone Fracture [see Warnings and Precautions (5.11)] Vitamin B12 Deficiency [see Warnings and Precautions (5.12)] Increases in Low-Density Lipoprotein (LDL-C) [see Warnings and Precautions (5.13)] Lactic Acidosis [see Boxed Warning and Warnings and Precautions (5.1, 5.5)] Lower Limb Amputation [see Boxed Warning and Warnings and Precautions (5.2)] Hypotension [see Warnings and Precautions (5.3)] Ketoacidosis [see Warnings and Precautions (5.4)] Acute Kidney Injury [see Warnings and Precautions (5.5)] Urosepsis and Pyelonephritis [see Warnings and Precautions (5.6)] Hypoglycemia with Concomitant Use of Sulfonylurea or Insulin [see Warnings and Precautions (5.7)] Necrotizing Fasciitis of the Perineum (Fourniers gangrene) [see Warnings and Precautions (5.8)] Genital Mycotic Infections [see Warnings and Precautions (5.9)] Hypersensitivity Reactions [see Warnings and Precautions (5.10)] Bone Fracture [see Warnings and Precautions (5.11)] Vitamin B12 Deficiency [see Warnings and Precautions (5.12)] Increases in Low-Density Lipoprotein (LDL-C) [see Warnings and Precautions (5.13)] Most common adverse reactions associated with canagliflozin (5% or greater incidence): female genital mycotic infections, urinary tract infection, and increased urination (6.1)Most common adverse reactions associated with metformin (5% or greater incidence) are diarrhea, nausea, vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Janssen Pharmaceuticals, Inc. at 1-800-526-7736 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. Most common adverse reactions associated with canagliflozin (5% or greater incidence): female genital mycotic infections, urinary tract infection, and increased urination (6.1). Most common adverse reactions associated with metformin (5% or greater incidence) are diarrhea, nausea, vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache (6.1). 6.1Clinical Studies Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.. Pool of Placebo-Controlled Trials. CanagliflozinThe data in Table is derived from four 26-week placebo-controlled trials where canagliflozin was used as monotherapy in one trial and as add-on therapy in three trials. These data reflect exposure of 1,667 patients to canagliflozin and mean duration of exposure to canagliflozin of 24 weeks with 1,275 patients exposed to combination of canagliflozin and metformin. Patients received canagliflozin 100 mg (N=833), canagliflozin 300 mg (N=834) or placebo (N=646) once daily. The mean daily dose of metformin HCl was 2,138 mg (SD 337.3) for the 1,275 patients in the three placebo-controlled metformin add-on trials. The mean age of the population was 56 years and 2% were older than 75 years of age. Fifty percent (50%) of the population was male and 72% were Caucasian, 12% were Asian, and 5% were Black or African American. At baseline the population had diabetes for an average of 7.3 years, had mean HbA1C of 8.0% and 20% had established microvascular complications of diabetes. Baseline renal function was normal or mildly impaired (mean eGFR 88 mL/min/1.73 m2).Table shows common adverse reactions associated with the use of canagliflozin. These adverse reactions were not present at baseline, occurred more commonly on canagliflozin than on placebo, and occurred in at least 2% of patients treated with either canagliflozin 100 mg or canagliflozin 300 mg.Table 1:Adverse Reactions From Pool of Four 26-Week Placebo-Controlled Studies Reported in >= 2% of Canagliflozin-Treated PatientsThe four placebo-controlled trials included one monotherapy trial and three add-on combination trials with metformin, metformin and sulfonylurea, or metformin and pioglitazone. Adverse ReactionPlaceboN=646 Canagliflozin100 mgN=833Canagliflozin300 mgN=834Note: Percentages were weighted by studies. Study weights were proportional to the harmonic mean of the three treatment sample sizes.Urinary tract infectionsUrinary tract infections include the following adverse reactions: Urinary tract infection, Cystitis, Kidney infection, and Urosepsis. 3.8%5.9%4.4%Increased urinationIncreased urination includes the following adverse reactions: Polyuria, Pollakiuria, Urine output increased, Micturition urgency, and Nocturia. 0.7%5.1%4.6%ThirstThirst includes the following adverse reactions: Thirst, Dry mouth, and Polydipsia. 0.1%2.8%2.4%Constipation0.9%1.8%2.4%Nausea1.6%2.1%2.3%N=312 N=425N=430Female genital mycotic infectionsFemale genital mycotic infections include the following adverse reactions: Vulvovaginal candidiasis, Vulvovaginal mycotic infection, Vulvovaginitis, Vaginal infection, Vulvitis, and Genital infection fungal. 2.8%10.6%11.6%Vulvovaginal pruritus0.0%1.6%3.2%N=334N=408N=404Male genital mycotic infectionsMale genital mycotic infections include the following adverse reactions: Balanitis or Balanoposthitis, Balanitis candida, and Genital infection fungal. 0.7%4.2%3.8%Abdominal pain was also more commonly reported in patients taking canagliflozin 100 mg (1.8%), 300 mg (1.7%) than in patients taking placebo (0.8%).. Canagliflozin and MetforminThe incidence and type of adverse reactions in the three 26-week placebo-controlled metformin add-on trials, representing majority of data from the four 26-week placebo-controlled trials, was similar to the adverse reactions described in Table 1. There were no additional adverse reactions identified in the pooling of these three placebo-controlled trials that included metformin relative to the four placebo-controlled trials.In trial with canagliflozin as initial combination therapy with metformin [see Clinical Studies (14.1)], an increased incidence of diarrhea was observed in the canagliflozin and metformin combination groups (4.2%) compared to canagliflozin or metformin monotherapy groups (1.7%).. Pool of Placebo- and Active-Controlled Trials CanagliflozinThe occurrence of adverse reactions for canagliflozin was evaluated in patients participating in placebo- and active-controlled trials and in an integrated analysis of two cardiovascular trials.The types and frequency of common adverse reactions observed in the pool of eight clinical trials (which reflect an exposure of 6,177 patients to canagliflozin) were consistent with those listed in Table 1. Percentages were weighted by studies. Study weights were proportional to the harmonic mean of the three treatment sample sizes. In this pool, canagliflozin was also associated with the adverse reactions of fatigue (1.8%, 2.2%, and 2.0% with comparator, canagliflozin 100 mg, and canagliflozin 300 mg, respectively) and loss of strength or energy (i.e., asthenia) (0.6%, 0.7%, and 1.1% with comparator, canagliflozin 100 mg, and canagliflozin 300 mg, respectively).In the pool of eight clinical trials, the incidence rate of pancreatitis (acute or chronic) was 0.1%, 0.2%, and 0.1% receiving comparator, canagliflozin 100 mg, and canagliflozin 300 mg, respectively.In the pool of eight clinical trials, hypersensitivity-related adverse reactions (including erythema, rash, pruritus, urticaria, and angioedema) was 3.0%, 3.8%, and 4.2% of patients receiving comparator, canagliflozin 100 mg, and canagliflozin 300 mg, respectively. Five patients experienced serious adverse reactions of hypersensitivity with canagliflozin, which included patients with urticaria and patient with diffuse rash and urticaria occurring within hours of exposure to canagliflozin. Among these patients, patients discontinued canagliflozin. One patient with urticaria had recurrence when canagliflozin was re-initiated.Photosensitivity-related adverse reactions (including photosensitivity reaction, polymorphic light eruption, and sunburn) occurred in 0.1%, 0.2%, and 0.2% of patients receiving comparator, canagliflozin 100 mg, and canagliflozin 300 mg, respectively.Other adverse reactions occurring more frequently on canagliflozin than on comparator were:. Lower Limb AmputationAn approximately 2-fold increased risk of lower limb amputations associated with canagliflozin was observed in CANVAS and CANVAS-R, two randomized, placebo-controlled trials evaluating patients with type diabetes who had either established cardiovascular disease or were at risk for cardiovascular disease. Patients in CANVAS and CANVAS-R were followed for an average of 5.7 and 2.1 years, respectively [see Clinical Studies (14.2)]. The amputation data for CANVAS and CANVAS-R are shown in Tables and 3, respectively [see Warnings and Precautions (5.2)]. Table 2:CANVAS AmputationsPlaceboN=1441Canagliflozin100 mgN=1445Canagliflozin300 mgN=1441Canagliflozin(Pooled)N=2886Note: Incidence is based on the number of patients with at least one amputation, and not the total number of amputation events. patients follow-up is calculated from Day to the first amputation event date. Some patients had more than one amputation.Patients with an amputation, (%)22 (1.5)50 (3.5)45 (3.1)95 (3.3)Total amputations338379162Amputation incidence rate(per 1000 patient-years)2.86.25.55.9Hazard Ratio (95% CI)--2.24 (1.36, 3.69)2.01 (1.20, 3.34)2.12 (1.34, 3.38)Table 3:CANVAS-R AmputationsPlaceboN=2903Canagliflozin100 mg(with up-titration to 300 mg)N=2904Note: Incidence is based on the number of patients with at least one amputation, and not the total number of amputation events. patients follow-up is calculated from Day to the first amputation event date. Some patients had more than one amputation.Patients with an amputation, (%)25 (0.9)45 (1.5)Total amputations3659Amputation incidence rate(per 1000 patient-years)4.27.5Hazard Ratio (95% CI)--1.80 (1.10, 2.93). Renal Cell CarcinomaIn the CANVAS trial (mean duration of follow-up of 5.7 years) [see Clinical Studies (14.2)], the incidence of renal cell carcinoma was 0.15% (2/1331) and 0.29% (8/2716) for placebo and canagliflozin, respectively, excluding patients with less than months of follow-up, less than 90 days of treatment, or history of renal cell carcinoma. causal relationship to canagliflozin could not be established due to the limited number of cases.. Volume Depletion-Related Adverse ReactionsCanagliflozin results in an osmotic diuresis, which may lead to reductions in intravascular volume. In clinical trials, treatment with canagliflozin was associated with dose-dependent increase in the incidence of volume depletion-related adverse reactions (e.g., hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration). An increased incidence was observed in patients on the 300 mg dose. The three factors associated with the largest increase in volume depletion-related adverse reactions were the use of loop diuretics, moderate renal impairment (eGFR 30 to less than 60 mL/min/1.73 m2), and age 75 years and older (Table 4) [see Dosage and Administration (2.1), Warnings and Precautions (5.3), and Use in Specific Populations (8.5 and 8.6)].Table 4:Patients With at Least One Volume Depletion-Related Adverse Reaction (Pooled Results from Clinical Trials)Baseline CharacteristicComparator GroupIncludes placebo and active-comparator groups %Canagliflozin 100 mg%Canagliflozin 300 mg%Overall population1.5%2.3%3.4%75 years of age and olderPatients could have more than of the listed risk factors 2.6%4.9%8.7%eGFR less than 60 mL/min/1.73 m2 2.5%4.7%8.1%Use of loop diuretic 4.7%3.2%8.8%. FallsIn pool of nine clinical trials with mean duration of exposure to canagliflozin of 85 weeks, the proportion of patients who experienced falls was 1.3%, 1.5%, and 2.1% with comparator, canagliflozin 100 mg, and canagliflozin 300 mg, respectively. The higher risk of falls for patients treated with canagliflozin was observed within the first few weeks of treatment.. Impairment in Renal FunctionInitiation of canagliflozin is associated with dose-dependent increase in serum creatinine and concomitant fall in estimated GFR (Table 5) [see Warnings and Precautions (5.5)]. The effect on eGFR was observed to reverse after treatment discontinuation suggesting acute hemodynamic changes may play role in the renal function changes observed with canagliflozin.Table 5:Changes in Serum Creatinine and eGFR Associated with Canagliflozin in the Pool of Four Placebo-Controlled Trials and Moderate Renal Impairment TrialPlaceboN=646Canagliflozin 100 mgN=833Canagliflozin 300 mgN=834Pool of Four Placebo-Controlled TrialsBaselineCreatinine (mg/dL)0.840.820.82eGFR (mL/min/1.73 m2)87.088.388.8Week ChangeCreatinine (mg/dL)0.010.030.05eGFR (mL/min/1.73 m2)-1.6-3.8-5.0End of Treatment ChangeWeek 26 in mITT LOCF population Creatinine (mg/dL)0.010.020.03eGFR (mL/min/1.73 m2)-1.6-2.3-3.4PlaceboN=90Canagliflozin 100 mgN=90Canagliflozin 300 mgN=89Moderate Renal Impairment TrialBaselineCreatinine (mg/dL)1.611.621.63eGFR (mL/min/1.73 m2)40.139.738.5Week ChangeCreatinine (mg/dL)0.030.180.28eGFR (mL/min/1.73 m2)-0.7-4.6-6.2End of Treatment Change Creatinine (mg/dL)0.070.160.18eGFR (mL/min/1.73 m2)-1.5-3.6-4.0In the pool of four placebo-controlled trials where patients had normal or mildly impaired baseline renal function, the proportion of patients who experienced at least one event of significant renal function decline, defined as an eGFR below 80 mL/min/1.73 m2 and 30% lower than baseline, was 2.1% with placebo, 2.0% with canagliflozin 100 mg, and 4.1% with canagliflozin 300 mg. At the end of treatment, 0.5% with placebo, 0.7% with canagliflozin 100 mg, and 1.4% with canagliflozin 300 mg had significant renal function decline.Patients with moderate renal impairment at baseline experience larger mean changes in eGFR relative to patients with normal or mildly impaired renal function. In trial in patients with moderate renal impairment with baseline eGFR of 30 to less than 50 mL/min/1.73 m2 (mean baseline eGFR 39 mL/min/1.73 m2) [see Clinical Studies (14.1)], the proportion of patients who experienced at least one event of significant renal function decline, defined as an eGFR 30% lower than baseline, was 6.9%, 18%, and 22.5% with placebo, canagliflozin 100 mg, canagliflozin 300 mg, respectively. At the end of treatment, 4.6%, 3.4%, and 2.2% of patients treated with placebo, canagliflozin 100 mg, and canagliflozin 300 mg, respectively, had significant renal function decline.. Genital Mycotic InfectionsIn the pool of four placebo-controlled clinical trials, female genital mycotic infections (e.g., vulvovaginal mycotic infection, vulvovaginal candidiasis, and vulvovaginitis) occurred in 2.8%, 10.6%, and 11.6% of females treated with placebo, canagliflozin 100 mg, and canagliflozin 300 mg, respectively. Patients with history of genital mycotic infections were more likely to develop genital mycotic infections on canagliflozin. Female patients who developed genital mycotic infections on canagliflozin were more likely to experience recurrence and require treatment with oral or topical antifungal agents and anti-microbial agents. In females, discontinuation due to genital mycotic infections occurred in 0% and 0.7% of patients treated with placebo and canagliflozin, respectively [see Warnings and Precautions (5.9)].In the pool of four placebo-controlled clinical trials, male genital mycotic infections (e.g., candidal balanitis, balanoposthitis) occurred in 0.7%, 4.2%, and 3.8% of males treated with placebo, canagliflozin 100 mg, and canagliflozin 300 mg, respectively. Male genital mycotic infections occurred more commonly in uncircumcised males and in males with prior history of balanitis or balanoposthitis. Male patients who developed genital mycotic infections on canagliflozin were more likely to experience recurrent infections (22% on canagliflozin versus none on placebo), and require treatment with oral or topical antifungal agents and anti-microbial agents than patients on comparators. In males, discontinuations due to genital mycotic infections occurred in 0% and 0.5% of patients treated with placebo and canagliflozin, respectively.In the pooled analysis of controlled trials, phimosis was reported in 0.3% of uncircumcised male patients treated with canagliflozin and 0.2% required circumcision to treat the phimosis [see Warnings and Precautions (5.9)].. HypoglycemiaIn canagliflozin clinical trials, hypoglycemia was defined as any event regardless of symptoms, where biochemical hypoglycemia was documented (any glucose value below or equal to 70 mg/dL). Severe hypoglycemia was defined as an event consistent with hypoglycemia where the patient required the assistance of another person to recover, lost consciousness, or experienced seizure (regardless of whether biochemical documentation of low glucose value was obtained). In individual clinical trials [see Clinical Studies (14.1)], episodes of hypoglycemia occurred at higher rate when canagliflozin was co-administered with insulin or sulfonylureas (Table 6) [see Warnings and Precautions (5.7)].Table 6:Incidence of HypoglycemiaNumber of patients experiencing at least one event of hypoglycemia based on either biochemically documented episodes or severe hypoglycemic events in the intent-to-treat population in Controlled Clinical StudiesMonotherapy(26 weeks)Placebo(N=192)Canagliflozin 100 mg(N=195)Canagliflozin 300 mg(N=197)Overall [N (%)]5 (2.6)7 (3.6)6 (3.0)In Combination with Metformin(26 weeks)Placebo Metformin(N=183)Canagliflozin 100 mg Metformin(N=368)Canagliflozin 300 mg Metformin(N=367)Overall [N (%)]3 (1.6)16 (4.3)17 (4.6)Severe [N (%)]Severe episodes of hypoglycemia were defined as those where the patient required the assistance of another person to recover, lost consciousness, or experienced seizure (regardless of whether biochemical documentation of low glucose value was obtained) (0)1 (0.3)1 (0.3)In Combination with Metformin (18 weeks)Phase clinical study with twice daily dosing (50 mg or 150 mg twice daily in combination with metformin)Placebo(N=93)Canagliflozin 100 mg(N=93)Canagliflozin 300 mg(N=93)Overall [N (%)]3 (3.2)4 (4.3)3 (3.2)In Combination with Metformin Sulfonylurea(26 weeks)Placebo Metformin Sulfonylurea(N=156)Canagliflozin 100 mg Metformin Sulfonylurea(N=157)Canagliflozin 300 mg Metformin Sulfonylurea(N=156)Overall [N (%)]24 (15.4)43 (27.4)47 (30.1)Severe [N (%)] (0.6)1 (0.6)0In Combination with Metformin Pioglitazone(26 weeks)Placebo Metformin Pioglitazone(N=115)Canagliflozin 100 mg Metformin Pioglitazone(N=113)Canagliflozin 300 mg Metformin Pioglitazone(N=114)Overall [N (%)]3 (2.6)3 (2.7)6 (5.3)In Combination with Insulin(18 weeks)Placebo(N=565)Canagliflozin 100 mg(N=566)Canagliflozin 300 mg(N=587)Overall [N (%)]208 (36.8)279 (49.3)285 (48.6)Severe [N (%)] 14 (2.5)10 (1.8)16 (2.7)In Combination with Insulin and Metformin (18 weeks)Subgroup of patients (N=287) from insulin substudy on canagliflozin in combination with metformin and insulin (with or without other antiglycemic agents)Placebo(N=145)Canagliflozin 100 mg(N=139)Canagliflozin 300 mg(N=148)Overall [N (%)]66 (45.5)58 (41.7)70 (47.3)Severe [N (%)] (2.8)1 (0.7)3 (2.0). Bone FractureIn the CANVAS trial [see Clinical Studies (14.2)], the incidence rates of all adjudicated bone fracture were 1.09, 1.59, and 1.79 events per 100 patient-years of follow-up to placebo, canagliflozin 100 mg, and canagliflozin 300 mg, respectively. The fracture imbalance was observed within the first 26 weeks of therapy and remained through the end of the trial. Fractures were more likely to be low trauma (e.g., fall from no more than standing height), and affect the distal portion of upper and lower extremities [see Warnings and Precautions (5.11)].. MetforminThe most common adverse reactions (5% or greater incidence) due to initiation of metformin are diarrhea, nausea, vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache.Long-term treatment with metformin has been associated with decrease in vitamin B12, which may result in clinically significant vitamin B12 deficiency (e.g., megaloblastic anemia) [see Warnings and Precautions (5.12)].. Laboratory and Imaging Tests. Increases in Serum PotassiumIn pooled population of patients (N=723) with moderate renal impairment (eGFR 45 to less than 60 mL/min/1.73 m2), increases in serum potassium to greater than 5.4 mEq/L and 15% above occurred in 5.3%, 5.0%, and 8.8% of patients treated with placebo, canagliflozin 100 mg, and canagliflozin 300 mg, respectively. Severe elevations (greater than or equal to 6.5 mEq/L) occurred in 0.4% of patients treated with placebo, no patients treated with canagliflozin 100 mg, and 1.3% of patients treated with canagliflozin 300 mg.In these patients, increases in potassium were more commonly seen in those with elevated potassium at baseline. Among patients with moderate renal impairment, approximately 84% were taking medications that interfere with potassium excretion, such as potassium-sparing diuretics, angiotensin-converting-enzyme inhibitors, and angiotensin-receptor blockers [see Warnings and Precautions (5.3) and Use in Specific Populations (8.6)]. Increases in Serum MagnesiumDose-related increases in serum magnesium were observed early after initiation of canagliflozin (within weeks) and remained elevated throughout treatment. In the pool of four placebo-controlled trials, the mean percent change in serum magnesium levels was 8.1% and 9.3% with canagliflozin 100 mg and canagliflozin 300 mg, respectively, compared to -0.6% with placebo. In trial of patients with moderate renal impairment, serum magnesium levels increased by 0.2%, 9.2%, and 14.8% with placebo, canagliflozin 100 mg, and canagliflozin 300 mg, respectively.. Increases in Serum PhosphateDose-related increases in serum phosphate levels were observed with canagliflozin. In the pool of four placebo-controlled trials, the mean percent change in serum phosphate levels were 3.6% and 5.1% with canagliflozin 100 mg and canagliflozin 300 mg, respectively, compared to 1.5% with placebo. In trial of patients with moderate renal impairment, the mean serum phosphate levels increased by 1.2%, 5.0%, and 9.3% with placebo, canagliflozin 100 mg, and canagliflozin 300 mg, respectively.. Increases in Low-Density Lipoprotein Cholesterol (LDL-C) and non-High-Density Lipoprotein Cholesterol (non-HDL-C)In the pool of four placebo-controlled trials, dose-related increases in LDL-C with canagliflozin were observed. Mean changes (percent changes) from baseline in LDL-C relative to placebo were 4.4 mg/dL (4.5%) and 8.2 mg/dL (8.0%) with canagliflozin 100 mg and canagliflozin 300 mg, respectively. The mean baseline LDL-C levels were 104 to 110 mg/dL across treatment groups [see Warnings and Precautions (5.13)].Dose-related increases in non-HDL-C with canagliflozin were observed. Mean changes (percent changes) from baseline in non-HDL-C relative to placebo were 2.1 mg/dL (1.5%) and 5.1 mg/dL (3.6%) with canagliflozin 100 mg and 300 mg, respectively. The mean baseline non-HDL-C levels were 140 to 147 mg/dL across treatment groups.. Increases in HemoglobinIn the pool of four placebo-controlled trials, mean changes (percent changes) from baseline in hemoglobin were -0.18 g/dL (-1.1%) with placebo, 0.47 g/dL (3.5%) with canagliflozin 100 mg, and 0.51 g/dL (3.8%) with canagliflozin 300 mg. The mean baseline hemoglobin value was approximately 14.1 g/dL across treatment groups. At the end of treatment, 0.8%, 4.0%, and 2.7% of patients treated with placebo, canagliflozin 100 mg, and canagliflozin 300 mg, respectively, had hemoglobin above the upper limit of normal.. Decreases in Bone Mineral DensityBone mineral density (BMD) was measured by dual-energy X-ray absorptiometry in clinical trial of 714 older adults (mean age 64 years). At years, patients randomized to canagliflozin 100 mg and canagliflozin 300 mg had placebo-corrected declines in BMD at the total hip of 0.9% and 1.2%, respectively, and at the lumbar spine of 0.3% and 0.7%, respectively. Additionally, placebo-adjusted BMD declines were 0.1% at the femoral neck for both canagliflozin doses and 0.4% at the distal forearm for patients randomized to canagliflozin 300 mg. The placebo-adjusted change at the distal forearm for patients randomized to canagliflozin 100 mg was 0%.. 6.2Postmarketing Experience. Additional adverse reactions have been identified during post-approval use of canagliflozin. Because these reactions are reported voluntarily from population of uncertain size, it is generally not possible to reliably estimate their frequency or establish causal relationship to drug exposure.CanagliflozinKetoacidosisAcute Kidney InjuryAnaphylaxis, AngioedemaUrosepsis and PyelonephritisNecrotizing Fasciitis of the Perineum (Fourniers gangrene)Metformin Cholestatic, hepatocellular, and mixed hepatocellular liver injury.

BOXED WARNING SECTION.

WARNING: LACTIC ACIDOSIS and LOWER LIMB AMPUTATION. WARNING:LACTIC ACIDOSIS and LOWER LIMB AMPUTATIONSee full prescribing information for complete boxed warning.Lactic AcidosisPostmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. Symptoms included malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Laboratory abnormalities included elevated blood lactate levels, anion gap acidosis, increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL. (5.1)Risk factors include renal impairment, concomitant use of certain drugs, age >65 years old, radiological studies with contrast, surgery and other procedures, hypoxic states, 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. (5.1)If lactic acidosis is suspected, discontinue INVOKAMET/INVOKAMET XR and institute general supportive measures in hospital setting. Prompt hemodialysis is recommended. (5.1)Risk of Lower Limb AmputationIn patients with type diabetes who have established cardiovascular disease (CVD) or at risk for CVD, canagliflozin, component of INVOKAMET/INVOKAMET XR, has been associated with lower limb amputations, most frequently of the toe and midfoot; some also involved the leg. (5.2)Before initiating, consider factors that may increase the risk of amputation. Monitor patients receiving INVOKAMET/INVOKAMET XR for infections or ulcers of the lower limbs, and discontinue if these occur. (5.2). Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. Symptoms included malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Laboratory abnormalities included elevated blood lactate levels, anion gap acidosis, increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL. (5.1). Risk factors include renal impairment, concomitant use of certain drugs, age >65 years old, radiological studies with contrast, surgery and other procedures, hypoxic states, 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. (5.1). If lactic acidosis is suspected, discontinue INVOKAMET/INVOKAMET XR and institute general supportive measures in hospital setting. Prompt hemodialysis is recommended. (5.1). In patients with type diabetes who have established cardiovascular disease (CVD) or at risk for CVD, canagliflozin, component of INVOKAMET/INVOKAMET XR, has been associated with lower limb amputations, most frequently of the toe and midfoot; some also involved the leg. (5.2). Before initiating, consider factors that may increase the risk of amputation. Monitor patients receiving INVOKAMET/INVOKAMET XR for infections or ulcers of the lower limbs, and discontinue if these occur. (5.2). Lactic AcidosisPost-marketing 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 (> mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL [see Warnings and Precautions (5.1)].Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment [see Warnings and Precautions (5.1)].Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the full prescribing information [see Dosage and Administration (2.2, 2.3), Contraindications (4), Warnings and Precautions (5.1), Drug Interactions (7), and Use in Specific Populations (8.6, 8.7)].If metformin-associated lactic acidosis is suspected, immediately discontinue INVOKAMET/INVOKAMET XR and institute general supportive measures in hospital setting. Prompt hemodialysis is recommended [see Warnings and Precautions (5.1)].. Post-marketing 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 (> mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL [see Warnings and Precautions (5.1)].. Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment [see Warnings and Precautions (5.1)].. Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the full prescribing information [see Dosage and Administration (2.2, 2.3), Contraindications (4), Warnings and Precautions (5.1), Drug Interactions (7), and Use in Specific Populations (8.6, 8.7)].. If metformin-associated lactic acidosis is suspected, immediately discontinue INVOKAMET/INVOKAMET XR and institute general supportive measures in hospital setting. Prompt hemodialysis is recommended [see Warnings and Precautions (5.1)].. Risk of Lower Limb AmputationAn approximately 2-fold increased risk of lower limb amputations associated with canagliflozin, component of INVOKAMET/INVOKAMET XR, was observed in CANVAS and CANVAS-R, two large, randomized, placebo-controlled trials in patients with type diabetes who had established cardiovascular disease (CVD) or were at risk for CVD [see Warnings and Precautions (5.2)].Amputations of the toe and midfoot were most frequent; however, amputations involving the leg were also observed. Some patients had multiple amputations, some involving both limbs [see Warnings and Precautions (5.2)]. Before initiating, consider factors that may increase the risk of amputation, such as history of prior amputation, peripheral vascular disease, neuropathy, and diabetic foot ulcers [see Warnings and Precautions (5.2)]. Monitor patients receiving INVOKAMET/INVOKAMET XR for infection, new pain or tenderness, sores or ulcers involving the lower limbs, and discontinue if these complications occur [see Warnings and Precautions (5.2)].. An approximately 2-fold increased risk of lower limb amputations associated with canagliflozin, component of INVOKAMET/INVOKAMET XR, was observed in CANVAS and CANVAS-R, two large, randomized, placebo-controlled trials in patients with type diabetes who had established cardiovascular disease (CVD) or were at risk for CVD [see Warnings and Precautions (5.2)].. Amputations of the toe and midfoot were most frequent; however, amputations involving the leg were also observed. Some patients had multiple amputations, some involving both limbs [see Warnings and Precautions (5.2)]. Before initiating, consider factors that may increase the risk of amputation, such as history of prior amputation, peripheral vascular disease, neuropathy, and diabetic foot ulcers [see Warnings and Precautions (5.2)]. Monitor patients receiving INVOKAMET/INVOKAMET XR for infection, new pain or tenderness, sores or ulcers involving the lower limbs, and discontinue if these complications occur [see Warnings and Precautions (5.2)].

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1Mechanism of Action. CanagliflozinSodium-glucose co-transporter (SGLT2), expressed in the proximal renal tubules, is responsible for the majority of the reabsorption of filtered glucose from the tubular lumen. Canagliflozin is an inhibitor of SGLT2. By inhibiting SGLT2, canagliflozin reduces reabsorption of filtered glucose and lowers the renal threshold for glucose (RTG), and thereby increases urinary glucose excretion (UGE).. MetforminMetformin is an antihyperglycemic agent which improves glucose tolerance in patients with type diabetes, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may decrease.. 12.2 Pharmacodynamics. CanagliflozinFollowing single and multiple oral doses of canagliflozin in patients with type diabetes, dose-dependent decreases in RTG and increases in urinary glucose excretion were observed. From starting RTG value of approximately 240 mg/dL, canagliflozin at 100 mg and 300 mg once daily suppressed RTG throughout the 24-hour period. Maximal suppression of mean RTG over the 24-hour period was seen with the 300 mg daily dose to approximately 70 to 90 mg/dL in patients with type diabetes in Phase trials. The reductions in RTG led to increases in mean UGE of approximately 100 g/day in patients with type diabetes treated with either 100 mg or 300 mg of canagliflozin. The 24-h mean RTG at steady state was similar following once daily and twice daily dosing regimens at the same total daily dose of 100 mg or 300 mg. In patients with type diabetes given 100 to 300 mg once daily over 16-day dosing period, reductions in RTG and increases in urinary glucose excretion were observed over the dosing period. In this trial, plasma glucose declined in dose-dependent fashion within the first day of dosing.. Cardiac ElectrophysiologyIn randomized, double-blind, placebo-controlled, active-comparator, 4-way crossover trial, 60 healthy subjects were administered single oral dose of canagliflozin 300 mg, canagliflozin 1,200 mg (4 times the maximum recommended dose), moxifloxacin, and placebo. No meaningful changes in QTc interval were observed with either the recommended dose of 300 mg or the 1,200 mg dose.. 12.3 Pharmacokinetics. INVOKAMETThe results of bioequivalence trial in healthy subjects demonstrated that INVOKAMET 50 mg/500 mg, 50 mg/1,000 mg, 150 mg/500 mg and 150 mg/1,000 mg combination tablets are bioequivalent to co-administration of corresponding doses of canagliflozin and metformin HCl as individual tablets under fed conditions.Administration of INVOKAMET 150 mg/1,000 mg fixed-dose combination with food resulted in no change in overall exposure of canagliflozin. There was no change in metformin AUC; however, the mean peak plasma concentration of metformin was decreased by 16% when administered with food. delayed time to peak plasma concentration was observed for both components (a delay of hours for canagliflozin and hour for metformin) under fed conditions. These changes are not likely to be clinically meaningful.. INVOKAMET XRAfter administration of INVOKAMET XR tablets with high-fat breakfast, the peak (Cmax) and total (AUC) exposure of canagliflozin were not altered relative to dosing in the fasted state. However, the AUC of metformin increased by approximately 61% and Cmax increased by approximately 13%.. CanagliflozinThe pharmacokinetics of canagliflozin is essentially similar in healthy subjects and patients with type diabetes. Following single-dose oral administration of 100 mg and 300 mg of canagliflozin, peak plasma concentrations (median Tmax) of canagliflozin occurs within to hours post-dose. Plasma Cmax and AUC of canagliflozin increased in dose-proportional manner from 50 mg to 300 mg. The apparent terminal half-life (t1/2) was 10.6 hours and 13.1 hours for the 100 mg and 300 mg doses, respectively. Steady-state was reached after to days of once-daily dosing with canagliflozin 100 mg to 300 mg. Canagliflozin does not exhibit time-dependent pharmacokinetics and accumulated in plasma up to 36% following multiple doses of 100 mg and 300 mg. The mean systemic exposure (AUC) at steady state was similar following once daily and twice daily dosing regimens at the same total daily dose of 100 mg or 300 mg.. Absorption. CanagliflozinThe mean absolute oral bioavailability of canagliflozin is approximately 65%.. MetforminThe absolute bioavailability of metformin HCl 500 mg tablet given under fasting conditions is approximately 50% to 60%. Trials using single oral doses of metformin hydrochloride 500 to 1,500 mg, and 850 to 2,550 mg, indicate that there is lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination.Following single oral dose of 1,000 mg (two 500 mg tablets) metformin HCl extended-release after meal, the time to reach maximum plasma metformin concentration (Tmax) is achieved at approximately 7-8 hours. In both single and multiple-dose trials in healthy subjects, once daily 1,000 mg (two 500 mg tablets) dosing results in up to 35% higher Cmax, of metformin relative to the immediate-release given as 500 mg twice daily without any change in overall systemic exposure, as measured by AUC.. Distribution. CanagliflozinThe mean steady-state volume of distribution of canagliflozin following single intravenous infusion in healthy subjects was 83.5 L, suggesting extensive tissue distribution. Canagliflozin is extensively bound to proteins in plasma (99%), mainly to albumin. Protein binding is independent of canagliflozin plasma concentrations. Plasma protein binding is not meaningfully altered in patients with renal or hepatic impairment.. MetforminThe apparent volume of distribution (V/F) of metformin following single oral doses of metformin HCl 850 mg immediate-release tablets averaged 654 +- 358 L. Metformin is negligibly bound to plasma proteins, in contrast to sulfonylureas, which are more than 90% protein bound. Metformin partitions into erythrocytes, most likely as function of time. At usual clinical doses and dosing schedules of metformin HCl tablets, steady-state plasma concentrations of metformin are reached within 24 to 48 hours and are generally less than mcg/mL.. Metabolism. CanagliflozinO-glucuronidation is the major metabolic elimination pathway for canagliflozin, which is mainly glucuronidated by UGT1A9 and UGT2B4 to two inactive O-glucuronide metabolites. CYP3A4-mediated (oxidative) metabolism of canagliflozin is minimal (approximately 7%) in humans.. MetforminIntravenous single-dose trials in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) or biliary excretion. Excretion. CanagliflozinFollowing administration of single oral [14C] canagliflozin dose to healthy subjects, 41.5%, 7.0%, and 3.2% of the administered radioactive dose was recovered in feces as canagliflozin, hydroxylated metabolite, and an O-glucuronide metabolite, respectively. Enterohepatic circulation of canagliflozin was negligible.Approximately 33% of the administered radioactive dose was excreted in urine, mainly as O-glucuronide metabolites (30.5%). Less than 1% of the dose was excreted as unchanged canagliflozin in urine. Renal clearance of canagliflozin 100 mg and 300 mg doses ranged from 1.30 to 1.55 mL/min.Mean systemic clearance of canagliflozin was approximately 192 mL/min in healthy subjects following intravenous administration.. MetforminRenal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be compartment of distribution.. Specific PopulationsTrials characterizing the pharmacokinetics of canagliflozin and metformin after administration of INVOKAMET/INVOKAMET XR were not conducted in patients with renal and hepatic impairment. Descriptions of the individual components in this patient population are described below.. Renal Impairment. CanagliflozinA single-dose, open-label trial evaluated the pharmacokinetics of canagliflozin 200 mg in subjects with varying degrees of renal impairment (classified using the MDRD-eGFR formula) compared to healthy subjects.Renal impairment did not affect the Cmax of canagliflozin. Compared to healthy subjects (N=3; eGFR greater than or equal to 90 mL/min/1.73 m2), plasma AUC of canagliflozin was increased by approximately 15%, 29%, and 53% in subjects with mild (N=10), moderate (N=9), and severe (N=10) renal impairment, respectively, (eGFR 60 to less than 90, 30 to less than 60, and 15 to less than 30 mL/min/1.73 m2, respectively), but was similar for ESRD (N=8) subjects and healthy subjects. Increases in canagliflozin AUC of this magnitude are not considered clinically relevant. The pharmacodynamic response to canagliflozin declines with increasing severity of renal impairment [see Contraindications (4) and Warnings and Precautions (5.5)]. Canagliflozin was negligibly removed by hemodialysis.. MetforminIn patients with decreased renal function, the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased [see Contraindications (4) and Warnings and Precautions (5.1)].Following single dose administration of metformin HCl extended-release 500 mg in patients with mild and moderate renal failure (based on measured creatinine clearance), the oral and renal clearance of metformin were decreased by 33% and 50% and 16% and 53%, respectively [see Warnings and Precautions (5.5)]. Metformin peak and systemic exposure was 27% and 61% greater, respectively in mild renal impaired and 74% and 2.36-fold greater in moderate renal impaired patients as compared to healthy subjects [see Contraindications (4) and Warnings and Precautions (5.1)].. Hepatic Impairment. CanagliflozinRelative to subjects with normal hepatic function, the geometric mean ratios for Cmax and AUC of canagliflozin were 107% and 110%, respectively, in subjects with Child-Pugh class (mild hepatic impairment) and 96% and 111%, respectively, in subjects with Child-Pugh class (moderate hepatic impairment) following administration of single 300 mg dose of canagliflozin.These differences are not considered to be clinically meaningful. There is no clinical experience in patients with Child-Pugh class (severe) hepatic impairment [see Warnings and Precautions (5.1)].. MetforminNo pharmacokinetic trials of metformin have been conducted in patients with hepatic insufficiency [see Warnings and Precautions (5.1)].. Pharmacokinetic Effects of Age, Body Mass Index (BMI)/Weight, Gender and Race. CanagliflozinBased on the population PK analysis with data collected from 1526 subjects, age, body mass index (BMI)/weight, gender, and race do not have clinically meaningful effect on the pharmacokinetics of canagliflozin [see Use in Specific Populations (8.5)].. MetforminMetformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type diabetes when analyzed according to gender.No trials of metformin pharmacokinetic parameters according to race have been performed.. CanagliflozinAge had no clinically meaningful effect on the pharmacokinetics of canagliflozin based on population pharmacokinetic analysis [see Adverse Reactions (6.1) and Use in Specific Populations (8.5)].. MetforminLimited data from controlled pharmacokinetic trials of metformin in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged, and Cmax is increased, compared with healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by change in renal function [see Warnings and Precautions (5.1, 5.5) and Use in Specific Populations (8.5)].. Drug-Drug Interactions. INVOKAMET and INVOKAMET XRPharmacokinetic drug interaction trials with INVOKAMET/INVOKAMET XR have not been performed; however, such trials have been conducted with the individual components canagliflozin and metformin hydrochloride.Co-administration of multiple doses of canagliflozin (300 mg) and metformin (2,000 mg) given once daily did not meaningfully alter the pharmacokinetics of either canagliflozin or metformin in healthy subjects.. Canagliflozin. In Vitro Assessment of Drug InteractionsCanagliflozin did not induce CYP450 enzyme expression (3A4, 2C9, 2C19, 2B6, and 1A2) in cultured human hepatocytes. Canagliflozin did not inhibit the CYP450 isoenzymes (1A2, 2A6, 2C19, 2D6, or 2E1) and weakly inhibited CYP2B6, CYP2C8, CYP2C9, and CYP3A4 based on in vitro studies with human hepatic microsomes. Canagliflozin is weak inhibitor of P-gp.Canagliflozin is also substrate of drug transporters P-glycoprotein (P-gp) and MRP2.. In Vivo Assessment of Drug InteractionsTable 7:Effect of Co-Administered Drugs on Systemic Exposures of CanagliflozinCo-Administered DrugDose of Co-Administered DrugSingle dose unless otherwise noted Dose of Canagliflozin Geometric Mean Ratio(Ratio With/Without Co-Administered Drug)No Effect 1.0AUCAUCinf for drugs given as single dose and AUC24h for drugs given as multiple doses (90% CI)Cmax (90% CI)QD once daily; BID twice dailySee Drug Interactions (7.2) for the clinical relevance of the following:Rifampin600 mg QD for days300 mg0.49(0.44; 0.54)0.72(0.61; 0.84)No dose adjustments of canagliflozin required for the following:Cyclosporine400 mg300 mg QD for days1.23(1.19; 1.27)1.01(0.91; 1.11)Ethinyl estradiol and levonorgestrel0.03 mg ethinyl estradiol and 0.15 mg levonorgestrel200 mg QD for days0.91(0.88; 0.94)0.92(0.84; 0.99)Hydrochlorothiazide25 mg QD for 35 days300 mg QD for days1.12(1.08; 1.17)1.15(1.06; 1.25)Metformin2,000 mg300 mg QD for days1.10(1.05; 1.15)1.05(0.96; 1.16)Probenecid500 mg BID for days300 mg QD for 17 days1.21(1.16; 1.25)1.13(1.00; 1.28)Table 8:Effect of Canagliflozin on Systemic Exposure of Co-Administered DrugsCo-Administered DrugDose of Co-Administered DrugSingle dose unless otherwise noted Dose of Canagliflozin Geometric Mean Ratio(Ratio With/Without Co-Administered Drug)No Effect 1.0AUCAUCinf for drugs given as single dose and AUC24h for drugs given as multiple doses (90% CI)Cmax (90% CI)QD once daily; BID twice daily; INR International Normalized RatioSee Drug Interactions (7.2) for the clinical relevance of the following:Digoxin0.5 mg QD first day followed by 0.25 mg QD for days300 mg QD for daysDigoxin1.20(1.12; 1.28)1.36(1.21; 1.53)No dose adjustments of co-administered drug required for the following:Acetaminophen1,000 mg300 mg BID for 25 daysAcetaminophen1.06AUC0-12h (0.98; 1.14)1.00(0.92; 1.09)Ethinyl estradiol and levonorgestrel0.03 mg ethinyl estradiol and 0.15 mg levonorgestrel200 mg QD for daysethinyl estradiol1.07(0.99; 1.15)1.22(1.10; 1.35)Levonorgestrel1.06(1.00; 1.13)1.22(1.11; 1.35)Glyburide1.25 mg200 mg QD for daysGlyburide1.02(0.98; 1.07)0.93(0.85; 1.01)3-cis-hydroxy-glyburide1.01(0.96; 1.07)0.99(0.91; 1.08)4-trans-hydroxy-glyburide1.03(0.97; 1.09)0.96(0.88; 1.04)Hydrochlorothiazide25 mg QD for 35 days300 mg QD for daysHydrochlorothiazide0.99(0.95; 1.04)0.94(0.87; 1.01)Metformin2,000 mg300 mg QD for daysMetformin1.20(1.08; 1.34)1.06(0.93; 1.20)Simvastatin40 mg300 mg QD for daysSimvastatin1.12(0.94; 1.33)1.09(0.91; 1.31)simvastatin acid1.18(1.03; 1.35)1.26(1.10; 1.45)Warfarin30 mg300 mg QD for 12 days(R)-warfarin1.01(0.96; 1.06)1.03(0.94; 1.13)(S)-warfarin1.06(1.00; 1.12)1.01(0.90; 1.13)INR1.00(0.98; 1.03)1.05(0.99; 1.12). MetforminTable 9:Effect of Co-Administered Drugs on Plasma Metformin Systemic ExposuresCo-Administered DrugDose of Co-Administered DrugSingle dose unless otherwise noted Dose of Metformin HCl Geometric Mean Ratio(Ratio With/Without Co-Administered Drug)No Effect 1.00AUCAUC AUC0- Cmax No dose adjustments required for the following:Glyburide5 mg500 mgMetformin HCl extended-release tablets 500 mg 0.98Ratio of arithmetic means 0.99 Furosemide40 mg850 mg1.09 1.22 Nifedipine10 mg850 mg1.161.21Propranolol40 mg850 mg0.900.94Ibuprofen400 mg850 mg1.05 1.07 Drugs that are eliminated by renal tubular secretion increase the accumulation of metformin [see Warnings and Precautions (5) and Drug Interactions (7)]Cimetidine400 mg850 mg1.401.61Carbonic anhydrase inhibitors may cause metabolic acidosis [see Warnings and Precautions (5) and Drug Interactions (7)]TopiramateHealthy volunteer study at steady state with topiramate 100 mg every 12 hours and metformin 500 mg every 12 hours for days. Study conducted to assess pharmacokinetics only 100 mg500 mg1.25Steady state AUC0-12h. 1.18Table 10:Effect of Metformin on Co-Administered Drug Systemic ExposuresCo-Administered DrugDose of Co-Administered DrugSingle dose unless otherwise noted Dose of Metformin HCl Geometric Mean Ratio(Ratio With/Without Co-Administered Drug)No Effect 1.00AUCAUC AUC0- Cmax No dose adjustments required for the following:Glyburide5 mg500 mgAUC0-24 hr reported 0.78Ratio of arithmetic means, p-value of difference <0.05 0.63 Furosemide40 mg850 mg0.87 0.69 Nifedipine10 mg850 mg1.10 1.08Propranolol40 mg850 mg1.01 0.94Ibuprofen400 mg850 mg0.97Ratio of arithmetic means. 1.01 Cimetidine400 mg850 mg0.95 1.01Metformin is negligibly bound to plasma proteins and is, therefore, less likely to interact with highly protein-bound drugs such as salicylates, sulfonamides, chloramphenicol, and probenecid.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. Canagliflozin has been studied in combination with metformin alone, metformin and sulfonylurea, metformin and sitagliptin, metformin and thiazolidinedione (i.e., pioglitazone), and metformin and insulin (with or without other anti-hyperglycemic agents). The efficacy of canagliflozin was compared to dipeptidyl peptidase-4 (DPP-4) inhibitor (sitagliptin), both as add-on combination therapy with metformin and sulfonylurea, and sulfonylurea (glimepiride), both as add-on combination therapy with metformin.There have been no clinical efficacy trials conducted with INVOKAMET/INVOKAMET XR; however, bioequivalence of INVOKAMET/INVOKAMET XR to canagliflozin and metformin HCl co-administered as individual tablets was demonstrated in healthy subjects.In patients with type diabetes, treatment with canagliflozin and metformin produced clinically and statistically significant improvements in HbA1C compared to placebo. Reductions in HbA1C were observed across subgroups including age, gender, race, and baseline body mass index (BMI).. 14.1Glycemic Control Trials in Adults with Type Diabetes Mellitus. Canagliflozin as Initial Combination Therapy with MetforminA total of 1,186 patients with type diabetes inadequately controlled with diet and exercise participated in 26-week double-blind, active-controlled, parallel-group, 5-arm, multicenter trial to evaluate the efficacy and safety of initial therapy with canagliflozin in combination with metformin XR. The median age was 56 years, 48% of patients were men, and the mean baseline eGFR was 87.6 mL/min/1.73 m2. The median duration of diabetes was 1.6 years, and 72% of patients were treatment naive. After completing 2-week single-blind placebo run-in period, patients were randomly assigned for double-blind treatment period of 26 weeks to of treatment groups (Table 11). The metformin HCl XR dose was initiated at 500 mg/day for the first week of treatment and then increased to 1,000 mg/day. Metformin HCl XR or matching placebo was up-titrated every 2-3 weeks during the next weeks of treatment to maximum daily dose of 1,500 to 2,000 mg/day, as tolerated; about 90% of patients reached 2,000 mg/day.At the end of treatment, canagliflozin 100 mg and canagliflozin 300 mg in combination with metformin HCl XR resulted in statistically significant greater improvement in HbA1C compared to their respective canagliflozin doses (100 mg and 300 mg) alone or metformin HCl XR alone.Table 11:Results from 26-Week Active-Controlled Clinical Study of Canagliflozin Alone or Canagliflozin as Initial Combination Therapy with Metformin HClIntent-to-treat population Efficacy ParameterMetformin XR(N=237)Canagliflozin 100 mg(N=237)Canagliflozin 300 mg(N=238)Canagliflozin 100 mg Metformin HCl XR(N=237)Canagliflozin 300 mg Metformin HCl XR(N=237)HbA1C (%)Baseline (mean)8.818.788.778.838.90Change from baseline (adjusted mean)There were 121 patients without week 26 efficacy data. Analyses addressing missing data gave consistent results with the results provided in this table. -1.30-1.37-1.42-1.77-1.78Difference from canagliflozin 100 mg (adjusted mean) (95% CI)Least squares mean adjusted for covariates including baseline value and stratification factor -0.40Adjusted p=0.001 (-0.59, -0.21)Difference from canagliflozin 300 mg (adjusted mean) (95% CI) -0.36 (-0.56, -0.17)Difference from metformin XR (adjusted mean) (95% CI) -0.46 (-0.66, -0.27)-0.48 (-0.67, -0.28)Percent of patients achieving HbA1C 7%38343947Adjusted p<0.05 51 Canagliflozin as Add-on Combination Therapy with MetforminA total of 1,284 patients with type diabetes inadequately controlled on metformin HCl monotherapy (greater than or equal to 2,000 mg/day or at least 1,500 mg/day if higher dose not tolerated) participated in 26-week, double-blind, placebo- and active-controlled trial to evaluate the efficacy and safety of canagliflozin in combination with metformin. The mean age was 55 years, 47% of patients were men, and the mean baseline eGFR was 89 mL/min/1.73 m2. Patients already on the required metformin HCl dose (N=1009) were randomized after completing 2-week, single-blind, placebo run-in period. Patients taking less than the required metformin HCl dose or patients on metformin HCl in combination with another antihyperglycemic agent (N=275) were switched to metformin HCl monotherapy (at doses described above) for at least weeks before entering the 2-week, single-blind, placebo run-in. After the placebo run-in period, patients were randomized to canagliflozin 100 mg, canagliflozin 300 mg, sitagliptin 100 mg, or placebo, administered once daily as add-on therapy to metformin HCl.At the end of treatment, canagliflozin 100 mg and 300 mg once daily resulted in statistically significant improvement in HbA1C (p<0.001 for both doses) compared to placebo when added to metformin HCl. Canagliflozin 100 mg and 300 mg once daily also resulted in greater proportion of patients achieving an HbA1C less than 7%, in significant reduction in fasting plasma glucose (FPG), in improved postprandial glucose (PPG), and in percent body weight reduction compared to placebo when added to metformin HCl (see Table 12). Statistically significant (p<0.001 for both doses) mean changes from baseline in systolic blood pressure relative to placebo were -5.4 mmHg and -6.6 mmHg with canagliflozin 100 mg and 300 mg, respectively.Table 12:Results from 26-Week Placebo-Controlled Clinical Study of Canagliflozin in Combination with Metformin HClIntent-to-treat population using last observation in study prior to glycemic rescue therapy Efficacy ParameterPlacebo Metformin HCl(N=183)Canagliflozin 100 mg Metformin HCl(N=368)Canagliflozin 300 mg Metformin HCl(N=367)HbA1C (%) Baseline (mean)7.967.947.95 Change from baseline (adjusted mean)-0.17-0.79-0.94 Difference from placebo (adjusted mean) (95% CI)Least squares mean adjusted for baseline value and stratification factors -0.62p<0.001 (-0.76, -0.48)-0.77 (-0.91, -0.64)Percent of patients achieving HbA1C 7%3046 58 Fasting Plasma Glucose (mg/dL) Baseline (mean)164169173 Change from baseline (adjusted mean)2-27-38 Difference from placebo (adjusted mean) (95% CI) -30 (-36, -24)-40 (-46, -34)2-hour Postprandial Glucose (mg/dL) Baseline (mean)249258262 Change from baseline (adjusted mean)-10-48-57 Difference from placebo (adjusted mean) (95% CI) -38 (-49, -27)-47 (-58, -36)Body Weight Baseline (mean) in kg86.788.785.4 change from baseline (adjusted mean)-1.2-3.7-4.2 Difference from placebo (adjusted mean) (95% CI) -2.5 (-3.1, -1.9)-2.9 (-3.5, -2.3). Canagliflozin Compared to Glimepiride, Both as Add-on Combination Therapy with MetforminA total of 1,450 patients with type diabetes inadequately controlled on metformin HCl monotherapy (greater than or equal to 2,000 mg/day or at least 1,500 mg/day if higher dose not tolerated) participated in 52-week, double-blind, active-controlled trial to evaluate the efficacy and safety of canagliflozin in combination with metformin.The mean age was 56 years, 52% of patients were men, and the mean baseline eGFR was 90 mL/min/1.73 m2. Patients tolerating maximally required metformin HCl dose (N=928) were randomized after completing 2-week, single-blind, placebo run-in period. Other patients (N=522) were switched to metformin HCl monotherapy (at doses described above) for at least 10 weeks, then completed 2--week single-blind run-in period. After the 2-week run-in period, patients were randomized to canagliflozin 100 mg, canagliflozin 300 mg, or glimepiride (titration allowed throughout the 52-week trial to or mg), administered once daily as add-on therapy to metformin HCl.As shown in Table 13 and Figure 1, at the end of treatment, canagliflozin 100 mg provided similar reductions in HbA1C from baseline compared to glimepiride when added to metformin HCl therapy. Canagliflozin 300 mg provided greater reduction from baseline in HbA1C compared to glimepiride, and the relative treatment difference was -0.12% (95% CI: -0.22; -0.02). As shown in Table 13, treatment with canagliflozin 100 mg and 300 mg daily provided greater improvements in percent body weight change, relative to glimepiride.Table 13:Results from 52-Week Clinical Study Comparing Canagliflozin to Glimepiride in Combination with MetforminIntent-to-treat population using last observation in study prior to glycemic rescue therapy Efficacy ParameterCanagliflozin 100 mg Metformin HCl(N=483)Canagliflozin 300 mg Metformin HCl(N=485)Glimepiride (titrated) Metformin HCl(N=482)HbA1C (%) Baseline (mean)7.787.797.83 Change from baseline (adjusted mean)-0.82-0.93-0.81 Difference from glimepiride (adjusted mean) (95% CI)Least squares mean adjusted for baseline value and stratification factors -0.01Canagliflozin metformin HCl is considered non-inferior to glimepiride metformin because the upper limit of this confidence interval is less than the pre-specified non-inferiority margin of 0.3%. (-0.11, 0.09)-0.12 (-0.22, -0.02)Percent of patients achieving HbA1C 7%546056Fasting Plasma Glucose (mg/dL) Baseline (mean)165164166 Change from baseline (adjusted mean)-24-28-18 Difference from glimepiride (adjusted mean) (95% CI) -6(-10, -2)-9(-13, -5)Body Weight Baseline (mean) in kg86.886.686.6 change from baseline (adjusted mean)-4.2-4.71.0 Difference from glimepiride (adjusted mean) (95% CI) -5.2p<0.001 (-5.7, -4.7)-5.7 (-6.2, -5.1)Figure 1:Mean HbA1C Change at Each Time Point (Completers) and at Week 52 Using Last Observation Carried Forward (mITT Population). Figure 1. Canagliflozin as Add-on Combination Therapy with Metformin and SitagliptinA total of 217 patients with type diabetes inadequately controlled on the combination of metformin HCl (greater than or equal to 1,500 mg/day) and sitagliptin 100 mg/day (or equivalent fixed-dose combination) participated in 26-week, double-blind, placebo-controlled trial to evaluate the efficacy and safety of canagliflozin in combination with metformin and sitagliptin. The mean age was 57 years, 58% of patients were men, 73% of patients were Caucasian, 15% were Asian, and 12% were Black or African-American. The mean baseline eGFR was 90 mL/min/1.73 m2 and the mean baseline BMI was 32 kg/m2. The mean duration of diabetes was 10 years. Eligible patients entered 2-week, single-blind, placebo run-in period and were subsequently randomized to canagliflozin 100 mg or placebo, administered once daily as add-on to metformin HCl and sitagliptin. Patients with baseline eGFR of 70 mL/min/1.73 m2 or greater who were tolerating canagliflozin 100 mg and who required additional glycemic control (fasting finger stick 100 mg/dL or greater at least twice within weeks) were up-titrated to canagliflozin 300 mg. While up-titration occurred as early as Week 4, most (90%) patients randomized to canagliflozin were up-titrated to canagliflozin 300 mg by to weeks.At the end of 26 weeks, canagliflozin once daily resulted in statistically significant improvement in HbA1C (p<0.001) compared to placebo when added to metformin HCl and sitagliptin (see Table 14).Table 14:Results from 26-Week Placebo-Controlled Clinical Study of Canagliflozin in Combination with Metformin HCl and SitagliptinEfficacy ParameterPlacebo Metformin HCl and Sitagliptin(N=108To preserve the integrity of randomization, all randomized patients were included in the analysis. The patient who was randomized once to each arm was analyzed on canagliflozin.)Canagliflozin Metformin HCl and Sitagliptin(N=109)HbA1C (%) Baseline (mean)8.408.50 Change from baseline (adjusted mean)-0.03-0.83 Difference from placebo (adjusted mean) (95% CI)Early treatment discontinuation before week 26, occurred in 11.0% and 24.1% of canagliflozin and placebo patients, respectively. Estimated using multiple imputation method modeling wash-out of the treatment effect for patients having missing data who discontinued treatment. Missing data was imputed only at week 26 and analyzed using ANCOVA. -0.81p<0.001 (-1.11; -0.51)Percent of patients achieving HbA1C 7%Patients without week 26 efficacy data were considered as non-responders when estimating the proportion achieving HbA1C 7%.928Fasting Plasma Glucose (mg/dL)Estimated using multiple imputation method modeling wash-out of the treatment effect for patients having missing data who discontinued treatment. mixed model for repeated measures was used to analyze the imputed data. Baseline (mean)180185 Change from baseline (adjusted mean)-3-28 Difference from placebo (adjusted mean) (95% CI)-25 (-39; -11). Canagliflozin as Add-on Combination Therapy with Metformin and SulfonylureaA total of 469 patients with type diabetes inadequately controlled on the combination of metformin HCl (greater than or equal to 2,000 mg/day or at least 1,500 mg/day if higher dose not tolerated) and sulfonylurea (maximal or near-maximal effective dose) participated in 26-week, double-blind, placebo-controlled trial to evaluate the efficacy and safety of canagliflozin in combination with metformin and sulfonylurea. The mean age was 57 years, 51% of patients were men, and the mean baseline eGFR was 89 mL/min/1.73 m2. Patients already on the protocol-specified doses of metformin HCl and sulfonylurea (N=372) entered 2-week, single-blind, placebo run-in period. Other patients (N=97) were required to be on stable protocol-specified dose of metformin HCl and sulfonylurea for at least weeks before entering the 2-week run-in period. Following the run-in period, patients were randomized to canagliflozin 100 mg, canagliflozin 300 mg, or placebo administered once daily as add-on to metformin HCl and sulfonylurea.At the end of treatment, canagliflozin 100 mg and 300 mg once daily resulted in statistically significant improvement in HbA1C (p<0.001 for both doses) compared to placebo when added to metformin HCl and sulfonylurea. Canagliflozin 100 mg and 300 mg once daily also resulted in greater proportion of patients achieving an HbA1C less than 7.0%, in significant reduction in fasting plasma glucose (FPG), and in percent body weight reduction compared to placebo when added to metformin HCl and sulfonylurea (see Table 15).Table 15:Results from 26-Week Placebo-Controlled Clinical Study of Canagliflozin in Combination with Metformin and SulfonylureaIntent-to-treat population using last observation in study prior to glycemic rescue therapy Efficacy ParameterPlacebo Metformin HCl and Sulfonylurea(N=156)Canagliflozin 100 mg Metformin HCland Sulfonylurea(N=157)Canagliflozin 300 mg Metformin HCland Sulfonylurea(N=156)HbA1C (%) Baseline (mean)8.128.138.13 Change from baseline (adjusted mean)-0.13-0.85-1.06 Difference from placebo (adjusted mean) (95% CI)Least squares mean adjusted for baseline value and stratification factors -0.71p<0.001 (-0.90, -0.52)-0.92 (-1.11, -0.73)Percent of patients achieving HbA1C 7%1843 57 Fasting Plasma Glucose (mg/dL) Baseline (mean)170173168 Change from baseline (adjusted mean)4-18-31 Difference from placebo (adjusted mean) (95% CI) -22 (-31, -13)-35 (-44, -25)Body Weight Baseline (mean) in kg90.893.593.5 change from baseline (adjusted mean)-0.7-2.1-2.6 Difference from placebo (adjusted mean) (95% CI) -1.4 (-2.1, -0.7)-2.0 (-2.7, -1.3). Canagliflozin Compared to Sitagliptin, Both as Add-on Combination Therapy with Metformin and SulfonylureaA total of 755 patients with type diabetes inadequately controlled on the combination of metformin HCl (greater than or equal to 2,000 mg/day or at least 1,500 mg/day if higher dose not tolerated) and sulfonylurea (near-maximal or maximal effective dose) participated in 52 week, double-blind, active-controlled trial to compare the efficacy and safety of canagliflozin 300 mg versus sitagliptin 100 mg in combination with metformin HCl and sulfonylurea. The mean age was 57 years, 56% of patients were men, and the mean baseline eGFR was 88 mL/min/1.73 m2. Patients already on protocol-specified doses of metformin HCl and sulfonylurea (N=716) entered 2-week single-blind, placebo run-in period. Other patients (N=39) were required to be on stable protocol-specified dose of metformin HCl and sulfonylurea for at least weeks before entering the 2-week run-in period. Following the run-in period, patients were randomized to canagliflozin 300 mg or sitagliptin 100 mg as add-on to metformin HCl and sulfonylurea.As shown in Table 16 and Figure 2, at the end of treatment, canagliflozin 300 mg provided greater HbA1C reduction compared to sitagliptin 100 mg when added to metformin HCl and sulfonylurea (p<0.05). Canagliflozin 300 mg resulted in mean percent change in body weight from baseline of -2.5% compared to +0.3% with sitagliptin 100 mg. mean change in systolic blood pressure from baseline of -5.06 mmHg was observed with canagliflozin 300 mg compared to +0.85 mmHg with sitagliptin 100 mg.Table 16:Results from 52-Week Clinical Study Comparing Canagliflozin to Sitagliptin in Combination with Metformin HCl and SulfonylureaIntent-to-treat population using last observation in study prior to glycemic rescue therapy Efficacy ParameterCanagliflozin 300 mg Metformin HCl and Sulfonylurea(N=377)Sitagliptin 100 mg Metformin HCl and SulfonylureaN=378)HbA1C (%) Baseline (mean)8.128.13 Change from baseline (adjusted mean)-1.03-0.66 Difference from sitagliptin (adjusted mean) (95% CI)Least squares mean adjusted for baseline value and stratification factors -0.37Canagliflozin metformin HCl sulfonylurea is considered non-inferior to sitagliptin metformin HCl sulfonylurea because the upper limit of this confidence interval is less than the pre-specified non-inferiority margin of 0.3%. (-0.50, -0.25)Percent of patients achieving HbA1C 7%4835Fasting Plasma Glucose (mg/dL) Baseline (mean)170164 Change from baseline (adjusted mean)-30-6 Difference from sitagliptin (adjusted mean) (95% CI) -24(-30, -18)Body Weight Baseline (mean) in kg87.689.6 change from baseline (adjusted mean)-2.50.3 Difference from sitagliptin (adjusted mean) (95% CI) -2.8p<0.001 (-3.3, -2.2)Figure 2:Mean HbA1C Change at Each Time Point (Completers) and at Week 52 Using Last Observation Carried Forward (mITT Population). Figure 2. Canagliflozin as Add-on Combination Therapy with Metformin and PioglitazoneA total of 342 patients with type diabetes inadequately controlled on the combination of metformin (greater than or equal to 2,000 mg/day or at least 1,500 mg/day if higher dose not tolerated) and pioglitazone (30 or 45 mg/day) participated in 26-week, double--blind, placebo-controlled trial to evaluate the efficacy and safety of canagliflozin in combination with metformin and pioglitazone. The mean age was 57 years, 63% of patients were men, and the mean baseline eGFR was 86 mL/min/1.73 m2. Patients already on protocol-specified doses of metformin HCl and pioglitazone (N=163) entered 2-week, single-blind, placebo run-in period. Other patients (N=181) were required to be on stable protocol-specified doses of metformin HCl and pioglitazone for at least weeks before entering the 2-week run-in period. Following the run-in period, patients were randomized to canagliflozin 100 mg, canagliflozin 300 mg, or placebo, administered once daily as add-on to metformin HCl and pioglitazone.At the end of treatment, canagliflozin 100 mg and 300 mg once daily resulted in statistically significant improvement in HbA1C (p<0.001 for both doses) compared to placebo when added to metformin HCl and pioglitazone. Canagliflozin 100 mg and 300 mg once daily also resulted in greater proportion of patients achieving an HbA1C less than 7%, in significant reduction in fasting plasma glucose (FPG), and in percent body weight reduction compared to placebo when added to metformin HCl and pioglitazone (see Table 17). Statistically significant (p<0.05 for both doses) mean changes from baseline in systolic blood pressure relative to placebo were -4.1 mmHg and -3.5 mmHg with canagliflozin 100 mg and 300 mg, respectively.Table 17:Results from 26-Week Placebo-Controlled Clinical Study of Canagliflozin in Combination with Metformin HCl and PioglitazoneIntent-to-treat population using last observation in study prior to glycemic rescue therapy Efficacy ParameterPlacebo Metformin HCl and Pioglitazone (N=115)Canagliflozin 100 mg Metformin HCl and Pioglitazone(N=113)Canagliflozin 300 mg Metformin HCl and Pioglitazone(N=114)HbA1C (%) Baseline (mean)8.007.997.84 Change from baseline (adjusted mean)-0.26-0.89-1.03 Difference from placebo (adjusted mean) (95% CI)Least squares mean adjusted for baseline value and stratification factors -0.62p<0.001 (-0.81, -0.44)-0.76 (-0.95, -0.58)Percent of patients achieving HbA1C 7%3347 64 Fasting Plasma Glucose (mg/dL) Baseline (mean)164169164 Change from baseline (adjusted mean)3-27-33 Difference from placebo (adjusted mean) (95% CI) -29 (-37, -22)-36 (-43, -28)Body Weight Baseline (mean) in kg94.094.294.4 change from baseline (adjusted mean)-0.1-2.8-3.8 Difference from placebo (adjusted mean) (95% CI) -2.7 (-3.6, -1.8)-3.7 (-4.6, -2.8). Canagliflozin as Add-on Combination Therapy with Insulin (With or Without Other Anti-Hyperglycemic Agents, Including Metformin)A total of 1,718 patients with type diabetes inadequately controlled on insulin greater than or equal to 30 units/day or insulin in combination with other antihyperglycemic agents participated in an 18-week, double-blind, placebo-controlled substudy of cardiovascular trial to evaluate the efficacy and safety of canagliflozin in combination with insulin. Of these patients, subgroup of 432 patients with inadequate glycemic control received canagliflozin or placebo plus metformin HCl and >= 30 units/day of insulin over 18 weeks.In this subgroup, the mean age was 61 years, 67% of patients were men, and the mean baseline eGFR was 81 mL/min/1.73 m2. Patients on metformin HCl in combination with basal, bolus, or basal/bolus insulin for at least 10 weeks entered 2-week, single-blind, placebo run-in period. Approximately 74% of these patients were on background of metformin HCl and basal/bolus insulin regimen. After the run-in period, patients were randomized to canagliflozin 100 mg, canagliflozin 300 mg, or placebo, administered once daily as add-on to metformin HCl and insulin. The mean daily insulin dose at baseline was 93 units, which was similar across treatment groups.At the end of treatment, canagliflozin 100 mg and 300 mg once daily resulted in statistically significant improvement in HbA1C (p<0.001 for both doses) compared to placebo when added to metformin HCl and insulin. Canagliflozin 100 mg and 300 mg once daily also resulted in greater proportion of patients achieving an HbA1C less than 7%, in significant reductions in fasting plasma glucose (FPG), and in percent body weight reductions compared to placebo (see Table 18). Statistically significant (p=0.023 for the 100 mg and p<0.001 for the 300 mg dose) mean change from baseline in systolic blood pressure relative to placebo was -3.5 mmHg and -6 mmHg with canagliflozin 100 mg and 300 mg, respectively. Fewer patients on canagliflozin in combination with metformin HCl and insulin required glycemic rescue therapy: 3.6% of patients receiving canagliflozin 100 mg, 2.7% of patients receiving canagliflozin 300 mg, and 6.2% of patients receiving placebo. An increased incidence of hypoglycemia was observed in this trial, which is consistent with the expected increase of hypoglycemia when an agent not associated with hypoglycemia is added to insulin [see Warnings and Precautions (5.7) and Adverse Reactions (6.1)].Table 18: Results from 18-Week Placebo-Controlled Clinical Study of Canagliflozin in Combination with Metformin HCl and Insulin >= 30 Units/DayIntent-to-treat population using last observation in study prior to glycemic rescue therapy Efficacy ParameterPlacebo Metformin HCl Insulin(N=145)Canagliflozin 100 mg Metformin HCl Insulin(N=139)Canagliflozin 300 mg Metformin HCl Insulin(N=148)HbA1C (%) Baseline (mean)8.158.208.22 Change from baseline (adjusted mean)0.03-0.64-0.79 Difference from placebo (adjusted mean) (95% CI)Least squares mean adjusted for baseline value and stratification factors -0.66p<=0.001 (-0.81, -0.51)-0.82 (-0.96, -0.67)Percent of patients achieving HbA1C 7%919p<=0.01 29 Fasting Plasma Glucose (mg/dL) Baseline163168167 Change from baseline (adjusted mean)1-16-24 Difference from placebo (adjusted mean) (97.5% CI) -16 (-28, -5)-25 (-36, -14)Body Weight Baseline (mean) in kg102.399.7101.1 change from baseline (adjusted mean)0.0-1.7-2.7 Difference from placebo (adjusted mean) (97.5% CI) -1.7 (-2.4, -1.0)-2.7 (-3.4, -2.0). 14.2Canagliflozin Cardiovascular Outcomes in Patients with Type Diabetes Mellitus and Atherosclerotic Cardiovascular Disease. Canagliflozin is indicated to reduce the risk of major adverse cardiovascular events in adults with type diabetes mellitus and established cardiovascular disease (CVD). However, the effectiveness of INVOKAMET/INVOKAMET XR on reducing the risk of major cardiovascular events in adults with type diabetes and cardiovascular disease has not been established.The CANVAS and CANVAS-R trials were multicenter, multi-national, randomized, double-blind parallel group, with similar inclusion and exclusion criteria. Patients eligible for enrollment in both CANVAS and CANVAS-R trials were: 30 years of age or older and had established, stable, cardiovascular, cerebrovascular, peripheral artery disease (66% of the enrolled population) or were 50 years of age or older and had two or more other specified risk factors for cardiovascular disease (34% of the enrolled population).The integrated analysis of the CANVAS and CANVAS-R trials compared the risk of Major Adverse Cardiovascular Event (MACE) between canagliflozin and placebo when these were added to and used concomitantly with standard of care treatments for diabetes and atherosclerotic cardiovascular disease. The primary endpoint, MACE, was the time to first occurrence of three-part composite outcome which included cardiovascular death, non-fatal myocardial infarction and non-fatal stroke.In CANVAS, patients were randomly assigned 1:1:1 to canagliflozin 100 mg, canagliflozin 300 mg, or matching placebo. In CANVAS-R, patients were randomly assigned 1:1 to canagliflozin 100 mg or matching placebo, and titration to 300 mg was permitted at the investigators discretion (based on tolerability and glycemic needs) after Week 13. Concomitant antidiabetic and atherosclerotic therapies could be adjusted, at the discretion of investigators, to ensure participants were treated according to the standard care for these diseases.A total of 10,134 patients were treated (4,327 in CANVAS and 5,807 in CANVAS-R; total of 4,344 randomly assigned to placebo and 5,790 to canagliflozin) and exposed for mean of 149 weeks (exposed for mean of 223 weeks [4.3 years] in CANVAS and 94 weeks [1.8 years] in CANVAS-R). Approximately 78% of the trial population was Caucasian, 13% was Asian, and 3% was Black. The mean age was 63 years and approximately 64% were male.The mean HbA1C at baseline was 8.2% and mean duration of diabetes was 13.5 years with 70% of patients having had diabetes for 10 years or more. Approximately 31%, 21% and 17% reported past history of neuropathy, retinopathy and nephropathy, respectively, and the mean eGFR 76 mL/min/1.73 m2). At baseline, patients were treated with one (19%) or more (80%) antidiabetic medications including metformin (77%), insulin (50%), and sulfonylurea (43%).At baseline, the mean systolic blood pressure was 137 mmHg, the mean diastolic blood pressure was 78 mmHg, the mean LDL was 89 mg/dL, the mean HDL was 46 mg/dL, and the mean urinary albumin to creatinine ratio (UACR) was 115 mg/g. At baseline, approximately 80% of patients were treated with renin angiotensin system inhibitors, 53% with beta-blockers, 13% with loop diuretics, 36% with non-loop diuretics, 75% with statins, and 74% with antiplatelet agents (mostly aspirin). During the trial, investigators could modify anti-diabetic and cardiovascular therapies to achieve local standard of care treatment targets with respect to blood glucose, lipid, and blood pressure. More patients receiving canagliflozin compared to placebo initiated anti-thrombotics (5.2% vs 4.2%) and statins (5.8% vs 4.8%) during the trial.For the primary analysis, stratified Cox proportional hazards model was used to test for non-inferiority against pre-specified risk margin of 1.3 for the hazard ratio of MACE.In the integrated analysis of CANVAS and CANVAS-R trials, canagliflozin reduced the risk of first occurrence of MACE. The estimated hazard ratio (95% CI) for time to first MACE was 0.86 (0.75, 0.97). Refer to Table 19. Vital status was obtained for 99.6% of patients across the trials. The Kaplan-Meier curve depicting time to first occurrence of MACE is shown in Figure 3.Table 19: Treatment Effect for the Primary Composite Endpoint, MACE, and its Components in the Integrated Analysis of CANVAS and CANVAS-R studiesIntent-To-Treat Analysis Set PlaceboN=4347CanagliflozinN=5795Hazard ratio(95% C.I.)Stratified Cox-proportional hazards model with treatment as factor and stratified by study and by prior CV disease Composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke(time to first occurrence)P-value for superiority (2-sided) 0.0158 Number and percentage of first events Due to pooling of unequal randomization ratios, Cochran-Mantel-Haenszel weights were applied to calculate percentages 426 (10.4)585 (9.2)0.86 (0.75, 0.97)Non-fatal myocardial infarction 159 (3.9)215 (3.4)0.85 (0.69, 1.05)Non-fatal Stroke 116 (2.8)158 (2.5)0.90 (0.71, 1.15)Cardiovascular Death 185 (4.6)268 (4.1)0.87 (0.72, 1.06)Figure 3:Time to First Occurrence of MACE Figure 3.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Individualize starting dose based on the patients current regimen (2.2, 2.3)INVOKAMET: one tablet, twice daily with meals, recommended starting dose of canagliflozin is 50 mg twice daily and metformin HCl 500 mg twice daily (2.2)INVOKAMET XR: two tablets, once daily with the morning meal. Swallow whole. Never crush, cut, or chew (2.2)4Canagliflozin dose can be increased to total daily dose of 300 mg in patients tolerating 100 mg who have an eGFR of 60 mL/min/1.73 m2 or greater and require additional glycemic control. Do not exceed total daily canagliflozin dose of 300 mg (2.2)Gradually escalate metformin HCl dose to reduce the gastrointestinal side effects while not exceeding total daily dose of 2000 mg (2.1)Assess renal function before initiating and periodically thereafter (2.1, 2.3)Limit the dose of the canagliflozin component to two 50 mg tablets daily in patients with an eGFR of 45 to less than 60 mL/min/1.73 m2 (2.4)May need to be discontinued at time of, or prior to, iodinated contrast imaging procedures (2.6). Individualize starting dose based on the patients current regimen (2.2, 2.3). INVOKAMET: one tablet, twice daily with meals, recommended starting dose of canagliflozin is 50 mg twice daily and metformin HCl 500 mg twice daily (2.2). INVOKAMET XR: two tablets, once daily with the morning meal. Swallow whole. Never crush, cut, or chew (2.2)4. Canagliflozin dose can be increased to total daily dose of 300 mg in patients tolerating 100 mg who have an eGFR of 60 mL/min/1.73 m2 or greater and require additional glycemic control. Do not exceed total daily canagliflozin dose of 300 mg (2.2). Gradually escalate metformin HCl dose to reduce the gastrointestinal side effects while not exceeding total daily dose of 2000 mg (2.1). Assess renal function before initiating and periodically thereafter (2.1, 2.3). Limit the dose of the canagliflozin component to two 50 mg tablets daily in patients with an eGFR of 45 to less than 60 mL/min/1.73 m2 (2.4). May need to be discontinued at time of, or prior to, iodinated contrast imaging procedures (2.6). 2.1Prior to Initiation of INVOKAMET/INVOKAMET XR Assess renal function before initiating INVOKAMET/INVOKAMET XR and periodically thereafter [see Warnings and Precautions (5.1, 5.5)]. In patients with volume depletion not previously treated with canagliflozin, normalize volume status before initiating INVOKAMET/INVOKAMET XR [see Warnings and Precautions (5.3), Use in Specific Populations (8.5, 8.6)].. Assess renal function before initiating INVOKAMET/INVOKAMET XR and periodically thereafter [see Warnings and Precautions (5.1, 5.5)]. In patients with volume depletion not previously treated with canagliflozin, normalize volume status before initiating INVOKAMET/INVOKAMET XR [see Warnings and Precautions (5.3), Use in Specific Populations (8.5, 8.6)].. 2.2Dosage Overview. INVOKAMET dosing is one tablet, twice daily with meals.INVOKAMET XR dosing is two tablets, once daily with the morning meal. Swallow each tablet whole and never crush, cut, or chew. The starting dose of INVOKAMET/INVOKAMET XR is based on the patients current regimen [see Dosage and Administration (2.2)]. The maximum recommended daily dose is canagliflozin 300 mg and metformin HCl 2,000 mg in patients with an estimated glomerular filtration rate (eGFR) of 60 mL/min/1.73 m2 or greater. For patients with renal impairment [see Dosage and Administration 2.4].. INVOKAMET dosing is one tablet, twice daily with meals.. INVOKAMET XR dosing is two tablets, once daily with the morning meal. Swallow each tablet whole and never crush, cut, or chew. The starting dose of INVOKAMET/INVOKAMET XR is based on the patients current regimen [see Dosage and Administration (2.2)]. The maximum recommended daily dose is canagliflozin 300 mg and metformin HCl 2,000 mg in patients with an estimated glomerular filtration rate (eGFR) of 60 mL/min/1.73 m2 or greater. For patients with renal impairment [see Dosage and Administration 2.4].. 2.3Starting Dose Based on Patients Current Regimen. Individualize the starting dose of INVOKAMET/INVOKAMET XR based on the patients current regimen:. Patients Currently not Treated with Either Canagliflozin or Metformin HClINVOKAMET: One tablet, twice daily, each tablet containing canagliflozin 50 mg and metformin HCl 500 mg;INVOKAMET XR: Two tablets, once daily, each tablet containing canagliflozin 50 mg and metformin HCl 500 mg. INVOKAMET: One tablet, twice daily, each tablet containing canagliflozin 50 mg and metformin HCl 500 mg;. INVOKAMET XR: Two tablets, once daily, each tablet containing canagliflozin 50 mg and metformin HCl 500 mg. Patients on MetforminINVOKAMET: One tablet, twice daily, where the total daily dose contains canagliflozin 100 mg and the same, or nearest appropriate, daily dose of metformin HCl;INVOKAMET XR: Two tablets, once daily, where the total daily dose contains canagliflozin 100 mg and the patients same, or nearest appropriate, daily dose of metformin HCl.. INVOKAMET: One tablet, twice daily, where the total daily dose contains canagliflozin 100 mg and the same, or nearest appropriate, daily dose of metformin HCl;. INVOKAMET XR: Two tablets, once daily, where the total daily dose contains canagliflozin 100 mg and the patients same, or nearest appropriate, daily dose of metformin HCl.. Patients on CanagliflozinINVOKAMET: One tablet, twice daily, where the total daily dose contains the same daily dose of canagliflozin and metformin HCl 1,000 mg;INVOKAMET XR: Two tablets, once daily, where the total daily dose contains the patients same daily dose of canagliflozin and metformin HCl 1,000 mg.. INVOKAMET: One tablet, twice daily, where the total daily dose contains the same daily dose of canagliflozin and metformin HCl 1,000 mg;. INVOKAMET XR: Two tablets, once daily, where the total daily dose contains the patients same daily dose of canagliflozin and metformin HCl 1,000 mg.. Patients Already Treated with Canagliflozin and MetforminINVOKAMET: One tablet, twice daily, where the total daily dose contains the same daily dose of canagliflozin and the same, or nearest appropriate, daily dose of metformin HCl;INVOKAMET XR: Two tablets, once daily, where the total daily dose contains the same daily dose of canagliflozin and the same, or nearest appropriate, daily dose of metformin HCl.. INVOKAMET: One tablet, twice daily, where the total daily dose contains the same daily dose of canagliflozin and the same, or nearest appropriate, daily dose of metformin HCl;. INVOKAMET XR: Two tablets, once daily, where the total daily dose contains the same daily dose of canagliflozin and the same, or nearest appropriate, daily dose of metformin HCl.. Patients with eGFR of 60 mL/min/1.73 m2 or Greater and Require Additional Glycemic ControlINVOKAMET: For patients tolerating canagliflozin 50 mg twice daily, increase the dose of canagliflozin to 150 mg twice daily, with gradual metformin HCl dose escalation based on tolerability [see Adverse Reactions (6.1)]; INVOKAMET XR: For patients tolerating daily dose of canagliflozin 100 mg, increase the dose to 300 mg once daily, with gradual metformin HCl dose escalation based on tolerability [see Adverse Reactions (6.1)]. INVOKAMET: For patients tolerating canagliflozin 50 mg twice daily, increase the dose of canagliflozin to 150 mg twice daily, with gradual metformin HCl dose escalation based on tolerability [see Adverse Reactions (6.1)]; INVOKAMET XR: For patients tolerating daily dose of canagliflozin 100 mg, increase the dose to 300 mg once daily, with gradual metformin HCl dose escalation based on tolerability [see Adverse Reactions (6.1)]. Patients on Evening Dose of Metformin HCl Extended-Release Patients taking an evening dose of metformin HCl extended-release should skip their last dose before starting INVOKAMET/INVOKAMET XR the following morning.. 2.4Recommended Dosage for Patients with Renal Impairment INVOKAMET/INVOKAMET XR is contraindicated in patients with an eGFR below 45 mL/min/1.73 m2 [see Contraindications (4) and Warnings and Precautions (5.1, 5.5)] Limit the dose of the canagliflozin component of INVOKAMET/INVOKAMET XR to 100 mg (two 50 mg tablets) daily in patients with moderate renal impairment with an eGFR of 45 to less than 60 mL/min/1.73 m2.. INVOKAMET/INVOKAMET XR is contraindicated in patients with an eGFR below 45 mL/min/1.73 m2 [see Contraindications (4) and Warnings and Precautions (5.1, 5.5)] . Limit the dose of the canagliflozin component of INVOKAMET/INVOKAMET XR to 100 mg (two 50 mg tablets) daily in patients with moderate renal impairment with an eGFR of 45 to less than 60 mL/min/1.73 m2.. 2.5Concomitant Use with UDP-Glucuronosyltransferase Enzyme Inducers. If an inducer of UDP-Glucuronosyltransferase (UGT) (e.g., rifampin, phenytoin, phenobarbital, ritonavir) is co-administered with INVOKAMET/INVOKAMET XR, consider increasing the total daily dose of canagliflozin to 300 mg in patients currently tolerating total daily dose of canagliflozin 100 mg who have an eGFR of 60 mL/min/1.73 m2 or greater and require additional glycemic control [see Drug Interactions (7.2)].Consider another antihyperglycemic agent in patients with an eGFR of 45 to less than 60 mL/min/1.73 m2 receiving concurrent therapy with UGT inducer.. 2.6Discontinuation for Iodinated Contrast Imaging Procedures. Discontinue INVOKAMET/INVOKAMET XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR of 45 to less than 60 mL/min/1.73 m2; in patients with 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 imaging procedure; restart INVOKAMET/INVOKAMET XR if renal function is stable [see Warnings and Precautions (5.1)].

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-Approved Patient Labeling (Medication Guide). Lactic Acidosis:Explain the risks of lactic acidosis, its symptoms, and conditions that predispose to its development, as noted in Warnings and Precautions (5.1). Advise patients to discontinue INVOKAMET/INVOKAMET XR immediately and to promptly notify their healthcare provider if unexplained hyperventilation, myalgias, malaise, unusual somnolence or other nonspecific symptoms occur. Once patient is stabilized on INVOKAMET/INVOKAMET XR, gastrointestinal symptoms, which are common during initiation of metformin, are unlikely to recur. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease.Counsel patients against excessive alcohol intake while receiving INVOKAMET/INVOKAMET XR.Inform patients about importance of regular testing of renal function and hematological parameters while receiving INVOKAMET/INVOKAMET XR.Instruct patients to inform their doctor that they are taking INVOKAMET/INVOKAMET XR prior to any surgical or radiological procedure, as temporary discontinuation of INVOKAMET/INVOKAMET XR may be required until renal function has been confirmed to be normal [see Warnings and Precautions (5.1)].. Lower Limb Amputation:Inform patients that INVOKAMET/INVOKAMET XR is associated with an increased risk of amputations. Counsel patients about the importance of routine preventative foot care. Instruct patients to monitor for new pain or tenderness, sores or ulcers, or infections involving the leg or foot and to seek medical advice immediately if such signs or symptoms develop [see Boxed Warning and Warnings and Precautions (5.2)].. Hypotension:Inform patients that symptomatic hypotension may occur with INVOKAMET/INVOKAMET XR and advise them to contact their doctor if they experience such symptoms [see Warnings and Precautions (5.3)]. Inform patients that dehydration may increase the risk for hypotension and to have adequate fluid intake.. Ketoacidosis:Inform patients that ketoacidosis is serious life-threatening condition. Cases of ketoacidosis have been reported during use of canagliflozin. Instruct patients to check ketones (when possible) if symptoms consistent with ketoacidosis occur even if blood glucose is not elevated. If symptoms of ketoacidosis (including nausea, vomiting, abdominal pain, tiredness, and labored breathing) occur, instruct patients to discontinue INVOKAMET/INVOKAMET XR and seek medical advice immediately [see Warnings and Precautions (5.4)].. Acute Kidney Injury:Inform patients that acute kidney injury has been reported during use of canagliflozin. Advise patients to seek medical advice immediately if they have reduced oral intake (such as due to acute illness or fasting), or increased fluid losses (such as due to vomiting, diarrhea, or excessive heat exposure), as it may be appropriate to temporarily discontinue INVOKAMET/INVOKAMET XR use in those settings [see Warnings and Precautions (5.5)].. Serious Urinary Tract Infections:Inform patients of the potential for urinary tract infections, which may be serious. Provide them with information on the symptoms of urinary tract infections. Advise them to seek medical advice if such symptoms occur [see Warnings and Precautions (5.6)].. Necrotizing Fasciitis of the Perineum (Fourniers Gangrene):Inform patients that necrotizing infections of the perineum (Fourniers gangrene) have occurred with INVOKAMET/INVOKAMET XR. Counsel patients to promptly seek medical attention if they develop pain or tenderness, redness, or swelling of the genitals or the area from the genitals back to the rectum, along with fever above 100.4F or malaise [see Warnings and Precautions (5.8)].. Genital Mycotic Infections in Females (e.g., Vulvovaginitis):Inform female patients that vaginal yeast infection (e.g., vulvovaginitis) may occur and provide them with information on the signs and symptoms of vaginal yeast infection. Advise them of treatment options and when to seek medical advice [see Warnings and Precautions (5.9)].. Genital Mycotic Infections in Males (e.g., Balanitis or Balanoposthitis): Inform male patients that yeast infection of penis (e.g., balanitis or balanoposthitis) may occur, especially in uncircumcised males and patients with prior history. Provide them with information on the signs and symptoms of balanitis and balanoposthitis (rash or redness of the glans or foreskin of the penis). Advise them of treatment options and when to seek medical advice [see Warnings and Precautions (5.9)].. Hypersensitivity Reactions:Inform patients that serious hypersensitivity reactions, such as urticaria, rash, anaphylaxis, and angioedema, have been reported with canagliflozin. Advise patients to report immediately any signs or symptoms suggesting allergic reaction and to discontinue drug until they have consulted prescribing physicians [see Warnings and Precautions (5.10)].. Bone Fracture: Inform patients that bone fractures have been reported in patients taking canagliflozin. Provide them with information on factors that may contribute to fracture risk [see Warnings and Precautions (5.11)].. Laboratory Tests: Inform patients that they will test positive for glucose in their urine while on INVOKAMET/INVOKAMET XR [see Drug Interactions (7.2)].. Females of Reproductive Age: Advise pregnant women, and females of reproductive potential of the potential risk to fetus with treatment with INVOKAMET/INVOKAMET XR [see Use in Specific Populations (8.1)]. Instruct females of reproductive potential to report pregnancies to their physicians as soon as possible.Inform females that treatment with INVOKAMET/INVOKAMET XR may result in ovulation in some premenopausal anovulatory women which may lead to unintended pregnancy [see Use in Specific Populations (8.3)].. Lactation: Advise women that breastfeeding is not recommended during treatment with INVOKAMET/INVOKAMET XR [see Use in Specific Populations (8.2)].. Administration:Instruct patients to keep INVOKAMET/INVOKAMET XR in the original bottle to protect from moisture. Advise patients that storage in pill box or pill organizer is allowed for up to 30 days.Instruct patients to take INVOKAMET only as prescribed twice daily with food. If dose is missed, advise patients not to take two doses of INVOKAMET at the same time.Instruct patients to take INVOKAMET XR only as prescribed once daily with the morning meal. If dose is missed, advise patients to take it as soon as it is remembered unless it is almost time for the next dose, in which case patients should skip the missed dose and take the medicine at the next regularly scheduled time. Advise patients not to take more than two tablets of INVOKAMET XR at the same time.Instruct patients that INVOKAMET XR must be swallowed whole and never crushed, cut, or chewed, and that the inactive ingredients may occasionally be eliminated in the feces as soft mass that may resemble the original tablet.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Pregnancy: Advise females of the potential risk to fetus especially during the second and third trimesters (8.1)Lactation: Not recommended when breastfeeding (8.2)Females and Males of Reproductive Potential: Advise premenopausal females of the potential for an unintended pregnancy (8.3).Geriatrics: Higher incidence of adverse reactions related to reduced intravascular volume. Assess renal function more frequently (5.3, 6.1, 8.5)Renal impairment: Higher incidence of adverse reactions related to reduced intravascular volume and renal function (2.4, 5.5, 8.6)Hepatic Impairment: Avoid use in patients with hepatic impairment (8.7). Pregnancy: Advise females of the potential risk to fetus especially during the second and third trimesters (8.1). Lactation: Not recommended when breastfeeding (8.2). Females and Males of Reproductive Potential: Advise premenopausal females of the potential for an unintended pregnancy (8.3).. Geriatrics: Higher incidence of adverse reactions related to reduced intravascular volume. Assess renal function more frequently (5.3, 6.1, 8.5). Renal impairment: Higher incidence of adverse reactions related to reduced intravascular volume and renal function (2.4, 5.5, 8.6). Hepatic Impairment: Avoid use in patients with hepatic impairment (8.7). 8.1 Pregnancy. Risk SummaryBased on animal data showing adverse renal effects, INVOKAMET/INVOKAMET XR is not recommended during the second and third trimesters of pregnancy.Limited data with INVOKAMET, INVOKAMET XR or canagliflozin in pregnant women are not sufficient to determine drug-associated risk for major birth defects or miscarriage. Published studies with metformin use during pregnancy have not reported clear association with metformin and major birth defect or miscarriage risk [see Data]. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy [see Clinical Considerations]. In animal studies, adverse renal pelvic and tubule dilatations that were not reversible were observed in rats when canagliflozin was administered at an exposure 0.5-times the 300 mg clinical dose, based on AUC during period of renal development corresponding to the late second and third trimesters of human pregnancy. No adverse developmental effects were observed when metformin was administered to pregnant Sprague Dawley rats and rabbits during the period of organogenesis at doses up to 2- and 6-times, respectively, 2000 mg clinical dose, based on body surface area [see Data].The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with an HbA1C >7 and has been reported to be as high as 20-25% in women with HbA1C >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.. Clinical Considerations. Disease-associated maternal and/or embryo/fetal riskPoorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, stillbirth and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity.. Data. Human DataPublished data from post-marketing studies have not reported clear association with metformin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin was used during pregnancy. However, these studies cannot definitely establish the absence of any metformin-associated risk because of methodological limitations, including small sample size and inconsistent comparator groups.. Animal Data. CanagliflozinCanagliflozin dosed directly to juvenile rats from postnatal day (PND) 21 until PND 90 at doses of 4, 20, 65, or 100 mg/kg increased kidney weights and dose dependently increased the incidence and severity of renal pelvic and tubular dilatation at all doses tested. Exposure at the lowest dose was greater than or equal to 0.5-times the 300 mg clinical dose, based on AUC. These outcomes occurred with drug exposure during periods of renal development in rats that correspond to the late second and third trimester of human renal development. The renal pelvic dilatations observed in juvenile animals did not fully reverse within 1 month recovery period.In embryo-fetal development studies in rats and rabbits, canagliflozin was administered for intervals coinciding with the first trimester period of organogenesis in humans. No developmental toxicities independent of maternal toxicity were observed when canagliflozin was administered at doses up to 100 mg/kg in pregnant rats and 160 mg/kg in pregnant rabbits during embryonic organogenesis or during study in which maternal rats were dosed from gestation day (GD) through PND 21, yielding exposures up to approximately 19-times the 300 mg clinical dose, based on AUC.. Metformin HydrochlorideMetformin hydrochloride did not cause adverse developmental effects when administered to pregnant Sprague Dawley rats and rabbits up to 600 mg/kg/day during the period of organogenesis. This represents an exposure of about 2- and 6-times 2000 mg clinical dose based on body surface area (mg/m2) for rats and rabbits, respectively.. Canagliflozin and MetforminNo adverse developmental effects were observed when canagliflozin and metformin were co-administered to pregnant rats during the period of organogenesis at exposures up to 11 and 13 times, respectively, the 300 mg and 2000 mg clinical doses of canagliflozin and metformin based on AUC.. 8.2 Lactation. Risk SummaryThere is no information regarding the presence of INVOKAMET, INVOKAMET XR or canagliflozin in human milk, the effects on the breastfed infant, or the effects on milk production. Limited published studies report that metformin is present in human milk [see Data]. However, there is insufficient information on the effects of metformin on the breastfed infant and no available information on the effects of metformin on milk production. Canagliflozin is present in the milk of lactating rats [see Data]. Since human kidney maturation occurs in utero and during the first years of life when lactational exposure may occur, there may be risk to the developing human kidney.Because of the potential for serious adverse reactions in breastfed infant, advise women that use of INVOKAMET/INVOKAMET XR is not recommended while breastfeeding.. Data. Human DataPublished clinical lactation studies report that metformin is present in human milk which resulted in infant doses approximately 0.11% to 1% of the maternal weight-adjusted dosage and milk/plasma ratio ranging between 0.13 and 1. However, the studies were not designed to definitely establish the risk of use of metformin during lactation because of small sample size and limited adverse event data collected in infants.. Animal DataRadiolabeled canagliflozin administered to lactating rats on day 13 post-partum was present at milk/plasma ratio of 1.40, indicating that canagliflozin and its metabolites are transferred into milk at concentration comparable to that in plasma. Juvenile rats directly exposed to canagliflozin showed risk to the developing kidney (renal pelvic and tubular dilatations) during maturation.. 8.3 Females and Males of Reproductive Potential. Discuss the potential for unintended pregnancy with premenopausal women as therapy with metformin may result in ovulation in some anovulatory women.. 8.4 Pediatric Use. Safety and effectiveness of INVOKAMET/INVOKAMET XR in pediatric patients under 18 years of age have not been established.. 8.5 Geriatric Use. INVOKAMET and INVOKAMET XRBecause renal function abnormalities can occur after initiating canagliflozin, metformin is substantially excreted by the kidney, and aging can be associated with reduced renal function, monitor renal function more frequently after initiating INVOKAMET/INVOKAMET XR in the elderly and then adjust dose based on renal function [see Dosage and Administration (2.4) and Warnings and Precautions (5.1, 5.5)].. CanagliflozinIn 13 clinical trials of canagliflozin, 2,294 patients 65 years and older, and 351 patients 75 years and older were exposed to canagliflozin. Of these patients, 1,534 patients 65 years and older and 196 patients 75 years and older were exposed to the combination of canagliflozin and metformin [see Clinical Studies (14)]. Patients 65 years and older had higher incidence of adverse reactions related to reduced intravascular volume with canagliflozin (such as hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration), particularly with the 300 mg daily dose, compared to younger patients; more prominent increase in the incidence was seen in patients who were 75 years and older [see Dosage and Administration (2.1) and Adverse Reactions (6.1)]. Smaller reductions in HbA1C with canagliflozin relative to placebo were seen in older (65 years and older; -0.61% with canagliflozin 100 mg and -0.74% with canagliflozin 300 mg relative to placebo) compared to younger patients (-0.72% with canagliflozin 100 mg and -0.87% with canagliflozin 300 mg relative to placebo).. MetforminControlled clinical trials of metformin did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients, although other reported clinical experience has not identified differences in responses between the elderly and younger patients. The initial and maintenance dosing of metformin should be conservative in patients with advanced age due to the potential for decreased renal function in this population. Any dose adjustment should be based on careful assessment of renal function [see Contraindications (4), Warnings and Precautions (5.5), and Clinical Pharmacology (12.3)].. 8.6Renal Impairment. CanagliflozinThe efficacy and safety of canagliflozin were evaluated in trial that included patients with moderate renal impairment (eGFR 30 to less than 50 mL/min/1.73 m2). These patients had less overall glycemic efficacy and had higher occurrence of adverse reactions related to reduced intravascular volume, renal-related adverse reactions, and decreases in eGFR compared to patients with mild renal impairment or normal renal function (eGFR greater than or equal to 60 mL/min/1.73 m2). Dose-related, transient mean increases in serum potassium were observed early after initiation of canagliflozin (i.e., within weeks) in this trial. Increases in serum potassium of greater than 5.4 mEq/L and 15% above baseline occurred in 16.1%, 12.4%, and 27.0% of patients treated with placebo, canagliflozin 100 mg, and canagliflozin 300 mg, respectively. Severe elevations (greater than or equal to 6.5 mEq/L) occurred in 1.1%, 2.2%, and 2.2% of patients treated with placebo, canagliflozin 100 mg, and canagliflozin 300 mg, respectively [see Dosage and Administration (2.4), Contraindications (4), Warnings and Precautions (5.3, 5.5), and Adverse Reactions (6.1)]. The efficacy and safety of canagliflozin have not been established in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m2), with ESRD, or receiving dialysis. Canagliflozin is not expected to be effective in these patient populations [see Contraindications (4) and Clinical Pharmacology (12.3)].. 8.7Hepatic Impairment. Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. INVOKAMET/INVOKAMET XR is not recommended in patients with hepatic impairment [see Warnings and Precautions (5.1)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Hypotension: Before initiating, assess volume status and correct hypovolemia in patients with renal impairment, the elderly, in patients with low systolic blood pressure, or on diuretics, ACEi, or ARB. Monitor for signs and symptoms during therapy (5.3)Ketoacidosis: Assess patients who present with signs and symptoms of metabolic acidosis for ketoacidosis, regardless of blood glucose level. If suspected, discontinue, evaluate and treat promptly. Before initiating, consider risk factors for ketoacidosis. Patients may require monitoring and temporary discontinuation in clinical situations known to predispose to ketoacidosis (5.4)Acute kidney injury: Consider temporarily discontinuing in settings of reduced oral intake or fluid losses. If acute kidney injury occurs, discontinue and promptly treat. Monitor renal function during therapy (5.5)Urosepsis and pyelonephritis: Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated (5.6)Hypoglycemia: Consider lower dose of insulin or insulin secretagogue to reduce the risk of hypoglycemia when used in combination (5.7)Necrotizing fasciitis of the perineum (Fourniers gangrene): Serious, life-threatening cases have occurred in both females and males. Assess patients presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise. If suspected, institute prompt treatment (5.8)Genital mycotic infections: Monitor and treat if indicated (5.9)Hypersensitivity reactions: Discontinue and monitor until signs and symptoms resolve (5.10)Bone fracture: Consider factors that contribute to fracture risk before initiating INVOKAMET/INVOKAMET XR (5.11)Vitamin B12 deficiency: Metformin may lower vitamin B12 levels. Measure hematological parameters annually and vitamin B12 at 2- to 3-year intervals and manage any abnormalities (5.12)Increased LDL-C: Monitor LDL-C and treat if appropriate (5.13). Hypotension: Before initiating, assess volume status and correct hypovolemia in patients with renal impairment, the elderly, in patients with low systolic blood pressure, or on diuretics, ACEi, or ARB. Monitor for signs and symptoms during therapy (5.3). Ketoacidosis: Assess patients who present with signs and symptoms of metabolic acidosis for ketoacidosis, regardless of blood glucose level. If suspected, discontinue, evaluate and treat promptly. Before initiating, consider risk factors for ketoacidosis. Patients may require monitoring and temporary discontinuation in clinical situations known to predispose to ketoacidosis (5.4). Acute kidney injury: Consider temporarily discontinuing in settings of reduced oral intake or fluid losses. If acute kidney injury occurs, discontinue and promptly treat. Monitor renal function during therapy (5.5). Urosepsis and pyelonephritis: Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated (5.6). Hypoglycemia: Consider lower dose of insulin or insulin secretagogue to reduce the risk of hypoglycemia when used in combination (5.7). Necrotizing fasciitis of the perineum (Fourniers gangrene): Serious, life-threatening cases have occurred in both females and males. Assess patients presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise. If suspected, institute prompt treatment (5.8). Genital mycotic infections: Monitor and treat if indicated (5.9). Hypersensitivity reactions: Discontinue and monitor until signs and symptoms resolve (5.10). Bone fracture: Consider factors that contribute to fracture risk before initiating INVOKAMET/INVOKAMET XR (5.11). Vitamin B12 deficiency: Metformin may lower vitamin B12 levels. Measure hematological parameters annually and vitamin B12 at 2- to 3-year intervals and manage any abnormalities (5.12). Increased LDL-C: Monitor LDL-C and treat if appropriate (5.13). 5.1Lactic Acidosis. There have been post-marketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate:pyruvate ratio; metformin plasma levels generally >5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk.If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in hospital setting, along with immediate discontinuation of INVOKAMET/INVOKAMET XR. In INVOKAMET/INVOKAMET XR-treated patients with diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin hydrochloride is dialyzable, with clearance of up to 170 mL/minute under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery.Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue INVOKAMET/INVOKAMET XR and report these symptoms to their healthcare provider.For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below:. Renal Impairment: The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patients renal function include [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].Before initiating INVOKAMET/INVOKAMET XR, obtain an estimated glomerular filtration rate (eGFR).INVOKAMET/INVOKAMET XR is contraindicated in patients with an eGFR less than 45 mL/minute/1.73 m2 [see Contraindications (4)].Obtain an eGFR at least annually in all patients taking INVOKAMET/INVOKAMET XR. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.. Before initiating INVOKAMET/INVOKAMET XR, obtain an estimated glomerular filtration rate (eGFR).. INVOKAMET/INVOKAMET XR is contraindicated in patients with an eGFR less than 45 mL/minute/1.73 m2 [see Contraindications (4)].. Obtain an eGFR at least annually in all patients taking INVOKAMET/INVOKAMET XR. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.. Drug Interactions: The concomitant use of INVOKAMET/INVOKAMET XR with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation (e.g. cationic drugs) [see Drug Interactions (7)]. Therefore, consider more frequent monitoring of patients.. Age 65 or Greater: The risk of metformin-associated lactic acidosis increases with the patients age because elderly patients have greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients [see Use in Specific Populations (8.5)].. Radiological Studies with Contrast: Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop INVOKAMET/INVOKAMET XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 45 and 60 mL/min/1.73 m2; in patients with history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart INVOKAMET/INVOKAMET XR if renal function is stable.. Surgery and Other Procedures: Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension and renal impairment.INVOKAMET/INVOKAMET XR should be temporarily discontinued while patients have restricted food and fluid intake.. Hypoxic States: Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause pre-renal azotemia. When such events occur, discontinue INVOKAMET/INVOKAMET XR.. Excessive Alcohol Intake: Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving INVOKAMET/INVOKAMET XR.. Hepatic Impairment: Patients with hepatic impairment have developed metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of INVOKAMET/INVOKAMET XR in patients with clinical or laboratory evidence of hepatic disease.. 5.2Lower Limb Amputation. An approximately 2-fold increased risk of lower limb amputations associated with canagliflozin, component of INVOKAMET/INVOKAMET XR, was observed in CANVAS and CANVAS-R, two randomized, placebo-controlled trials evaluating patients with type diabetes who had either established cardiovascular disease or were at risk for cardiovascular disease. The risk of lower limb amputations was observed at both the 100 mg and 300 mg once daily dosage regimens. The amputation data for CANVAS and CANVAS-R are shown in Tables and 3, respectively [see Adverse Reactions (6.1)].Amputations of the toe and midfoot (99 out of 140 patients with amputations receiving canagliflozin in the two trials) were the most frequent; however, amputations involving the leg, below and above the knee, were also observed (41 out of 140 patients with amputations receiving canagliflozin in the two trials). Some patients had multiple amputations, some involving both lower limbs.Lower limb infections, gangrene, and diabetic foot ulcers were the most common precipitating medical events leading to the need for an amputation. The risk of amputation was highest in patients with baseline history of prior amputation, peripheral vascular disease, and neuropathy.Before initiating INVOKAMET/INVOKAMET XR, consider factors in the patient history that may predispose to the need for amputations, such as history of prior amputation, peripheral vascular disease, neuropathy and diabetic foot ulcers. Counsel patients about the importance of routine preventative foot care. Monitor patients receiving INVOKAMET/INVOKAMET XR for signs and symptoms of infection (including osteomyelitis), new pain or tenderness, sores or ulcers involving the lower limbs, and discontinue INVOKAMET/INVOKAMET XR if these complications occur.. 5.3Hypotension. Canagliflozin causes intravascular volume contraction. Symptomatic hypotension can occur after initiating INVOKAMET/INVOKAMET XR [see Adverse Reactions (6.1)] particularly in patients with impaired renal function (eGFR less than 60 mL/min/1.73 m2), elderly patients, patients on either diuretics or medications that interfere with the renin-angiotensin-aldosterone system (e.g., angiotensin-converting-enzyme [ACE] inhibitors, angiotensin receptor blockers [ARBs]), or patients with low systolic blood pressure. Before initiating INVOKAMET/INVOKAMET XR in patients with one or more of these characteristics who were not already on canagliflozin, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy.. 5.4Ketoacidosis. Reports of ketoacidosis, serious life-threatening condition requiring urgent hospitalization have been identified in postmarketing surveillance in patients with type and type diabetes mellitus receiving sodium glucose co-transporter-2 (SGLT2) inhibitors, including canagliflozin. Fatal cases of ketoacidosis have been reported in patients taking canagliflozin. INVOKAMET/INVOKAMET XR is not indicated for the treatment of patients with type diabetes mellitus [see Indications and Usage (1)].Patients treated with INVOKAMET/INVOKAMET XR who present with signs and symptoms consistent with severe metabolic acidosis should be assessed for ketoacidosis regardless of presenting blood glucose levels, as ketoacidosis associated with INVOKAMET/INVOKAMET XR may be present even if blood glucose levels are less than 250 mg/dL. If ketoacidosis is suspected, INVOKAMET/INVOKAMET XR should be discontinued, patient should be evaluated, and prompt treatment should be instituted. Treatment of ketoacidosis may require insulin, fluid and carbohydrate replacement.In many of the postmarketing reports, and particularly in patients with type diabetes, the presence of ketoacidosis was not immediately recognized and institution of treatment was delayed because presenting blood glucose levels were below those typically expected for diabetic ketoacidosis (often less than 250 mg/dL). Signs and symptoms at presentation were consistent with dehydration and severe metabolic acidosis and included nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. In some but not all cases, factors predisposing to ketoacidosis such as insulin dose reduction, acute febrile illness, reduced caloric intake due to illness or surgery, pancreatic disorders suggesting insulin deficiency (e.g., type diabetes, history of pancreatitis or pancreatic surgery), and alcohol abuse were identified.Before initiating INVOKAMET/INVOKAMET XR consider factors in the patient history that may predispose to ketoacidosis including pancreatic insulin deficiency from any cause, caloric restriction, and alcohol abuse. In patients treated with INVOKAMET/INVOKAMET XR consider monitoring for ketoacidosis and temporarily discontinuing INVOKAMET/INVOKAMET XR in clinical situations known to predispose to ketoacidosis (e.g., prolonged fasting due to acute illness or surgery).. 5.5Acute Kidney Injury. Canagliflozin causes intravascular volume contraction [see Warnings and Precautions (5.3)] and can cause acute kidney injury. There have been postmarketing reports of acute kidney injury, some requiring hospitalization and dialysis, in patients receiving canagliflozin; some reports involved patients younger than 65 years of age.Before initiating INVOKAMET/INVOKAMET XR, consider factors that may predispose patients to acute kidney injury including hypovolemia, chronic renal insufficiency, congestive heart failure, and concomitant medications (diuretics, ACE inhibitors, ARBs, NSAIDs). Consider temporarily discontinuing INVOKAMET/INVOKAMET XR in any setting of reduced oral intake (such as acute illness or fasting) or fluid losses (such as gastrointestinal illness or excessive heat exposure); monitor patients for signs and symptoms of acute kidney injury. If acute kidney injury occurs, discontinue INVOKAMET/INVOKAMET XR promptly and institute treatment.Initiation of canagliflozin may increase serum creatinine and decrease eGFR. Patients with hypovolemia may be more susceptible to these changes. [see Adverse Reactions (6.1)]. Renal function should be evaluated prior to initiation of INVOKAMET/INVOKAMET XR and monitored periodically thereafter. Dosage adjustment and more frequent renal function monitoring are recommended in patients with an eGFR below 60 mL/min/1.73 m2. INVOKAMET/INVOKAMET XR is contraindicated in patients with an eGFR below 45 mL/min/1.73 m2 [see Dosage and Administration (2.4), Contraindications (4), Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. 5.6Urosepsis and Pyelonephritis. There have been postmarketing reports of serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalization in patients receiving SGLT2 inhibitors, including canagliflozin. Treatment with SGLT2 inhibitors increases the risk for urinary tract infections. Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated [see Adverse Reactions (6)].. 5.7Hypoglycemia with Concomitant Use of Sulfonylurea or Insulin. Insulin and insulin secretagogues are known to cause hypoglycemia. INVOKAMET/INVOKAMET XR may increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue [see Adverse Reactions (6.1)]. Therefore, lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with INVOKAMET/INVOKAMET XR.. 5.8Necrotizing Fasciitis of the Perineum (Fourniers Gangrene). Reports of necrotizing fasciitis of the perineum (Fourniers gangrene), rare but serious and life-threatening necrotizing infection requiring urgent surgical intervention, have been identified in postmarketing surveillance in patients with diabetes mellitus receiving SGLT2 inhibitors, including canagliflozin. Cases have been reported in both females and males. Serious outcomes have included hospitalization, multiple surgeries, and death.Patients treated with INVOKAMET/INVOKAMET XR presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise, should be assessed for necrotizing fasciitis. If suspected, start treatment immediately with broad-spectrum antibiotics and, if necessary, surgical debridement. Discontinue INVOKAMET/INVOKAMET XR, closely monitor blood glucose levels, and provide appropriate alternative therapy for glycemic control.. 5.9Genital Mycotic Infections. Canagliflozin increases the risk of genital mycotic infections. Patients with history of genital mycotic infections and uncircumcised males were more likely to develop genital mycotic infections [see Adverse Reactions (6.1)]. Monitor and treat appropriately.. 5.10Hypersensitivity Reactions. Hypersensitivity reactions, including angioedema and anaphylaxis, have been reported with canagliflozin. These reactions generally occurred within hours to days after initiating canagliflozin. If hypersensitivity reactions occur, discontinue use of INVOKAMET/INVOKAMET XR; treat and monitor until signs and symptoms resolve [see Contraindications (4) and Adverse Reactions (6.1, 6.2)].. 5.11Bone Fracture. An increased risk of bone fracture, occurring as early as 12 weeks after treatment initiation, was observed in patients using canagliflozin in the CANVAS trial [see Clinical Studies (14.2)]. Consider factors that contribute to fracture risk prior to initiating INVOKAMET/INVOKAMET XR [see Adverse Reactions (6.1)].. 5.12Vitamin B12 Levels. In metformin HCl clinical trials of 29-week duration, decrease to subnormal levels of previously normal serum vitamin B12 levels was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation. Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. Measure hematologic parameters on an annual basis and vitamin B12 at 2- to 3-year intervals in patients on INVOKAMET/INVOKAMET XR and manage any abnormalities [see Adverse Reactions (6.1)]. 5.13Increases in Low-Density Lipoprotein (LDL-C). Dose-related increases in LDL-C occur with canagliflozin [see Adverse Reactions (6.1)]. Monitor LDL-C and treat if appropriate after initiating INVOKAMET/INVOKAMET XR.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1Clinical Studies Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.. Pool of Placebo-Controlled Trials for Glycemic Control. CanagliflozinThe data in Table is derived from four 26-week placebo-controlled trials where canagliflozin was used as monotherapy in one trial and as add-on therapy in three trials. These data reflect exposure of 1,667 patients to canagliflozin and mean duration of exposure to canagliflozin of 24 weeks with 1,275 patients exposed to combination of canagliflozin and metformin HCl. Patients received canagliflozin 100 mg (N=833), canagliflozin 300 mg (N=834) or placebo (N=646) once daily. The mean daily dose of metformin HCl was 2,138 mg (SD 337.3) for the 1,275 patients in the three placebo-controlled metformin HCl add-on trials. The mean age of the population was 56 years and 2% were older than 75 years of age. Fifty percent (50%) of the population was male and 72% were Caucasian, 12% were Asian, and 5% were Black or African American. At baseline the population had diabetes for an average of 7.3 years, had mean HbA 1C of 8.0% and 20% had established microvascular complications of diabetes. Baseline renal function was normal or mildly impaired (mean eGFR 88 mL/min/1.73 2). Table shows common adverse reactions associated with the use of canagliflozin. These adverse reactions were not present at baseline, occurred more commonly on canagliflozin than on placebo, and occurred in at least 2% of patients treated with either canagliflozin 100 mg or canagliflozin 300 mg.Table 2:Adverse Reactions from Pool of Four 26-Week Placebo-Controlled Studies Reported in >= 2% of Canagliflozin-Treated Patients The four placebo-controlled trials included one monotherapy trial and three add-on combination trials with metformin HCl, metformin HCl and sulfonylurea, or metformin HCl and pioglitazone. Adverse ReactionPlacebo N=646 Canagliflozin 100 mg N=833 Canagliflozin 300 mg N=834 Note: Percentages were weighted by studies. Study weights were proportional to the harmonic mean of the three treatment sample sizes.Urinary tract infections Urinary tract infections include the following adverse reactions: Urinary tract infection, Cystitis, Kidney infection, and Urosepsis. 3.8%5.9%4.4%Increased urination Increased urination includes the following adverse reactions: Polyuria, Pollakiuria, Urine output increased, Micturition urgency, and Nocturia. 0.7%5.1%4.6%Thirst Thirst includes the following adverse reactions: Thirst, Dry mouth, and Polydipsia. 0.1%2.8%2.4%Constipation0.9%1.8%2.4%Nausea1.6%2.1%2.3%N=312 N=425N=430Female genital mycotic infections Female genital mycotic infections include the following adverse reactions: Vulvovaginal candidiasis, Vulvovaginal mycotic infection, Vulvovaginitis, Vaginal infection, Vulvitis, and Genital infection fungal. 2.8%10.6%11.6%Vulvovaginal pruritus0.0%1.6%3.2%N=334N=408N=404Male genital mycotic infections Male genital mycotic infections include the following adverse reactions: Balanitis or Balanoposthitis, Balanitis candida, and Genital infection fungal. 0.7%4.2%3.8%Abdominal pain was also more commonly reported in patients taking canagliflozin 100 mg (1.8%), 300 mg (1.7%) than in patients taking placebo (0.8%).. Canagliflozin and Metformin HClThe incidence and type of adverse reactions in the three 26-week placebo-controlled metformin HCl tablets add-on trials, representing majority of data from the four 26-week placebo-controlled trials, was similar to the adverse reactions described in Table 2. There were no additional adverse reactions identified in the pooling of these three placebo-controlled trials that included metformin HCl tablets relative to the four placebo-controlled trials.In trial with canagliflozin as initial combination therapy with metformin HCl [see Clinical Studies (14.1)] an increased incidence of diarrhea was observed in the canagliflozin and metformin HCl combination groups (4.2%) compared to canagliflozin or metformin HCl monotherapy groups (1.7%). Placebo-Controlled Trial in Diabetic NephropathyThe occurrence of adverse reactions for canagliflozin was evaluated in patients participating in CREDENCE, study in patients with type diabetes mellitus and diabetic nephropathy with albuminuria 300 mg/day [see Clinical Studies (14.3)] These data reflect exposure of 2,201 patients to canagliflozin and mean duration of exposure to canagliflozin of 137 weeks. The rate of lower limb amputations associated with the use of canagliflozin 100 mg relative to placebo was 12.3 vs 11.2 events per 1000 patient-years, respectively, with 2.6 years mean duration of follow-up.Incidence rates of adjudicated events of diabetic ketoacidosis (DKA) were 0.21 (0.5%, 12/2,200) and 0.03 (0.1%, 2/2,197) per 100 patient-years of follow-up with canagliflozin 100 mg and placebo, respectively.The incidence of hypotension was 2.8% and 1.5% on canagliflozin 100 mg and placebo, respectively.. The rate of lower limb amputations associated with the use of canagliflozin 100 mg relative to placebo was 12.3 vs 11.2 events per 1000 patient-years, respectively, with 2.6 years mean duration of follow-up.. Incidence rates of adjudicated events of diabetic ketoacidosis (DKA) were 0.21 (0.5%, 12/2,200) and 0.03 (0.1%, 2/2,197) per 100 patient-years of follow-up with canagliflozin 100 mg and placebo, respectively.. The incidence of hypotension was 2.8% and 1.5% on canagliflozin 100 mg and placebo, respectively.. Pool of Placebo- and Active-Controlled Trials for Glycemic Control and Cardiovascular OutcomesThe occurrence of adverse reactions for canagliflozin was evaluated in patients participating in placebo- and active-controlled trials and in an integrated analysis of two cardiovascular trials, CANVAS and CANVAS-R.The types and frequency of common adverse reactions observed in the pool of eight clinical trials (which reflect an exposure of 6,177 patients to canagliflozin) were consistent with those listed in Table 2. Percentages were weighted by studies. Study weights were proportional to the harmonic mean of the three treatment sample sizes. In this pool, canagliflozin was also associated with the adverse reactions of fatigue (1.8%, 2.2%, and 2.0% with comparator, canagliflozin 100 mg, and canagliflozin 300 mg, respectively) and loss of strength or energy (i.e., asthenia) (0.6%, 0.7%, and 1.1% with comparator, canagliflozin 100 mg, and canagliflozin 300 mg, respectively).In the pool of eight clinical trials, the incidence rate of pancreatitis (acute or chronic) was 0.1%, 0.2%, and 0.1% receiving comparator, canagliflozin 100 mg, and canagliflozin 300 mg, respectively.In the pool of eight clinical trials, hypersensitivity-related adverse reactions (including erythema, rash, pruritus, urticaria, and angioedema) was 3.0%, 3.8%, and 4.2% of patients receiving comparator, canagliflozin 100 mg, and canagliflozin 300 mg, respectively. Five patients experienced serious adverse reactions of hypersensitivity with canagliflozin, which included patients with urticaria and patient with diffuse rash and urticaria occurring within hours of exposure to canagliflozin. Among these patients, patients discontinued canagliflozin. One patient with urticaria had recurrence when canagliflozin was re-initiated.Photosensitivity-related adverse reactions (including photosensitivity reaction, polymorphic light eruption, and sunburn) occurred in 0.1%, 0.2%, and 0.2% of patients receiving comparator, canagliflozin 100 mg, and canagliflozin 300 mg, respectively.Other adverse reactions occurring more frequently on canagliflozin than on comparator were:. Lower Limb AmputationAn increased risk of lower limb amputations associated with canagliflozin was observed in CANVAS (5.9 vs 2.8 events per 1000 patient-years) and CANVAS-R (7.5 vs 4.2 events per 1000 patient-years), two randomized, placebo-controlled trials evaluating patients with type diabetes who had either established cardiovascular disease or were at risk for cardiovascular disease. Patients in CANVAS and CANVAS-R were followed for an average of 5.7 and 2.1 years, respectively [see Clinical Studies (14.2)] The amputation data for CANVAS and CANVAS-R are shown in Tables and 4, respectively Table 3:CANVAS AmputationsPlacebo N=1441 Canagliflozin 100 mg N=1445 Canagliflozin 300 mg N=1441 Canagliflozin (Pooled) N=2886 Note: Incidence is based on the number of patients with at least one amputation, and not the total number of amputation events. patients follow-up is calculated from Day to the first amputation event date. Some patients had more than one amputation.Patients with an amputation, (%)22 (1.5)50 (3.5)45 (3.1)95 (3.3)Total amputations338379162Amputation incidence rate (per 1000 patient-years) 2.86.25.55.9Hazard Ratio (95% CI)--2.24 (1.36, 3.69)2.01 (1.20, 3.34)2.12 (1.34, 3.38)Table 4:CANVAS-R AmputationsPlacebo N=2903 Canagliflozin 100 mg (with up-titration to 300 mg) N=2904 Note: Incidence is based on the number of patients with at least one amputation, and not the total number of amputation events. patients follow-up is calculated from Day to the first amputation event date. Some patients had more than one amputation.Patients with an amputation, (%)25 (0.9)45 (1.5)Total amputations3659Amputation incidence rate (per 1000 patient-years) 4.27.5Hazard Ratio (95% CI)--1.80 (1.10, 2.93). Renal Cell CarcinomaIn the CANVAS trial (mean duration of follow-up of 5.7 years) [see Clinical Studies (14.2)] the incidence of renal cell carcinoma was 0.15% (2/1331) and 0.29% (8/2716) for placebo and canagliflozin, respectively, excluding patients with less than months of follow-up, less than 90 days of treatment, or history of renal cell carcinoma. causal relationship to canagliflozin could not be established due to the limited number of cases. Volume Depletion-Related Adverse ReactionsCanagliflozin results in an osmotic diuresis, which may lead to reductions in intravascular volume. In clinical trials for glycemic control, treatment with canagliflozin was associated with dose-dependent increase in the incidence of volume depletion-related adverse reactions (e.g., hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration). An increased incidence was observed in patients on the 300 mg dose. The three factors associated with the largest increase in volume depletion-related adverse reactions in these trials were the use of loop diuretics, moderate renal impairment (eGFR 30 to less than 60 mL/min/1.73 2), and age 75 years and older (Table 5) [see Use in Specific Populations (8.5 and 8.6)] Table 5:Patients With at Least One Volume Depletion-Related Adverse Reaction (Pooled Results from Clinical Trials for Glycemic Control)Baseline CharacteristicComparator Group Includes placebo and active-comparator groups Canagliflozin 100 mg Canagliflozin 300 mg Overall population1.5%2.3%3.4%75 years of age and older Patients could have more than of the listed risk factors 2.6%4.9%8.7%eGFR less than 60 mL/min/1.73 2 2.5%4.7%8.1%Use of loop diuretic 4.7%3.2%8.8%. FallsIn pool of nine clinical trials with mean duration of exposure to canagliflozin of 85 weeks, the proportion of patients who experienced falls was 1.3%, 1.5%, and 2.1% with comparator, canagliflozin 100 mg, and canagliflozin 300 mg, respectively. The higher risk of falls for patients treated with canagliflozin was observed within the first few weeks of treatment.. Genital Mycotic InfectionsIn the pool of four placebo-controlled clinical trials for glycemic control, female genital mycotic infections (e.g., vulvovaginal mycotic infection, vulvovaginal candidiasis, and vulvovaginitis) occurred in 2.8%, 10.6%, and 11.6% of females treated with placebo, canagliflozin 100 mg, and canagliflozin 300 mg, respectively. Patients with history of genital mycotic infections were more likely to develop genital mycotic infections on canagliflozin. Female patients who developed genital mycotic infections on canagliflozin were more likely to experience recurrence and require treatment with oral or topical antifungal agents and anti-microbial agents. In females, discontinuation due to genital mycotic infections occurred in 0% and 0.7% of patients treated with placebo and canagliflozin, respectively.In the pool of four placebo-controlled clinical trials, male genital mycotic infections (e.g., candidal balanitis, balanoposthitis) occurred in 0.7%, 4.2%, and 3.8% of males treated with placebo, canagliflozin 100 mg, and canagliflozin 300 mg, respectively. Male genital mycotic infections occurred more commonly in uncircumcised males and in males with prior history of balanitis or balanoposthitis. Male patients who developed genital mycotic infections on canagliflozin were more likely to experience recurrent infections (22% on canagliflozin versus none on placebo), and require treatment with oral or topical antifungal agents and anti-microbial agents than patients on comparators. In males, discontinuations due to genital mycotic infections occurred in 0% and 0.5% of patients treated with placebo and canagliflozin, respectively.In the pooled analysis of randomized trials evaluating glycemic control, phimosis was reported in 0.3% of uncircumcised male patients treated with canagliflozin and 0.2% required circumcision to treat the phimosis.. HypoglycemiaIn canagliflozin glycemic control trials, hypoglycemia was defined as any event regardless of symptoms, where biochemical hypoglycemia was documented (any glucose value below or equal to 70 mg/dL). Severe hypoglycemia was defined as an event consistent with hypoglycemia where the patient required the assistance of another person to recover, lost consciousness, or experienced seizure (regardless of whether biochemical documentation of low glucose value was obtained). In individual clinical trials of glycemic control [see Clinical Studies (14.1)] episodes of hypoglycemia occurred at higher rate when canagliflozin was co-administered with insulin or sulfonylureas (Table 6). Table 6:Incidence of Hypoglycemia Number of patients experiencing at least one event of hypoglycemia based on either biochemically documented episodes or severe hypoglycemic events in the intent-to-treat population in Randomized Clinical Studies of Glycemic Control Monotherapy (26 weeks) Placebo (N=192) Canagliflozin 100 mg (N=195) Canagliflozin 300 mg (N=197) Overall [N (%)]5 (2.6)7 (3.6)6 (3.0)In Combination with Metformin HCl (26 weeks) Placebo Metformin HCl (N=183) Canagliflozin 100 mg Metformin HCl (N=368) Canagliflozin 300 mg Metformin HCl (N=367) Overall [N (%)]3 (1.6)16 (4.3)17 (4.6)Severe [N (%)] Severe episodes of hypoglycemia were defined as those where the patient required the assistance of another person to recover, lost consciousness, or experienced seizure (regardless of whether biochemical documentation of low glucose value was obtained) (0)1 (0.3)1 (0.3)In Combination with Metformin HCl (18 weeks) Phase clinical study with twice daily dosing (50 mg or 150 mg twice daily in combination with metformin HCl)Placebo (N=93) Canagliflozin 100 mg (N=93) Canagliflozin 300 mg (N=93) Overall [N (%)]3 (3.2)4 (4.3)3 (3.2)In Combination with Metformin HCl Sulfonylurea (26 weeks) Placebo Metformin HCl Sulfonylurea (N=156) Canagliflozin 100 mg Metformin HCl Sulfonylurea (N=157) Canagliflozin 300 mg Metformin HCl Sulfonylurea (N=156) Overall [N (%)]24 (15.4)43 (27.4)47 (30.1)Severe [N (%)] (0.6)1 (0.6)0In Combination with Metformin HCl Pioglitazone (26 weeks) Placebo Metformin HCl Pioglitazone (N=115) Canagliflozin 100 mg Metformin HCl Pioglitazone (N=113) Canagliflozin 300 mg Metformin HCl Pioglitazone (N=114) Overall [N (%)]3 (2.6)3 (2.7)6 (5.3)In Combination with Insulin (18 weeks) Placebo (N=565) Canagliflozin 100 mg (N=566) Canagliflozin 300 mg (N=587) Overall [N (%)]208 (36.8)279 (49.3)285 (48.6)Severe [N (%)] 14 (2.5)10 (1.8)16 (2.7)In Combination with Insulin and Metformin HCl (18 weeks)Subgroup of patients (N=287) from insulin substudy on canagliflozin in combination with metformin HCl and insulin (with or without other antiglycemic agents)Placebo (N=145) Canagliflozin 100 mg (N=139) Canagliflozin 300 mg (N=148) Overall [N (%)]66 (45.5)58 (41.7)70 (47.3)Severe [N (%)] (2.8)1 (0.7)3 (2.0). Bone FractureIn the CANVAS trial [see Clinical Studies (14.2)] the incidence rates of all adjudicated bone fracture were 1.09, 1.59, and 1.79 events per 100 patient-years of follow-up to placebo, canagliflozin 100 mg, and canagliflozin 300 mg, respectively. The fracture imbalance was observed within the first 26 weeks of therapy and remained through the end of the trial. Fractures were more likely to be low trauma (e.g., fall from no more than standing height), and affect the distal portion of upper and lower extremities. Metformin HClThe most common adverse reactions (5% or greater incidence) due to initiation of metformin HCl are diarrhea, nausea, vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache.Long-term treatment with metformin HCl has been associated with decrease in vitamin 12, which may result in clinically significant vitamin 12 deficiency (e.g., megaloblastic anemia) [see Warnings and Precautions (5.11)] . Laboratory and Imaging Tests. Increases in Serum Creatinine and Decreases in eGFRInitiation of canagliflozin causes an increase in serum creatinine and decrease in estimated GFR. In patients with moderate renal impairment, the increase in serum creatinine generally does not exceed 0.2 mg/dL, occurs within the first weeks of starting therapy, and then stabilizes. Increases that do not fit this pattern should prompt further evaluation to exclude the possibility of acute kidney injury [see Clinical Pharmacology (12.1)] The acute effect on eGFR reverses after treatment discontinuation suggesting acute hemodynamic changes may play role in the renal function changes observed with canagliflozin. Increases in Serum PotassiumIn pooled population of patients (N=723) in glycemic control trials with moderate renal impairment (eGFR 45 to less than 60 mL/min/1.73 2), increases in serum potassium to greater than 5.4 mEq/L and 15% above occurred in 5.3%, 5.0%, and 8.8% of patients treated with placebo, canagliflozin 100 mg, and canagliflozin 300 mg, respectively. Severe elevations (greater than or equal to 6.5 mEq/L) occurred in 0.4% of patients treated with placebo, no patients treated with canagliflozin 100 mg, and 1.3% of patients treated with canagliflozin 300 mg. In these patients, increases in potassium were more commonly seen in those with elevated potassium at baseline. Among patients with moderate renal impairment, approximately 84% were taking medications that interfere with potassium excretion, such as potassium-sparing diuretics, angiotensin-converting-enzyme inhibitors, and angiotensin-receptor blockers [see Use in Specific Populations (8.6)]. In CREDENCE, no difference in serum potassium, no increase in adverse events of hyperkalemia, and no increase in absolute (> 6.5 mEq/L) or relative (> upper limit of normal and 15% increase from baseline) increases in serum potassium were observed with canagliflozin 100 mg relative to placebo.. Increases in Low-Density Lipoprotein Cholesterol (LDL-C) and non-High-Density Lipoprotein Cholesterol (non-HDL-C)In the pool of four glycemic control placebo-controlled trials, dose-related increases in LDL-C with canagliflozin were observed. Mean changes (percent changes) from baseline in LDL-C relative to placebo were 4.4 mg/dL (4.5%) and 8.2 mg/dL (8.0%) with canagliflozin 100 mg and canagliflozin 300 mg, respectively. The mean baseline LDL-C levels were 104 to 110 mg/dL across treatment groups.Dose-related increases in non-HDL-C with canagliflozin were observed. Mean changes (percent changes) from baseline in non-HDL-C relative to placebo were 2.1 mg/dL (1.5%) and 5.1 mg/dL (3.6%) with canagliflozin 100 mg and 300 mg, respectively. The mean baseline non-HDL-C levels were 140 to 147 mg/dL across treatment groups.. Increases in HemoglobinIn the pool of four placebo-controlled trials of glycemic control, mean changes (percent changes) from baseline in hemoglobin were -0.18 g/dL (-1.1%) with placebo, 0.47 g/dL (3.5%) with canagliflozin 100 mg, and 0.51 g/dL (3.8%) with canagliflozin 300 mg. The mean baseline hemoglobin value was approximately 14.1 g/dL across treatment groups. At the end of treatment, 0.8%, 4.0%, and 2.7% of patients treated with placebo, canagliflozin 100 mg, and canagliflozin 300 mg, respectively, had hemoglobin above the upper limit of normal.. Decreases in Bone Mineral DensityBone mineral density (BMD) was measured by dual-energy X-ray absorptiometry in clinical trial of 714 older adults (mean age 64 years). At years, patients randomized to canagliflozin 100 mg and canagliflozin 300 mg had placebo-corrected declines in BMD at the total hip of 0.9% and 1.2%, respectively, and at the lumbar spine of 0.3% and 0.7%, respectively. Additionally, placebo-adjusted BMD declines were 0.1% at the femoral neck for both canagliflozin doses and 0.4% at the distal forearm for patients randomized to canagliflozin 300 mg. The placebo-adjusted change at the distal forearm for patients randomized to canagliflozin 100 mg was 0%.