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Frequently Asked Questions

Below are frequently asked questions about INVOKANA®. Expand each question to view the answer.

 

Drug-drug interactions

What drug-drug interactions are associated with INVOKANA®?
  • Coadministration of drugs that induce UGT (UDP-glucuronosyl transferase) enzymes, such as rifampin, which is used to treat conditions such as tuberculosis and Neisseria meningitidis, may decrease the efficacy of INVOKANA®1,2
    —Monitor A1C and consider increasing the dosage of INVOKANA® to 300 mg once daily if patients are tolerating INVOKANA® 100 mg and require additional glycemic control1
  • Coadministration with digoxin, which is used to treat conditions such as heart failure and arrhythmias, may increase digoxin concentration1,3

References: 1. INVOKANA® [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc. 2. Rifampin. MedlinePlus Web site. http://www.nlm.nih.gov/medlineplus/druginfo/meds/a682403.html. Updated December 15, 2012. Accessed September 1, 2016. 3. Digoxin oral. MedlinePlus Web site. http://www.nlm.nih.gov/medlineplus/druginfo/meds/a682301.html. Updated October 19, 2015. Accessed September 1, 2016.

 

Amputation

Why does INVOKANA® have a boxed warning?

A 2-fold increased risk of lower-limb amputation with INVOKANA® was observed in CANVAS and CANVAS-R, 2 large, randomized controlled trials in patients with type 2 diabetes who had established cardiovascular disease or were at risk for CVD.1

The amputation event rate was 6.3 events/1000 patient-years in the pooled INVOKANA® group and 3.4 events/1000 patient-years in the placebo group.2 The incidence of any atraumatic lower-limb amputation event was 2.4% in the INVOKANA® group and 1.1% in the placebo group.3

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

References: 1. INVOKANA® [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc. 2. Neal B, Perkovic V, Mahaffey KW, et al; CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes [published online ahead of print June 12, 2017]. N Engl J Med. doi:10.1056/NEJMoa1611925. 3. Data on file. Janssen Research and Development, LLC, Titusville, NJ.

 

In how many patients did an amputation occur during the CANVAS Program?

The finding of increased risk of lower-limb amputation was observed with INVOKANA® in the integrated analysis of the CANVAS Program, which included patients with type 2 diabetes who had established cardiovascular disease or were at risk for CVD.1

A total of 187 patients (140/5790 on INVOKANA® and 47/4344 on placebo) in the CANVAS Program had an atraumatic lower-limb amputation, equivalent to 2.4% of patients in the INVOKANA® group and 1.1% in the placebo group.2

Other adverse events observed in the CANVAS Program were generally consistent with the known safety profile of INVOKANA®.1

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

References: 1. Neal B, Perkovic V, Mahaffey KW, et al; CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes [published online ahead of print June 12, 2017]. N Engl J Med. doi:10.1056/NEJMoa1611925. 2. Data on file. Janssen Research and Development, LLC, Titusville, NJ.

 

What were the most common types of amputations?

Amputations of the toe and midfoot were the most frequent.1

Reference: 1. INVOKANA® [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc.

 

Was there a dose response in the amputation risk with INVOKANA®?

No dose response was observed.1

Reference: 1. INVOKANA® [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc.

 

What types of patients were more prone to amputation?

The highest risk of lower-limb amputation across treatments was seen in patients with a baseline history of prior amputation, peripheral vascular disease, and neuropathy.1

Of note, 96% (45/47) of the placebo-treated patients and 92% (129/140) of the INVOKANA®-treated patients who experienced an atraumatic lower-limb amputation had either one or more of the following etiologies—lower-extremity infection, gangrene, diabetic foot ulcer, or acute limb ischemia—and/or had a history of a prior amputation.2

References: 1. INVOKANA® [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc. 2. Data on file. Janssen Research and Development, LLC, Titusville, NJ.

 

How can I help reduce the risk of amputation in patients taking INVOKANA®?

Before initiating INVOKANA®, consider factors in the patient history that may predispose to the need for amputation, such as a history of prior amputation, peripheral vascular disease, neuropathy, and diabetic foot ulcers.1

As with any patient with type 2 diabetes, counsel them about the importance of routine preventive foot care.

Monitor patients receiving INVOKANA® for signs and symptoms of infection (including osteomyelitis), new pain or tenderness, and sores or ulcers involving the lower limbs, and discontinue INVOKANA® if these complications occur.1

Reference: 1. INVOKANA® [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc.

 

Facts about diabetic ketoacidosis (DKA)

How many cases of DKA were seen in clinical trials for INVOKANA®, and can you describe them?

Incidence of Serious DKA Adverse Events and Related Events1

Overall
  Non-INVOKANA®
(n=6909)
INVOKANA® 100 mg
(n=5337)
INVOKANA® 300 mg 
(n=5350)
Total
(N=17,596)
Incidence (%) 0.03 0.07 0.11 0.07
Incidence rate, per 1000 patient-years 0.238 0.522 0.763 N/A
Excluding autoimmune diabetes*
  Non-INVOKANA®
(n=6909)
INVOKANA® 100 mg
(n=5334)
INVOKANA® 300 mg
(n=5347)
Total
(n=17,590)
Incidence (%) 0.03 0.02 0.06 0.03
Incidence rate, per 1000 patient-years 0.238 0.130 0.381 N/A
Overall
Non-INVOKANA®
(n=6909)
INVOKANA® 100 mg
(n=5337)
INVOKANA® 300 mg
(n=5350)
Total
(N=17,596)
Incidence (%)
0.03 0.07 0.11 0.07
Incidence rate, per 1000 patient-years
0.238 0.522 0.763 N/A
Excluding autoimmune diabetes*
Non-INVOKANA®
(n=6909)
INVOKANA® 100 mg
(n=5334)
INVOKANA® 300 mg
(n=5347)
Total
(n=17,590)
Incidence (%)
0.03 0.02 0.06 0.03
Incidence rate, per 1000 patient-years
0.238 0.130 0.381 N/A

*After being diagnosed with a DKA-related event, 6 patients on INVOKANA® (3 patients in the INVOKANA® 100 mg group, 3 patients in the INVOKANA® 300 mg group) were reported to have autoimmune diabetes (LADA or T1DM) or tested positive for GAD65 antibodies.

  • In the 17,596 patients included in the analysis, 12 patients overall had a DKA-related adverse event1
    —The incidence was less than 0.1% overall, with events occurring both in patients on INVOKANA® and patients not on INVOKANA®
  • Additional analyses of the 12 patients revealed that 6 patients, all treated with INVOKANA®, had undiagnosed T1DM or LADA, or tested positive for GAD65 antibodies. When we exclude these patients from the original analysis, the incidence of DKA-related AEs is similar across treatment groups1

GAD65=glutamic acid decarboxylase; LADA=latent autoimmune diabetes of adulthood; T1DM=type 1 diabetes mellitus.

Reference: 1. Erondu N, Desai M, Ways K, Meininger G. Diabetic ketoacidosis and related events in the canagliflozin type 2 diabetes clinical program. Diabetes Care. 2015;38(9):1680-1686.

 

Nocturia

What is the incidence of nocturia with INVOKANA®?

In 4 pooled 26-week placebo-controlled trials, the incidence of nocturia was1:

  • 0.4% with INVOKANA® 100 mg (n=833)
  • 0.1% with INVOKANA® 300 mg (n=834)
  • 0.2% with placebo (n=646)

Reference: 1. Data on file. Janssen Pharmaceuticals, Inc., Titusville, NJ.

 

Genital mycotic infection

What types of patients were more prone to genital mycotic infection?

In 4 pooled 26-week placebo-controlled trials,1

  • Male patients with a history of genital mycotic infection and uncircumcised men were more likely to experience infection
  • Female patients with a history of genital mycotic infection were more likely to experience infection

Reference: 1. INVOKANA® [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc.

How can I reduce the risk of genital mycotic infection in patients taking INVOKANA®?

Males: In general, good hygiene is always recommended, and cleaning beneath the foreskin with soap and water is advised in uncircumcised patients.1

Females: Inform female patients of the potential for genital mycotic infection and provide them with information on the signs and symptoms. In general, women can reduce their risk of developing genital mycotic infection by2:

  • Avoiding douches
  • Avoiding scented hygiene products
  • Changing tampons and pads often during menstruation
  • Avoiding tight underwear or clothes made of synthetic fibers
  • Wearing cotton underwear and pantyhose with a cotton crotch
  • Changing out of wet swimsuits and exercise clothes as soon as possible
  • Avoiding hot tubs and very hot baths
  • Avoiding stress
  • Getting plenty of sleep
  • Eating well and avoiding sugary foods

 

References: 1. Penis health: identify and prevent problems. Mayo Clinic Web site. http://www.mayoclinic.org/healthy-lifestyle/mens-health/in-depth/penis-health/art-20046175. Accessed September 1, 2016. 2. Vaginal yeast infection fact sheet. Womenshealth.gov Web site. http://www.womenshealth.gov/publications/our-publications/fact-sheet/vaginal-yeast-infections.html. Updated January 6, 2015. Accessed September 1, 2016.

How was genital mycotic infection treated in clinical trials of INVOKANA®?

In 4 pooled 26-week placebo-controlled trials, patients taking INVOKANA® who experienced genital mycotic infection were generally treated with oral or topical antifungal and antimicrobial agents.1

Reference: 1. INVOKANA® [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc.

 

Hypoglycemia

Should I adjust the dose of sulfonylurea or insulin when used in combination with INVOKANA® to reduce the risk of hypoglycemia?

Insulin and insulin secretagogues (such as sulfonylureas) are known to cause hypoglycemia. INVOKANA® can increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with INVOKANA®.

Reference: 1. INVOKANA® [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc. 

How was hypoglycemia defined in clinical trials of INVOKANA®?

In all clinical trials of INVOKANA®, hypoglycemia was defined as any event, regardless of symptoms, where biochemical hypoglycemia was documented (any glucose value ≤70 mg/dL) or any hypoglycemic episode considered severe.1

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).

Reference: 1. INVOKANA® [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc. 

 

Kidney function

How does INVOKANA® affect kidney function?
  • INVOKANA® is associated with a dose-dependent increase in serum creatinine and a concomitant fall in estimated GFR. Patients with moderate renal impairment at baseline had larger mean changes1
  • Changes in serum creatinine and eGFR associated with INVOKANA® in a pool of 4 placebo-controlled trials and a dedicated study of patients with moderate renal impairment are shown below1

Changes in Serum Creatinine and eGFR Associated With INVOKANA® in a Pool of 4 Placebo-Controlled Trials and in a Dedicated Study of Patients With Moderate Renal Impairment1

Pool of 4 Placebo-Controlled Trials

 

Placebo
(n=646)

INVOKANA® 100 mg
(n=833)

INVOKANA® 300 mg
(n=834)

Baseline Creatinine
(mg/dL)
0.84 0.82 0.82
Baseline eGFR
(mL/min/1.73 m2)
87.0 88.3 88.8
Week 6 change Creatinine
(mg/dL)
0.01 0.03 0.05
Week 6 change eGFR
(mL/min/1.73 m2)
–1.6 –3.8 –5.0
End of treatment (week 26) Creatinine
(mg/dL)
0.01 0.02 0.03
End of treatment (week 26) eGFR
(mL/min/1.73 m2)
–1.6 –2.3 –3.4
Moderate Renal Impairment Trial   Placebo
(n=90)
INVOKANA® 100 mg
(n=90)
INVOKANA® 300 mg
(n=89)
Baseline Creatinine
(mg/dL)
1.61 1.62 1.63
Baseline eGFR
(mL/min/1.73 m2)
40.1 39.7 38.5
Week 3 change Creatinine
(mg/dL)
0.03 0.18 0.28
Week 3 change eGFR
(mL/min/1.73 m2)
–0.7 –4.6 –6.2
End of treatment (week 26) Creatinine
(mg/dL)
0.07 0.16 0.18
End of treatment (week 26) eGFR
(mL/min/1.73 m2)
–1.5 –3.6 –4.0
Pool of 4 Placebo-Controlled Trials

 

Placebo (n=646)

INVOKANA® 100 mg (n=833)

INVOKANA® 300 mg (n=834)

Baseline
Creatinine
(mg/dL)
0.84 0.82 0.82
eGFR
(mL/min/1.73 m2)
87.0 88.3 88.8
Week 6 change
Creatinine
(mg/dL)
0.01 0.03 0.05
eGFR
(mL/min/1.73 m2)
–1.6 –3.8 –5.0
End of treatment (week 26)
Creatinine
(mg/dL)
0.01 0.02 0.03
eGFR
(mL/min/1.73 m2)
–1.6 –2.3 –3.4
Moderate Renal Impairment Trial
  Placebo (n=90) INVOKANA® 100 mg (n=90) INVOKANA® 300 mg (n=89)
Baseline
Creatinine
(mg/dL)
1.61 1.62 1.63
eGFR
(mL/min/1.73 m2)
40.1 39.7 38.5
Week 3 change
Creatinine
(mg/dL)
0.03 0.18 0.28
eGFR
(mL/min/1.73 m2)
–0.7 –4.6 –6.2
End of treatment (week 26)
Creatinine
(mg/dL)
0.07 0.16 0.18
eGFR
(mL/min/1.73 m2)
–1.5 –3.6 –4.0

 

Reference: 1. INVOKANA® [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc. 

What is the effect of INVOKANA® on eGFR in active-controlled studies?

INVOKANA® 300 mg vs Januvia® 100 mg in patients inadequately controlled on metformin + a sulfonylurea

  • Similar reductions in mean eGFR were noted in both groups1

Mean eGFR Values Over 52 Weeks (mL/min/1.73 m2)1

Adjusted mean change in eGFR clinical trial results: INVOKANA® vs Januvia® Adjusted mean change in eGFR clinical trial results: INVOKANA® vs Januvia®

Reference: 1. Data on file. Janssen Pharmaceuticals, Inc., Titusville, NJ.

What is the long-term effect of INVOKANA® on the kidneys?
  • There is no evidence across multiple clinical trials conducted to date and lasting up to 2 years that indicates treatment with INVOKANA® was associated with an increased risk of renal damage or failure1-3
  • In clinical studies, small increases from baseline in serum creatinine and reductions in eGFR were observed with INVOKANA® during the initial treatment period. The changes tended to return toward baseline by the end of the treatment period1,4
  • These changes are likely attributed to adjustments by the kidneys to early volume-related changes resulting from osmotic diuresis1,4

 

INVOKANA® 100 mg and INVOKANA® 300 mg vs glimepiride in patients inadequately controlled on metformin: eGFR at 104 weeks

  • With both INVOKANA® doses, mean eGFR decreases were noted at week 45
  • With both INVOKANA® doses, the mean eGFR was generally stable from week 12 to week 1043,5
  • With glimepiride, the mean eGFR progressively decreased from baseline to week 1043

Mean eGFR Values Over 104 Weeks (mL/min/1.73 m2)3

Adjusted mean change in eGFR in clinical trial results: INVOKANA® vs glimepiride Adjusted mean change in eGFR in clinical trial results: INVOKANA® vs glimepiride

  • In the head-to-head clinical studies, changes in eGFR at study endpoints were comparable between INVOKANA® and glimepiride at 52 weeks; and at 104 weeks, greater decreases in eGFR were seen in the glimepiride group than in the INVOKANA® groups3,5

*Mean daily dose=5.6 mg. Glimepiride titration up to 6 mg or 8 mg was allowed throughout the study.

 

References: 1. INVOKANA® [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc. 2. Bode B, Stenlöf K, Harris S, et al. Long-term efficacy and safety of canagliflozin over 104 weeks in patients aged 55-80 years with type 2 diabetes. Diabetes Obes Metab. 2015;17(3):294-303. 3. Leiter LA, Yoon K-H, Arias P, et al. Canagliflozin provides durable glycemic improvements and body weight reduction over 104 weeks versus glimepiride in patients with type 2 diabetes on metformin: a randomized, double-blind, phase 3 study. Diabetes Care. 2015;38(3):355-364. 4. Yale JF, Bakris G, Cariou B, et al. Efficacy and safety of canagliflozin in subjects with type 2 diabetes and chronic kidney disease. Diabetes Obes Metab. 2013;15(5):463-473. 5. Cefalu WT, Leiter LA, Yoon K-H, et al. Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomised, double-blind, phase 3 non-inferiority trial. Lancet. 2013;382(9896):941-950.

 

Lipids

What are the effects of INVOKANA® on various lipids, including LDL-C? 

INVOKANA® has been associated with lipid changes.

In 4 pooled 26-week placebo-controlled trials, dose-related increases in LDL-C with INVOKANA® were observed1:

  • 4.4 mg/dL difference from placebo with INVOKANA® 100 mg
  • 8.2 mg/dL difference from placebo with INVOKANA® 300 mg

The INVOKANA® label has a warning stating that dose-related increases in LDL-C can occur with INVOKANA®.1

The reprint of the Stenlöf and colleagues 26-week placebo-controlled INVOKANA® monotherapy study is available. In addition to LDL-C increases, this study demonstrates increases in HDL-C and a relatively unchanged LDL/HDL ratio, though the clinical relevance of the changes in HDL is not known. Please see the reprint for more information. You may find this paper interesting and relevant to your question.

The citation is:
Stenlöf K, Cefalu WT, Kim KA, et al. Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetes Obes Metab. 2013;15(4):372-382.

Reference: 1. INVOKANA® [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc. 

 

Renal threshold for glucose

What is the renal threshold for glucose? 

The renal threshold refers to the plasma glucose level above which the glucose reabsorption capacity of the kidneys is exceeded and significant urinary glucose excretion occurs.1 

Renal glucose reabsorption takes place primarily via sodium-glucose co-transporter 2 (SGLT2).2 

By inhibiting SGLT2, INVOKANA®2

  • Reduces the reabsorption of filtered glucose
  • Lowers the renal threshold for glucose
  • Thereby increases urinary glucose excretion

References: 1. Beaser RS and the staff of Joslin Diabetes Center, eds. Joslin’s Diabetes Deskbook: A Guide for Primary Care Providers. 2nd ed. Boston, MA: Joslin Diabetes Center; 2010. 2. INVOKANA® [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc. 

 

Urinary tract infection (UTI)

What is the incidence of UTI with INVOKANA®?

In 4 pooled 26-week placebo-controlled studies, incidence of UTI was1

  • 4.0% with placebo
  • 5.9% with INVOKANA® 100 mg
  • 4.3% with INVOKANA® 300 mg

The majority of UTIs in patients taking INVOKANA® were2

  • Mild to moderate in severity
  • Lower UTIs
    —0.1% of patients experienced an upper UTI across clinical studies
  • None led to study discontinuation

References: 1. INVOKANA® [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc. 2. Stenlöf K, Cefalu WT, Kim KA, et al. Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetes Obes Metab. 2013;15(4):372-382.

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