Invokamet XR

WARNING: LACTIC ACIDOSIS

• Lactic acidosis is a rare but serious complication that can occur due to metformin accumulation. The risk increases with conditions such as renal impairment, sepsis, dehydration, excess alcohol intake, hepatic impairment, and acute congestive heart failure.
• The onset is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress.
• Laboratory abnormalities include low pH, increased anion gap, and elevated blood lactate.
• If lactic acidosis is suspected, Invokamet should be discontinued and the patient hospitalized immediately

Canagliflozin and metformin are oral diabetes medicines that help control blood sugar levels.

Canagliflozin and metformin is a combination medicine used with diet and exercise to improve blood sugar control in adults with type 2 diabetes.

Canagliflozin and metformin may also be used for purposes not listed in this medication guide.

You should not use this medicine if you have moderate to severe kidney disease, diabetic ketoacidosis, or if you are on dialysis.

This medicine may cause a serious condition called lactic acidosis. Get emergency medical help if you have: muscle pain or weakness, numb or cold feeling in your arms and legs, trouble breathing, stomach pain, nausea with vomiting, slow or uneven heart rate, dizziness, or feeling very weak or tired.

In the U.S.

• Invokamet
• Invokamet XR

Available Dosage Forms:

• Tablet
• Tablet, Extended Release

Therapeutic Class: Antidiabetic

Pharmacologic Class: Sodium Glucose Co-Transporter 2 Inhibitor

Chemical Class: Metformin

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

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

• Abdominal or stomach discomfort
• bladder pain
• bloody or cloudy urine
• decreased appetite
• diarrhea
• difficult, burning, or painful urination
• fast, shallow breathing
• frequent urge to urinate
• frequent urination
• general feeling of discomfort
• increased urge to urinate during the night
• increased volume of pale, dilute urine
• itching of the vagina or genitals
• itching, stinging, or redness of the vaginal area
• lower back or side pain
• muscle pain or cramping
• nausea
• shortness of breath
• sleepiness
• thick, white vaginal discharge with mild or no odor
• unusual tiredness or weakness
• waking to urinate at night

• Dry mouth
• increased thirst

• Anxiety
• blurred vision
• chills
• cold sweats
• coma
• confusion
• cool, pale skin
• depression
• difficulty with swallowing
• dizziness
• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• fast heartbeat
• fever
• headache
• hives
• increased hunger
• irregular heartbeat
• nightmares
• numbness or tingling in the hands, feet, or lips
• pain in the skin around the penis
• reddening of the skin, especially around the ears
• redness, itching, or swelling of the penis
• seizures
• shakiness
• slurred speech
• stomach pain
• sweating
• swelling of the eyes, face, or inside of the nose
• vomiting
• weakness or heaviness of the legs

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

• Difficulty having a bowel movement (stool)

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

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

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

Pregnancy

Risk Summary

Based on animal data showing adverse renal effects, Invokamet XR is not recommended during the second and third trimesters of pregnancy.

Limited data with Invokamet XR or canagliflozin in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. Published studies with metformin use during pregnancy have not reported a 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 a 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, a 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 a 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 risk

Poorly 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 Data

Published data from post-marketing studies have not reported a 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

Canagliflozin

Canagliflozin 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 a 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 a study in which maternal rats were dosed from gestation day (GD) 6 through PND 21, yielding exposures up to approximately 19-times the 300 mg clinical dose, based on AUC.

Metformin Hydrochloride

Metformin 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 a 2000 mg clinical dose based on body surface area (mg/m2) for rats and rabbits, respectively.

Canagliflozin and Metformin

No 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.

Lactation

Risk Summary

There is no information regarding the presence of 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 2 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 a breastfed infant, advise women that use of Invokamet XR is not recommended while breastfeeding.

Data

Human Data

Published 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 a 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 Data

Radiolabeled canagliflozin administered to lactating rats on day 13 post-partum was present at a milk/plasma ratio of 1.40, indicating that canagliflozin and its metabolites are transferred into milk at a concentration comparable to that in plasma. Juvenile rats directly exposed to canagliflozin showed a risk to the developing kidney (renal pelvic and tubular dilatations) during maturation.

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.

Pediatric Use

Safety and effectiveness of Invokamet XR in pediatric patients under 18 years of age have not been established.

Geriatric Use

Invokamet XR

Because 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 XR in the elderly and then adjust dose based on renal function [see Dosage and Administration (2.2) and Warnings and Precautions (5.1, 5.5)].

Canagliflozin

Two thousand thirty-four (2034) patients 65 years and older, and 345 patients 75 years and older were exposed to canagliflozin in nine clinical studies of canagliflozin. Of these patients, 1334 patients 65 years and older and 181 patients 75 years and older were exposed to the combination of canagliflozin and metformin [see Clinical Studies (14)]. Patients 65 years and older had a 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; a 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).

Metformin

Controlled clinical studies 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 a careful assessment of renal function [see Contraindications (4), Warnings and Precautions (5.5), and Clinical Pharmacology (12.3)].

Renal Impairment

Canagliflozin

The efficacy and safety of canagliflozin were evaluated in a study 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 a 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 3 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 (2.2), Contraindications (4), Warnings and Precautions (5.1, 5.4, 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)].

Hepatic Impairment

Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. Invokamet XR is not recommended in patients with hepatic impairment. [see Warnings and Precautions (5.1)]

Canagliflozin has been studied in combination with metformin alone, metformin and sulfonylurea, metformin and a thiazolidinedione (i.e. pioglitazone), and metformin and insulin (with or without other anti-hyperglycemic agents). The efficacy of canagliflozin was compared to a dipeptidyl peptidase-4 (DPP-4) inhibitor (sitagliptin) and a sulfonylurea (glimepiride).

There have been no clinical efficacy studies conducted with Invokamet XR; however, bioequivalence of Invokamet XR to canagliflozin and metformin co-administered as individual tablets was demonstrated in healthy subjects.

In patients with type 2 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).

Canagliflozin as Initial Combination Therapy with Metformin

A total of 1186 patients with type 2 diabetes inadequately controlled with diet and exercise participated in a 26-week double-blind, active-controlled, parallel-group, 5-arm, multicenter study 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 naïve. After completing a 2-week single-blind placebo run-in period, patients were randomly assigned for a double-blind treatment period of 26 weeks to 1 of 5 treatment groups (Table 11). The metformin XR dose was initiated at 500 mg/day for the first week of treatment and then increased to 1000 mg/day. Metformin XR or matching placebo was up-titrated every 2–3 weeks during the next 8 weeks of treatment to a maximum daily dose of 1500 to 2000 mg/day, as tolerated; about 90% of patients reached 2000 mg/day.

At the end of treatment, canagliflozin 100 mg and canagliflozin 300 mg in combination with metformin XR resulted in a statistically significant greater improvement in HbA1C compared to their respective canagliflozin doses (100 mg and 300 mg) alone or metformin XR alone.

Canagliflozin as Add-on Combination Therapy with Metformin

A total of 1284 patients with type 2 diabetes inadequately controlled on metformin monotherapy (greater than or equal to 2,000 mg/day or at least 1,500 mg/day if higher dose not tolerated) participated in a 26-week, double-blind, placebo- and active-controlled study 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 dose (N=1009) were randomized after completing a 2-week, single-blind, placebo run-in period. Patients taking less than the required metformin dose or patients on metformin in combination with another antihyperglycemic agent (N=275) were switched to metformin monotherapy (at doses described above) for at least 8 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.

At the end of treatment, canagliflozin 100 mg and 300 mg once daily resulted in a statistically significant improvement in HbA1C (p<0.001 for both doses) compared to placebo when added to metformin. Canagliflozin 100 mg and 300 mg once daily also resulted in a 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 (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.

Canagliflozin Compared to Glimepiride, Both as Add-on Combination Therapy with Metformin

A total of 1450 patients with type 2 diabetes inadequately controlled on metformin monotherapy (greater than or equal to 2,000 mg/day or at least 1,500 mg/day if higher dose not tolerated) participated in a 52-week, double-blind, active-controlled study 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 dose (N=928) were randomized after completing a 2-week, single-blind, placebo run-in period. Other patients (N=522) were switched to metformin monotherapy (at doses described above) for at least 10 weeks, then completed a 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 study to 6 or 8 mg), administered once daily as add-on therapy to metformin.

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 therapy. Canagliflozin 300 mg provided a 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.

Figure 1: Mean HbA1C Change at Each Time Point (Completers) and at Week 52 Using Last Observation Carried Forward (mITT Population)

Canagliflozin as Add-on Combination Therapy with Metformin and Sulfonylurea

A total of 469 patients with type 2 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 sulfonylurea (maximal or near-maximal effective dose) participated in a 26-week, double-blind, placebo-controlled study 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 and sulfonylurea (N=372) entered a 2-week, single-blind, placebo run-in period. Other patients (N=97) were required to be on a stable protocol-specified dose of metformin and sulfonylurea for at least 8 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 and sulfonylurea.

At the end of treatment, canagliflozin 100 mg and 300 mg once daily resulted in a statistically significant improvement in HbA1C (p<0.001 for both doses) compared to placebo when added to metformin and sulfonylurea. Canagliflozin 100 mg and 300 mg once daily also resulted in a greater proportion of patients achieving an HbA1C less than 7.0%, in a significant reduction in fasting plasma glucose (FPG), and in percent body weight reduction compared to placebo when added to metformin and sulfonylurea (see Table 14).

Canagliflozin Compared to Sitagliptin, Both as Add-on Combination Therapy with Metformin and Sulfonylurea

A total of 755 patients with type 2 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 sulfonylurea (near-maximal or maximal effective dose) participated in a 52 week, double-blind, active-controlled study to compare the efficacy and safety of canagliflozin 300 mg versus sitagliptin 100 mg in combination with metformin 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 and sulfonylurea (N=716) entered a 2-week single-blind, placebo run-in period. Other patients (N=39) were required to be on a stable protocol-specified dose of metformin and sulfonylurea for at least 8 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 and sulfonylurea.

As shown in Table 15 and Figure 2, at the end of treatment, canagliflozin 300 mg provided greater HbA1C reduction compared to sitagliptin 100 mg when added to metformin and sulfonylurea (p<0.05). Canagliflozin 300 mg resulted in a mean percent change in body weight from baseline of -2.5% compared to +0.3% with sitagliptin 100 mg. A 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.

Figure 2: Mean HbA1C Change at Each Time Point (Completers) and at Week 52 Using Last Observation Carried Forward (mITT Population)

Canagliflozin as Add-on Combination Therapy with Metformin and Pioglitazone

A total of 342 patients with type 2 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 a 26-week, double-blind, placebo-controlled study 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 and pioglitazone (N=163) entered a 2-week, single-blind, placebo run-in period. Other patients (N=181) were required to be on stable protocol-specified doses of metformin and pioglitazone for at least 8 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 and pioglitazone.

At the of end of treatment, canagliflozin 100 mg and 300 mg once daily resulted in a statistically significant improvement in HbA1C (p<0.001 for both doses) compared to placebo when added to metformin and pioglitazone. Canagliflozin 100 mg and 300 mg once daily also resulted in a 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 and pioglitazone (see Table 16). 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.

Canagliflozin as Add-on Combination Therapy with Insulin (With or Without Other Anti-Hyperglycemic Agents, Including Metformin)

A total of 1718 patients with type 2 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 a cardiovascular study to evaluate the efficacy and safety of canagliflozin in combination with insulin. Of these patients, a subgroup of 432 patients with inadequate glycemic control received canagliflozin or placebo plus metformin 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 in combination with basal, bolus, or basal/bolus insulin for at least 10 weeks entered a 2-week, single-blind, placebo run-in period. Approximately 74% of these patients were on a background of metformin 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 and insulin. The mean daily insulin dose at baseline was 93 units, which was similar across treatment groups.

At the of end of treatment, canagliflozin 100 mg and 300 mg once daily resulted in a statistically significant improvement in HbA1C (p<0.001 for both doses) compared to placebo when added to metformin and insulin. Canagliflozin 100 mg and 300 mg once daily also resulted in a 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 17). 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 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 study, which is consistent with the expected increase of hypoglycemia when an agent not associated with hypoglycemia is added to insulin [see Warnings and Precautions (5.8) and Adverse Reactions (6.1)].

Invokamet XR (canagliflozin and metformin hydrochloride extended-release) tablets are available in the strengths and packages listed below:

Canagliflozin 50 mg and metformin hydrochloride 500 mg extended-release tablets are oblong, biconvex, almost white to light orange film-coated tablets with "CM1" on one side. A thin line on the tablet side may be visible.

• NDC 50458-940-01     Bottle of 60

Canagliflozin 50 mg and metformin hydrochloride 1,000 mg extended-release tablets are oblong, biconvex, pink film-coated tablets with "CM3" on one side. A thin line on the tablet side may be visible.

• NDC 50458-941-01     Bottle of 60

Canagliflozin 150 mg and metformin hydrochloride 500 mg extended-release tablets are oblong, biconvex, orange, film-coated tablets with "CM2" on one side. A thin line on the tablet side may be visible.

• NDC 50458-942-01     Bottle of 60

Canagliflozin 150 mg and metformin hydrochloride 1,000 mg extended-release tablets are oblong, biconvex, reddish brown, film-coated tablets with "CM4" on one side. A thin line on the tablet side may be visible.

• NDC 50458-943-01     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.

NDC 50458-943-01
60 tablets

Invokamet® XR
(canagliflozin and metformin HCl
extended-release) tablets

150 mg/1000 mg

Dispense with Medication Guide

Store and Dispense in the original
container.

May be stored in a pill box
for up to 30 days.

janssen

Rx only

Applies to canagliflozin / metformin: oral tablet, oral tablet extended release

General

Canagliflozin:
-The most commonly reported adverse reactions included hypoglycemia in combination with insulin or a sulfonylurea, vulvovaginal candidiasis, urinary tract infection, polyuria or pollakiuria.

Metformin:
- The most commonly reported adverse reactions included diarrhea, nausea, vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache.[Ref]

Musculoskeletal

In the CANVAS trial, amputations per 1000 patients per year in patients receiving canagliflozin (100 mg or 300 mg per day) were 5.8 compared to 2.8 amputations per 1000 patients per year in the placebo group. In the CANVAS-R trials, these numbers were 7.5 and 4.2, respectively. The total number of amputations among canagliflozin-treated patients (n=5790) was 221 compared with 69 in the placebo group (n=4344). Amputations of the toe and midfoot were the most frequent; however, amputations involving the leg, below and above the knee, also occurred.

On September 10, 2015, the US Food and Drug Administration issued a drug safety communication regarding new information on bone fracture risk and decreased bone mineral density with use of canagliflozin. Based on updated data, fractures have occurred as early as 12 weeks after starting therapy with trauma that is usually minor, such as falling from standing height. Additionally, a 2-year study (n=714) has shown a greater loss of bone mineral density at the hip and lower spine in canagliflozin treated patients compared with placebo.[Ref]

Canagliflozin:
Common (1% to 10%): Lower limb amputations
Frequency not reported: Bone fracture, upper extremity fracture, loss of bone mineral density at hip and lower spine[Ref]

Genitourinary

Canagliflozin:
Very common (10% or more): Female genital mycotic infections (up to 11.4%)
Common (1% to 10%): Urinary tract infections, increased urination, male genital mycotic infections, vulvovaginal pruritus[Ref]

Cardiovascular

Volume depletion-related reactions included hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration.[Ref]

Canagliflozin:
Common (1% to 10%): Volume depletion-related reactions[Ref]

Metabolic

Canagliflozin:
Very common (10% or more): Elevated serum potassium, elevated serum magnesium, elevated serum phosphate
Common (1% to 10%): Increased low-density lipoprotein cholesterol, increased non-high-density lipoprotein cholesterol
Postmarketing reports: Acidosis including diabetic ketoacidosis, ketoacidosis, or ketosis

Metformin:
Very rare (less than 0.01%): Lactic acidosis, vitamin B12 deficiency[Ref]

Twenty reports of acidosis have been identified in the US Food and Drug Administration Adverse Event Reporting System (FAERS) database during the period March 2013 through 06 June 2014. All patients required emergency room treatment or hospitalization. These cases were not typical of ketoacidosis or diabetic ketoacidosis (DKA) in that they occurred in patients with type 2 diabetes and their blood sugar levels were only slightly increased. Some factors identified as potentially triggering the acidosis included major illness, reduced food and fluid intake, and reduced insulin dose.[Ref]

Renal

Canagliflozin:
Common (1% to 10%): Renal function decline
Frequency not reported: Increased serum creatinine increases, decreased GFR
Postmarketing reports: Acute kidney injury, renal function impairment, urosepsis, pyelonephritis[Ref]

Hepatic

Metformin:
Very rare (less than 0.01%): Liver function disorders, liver function tests abnormalities, hepatitis[Ref]

Endocrine

Canagliflozin:
Very common (10% or more): Hypoglycemia in combination with insulin or sulfonylurea[Ref]

Hypersensitivity

Hypersensitivity-related reactions included erythema, rash, pruritus, urticaria, and angioedema.[Ref]

Canagliflozin:
Common (1% to 10%): Hypersensitivity-related reactions
Postmarketing reports: Anaphylaxis, angioedema[Ref]

Gastrointestinal

Canagliflozin:
Common (1% to 10%): Constipation, nausea, abdominal pain, thirst, pancreatitis[Ref]

Hematologic

Canagliflozin:
Common (1% to 10%): Increased hemoglobin[Ref]

Other

Canagliflozin:
Common (1% to 10%): Fatigue, asthenia, falls
Uncommon (0.1% to 1%): Leg and foot amputations[Ref]

Final results from 2 clinical trials, the CANVAS (Canagliflozin Cardiovascular Assessment Study) and the CANVAS-R (A Study of the Effects of Canagliflozin on Renal Endpoints in Adult Participants with Type 2 Diabetes Mellitus) have shown leg and foot amputations occurred almost twice as often in canagliflozin treated patients compared with placebo treated patients. Amputations of the toe and middle of the foot were most common, however some amputations involved the leg, below and above the knee. Some patients had more than 1 amputation; some involved both limbs.

The risk of amputation calculated from the CANVAS trial showed 5.9 per 1000 patients per year for canagliflozin treated patients compared to 2.8 per 1000 patients per year for placebo patients. The CANVAS-R trial showed 7.5 per 1000 patients per year compared to 4.2 per 1000 patients per year for canagliflozin treated patients and placebo patients, respectively.[Ref]

Dermatologic

Rash includes erythematous, generalized, macular, maculopapular, papular, pruritic, pustular and vesicular rashes.[Ref]

Canagliflozin:
Uncommon (0.1% to 1%): Rash, urticaria, photosensitivity-related reactions

Metformin:
Very rare (less than 0.01%): Urticaria, erythema, pruritus[Ref]

Nervous system

Metformin:
Common (1% to 10%): Taste disturbance[Ref]

Some side effects of Invokamet XR may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.