INVOKAMET SIDE EFFECTS

Last updated on MDtodate: 10/04/2022

SIDE EFFECTS

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

• Lactic Acidosis
• Lower Limb Amputation
• Volume Depletion
• Ketoacidosis
• Urosepsis and Pyelonephritis
• Hypoglycemia with Concomitant Use of Sulfonylurea or Insulin
• Necrotizing Fasciitis of the Perineum (Fournier’s gangrene)
• Genital Mycotic Infections
• Hypersensitivity Reactions
• Bone Fracture
• Vitamin B12 Deficiency

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 For Glycemic Control

Canagliflozin

The data in Table 2 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 a mean duration of exposure to canagliflozin of 24 weeks with 1,275 patients exposed to a 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 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 2 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*

Adverse Reaction	Placebo N=646	Canagliflozin 100 mg N=833	Canagliflozin 300 mg N=834
Urinary tract infections‡	3.8%	5.9%	4.4%
Increased urination§	0.7%	5.1%	4.6%
Thirst#	0.1%	2.8%	2.4%
Constipation	0.9%	1.8%	2.4%
Nausea	1.6%	2.1%	2.3%
	N=312	N=425	N=430
Female genital mycotic infections†	2.8%	10.6%	11.6%
Vulvovaginal pruritus	0.0%	1.6%	3.2%
	N=334	N=408	N=404
Male genital mycotic infections¶	0.7%	4.2%	3.8%
* 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. † Female genital mycotic infections include the following adverse reactions: Vulvovaginal candidiasis, Vulvovaginal mycotic infection, Vulvovaginitis, Vaginal infection, Vulvitis, and Genital infection fungal. ‡ Urinary tract infections include the following adverse reactions: Urinary tract infection, Cystitis, Kidney infection, and Urosepsis. § Increased urination includes the following adverse reactions: Polyuria, Pollakiuria, Urine output increased, Micturition urgency, and Nocturia. ¶ Male genital mycotic infections include the following adverse reactions: Balanitis or Balanoposthitis, Balanitis candida, and Genital infection fungal. # Thirst includes the following adverse reactions: Thirst, Dry mouth, and Polydipsia. Note: Percentages were weighted by studies. Study weights were proportional to the harmonic mean of the three treatment sample sizes.

 

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 HCl

The incidence and type of adverse reactions in the three 26-week placebo-controlled metformin HCl tablets add-on trials, representing a 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 a trial with canagliflozin as initial combination therapy with metformin HCl , 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 Nephropathy

The occurrence of adverse reactions for canagliflozin was evaluated in patients participating in CREDENCE, a study in patients with type 2 diabetes mellitus and diabetic nephropathy with albuminuria > 300 mg/dayical. These data reflect exposure of 2,201 patients to canagliflozin and a 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.

Pool Of Placebo-And Active-Controlled Trials For Glycemic Control And Cardiovascular Outcomes

The 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 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 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 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 3 and 4, respectively.

Table 3: CANVAS Amputations

	Placebo N=1441	Canagliflozin 100 mg N=1445	Canagliflozin 300 mg N=1441	Canagliflozin (Pooled) N=2886
Patients with an amputation, n (%)	22 (1.5)	50 (3.5)	45 (3.1)	95 (3.3)
Total amputations	33	83	79	162
Amputation incidence rate (per 1000 patient-years)	2.8	6.2	5.5	5.9
Hazard Ratio (95% CI)	—	2.24 (1.36, 3.69)	2.01 (1.20, 3.34)	2.12 (1.34, 3.38)
Note: Incidence is based on the number of patients with at least one amputation, and not the total number of amputation events. A patient’s follow-up is calculated from Day 1 to the first amputation event date. Some patients had more than one amputation.

 

Table 4: CANVAS-R Amputations

	Placebo N=2903	Canagliflozin 100 mg (with up-titration to 300 mg) N=2904
Patients with an amputation, n (%)	25 (0.9)	45 (1.5)
Total amputations	36	59
Amputation incidence rate (per 1000 patient-years)	4.2	7.5
Hazard Ratio (95% CI)	—	1.80 (1.10, 2.93)
Note: Incidence is based on the number of patients with at least one amputation, and not the total number of amputation events. A patient’s follow-up is calculated from Day 1 to the first amputation event date. Some patients had more than one amputation.

 

Renal Cell Carcinoma

In the CANVAS trial (mean duration of follow-up of 5.7 years), 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 6 months of follow-up, less than 90 days of treatment, or a history of renal cell carcinoma. A causal relationship to canagliflozin could not be established due to the limited number of cases.

Volume Depletion-Related Adverse Reactions

Canagliflozin 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 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 in these trials 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 5) [see Use In Specific Populations].

Table 5: Patients With at Least One Volume Depletion-Related Adverse Reaction (Pooled Results from 8 Clinical Trials for Glycemic Control)

Baseline Characteristic	Comparator Group* %	Canagliflozin 100 mg %	Canagliflozin 300 mg %
Overall population	1.5%	2.3%	3.4%
75 years of age and older†	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%
* Includes placebo and active-comparator groups † Patients could have more than 1 of the listed risk factors

 

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.

Genital Mycotic Infections

In 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 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.

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 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.

Hypoglycemia

In 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 a seizure (regardless of whether biochemical documentation of a low glucose value was obtained). In individual clinical trials of glycemic control, episodes of hypoglycemia occurred at a higher rate when canagliflozin was co-administered with insulin or sulfonylureas (Table 6).

Table 6: Incidence of Hypoglycemia* 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 (%)]†	0 (0)	1 (0.3)	1 (0.3)
In Combination with Metformin HCl (18 weeks)‡	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 (%)]†	1 (0.6)	1 (0.6)	0
In 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)§	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 (%)]†	4 (2.8)	1 (0.7)	3 (2.0)
* 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 † Severe episodes of hypoglycemia were defined as those 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) ‡ Phase 2 clinical study with twice daily dosing (50 mg or 150 mg twice daily in combination with metformin HCl) § Subgroup of patients (N=287) from insulin substudy on canagliflozin in combination with metformin HCl and insulin (with or without other antiglycemic agents)

 

Bone Fracture

In the CANVAS trial, 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 HCl

The 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 a decrease in vitamin B12, which may result in clinically significant vitamin B12 deficiency (e.g., megaloblastic anemia).

Laboratory And Imaging Tests

Increases In Serum Creatinine And Decreases In eGFR

Initiation 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 6 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. The acute effect on eGFR reverses after treatment discontinuation suggesting acute hemodynamic changes may play a role in the renal function changes observed with canagliflozin.

Increases In Serum Potassium

In a pooled population of patients (N=723) in glycemic control trials 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.

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 Hemoglobin

In 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 Density

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 post-approval 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.

Canagliflozin

Ketoacidosis
Acute Kidney Injury
Anaphylaxis, Angioedema
Urosepsis and Pyelonephritis
Necrotizing Fasciitis of the Perineum (Fournier’s gangrene)

Metformin HCl

Cholestatic, hepatocellular, and mixed hepatocellular liver injury