Canagliflozin and Metformin Hydrochloride Tablets

Dosage Forms And Strengths

INVOKAMET (canagliflozin and metformin hydrochloride) film-coated tablets for oral administration are available in the following strengths:

• Canagliflozin 50 mg and metformin hydrochloride 500 mg tablets are immediate-release, capsule-shaped, white film-coated tablets with “CM” on one side and “155” on the other side.
• Canagliflozin 50 mg and metformin hydrochloride 1,000 mg tablets are immediate-release, capsule-shaped, beige, film-coated tablets with “CM” on one side and “551” on the other side.
• Canagliflozin 150 mg and metformin hydrochloride 500 mg tablets are immediate-release, capsule-shaped, yellow, film-coated tablets with “CM” on one side and “215” on the other side.
• Canagliflozin 150 mg and metformin hydrochloride 1,000 mg tablets are immediate-release, capsule-shaped, purple, film-coated tablets with “CM” on one side and “611” on the other side.

INVOKAMET (canagliflozin and metformin hydrochloride) tablets are available in the strengths and packages listed below:

Canagliflozin 50 mg and metformin hydrochloride 500 mg tablets are immediate-release, capsule-shaped, white film-coated tablets with “CM” on one side and “155” on the other side.

• NDC 50458-540-60 Bottle of 60

Canagliflozin 50 mg and metformin hydrochloride 1,000 mg tablets are immediate-release, capsule-shaped, beige film-coated tablets with “CM” on one side and “551” on the other side.

• NDC 50458-541-60 Bottle of 60

Canagliflozin 150 mg and metformin hydrochloride 500 mg tablets are immediate-release, capsule-shaped, yellow film-coated tablets with “CM” on one side and “215” on the other side.

• NDC 50458-542-60 Bottle of 60

Canagliflozin 150 mg and metformin hydrochloride 1,000 mg tablets are immediate-release, capsule-shaped, purple film-coated tablets with “CM” on one side and “611” on the other side.

• NDC 50458-543-60 Bottle of 60

Storage And Handling

Keep out of reach of children.

Store at 68-77°F (20-25°C); excursions permitted between 59°F and 86°F (15°C and 30°C) [see USP Controlled Room Temperature]. Store and dispense in the original container. Storage in a pill box or pill organizer is allowed for up to 30 days.

Manufactured by: Janssen Ortho LLC, Gurabo, PR 00778. Revised July 2017

The following adverse reactions are also discussed elsewhere in the labeling:

• Lactic Acidosis [see BOX WARNING and WARNINGS AND PRECAUTIONS]
• Lower Limb Amputation [see BOX WARNING and WARNINGS AND PRECAUTIONS]
• Hypotension [see WARNINGS AND PRECAUTIONS]
• Ketoacidosis [see WARNINGS AND PRECAUTIONS]
• Acute Kidney Injury and Impairment in Renal Function [see WARNINGS AND PRECAUTIONS]
• Hyperkalemia [see WARNINGS AND PRECAUTIONS]
• Urosepsis and Pyelonephritis [see WARNINGS AND PRECAUTIONS]
• Hypoglycemia with Concomitant Use of Sulfonylurea or Insulin [see WARNINGS AND PRECAUTIONS]
• Genital Mycotic Infections [see WARNINGS AND PRECAUTIONS]
• Hypersensitivity Reactions [see WARNINGS AND PRECAUTIONS]
• Bone Fracture [see WARNINGS AND PRECAUTIONS]
• Vitamin B12 Deficiency [see WARNINGS AND PRECAUTIONS]
• Increases in Low-Density Lipoprotein (LDL-C) [see WARNINGS AND PRECAUTIONS]

Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a 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

The data in Table 1 is derived from four 26-week placebo-controlled trials. In one trial canagliflozin was used as monotherapy and in three trials canagliflozin was used as add-on therapy with metformin (with or without other agents) [see Clinical Studies]. These data reflect exposure of 1667 patients to canagliflozin and a mean duration of exposure to canagliflozin of 24 weeks with 1275 patients exposed to a 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 was 2138 mg (SD 337.3) for the 1275 patients in the three placebo-controlled metformin add-on studies. 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 a 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 1 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 Patients*

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%).

The incidence and type of adverse reactions in the three 26-week placebo-controlled metformin add-on studies, representing a 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 studies that included metformin relative to the four placebo-controlled studies.

In a trial with canagliflozin as initial combination therapy with metformin [see Clinical Studies], 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

The occurrence of adverse reactions for canagliflozin was evaluated in a larger pool of patients participating in placebo-and active-controlled trials.

The data combined eight clinical trials and reflect exposure of 6177 patients to canagliflozin. The mean duration of exposure to canagliflozin was 38 weeks with 1832 individuals exposed to canagliflozin for greater than 50 weeks. Patients received canagliflozin 100 mg (N=3092), canagliflozin 300 mg (N=3085) or comparator (N=3262) once daily. The mean age of the population was 60 years and 5% were older than 75 years of age. Fifty-eight percent (58%) of the population was male and 73% were Caucasian, 16% were Asian, and 4% were Black or African American. At baseline, the population had diabetes for an average of 11 years, had a mean HbA1C of 8.0% and 33% had established microvascular complications of diabetes. Baseline renal function was normal or mildly impaired (mean eGFR 81 mL/min/1.73 m2).

The types and frequency of common adverse reactions observed in the pool of eight clinical trials 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% with comparator, 2.2% with canagliflozin 100 mg, and 2.0% with canagliflozin 300 mg) and loss of strength or energy (i.e., asthenia) (0.6% with comparator, 0.7% with canagliflozin 100 mg, and 1.1% with canagliflozin 300 mg).

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) occurred in 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 4 patients with urticaria and 1 patient with a diffuse rash and urticaria occurring within hours of exposure to canagliflozin. Among these patients, 2 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 Amputation

An approximately 2-fold increased risk of lower limb amputations associated with canagliflozin, a component of INVOKAMET, was observed in CANVAS and CANVAS-R, two large, randomized, placebo-controlled trials evaluating patients with type 2 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. The amputation data for CANVAS and CANVAS-R are shown in Tables 2 and 3, respectively [see WARNINGS AND PRECAUTIONS].

Table 2: CANVAS AMPUTATIONS

Table 3: CANVAS-R AMPUTATIONS

Volume Depletion-Related Adverse Reactions

Canagliflozin results in an osmotic diuresis, which may lead to reductions in intravascular volume. In clinical studies, treatment with canagliflozin was associated with a 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, WARNINGS AND PRECAUTIONS , and Use In Specific Populations].

Table 4: Proportion of Patients With at Least One Volume Depletion-Related Adverse Reaction (Pooled Results from 8 Clinical Trials)

Falls

In a 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 Function

Canagliflozin is associated with a dose-dependent increase in serum creatinine and a concomitant fall in estimated GFR (Table 5). Patients with moderate renal impairment at baseline had larger mean changes.

Table 5: Changes in Serum Creatinine and eGFR Associated with Canagliflozin in the Pool of Four Placebo-Controlled Trials and Moderate Renal Impairment Trial

In 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 a significant renal function decline.

In a trial carried out in patients with moderate renal impairment with a baseline eGFR of 30 to less than 50 mL/min/1.73 m2 (mean baseline eGFR 39 mL/min/1.73 m2), 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% with placebo, 18% with canagliflozin 100 mg, and 22.5% with canagliflozin 300 mg. At the end of treatment, 4.6% with placebo, 3.4% with canagliflozin 100 mg, and 2.2% with canagliflozin 300 mg had a significant renal function decline.

In a pooled population of patients with moderate renal impairment (N=1085) with baseline eGFR of 30 to less than 60 mL/min/1.73 m2 (mean baseline eGFR 48 mL/min/1.73 m2), the overall incidence of these events was lower than in the dedicated trial but a dose-dependent increase in incident episodes of significant renal function decline compared to placebo was still observed. Use of canagliflozin has been associated with an increased incidence of renal-related adverse reactions (e.g., increased blood creatinine, decreased glomerular filtration rate, renal impairment, and acute renal failure), particularly in patients with moderate renal impairment.

In the pooled analysis of patients with moderate renal impairment, the incidence of renal-related adverse reactions was 3.7% with placebo, 8.9% with canagliflozin 100 mg, and 9.3% with canagliflozin 300 mg. Discontinuations due to renal-related adverse events occurred in 1.0% with placebo, 1.2% with canagliflozin 100 mg, and 1.6% with canagliflozin 300 mg [see WARNINGS AND PRECAUTIONS].

Genital Mycotic Infections

In 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 a 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].

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 a 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 8 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].

Hypoglycemia

In 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 a seizure (regardless of whether biochemical documentation of a low glucose value was obtained). In individual clinical trials [see Clinical Studies], episodes of hypoglycemia occurred at a higher rate when canagliflozin was co-administered with insulin or sulfonylureas (Table 6) [see WARNINGS AND PRECAUTIONS].

Table 6: Incidence of Hypoglycemia* in Controlled Clinical Studies

Bone Fracture

The occurrence of bone fractures was evaluated in a pool of nine clinical trials with a mean duration of exposure to canagliflozin of 85 weeks. The incidence rates of adjudicated bone fractures were 1.1, 1.4, and 1.5 per 100 patient-years of exposure in the comparator, canagliflozin 100 mg, and canagliflozin 300 mg groups, respectively. Fractures were observed as early as 12 weeks after treatment initiation and were more likely to be low trauma (e.g., fall from no more than standing height), and affect the upper extremities [see WARNINGS AND PRECAUTIONS].

The 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 a decrease in vitamin B12, which may very rarely result in clinically significant vitamin B12 deficiency (e.g., megaloblastic anemia) [see WARNINGS AND PRECAUTIONS].

Laboratory And Imaging Tests

In a 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 baseline 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 and Use In Specific Populations].

Dose-related increases in serum magnesium were observed early after initiation of canagliflozin (within 6 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 a 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.

Dose-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 a 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.

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].

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.

In 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 levels above the upper limit of normal.

Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry in a clinical trial of 714 older adults (mean age 64 years). At 2 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%.

Postmarketing Experience

Additional adverse reactions have been identified during postapproval use of canagliflozin. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Ketoacidosis [see WARNINGS AND PRECAUTIONS]

Acute Kidney Injury and Impairment in Renal Function [see WARNINGS AND PRECAUTIONS]

Anaphylaxis, Angioedema [see WARNINGS AND PRECAUTIONS]

Urosepsis and Pyelonephritis [see WARNINGS AND PRECAUTIONS]

Included as part of the "PRECAUTIONS" Section

In the event of an overdose with INVOKAMET, contact the Poison Control Center. Employ the usual supportive measures (e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive treatment) as dictated by the patient’s clinical status. Canagliflozin was negligibly removed during a 4-hour hemodialysis session. Canagliflozin is not expected to be dialyzable by peritoneal dialysis. Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful partly for removal of accumulated metformin from patients in whom INVOKAMET overdosage is suspected.

Canagliflozin

There were no reports of overdose during the clinical development program of canagliflozin.

Metformin

Overdose of metformin hydrochloride has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin hydrochloride has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases [see WARNINGS AND PRECAUTIONS].

INVOKAMET®
(in vok’ a met)
(canagliflozin and metformin hydrochloride) Tablets for oral use

What is the most important information I should know about INVOKAMET?

INVOKAMET can cause serious side effects, including:

• Lactic Acidosis. Metformin, one of the medicines in INVOKAMET, can cause a rare but serious condition called lactic acidosis (a build-up of lactic acid in the blood) that can cause death. Lactic acidosis is a 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 have a slow or irregular heartbeat
  • you feel very weak or tired
  • you have unusual (not normal) muscle pain
  • you have trouble breathing
  • you have stomach pains, nausea, or vomiting
  • you have unusual sleepiness or sleep longer than usual
  • you feel dizzy or lightheaded

Most 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 a higher chance for getting lactic acidosis with INVOKAMET 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 a lot of alcohol in short-term "binge" drinking.
• get dehydrated (lose a large amount of body fluids). This can happen if you are sick with a fever, vomiting, or diarrhea. Dehydration can also happen when you sweat a lot with activity or exercise and do not drink enough fluids.
• have surgery.
• have a heart attack, severe infection, or stroke.

The best way to keep from having a 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 for a while if you have any of these things.

• Amputations. INVOKANA 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 a higher risk of lower limb amputation if you:

  • have a 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

Call 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 for a while if you have any of these signs or symptoms.

Talk to your doctor about proper foot care.

INVOKAMET can have other serious side effects. See “What are the possible side effects of INVOKAMET?”

What is INVOKAMET?

• INVOKAMET contains 2 prescription medicines called canagliflozin (INVOKANA) and metformin hydrochloride (GLUCOPHAGE). INVOKAMET can be used along with diet and exercise to improve blood sugar (glucose) control in adults with type 2 diabetes when treatment with both canagliflozin and metformin is appropriate.
• INVOKAMET is not for people with diabetic ketoacidosis (increased ketones in blood or urine).
• It is not known if INVOKAMET is safe and effective in children under 18 years of age.

Who should not take INVOKAMET?

Do not take INVOKAMET if you:

• have moderate to severe kidney problems or are on dialysis.
• have a 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. See the end of this Medication Guide for a list of ingredients in INVOKAMET. Symptoms of allergic reaction to INVOKAMET may include:
  • 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

What should I tell my doctor before taking INVOKAMET?

Before you take INVOKAMET, tell your doctor if you:

• have a 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 a history of urinary tract infections or problems with urination.
• are on a low sodium (salt) diet. Your doctor may change your diet or your dose of INVOKAMET.
• have ever had an allergic reaction to INVOKAMET.
• are going to get an injection of dye or contrast agents for an x-ray procedure. INVOKAMET may need to be stopped for a short time. Talk to your doctor about when you should stop INVOKAMET and when you should start INVOKAMET again. See "What is the most important information I should know about INVOKAMET?”
• have heart problems, including congestive heart failure.
• are going to have surgery.
• are eating less due to illness, surgery, or a 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 a lot of alcohol in the short-term ("binge" drinking).
• have other medical conditions.
• are pregnant or plan to become pregnant. INVOKAMET may harm your unborn baby. If you become pregnant while taking INVOKAMET, 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 a premenopausal woman (before the “change of life”), who does not have periods regularly or at all. INVOKAMET may increase your chance of becoming pregnant. Talk to your doctor about birth control choices while taking INVOKAMET, if you are not planning to become pregnant. Tell your doctor right away if you become pregnant while taking INVOKAMET.
• are breastfeeding or plan to breastfeed. INVOKAMET 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. Do not breastfeed while taking INVOKAMET.

Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

INVOKAMET may affect the way other medicines work and other medicines may affect how INVOKAMET works. Especially tell your doctor if you take:

• diuretics (water pills)
• rifampin (used to treat or prevent tuberculosis)
• phenytoin or phenobarbital (used to control seizures)
• ritonavir (Norvir® , Kaletra®)* (used to treat HIV infection)
• digoxin (Lanoxin®)* (used to treat heart problems)

Ask your doctor or pharmacist for a list of these medicines if you are not sure if your medicine is listed above.

Know the medicines you take. Keep a list of them and show it to your doctor and pharmacist when you get a new medicine.

How should I take INVOKAMET?

• Take INVOKAMET by mouth 2 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.
• Your doctor will tell you how much INVOKAMET to take and when to take it. Your doctor may change your dose if needed.
• Your doctor may tell you to take INVOKAMET along with other diabetes medicines. Low blood sugar can happen more often when INVOKAMET is taken with certain other diabetes medicines. See “What are the possible side effects of INVOKAMET?”
• If you miss a dose, 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 2 doses of INVOKAMET at the same time. Talk to your doctor if you have questions about a missed dose.
• If you take too much INVOKAMET, 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 a 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 doctor’s instructions.
• Stay on your prescribed diet and exercise program while taking INVOKAMET.
• Check your blood sugar as your doctor tells you to.
• INVOKAMET will cause your urine to test positive for glucose.
• Your doctor may do certain blood tests before you start INVOKAMET and during treatment as needed. Your doctor may change your dose of INVOKAMET 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 I avoid while taking INVOKAMET?

• Avoid drinking alcohol very often, or drinking a lot of alcohol in a short period of time ("binge" drinking). It can increase your chances of getting serious side effects.

What are the possible side effects of INVOKAMET?

INVOKAMET may cause serious side effects including:

• See "What is the most important information I should know about INVOKAMET?”
• dehydration. INVOKAMET 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 pressure
  • take medicines to lower your blood pressure, including diuretics (water pill)
  • are on a low sodium (salt) diet
  • have kidney problems
  • are 65 years of age or older

Talk to your doctor about what you can do to prevent dehydration including how much fluid you should drink on a daily basis.

• ketoacidosis (increased ketones in your blood or urine). Ketoacidosis has happened in people who have type 1 diabetes or type 2 diabetes, during treatment with canagliflozin, one of the medicines in INVOKAMET. Ketoacidosis is a serious condition, which may need to be treated in a hospital. Ketoacidosis may lead to death. Ketoacidosis can happen with INVOKAMET, even if your blood sugar is less than 250 mg/dL. Stop taking INVOKAMET and call your doctor right away if you get any of the following symptoms:
  • nausea
  • tiredness
  • vomiting
  • trouble breathing
  • stomach area (abdominal) pain

If you get any of these symptoms during treatment with INVOKAMET, 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. 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 or
  • you start to lose liquids from your body for example, from vomiting, diarrhea or being in the sun too long.
• a high amount of potassium in your blood.
• 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. Tell your doctor if you have any signs or symptoms of a urinary tract infection such as a burning feeling when passing urine, a 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 a fever, back pain, nausea, or vomiting.
• low blood sugar (hypoglycemia). If you take INVOKAMET with another medicine that can cause low blood sugar, such as a 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. Signs and symptoms of low blood sugar may include:
  • headache
  • drowsiness
  • weakness
  • confusion
  • dizziness
  • irritability
  • hunger
  • fast heartbeat
  • sweating
  • shaking or feeling jittery
• vaginal yeast infection. Women who take INVOKAMET may get vaginal yeast infections. Symptoms of a vaginal yeast infection include:
  • 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 may get a 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
  • rash of the penis
  • foul smelling discharge from the penis
  • pain in the skin around the penis

Talk to your doctor about what to do if you get symptoms of a 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 a serious allergic reaction, stop taking INVOKAMET and call your doctor right away or go to the nearest hospital emergency room. See “Who should not take INVOKAMET?”. Your doctor may give you a medicine for your allergic reaction and prescribe a 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 a 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 include:

• nausea and vomiting
• diarrhea
• weakness
• gas
• upset stomach
• indigestion
• headache
• changes in urination, including urgent need to urinate more often, in larger amounts, or at night

Tell 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. 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 I store INVOKAMET?

• Store INVOKAMET at room temperature between 68°F to 77°F (20°C to 25°C).
• Store in the original container to protect from moisture. Storage in a pill box or pill organizer is allowed for up to 30 days.

Keep INVOKAMET and all medicines out of the reach of children.

General information about the safe and effective use of INVOKAMET.

Medicines are sometimes prescribed for purposes other than those listed in the Medication Guide. Do not use INVOKAMET for a condition for which it was not prescribed. Do not give INVOKAMET 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. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about INVOKAMET that is written for healthcare professionals.

For more information about INVOKAMET, call 1-800-526-7736 or visit our website at www.invokamet.com.

What are the ingredients of INVOKAMET?

Active ingredients: canagliflozin and metformin hydrochloride

Inactive 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/PEG, 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).

This Medication Guide has been approved by the U.S. Food and Drug Administration.