SUMMARY

• INVOKANAresults in osmotic diuresis which may lead to reductions in intravascular volume.¹
• In a pooled analysis of four^2-5 26-week, placebo (PBO)-controlled phase 3, adverse reaction of increased urination (which includes polyuria, pollakiuria, urine output increased, micturition urgency, and nocturia) occurred more commonly with INVOKANA than PBO (100 mg [5.3%], 300 mg [4.6%], and PBO [0.8%]).^1,6
• Urine Output: In phase 3 and 4 INVOKANAstudies, timed 24-hour urine collections were not routinely performed.^{3-5, 7-13} Timed 24-hour urine collections were detailed in three phase 1 studies.^14-16.
• Day and Night Time Urination: A phase 1 study evaluated the safety and tolerability of canagliflozin (liquid suspension formulation) 30 mg, 100 mg, 200 mg and 400 mg once daily, and 300 mg twice daily vs PBO. There were no apparent differences in day or evening urination symptoms between INVOKANA groups and the PBO group based on patient-reported questionnaires.^14,17
• Other Urine Parameters: In a pooled analysis of four^2-5 26-week, PBO-controlled phase 3 studies there were no notable changes in urine specific gravity with INVOKANAand PBO.¹⁸
  • In the same analysis, there was a slight non-dose-dependent mean percent reduction (-0.14%) in urine pH with the combined INVOKANAgroup (100 mg and 300 mg), and a slight increase (0.06%) in the PBO group.¹⁸
  • In a phase 1 study, urine osmolality increased in the combined INVOKANAgroup relative to PBO with greater increase observed with INVOKANA300 mg twice daily.¹⁶
• Polyuria/pollakiuria: In a post-marketing surveillance study, pollakiuria, nocturia, polyuria, increased urine output, and micturition disorder was reported in 96 (0.79%), 21 (0.17%), 12 (0.10%), 2 (0.02%), and 1 (0.01%) patients, respectively.¹⁹

BACKGROUND

Fluid Intake

In INVOKANA phase 3 and 4 studies, there were no specific instructions or restrictions given to patients regarding fluid intake. In some phase 1 studies that measured timed 24-hour urine collections, water was allowed ad libitum.^{14, 16, 17}

CLINICAL DATA

Urine Output

Phase 3 Studies

• In a pooled analysis of four^2-5 26-week, PBO-controlled phase 3 studies (including one INVOKANAmonotherapy study² and 3 studies with INVOKANAas add-on to metforminbased therapy^3-5), the adverse reaction of increased urination (which includes polyuria, pollakiuria, urine output increased, micturition urgency, and nocturia) occurred more commonly with INVOKANA than PBO, and occurred in at least 2% of patients treated with INVOKANA (100 mg [5.3%], 300 mg [4.6%], and PBO [0.8%]).^1,6
• Timed 24-hour urine collections were not routinely performed in INVOKANA phase 3 studies.^{2-5, 7-11}

Osmotic Diuresis-Related Adverse Events

• In a pooled analysis of four^2-5 26-week, PBO-controlled phase 3 studies (including one INVOKANAmonotherapy study² and 3 studies with INVOKANAas add-on to metforminbased therapy^3-5), incidences of adverse events (AEs) related to osmotic diuresis were increased with INVOKANA 100 and 300 mg relative to PBO. Three patients in the INVOKANA group (two patients in 300 mg group and one patient in 100 mg group) discontinued due to osmotic diuresis-related pollakiuria.^{6, 20} See Table: Osmotic Diuresis-Related AEs in a Pool of Four 26-Week PBO-Controlled Studies

• In a pooled analysis of six phase 3, double-blind, PBO-controlled studies^{2-5, 7, 21, 22} evaluating efficacy and safety of INVOKANA in subgroups of patients <75 and ≥75 years of age, the incidence of osmotic diuresis-related AEs (including dry mouth, dry throat, micturition disorder, micturition urgency, nocturia, pollakiuria, polydipsia, polyuria, thirst, and high urine output) with INVOKANA 100 and 300 mg and non-INVOKANA was 6.9%, 6.9%, and 1.8%, respectively, in patients aged <75, and 4.3%, 9.9%, and 4.5%, respectively, in those aged >75.²³
  • Osmotic diuresis-related AEs that led to discontinuation occurred in 16 patients younger than 75 years (seven with INVOKANA 100 mg, eight with INVOKANA 300 mg, one with non-INVOKANA) and in one patient aged >75 (INVOKANA 300 mg). None of the AEs leading to discontinuation were considered serious.

Osmotic Diuresis-Related AEs in Extension Phase of Glycemic Control Trials

In the seven INVOKANAphase 3 studies with extension phases, safety endpoints were evaluated in core and extension study periods. The core study period was up to 26 weeks in majority of the studies; ^{2-5, 7-11} and 52 weeks in two studies.^8,9 Several phase 3 INVOKANAstudies included an extension phase,^{3, 4, 24-27}  with the longest extension data available through 104 weeks.^25,26

• Most osmotic diuresis-related AEs occurred during the first 26 weeks (core period) of treatment.^3,5,24,26,27

Osmotic Diuresis-Related AEs in the CANVAS Program

The CANVAS (CANagliflozin cardioVascular Assessment Study) Program^{28, 29} (N=10,142) comprises the two large INVOKANA cardiovascular (CV) outcome studies, CANVAS^{10, 30} and CANVAS-R^{12, 31}, and includes a pre-specified integrated analysis of these two studies to meet Food and Drug Administration post-marketing requirement (PMR) for CV safety, as well as to evaluate potential for CV protection of INVOKANA in type 2 diabetes mellitus (T2DM) patients who had either a prior history of CV disease or ≥2 CV risk factors.^{28, 29}

• In the CANVAS study, osmotic diuresis-related events were reported at a rate of 34.5 and 13.3 per 1000 patient-years (PY) for the INVOKANA and PBO group, respectively (hazard ratio [HR], 2.80; 95% confidence interval [CI], 2.06 to 3.81; P<0.001).^{28, 32} For these events, the annualized incidence rates are reported through January 7, 2014; after this time, only serious AEs or AEs leading to discontinuation were collected.²⁸
• In a secondary analysis based on baseline estimated glomerular filtration rate (eGFR; <45, 45-<60, 60-<90, and ≥ 90 mL/min/1.73 m²), osmotic diuresis-related events within the CANVAS program were similar across eGFR subgroups (P=0.17 for heterogeneity).³³
• Absolute risk of osmotic diuresis-related events was significantly lower in patients with a history of heart failure in the CANVAS study compared to those without (P interaction = 0.029).³⁴

Osmotic Diuresis-Related AEs in CREDENCE

• CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation), was a randomized, double-blind, PBO-controlled, parallel group multicenter, event-driven trial (N=4401) to assess the effects of INVOKANA (100 mg) vs. PBO on clinically important renal outcomes in people with T2DM and established chronic kidney disease (CKD) and albuminuria who were receiving a stable, maximum tolerated or labeled dose (for >4 weeks prior to randomization) of an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin II receptor blocker (ARB).^{13, 35-39}
• In CREDENCE, osmotic diuresis-related events were reported at a rate of 10.0 and 8.2 per 1000 PY for the INVOKANA and PBO group, respectively (HR, 1.25; 95% CI, 0.83 – 1.89).³⁶

Phase 1 Studies

A transient and variable increase in urine output was observed that attenuated with continued treatment.¹⁸ Timed 24-hour urine collections were detailed in three phase 1 studies in T2DM patients: Sha et al (2014a), Sha et al (2014b), and Devineni et al (2012).^14-16

Sha et al (2014) in a 12-week phase 1, double-blind, PBO-controlled, randomized, parallel group study evaluated the effects of INVOKANA 300 mg once daily vs PBO on 24-hour urine volume in patients with T2DM with inadequate glycemic control on metformin with or without other antihyperglycemic agents (N=36).¹⁵

• Patients were also receiving concomitant therapy with ACEis or ARBs.

Results

• Baseline mean 24-hour urine volume was comparable between INVOKANA 300 mg (3100 mL) and PBO (3272 mL).
• At week 1, least square mean (LSM) change in 24-hour urine volume was 269.3 mL and 108.3 mL in the INVOKANA and PBO groups, respectively (PBO-subtracted LSM difference of 161.0; 95% CI [-397.6 to 719.6]).
• At week 12, LSM change in 24-hour urine volume was 149.1 mL and 100.4 mL in the INVOKANA and PBO groups respectively (PBO-subtracted LSM difference of 48.7; 95% CI [-509.9 to 607.3]).
• For additional information please visit https://clinicaltrials.gov/show/NCT01483781.

In another phase 1, randomized, double-blind, PBO-controlled study, Sha et al (2014) evaluated safety and tolerability of single and escalating doses of canagliflozin (liquid suspension formulation) 30 mg, 100 mg, 200 mg, and 400 mg once daily, and 300 mg twice daily vs PBO for 2 weeks in inpatient patients with T2DM (N=111).^18,14

• At baseline, mean 24-hour urine volume was ~3-4L in all treatment groups.
• Water was allowed ad libitum throughout the study.
• At canagliflozin doses ≥200 mg once daily, an increase in 24-hour urine volume occurred on day 1. Transient increases in 24- hour urine volume occurred with canagliflozin doses ≥200 mg on Day 1, ranging from ~200-700 mL, and declined toward baseline over the 2-week dosing period.

Devineni et al (2012), a phase 1, randomized, double-blind, PBO-controlled study, evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of INVOKANA 100 mg once daily and 300 mg twice daily vs PBO for 28 days in patients with T2DM not optimally controlled on insulin (N=29).¹⁶ Water was allowed ad libitum.

• At baseline, mean 24-hour urine volume was ~3.5-4L in all treatment groups.¹⁸
• Changes from baseline in the 24-hour urine volume were minimal across treatment groups [mean (standard deviation [SD]) changes]: -143.1 (433.8) mL for PBO, 47.2 (739.0) mL for INVOKANA 100 mg, and 97.0 (874.4) mL for INVOKANA 300 mg.¹⁶

Day and Night Time Urination

Day and night time urination were investigated in a phase 1 study.^14,17

• Water was allowed ad libitum throughout the study. The mean 24-hour fluid intake over a 2-week treatment period was 2.6-3.7L (PBO), 2.6-3.7L (30 mg), 2.1 to 4.0L (100 mg), 2.7-4.0L (200 mg), 3.0-4.4L (400 mg) daily, and 2.5-4.1L (300 mg twice daily).
• Total daily fluid intake (including meal-related fluids) generally matched total daily urine volumes.
• Patient-reported outcomes consisted of a questionnaire on frequency to urinate during day time hours, an uncomfortable urge to urinate, waking up at night due to the urge to urinate, and awakening due to other reasons than to urinate. These outcomes were collected on days -2, 4, 7, and 14. There were no apparent differences in day or evening urination symptoms between INVOKANA groups and the PBO group based on patientreported questionnaires.

Urine Specific Gravity

• In pooled data from four^2-5 26-week, PBO-controlled phase 3 studies, there were no notable changes in urine specific gravity with the combined INVOKANA group (100 mg and 300 mg, [n=1425]) and the PBO group (n=521).¹⁸

Urine pH

• In pooled data from four^2-5 26-week, PBO-controlled phase 3 studies, there was a slight non-dose-dependent mean percent reduction (-0.14%) in urine pH with the combined INVOKANA group (including 100 mg and 300 mg, [n=1425]) and a slight increase (0.06%) in the PBO group (n=521).¹⁸

Urine Osmolality

• In a phase 1 study, urine osmolality increased in the combined INVOKANA group relative to PBO with greater increases observed in the INVOKANA 300 mg twice daily group.¹⁶

Dysuria

• In a pooled analysis from four^2-5 26-week, PBO-controlled studies, AEs of dysuria were reported with an incidence of 0.7% (6/833), 0.5% (4/834), and 0.3% (2/646) patients in the INVOKANA 100 mg, INVOKANA 300 mg, and PBO groups, respectively.¹⁸

A 7-day phase 1 study in patients with T2DM evaluated pharmacokinetics and pharmacodynamics of INVOKANA 50 mg, 100 mg or 300 mg once daily vs PBO. No notable difference was observed in median 24-hour urine volumes between the INVOKANA and PBO groups.⁴⁰

A 1-year post-marketing observational study evaluating safety and efficacy of INVOKANA in Japanese patients >65 years of age with T2DM (N=1375) reported 1.31% (n=18) experienced 23 polyuria or pollakiuria events, including thirst, pollakiuria, nocturia, polyuria, and urine volume increased. None of the events were classified as serious.⁴¹

Polyuria/Pollakiuria

Real-World Evidence

Inagaki et al (2022) conducted a real-world, long-term, post-market surveillance study over the period of 3 years in Japanese patients with T2DM who were prescribed INVOKANA 100 mg once daily for the first time from December 2014 through September 2016.⁴²

Results

• Overall, 12,227 patients were included in the safety analysis, of whom 312 (10.73%) reported 1836 adverse drug reactions (ADRs) and 225 (1.84%) reported 268 serious ADRs.⁴²
• ADRs associated with polyuria/pollakiuria were reported in 150 (1.23%) patients. Pollakiuria 96 (0.79%), cystitis 63 (0.52%), pruritus genital 59 (0.48%), and urinary tract infections 58 (0.47%) were the most common ADRs.^{19, 42}
• Except for 1 ADR of thirst, all ADRs associated with polyuria/pollakiuria were nonserious.⁴² See Table: ADRs Associated With Polyuria/Pollakiuria.
• Median time of onset of ADRs associated with polyuria/pollakiuria was 36 days.¹⁹
• In the following patient subgroups, the incidence of ADRs associated with polyuria/pollakiuria was higher: age ≥ 75 years; duration of T2DM ≥5 to <10, ≥10 to <15, or ≥15 years; and concurrent dyslipidemia.⁴² See Table: ADRs Associated With Polyuria/Pollakiuria Based on Age, Duration of T2DM, and eGFR.

Additional analyses evaluating urine outcomes have also been conducted.^43-47

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 11 May 2023.