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INVOKAMET® XR and INVOKAMET® (canagliflozin/metformin HCl) safety, tolerability, and common adverse events

There have been no clinical efficacy studies conducted with INVOKAMET® XR or INVOKAMET®. The efficacy and safety of INVOKAMET® XR were assessed in a clinical study as initial combination of canagliflozin and metformin XR coadministered as individual tablets.1,2

Bioequivalence of INVOKAMET® XR to canagliflozin and metformin XR and of INVOKAMET® to canagliflozin and metformin coadministered as individual tablets was demonstrated in healthy subjects.1,2

  • Canagliflozin: In 4 pooled 26-week placebo-controlled trials, the most commonly reported adverse events (≥5%) were female genital mycotic infection, urinary tract infection (UTI), and increased urination1
  • There were no additional adverse events identified when 3 of the placebo-controlled studies that included metformin were pooled separately, compared with the total 4 pooled placebo-controlled studies1

Adverse Events Reported in ≥2% of Patients Treated With Canagliflozin in 4 Pooled 26-Week Placebo-Controlled Trials1

  Placebo (n=646) Canagliflozin 100 mg (n=833) Canagliflozin 300 mg (n=834)
UTI* 3.8% 5.9% 4.4%
Male genital mycotic infection 0.7% 4.2% 3.8%
Female genital mycotic infection 2.8% 10.6% 11.6%
Vulvovaginal pruritus§ 0% 1.6% 3.2%
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%

The 4 placebo-controlled trials included 1 monotherapy trial and 3 add-on combination trials with metformin, metformin + a sulfonylurea, or metformin + pioglitazone.
*Urinary tract infection includes urinary tract infection, cystitis, kidney infection, and urosepsis.
Male genital mycotic infection includes balanitis or balanoposthitis, balanitis Candida, and genital infection fungal; placebo (n=334), canagliflozin 100 mg (n=408), and canagliflozin 300 mg (n=404).
Female genital mycotic infection includes vulvovaginal candidiasis, vulvovaginal mycotic infection, vulvovaginitis, vaginal infection, vulvitis, and genital infection fungal; placebo (n=312), canagliflozin 100 mg (n=425), and canagliflozin 300 mg (n=430).
§Placebo (n=312), canagliflozin 100 mg (n=425), canagliflozin 300 mg (n=430).
llIncreased urination includes polyuria, pollakiuria, urine output increased, micturition urgency, and nocturia.
Thirst includes thirst, dry mouth, and polydipsia.

  • Metformin: The most common adverse events due to initiation of metformin are diarrhea, nausea and vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache1

Additional safety information

LDL-C increases

Dose-Related Increases in LDL-C With Canagliflozin in 4 Pooled 26-Week Placebo-Controlled Trials1

  Canagliflozin 100 mg (n=833) Canagliflozin 300 mg (n=834)
Baseline 104-110 mg/dL 104-110 mg/dL
Change from baseline# 4.4 mg/dL 8.2 mg/dL
Percent change from baseline# 4.5% 8.0%

The 4 placebo-controlled trials included 1 monotherapy trial and 3 add-on combination trials with metformin, metformin + a sulfonylurea, or metformin + pioglitazone.

#Data are placebo adjusted.

Volume depletion–related adverse events

Proportion of Patients With ≥1 Volume Depletion–Related Adverse Event (Pooled Results From 8 Clinical Trials; N=9439)1

Baseline characteristics Control group** Canagliflozin 100 mg Canagliflozin 300 mg
Overall population 1.5% 2.3% 3.4%
≥75 years of age†† 2.6% 4.9% 8.7%
eGFR <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 characteristic.

Patients’ volume status should be assessed and corrected, as necessary, before and during treatment with canagliflozin.1


Insulin and insulin secretagogues (eg, sulfonylureas) are known to cause hypoglycemia. The use of canagliflozin in combination with insulin therapy or an insulin secretagogue1:

  • Was associated with a higher incidence of hypoglycemia
  • May require a lower dose of insulin or insulin secretagogue to reduce the risk of hypoglycemia

Incidence of Hypoglycemia With Canagliflozin in Combination With Insulin or a Sulfonylurea (With or Without Metformin)1

  Placebo Canagliflozin 100 mg Canagliflozin 300 mg
+ a sulfonylurea (18 weeks) n=69 n=74 n=72
Overall 5.8% 4.1% 12.5%
Severe 0% 0% 0%
+ metformin and a sulfonylurea (26 weeks) n=156 n=157 n=156
Overall 15.4% 27.4% 30.1%
Severe 0.6% 0.6% 0%
+ insulin (18 weeks) n=565 n=566 n=587
Overall 36.8% 49.3% 48.6%
Severe 2.5% 1.8% 2.7%


In a head-to-head trial of canagliflozin 300 mg vs sitagliptin 100 mg, each in combination with metformin and a sulfonylurea, incidence of hypoglycemia was:

  • 43.2% vs 40.7%, respectively3
  • Severe hypoglycemia: 4.0% and 3.4%, respectively3

Incidence of Hypoglycemia With Canagliflozin as Monotherapy, in Combination With Metformin, or With Metformin + Pioglitazone1

  Placebo Canagliflozin 100 mg Canagliflozin 300 mg
(26 weeks)
n=192 n=195 n=197
Overall 2.6% 3.6% 3.0%
Severe 0% 0% 0%
+ metformin (26 weeks) n=183 n=368 n=367
Overall 1.6% 4.3% 4.6%
Severe 0% 0.3% 0.3%
+ metformin and pioglitazone (26 weeks) n=115 n=113 n=114
Overall 2.6% 2.7% 5.3%
Severe 0% 0% 0%


In a head-to-head trial vs glimepiride, each in combination with metformin, canagliflozin demonstrated a lower incidence of hypoglycemia3:

  • Glimepiride: 34.2%
  • Canagliflozin 100 mg: 5.6%
  • Canagliflozin 300 mg: 4.9%

Lower-limb amputation

An increased risk of lower-limb amputation with canagliflozin, a component of INVOKAMET® XR and of INVOKAMET®, was observed in the CANVAS and CANVAS-R trials, 2 large, randomized controlled trials in patients with type 2 diabetes who had established cardiovascular disease (CVD) or were at risk for CVD.1,2

In the CANVAS Program, the amputation rate was 0.63 events/100 patient-years in the pooled canagliflozin group and 0.34 events/100 patient-years in the placebo group. In other words, the CANVAS Program showed that treating 100 patients with established CVD or CV risk with canagliflozin for a year led to an additional 0.3 events. 4

The risk of amputation was highest in patients with a baseline history of prior amputation, peripheral vascular disease, and neuropathy.1,2

The increase in amputation was not observed across 12 other completed phase 3 and 4 canagliflozin clinical trials comprising >8100 patients with type 2 diabetes.5



References: 1. INVOKAMET® [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc. 2. INVOKAMET® XR [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc. 3. INVOKANA® [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc. 4. Neal B, Perkovic V, Mahaffey KW, et al; CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(7):644-657. 5. Data on file. Janssen Research and Development, LLC, Titusville, NJ.