Summary

• INVOKANA increases the risk of genital mycotic infections (GMIs). Patients with a history of GMIs and uncircumcised males were more likely to develop GMIs. Monitor and treat appropriately.¹
• A post hoc analysis of the CREDENCE study found that INVOKANA increased the risk of GMIs, but not urinary tract infections (UTIs). The proportional increase in GMIs with INVOKANA was observed to be greater in men and in those with higher body mass index (BMI). In INVOKANA-treated patients, higher BMI and longer diabetes duration were independent predictors of GMI risk.²
• A post hoc analysis assessing the short-term efficacy and safety of INVOKANA in type 2 diabetes mellitus (T2DM) patients in the CANVAS study, who were also on incretin mimetic therapy, reported a higher incidence of GMIs in the INVOKANA groups compared to the placebo group.³
• Female GMIs in Pooled, Phase 3, Placebo-Controlled Studies: In the pool of 4, 26-week placebo-controlled clinical studies^4-6,7 female GMIs (e.g., vulvovaginal mycotic infection, vulvovaginal candidiasis, and vulvovaginitis) occurred in 3.2% (10/312), 10.4% (44/425), and 11.4% (49/430) of females treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively.⁸
• Male GMIs in Pooled, Phase 3, Placebo-Controlled Studies: In the pool of 4, 26-week placebo-controlled clinical studies^4-7, male GMIs (e.g., candidal balanitis, balanoposthitis) occurred in 0.6% (2/334), 4.2% (17/408), and 3.7% (15/404) of males treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Male GMIs occurred more commonly in uncircumcised males and in males with a prior history of balanitis or balanoposthitis.⁸
• Phase 3, Active-Controlled Studies: INVOKANA 100 mg and 300 mg once daily were associated with higher incidences of male and female GMIs compared with glimepiride at week 104⁹ and compared with sitagliptin 100 mg at week 52.^5,7 INVOKANA 300 mg was associated with a higher incidence of male and female GMIs compared with sitagliptin 100 mg at week 52.¹⁰
• Several phase 3 studies completed in Japanese T2DM patients on INVOKANA 100 mg or 200 mg report GMI adverse events.^11-14

PHASE 3 STUDIES

CREDENCE

CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) was a randomized, double-blind, placebo-controlled, parallel-group, multicenter, event-driven study designed to assess effects of INVOKANA (100 mg once daily) vs placebo on clinically important renal outcomes in patients with T2DM and established chronic kidney disease (estimated glomerular filtration rate 30 to <90 mL/min/1.73 m²) and albuminuria (urinary albumin to creatinine ratio >300 to 5000 mg/g), who were receiving a stable, maximum tolerated labelled dose (for >4 weeks prior to randomization) of an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker.^15-19

In a post hoc analysis of CREDENCE, Kang et al (2020)² analyzed the risk of GMI and UTI with INVOKANA compared to placebo, both overall and in subgroups, in addition to predictors of risk for GMIs.

• The primary analysis was conducted in the on-treatment population. When INVOKANA increased risk, patient risk factors for GMIs were determined using multivariable Cox regression models.
• Overall, 1.1% (31/2905) of men and 2.1% (32/1492) of women experienced 91 GMIs, of which none were reported as serious. The majority of patients continued treatment following their first infection, with similar recurrence rates in the INVOKANA and placebo groups.
• Overall, INVOKANA increased the risk of GMI (hazard ratio [HR], 3.83; [95% confidence interval [CI], 2.08-7.06]; P<0.0001).
• Compared to placebo, the HR for INVOKANA was consistent across most subgroups; however, INVOKANA led to greater increase in risk in patients with BMI >30 kg/m² vs those with BMI <30 kg/m² (HR, 5.91 vs 1.36, respectively; P interaction=0.03) and in men vs women (HR, 9.30 vs 2.10, respectively; P interaction=0.04).
• In INVOKANA-treated patients, independent risk factors for GMI included higher BMI (HR, 1.53; 95% CI, 1.29-1.83 per 5 units; P<0.0001) and longer diabetes duration (HR, 1.18; 95% CI, 1.01-1.40 per 5 years; P=0.04).

Pooled Analysis of Phase 3, Placebo-Controlled Studies

Qiu et al (2017)²⁰ conducted a pooled analysis of 7 placebo- and active-controlled phase 3 studies^{3,4,5,7,8,14,16}, 52 to 104 weeks in duration, to evaluate the longer-term safety of INVOKANA 100 and 300 mg compared to non-INVOKANA treatment in patients with T2DM.

• The overall incidence rate of GMIs per 100 patient-years was higher with INVOKANA 100 mg (5.4, males; 12.3 females; n=1557) and 300 mg (6.6 males; 12.9 females; n=1932) than it was with non-INVOKANA treatments (1.0 males; 3.4 females; n=2109).
• When the results were stratified based on the baseline HbA1c %, the incidence of GMIs with non-INVOKANA, INVOKANA 100 mg and INVOKANA 300 mg treatments showed no consistent trend.
• GMI adverse events were also analyzed using pooled data from only the 104-week studies^7,14. The incidence of male GMIs for INVOKANA 100 mg, INVOKANA 300 mg and non-INVOKANA treatments was 8.2%, 9.7%, and 1.7%, respectively. The incidence of female GMIs was 17.2%, 16.5% and 3.2%, respectively. GMI events were generally considered mild to moderate in intensity, with few leading to discontinuation.
  • The incidence of GMIs with INVOKANA 100mg and 300mg was highest from 0 to 3 months in both genders. In males, the incidence declined between 3 to 12 months and remained low until the conclusion of the studies. In females, the incidence declined between 3 to 6 months, further declined between 12 to 15 months, and remained low until the completion of the studies thereafter.

Nyirjesy et al (2014)⁸ conducted an analysis to characterize GMIs with INVOKANA, in patients with T2DM using pooled data from phase 3 studies.

Population 1

Female GMI

In the pool of 4, 26-week placebo-controlled clinical studies^4-7, Female GMIs (e.g., vulvovaginal mycotic infection, vulvovaginal candidiasis, and vulvovaginitis) occurred in 3.2% (10/312), 10.4% (44/425), and 11.4% (49/430) of females treated with placebo, canagliflozin 100 mg, and canagliflozin 300 mg, respectively. Patients with a history of GMIs were more likely to develop GMIs on canagliflozin.⁸ The majority of females with a GMI had a single event. In the combined INVOKANA group, 2.3% (20/855) of women had more than 1 GMI.⁸

• Demographics: Women in the combined INVOKANA group (100 mg and 300 mg) experiencing GMI AEs were slightly younger (mean age, 53.8 vs 55.8 years), had a slightly higher median BMI (33.7 vs 31.5 kg/m²), were more likely to have a prior history of vulvovaginitis (29.0% vs 11.8%), be premenopausal (35.5% vs 26.9%), and reside in North America (60.2% vs 42.3%) than those without GMIs. No differences between women in the INVOKANA groups experiencing vulvovaginal AEs were noted in baseline A1C, history of vulvovaginal yeast infection, or duration of T2DM compared with placebo.⁸
• Recurrence: In the combined INVOKANA group (100 mg and 300 mg), 21.5% (20/93) had ≥1 recurrence compared to 10.0% (1/10) in the placebo group. The majority of females with a GMI had a single event.⁸
• Severity and Treatment: The majority of events were reported as mild or moderate in intensity as assessed by the investigator. No serious AEs were reported. Of the 119 GMI events in the pooled INVOKANA group with treatment information, 81.5% were treated with antifungal agents, 2.5% were treated with antibacterial agents, 8.4% were treated with both antifungal and antibacterial agents, and 7.6% were not treated.⁸
• Duration and Discontinuation: Once therapy was initiated, the median duration of symptoms was 7.0 days in the combined INVOKANA treatment group and 6.0 days in the placebo group. Six (0.7%) subjects discontinued study drug due to GMI AEs in the combined INVOKANA 100 mg and 300 mg group.⁸
• Diagnosis: In the combined INVOKANA group, the diagnosis of vulvovaginitis was made on the basis of the clinical history and/or response to treatment without confirmatory physical examination or laboratory testing in 72.0% of events.⁸

Male GMI

In the pool of 4, 26-week placebo-controlled clinical studies^4-7, Male GMIs (e.g., candidal balanitis, balanoposthitis) occurred in 0.6% (2/334), 4.2% (17/408), and 3.7% (15/404) of males treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Male GMIs occurred more commonly in uncircumcised males and in males with a prior history of balanitis or balanoposthitis. In the combined INVOKANA group, 0.9% of men reported more than 1 event.⁸

• Demographics:  In the combined INVOKANA group, the mean duration of T2DM was slightly longer in men with GMI AEs compared with men without this AE (9.3 yrs and 7.2 yrs, respectively). In the combined INVOKANA group, experiencing an AE of a Male GMI compared with men not having this AE did not notably differ in baseline A1C, age, and BMI. INVOKANA-treated males with GMIs were more likely to have a prior history of balanitis/balanoposthitis (25.0% vs 2.3%) and reside in Europe (43.8% vs 26.0%) than those without GMIs. GMIs were more common in males who were uncircumcised than those who were circumcised (5.7% vs 0.7%) in the INVOKANA-treated group.⁸
• Recurrence: Male patients who developed GMIs on INVOKANA were more likely to experience recurrent infections (21.9% [7/32]) versus no subjects in the placebo group.⁸
• Severity and Treatment: All events were assessed by the investigator as mild or moderate in intensity and none were reported as severe in intensity. The majority of events (82.9%) were treated with antifungal agents, 7.3% were treated with antimicrobial agents, 2.4% were treated with both antifungal and antimicrobial agents, and 7.3% were not treated.⁸
• Duration and Discontinuation: Median duration of symptoms after initiation of treatment was 18.0 days in the combined INVOKANA group and 12.5 days in the placebo group. Two (0.5%) men in each of the INVOKANA treatment groups and no men in the placebo group discontinued due to GMI AEs.⁸
• Diagnosis: In most male patients in the pooled INVOKANA group with GMI AEs (95.1%), diagnosis was made clinically and not based upon culture.⁸

Population 2

In the broader pooled dataset (Population 2) of 8 placebo and active-controlled studies with a longer mean treatment exposure which included the 4 studies in Population 1^4-7,21-24, the incidence of GMI AEs was higher with INVOKANA 100 mg (14.7%, females; 7.3%, males) and 300 mg (13.9%, females; 9.3% males) compared to the non-INVOKANA (3.1%, females; 1.6%, males) group. The majority of male and female GMIs AEs were considered to be mild to moderate in intensity and few AEs led to discontinuation (INVOKANA 100 mg: 1.0%, females; 0.8%, males; INVOKANA 300 mg: 1.3%, females; 1.1%, males; non- INVOKANA: 0% in both males and females).⁸

Pooled Analysis of Phase 3 Studies – Two-Year Data

Sobel et al (2015)²⁵ conducted a pooled analysis of two^9,26 phase 3 randomized studies to evaluate GMIs over 2 years (week 104) in T2DM patients treated with INVOKANA. In one study patients were randomized to receive INVOKANA 100 mg, 300 mg, or glimepiride (glimepiride was administered at a starting dose of 1 mg, and up-titrated to a maximum dose of 6 or 8 mg) once daily (N=1450).⁹ In the other study, older patients (≥55 to ≤80 years) received INVOKANA 100 mg, INVOKANA 300 mg, or placebo (N=714).²⁶

• Female GMIs occurred in 3.2% (10/313), 17.2% (60/348), and 16.5% (58/351) of patients treated with glimepiride/placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. The majority of GMI events occurred within the first 9 months of treatment and decreased over time.
• The recurrence rate (>1 GMI) for the pooled INVOKANA and glimepiride/placebo group was 28.8% (34/118) and 10.0% (1/10), respectively in female subjects who had a GMI.
• Male GMIs occurred in 1.7% (7/406), 8.2% (31/376), and 9.7% (36/370) of males treated with glimepiride/placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. The majority of GMI events occurred within the first 6 months of treatment and decreased over time.
• In male subjects who had a GMI, the recurrence rate (>1 GMI) for the pooled INVOKANA and glimepiride/placebo was 34.3% (23/67) and 14.3% (1/7), respectively.
• GMIs were mild to moderate in intensity and responded well to standard treatment in both females and males.

Phase 3 Studies

In a 26-week double-blind, active-controlled, parallel-group, 5-arm, multicenter study (Rosenstock et al [2016]³¹; N=1,186) evaluating the efficacy and safety of initial therapy with INVOKANA in combination with metformin XR (MET XR), the incidence of female GMI was 2.3% (3/129), 3.3% (4/122), 2.3% (3/132), 4.4% (5/113) and 0% in the INVOKANA 100 mg/MET XR, INVOKANA 300 mg/MET XR, INVOKANA 100 mg, INVOKANA 300 mg, and MET XR groups, respectively. The incidence of Male GMI was 0.9% (1/108), 1.7% (2/115), 1.9% (2/105), 4.0% (5/125), and 0% in the INVOKANA 100 mg/MET XR, INVOKANA 300 mg/MET XR, INVOKANA 100 mg, INVOKANA 300 mg, and MET XR groups, respectively.³¹

PHASE 2 STUDIES

Rosenstock et al (2012)³² evaluated the efficacy and safety of INVOKANA in a 12-week, phase 2b, dose-ranging study in adult subjects with T2DM with inadequate glycemic control while on existing metformin monotherapy (N=451). Patients were randomized to 1 of 7 groups: INVOKANA 50, 100, 200 or 300 mg once daily, 300 mg twice daily, sitagliptin 100 mg once daily, or placebo. A non-dose-dependent increase in symptomatic GMIs with INVOKANA (3-8%) versus placebo and sitagliptin (2%) was reported. A safety analysis was conducted to evaluate the vaginal candida colonization and the symptomatic vulvovaginal AEs.³³

• Women with vulvovaginal symptoms suggestive of vulvovaginal candidiasis (VVC) within 3 months of screening were excluded.
• Self-administered vaginal swab at baseline and at week 12 was cultured for Candida (also performed during study period if a subject reported vulvovaginal symptoms consistent with VVC).
• There was no evidence of dose-dependent increase in the occurrence of positive Candida cultures at endpoint in the INVOKANA treatment groups.
• C. albicans and C. glabrata were the most common conversions from negative culture to positive culture at endpoint.
• INVOKANA treatment was predictive of conversion to a positive culture in logistic regression analyses (OR, 2.8; 95% CI, 1.0-7.3).
• Vulvovaginal AEs were reported in 2 (3%) female subjects in the placebo/sitagliptin group and 16 (10%) (P=0.11 by Fisher's exact test) females treated with INVOKANA without evidence for dose-dependency.
  • None of the vulvovaginal AEs led to study discontinuation; they were mild or moderate in intensity.
• The median time of onset relative to initiation of the study drug was 19 days for the pooled INVOKANA group. One subject (in the INVOKANA 300 mg twice daily group) experienced more than a single episode of VVAE. Most VVAEs were treated with topical antifungal therapy (n=7), oral antifungal therapy (n=5), or both (n=5), and resolved without discontinuation.

MECHANISM OF DEVELOPMENT OF GMIS

The exact mechanism of the increase in incidence of these GMIs is not clear but is likely to be related to the changes in the perineal environment, with increased urinary glucose excretion (UGE) induced with SGLT2 inhibition. Because increases in UGE could increase fungal growth in the perineum, which could increase vulvovaginal colonization with Candida, a risk factor for the development of vulvovaginal candidiasis may exist. The effect of INVOKANA treatment on vulvovaginal Candida colonization was examined in phase 2 studies.³²

pH EFFECTS

In INVOKANA clinical studies, pH effects or acidification of urine and its impact on the incidence of GMI were not studied.

CONCOMITANT ESTROGEN THERAPY AND INCIDENCE OF GMIs

An analysis of INVOKANA phase 3 studies was not conducted to determine the incidence of adverse events of GMI in patients who were on concomitant estrogen therapy.

PREVENTATIVE THERAPY

In INVOKANA clinical studies, pharmacological prophylactic therapy (including use of probiotics) was not administered for the prevention of GMIs. Please refer to the following website on Women's Health.gov for general information on non-pharmacological preventative methods: https://www.womenshealth.gov/a-z-topics/vaginal-yeast-infections.

LITERATURE SEARCH

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 14 August 2024.