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Invokana

"The U.S. Food and Drug Administration today approved Tanzeum (albiglutide) subcutaneous injection to improve glycemic control, along with diet and exercise, in adults with type 2 diabetes.

Type 2 diabetes affects approximately 24 million pe"...

Invokana

CLINICAL PHARMACOLOGY

Mechanism Of Action

Sodium-glucose co-transporter 2 (SGLT2), expressed in the proximal renal tubules, is responsible for the majority of the reabsorption of filtered glucose from the tubular lumen. Canagliflozin is an inhibitor of SGLT2. By inhibiting SGLT2, canagliflozin reduces reabsorption of filtered glucose and lowers the renal threshold for glucose (RTG), and thereby increases urinary glucose excretion.

Pharmacodynamics

Following single and multiple oral doses of canagliflozin to patients with type 2 diabetes, dose-dependent decreases in the renal threshold for glucose (RTG) and increases in urinary glucose excretion were observed. From a starting value of RTG of approximately 240 mg/dL, canagliflozin at 100 mg and 300 mg once daily suppressed RTG throughout the 24-hour period. Maximal suppression of mean RTG over the 24-hour period was seen with the 300 mg daily dose to approximately 70 to 90 mg/dL in patients with type 2 diabetes in Phase 1 studies. In patients with type 2 diabetes given 100 mg to 300 mg once daily over a 16-day dosing period, reductions in RTG and increases in urinary glucose excretion were observed over the dosing period. In this study, plasma glucose declined in a dose-dependent fashion within the first day of dosing. In single-dose studies in healthy and type 2 diabetic subjects, treatment with canagliflozin 300 mg before a mixed-meal delayed intestinal glucose absorption and reduced postprandial glucose.

Cardiac Electrophysiology

In a randomized, double-blind, placebo-controlled, active-comparator, 4-way crossover study, 60 healthy subjects were administered a single oral dose of canagliflozin 300 mg, canagliflozin 1,200 mg (4 times the maximum recommended dose), moxifloxacin, and placebo. No meaningful changes in QTc interval were observed with either the recommended dose of 300 mg or the 1,200 mg dose.

Pharmacokinetics

The pharmacokinetics of canagliflozin is similar in healthy subjects and patients with type 2 diabetes. Following single-dose oral administration of 100 mg and 300 mg of INVOKANA, peak plasma concentrations (median Tmax) of canagliflozin occurs within 1 to 2 hours post-dose. Plasma Cmax and AUC of canagliflozin increased in a dose-proportional manner from 50 mg to 300 mg. The apparent terminal half-life (t½) was 10.6 hours and 13.1 hours for the 100 mg and 300 mg doses, respectively. Steady-state was reached after 4 to 5 days of once-daily dosing with canagliflozin 100 mg to 300 mg. Canagliflozin does not exhibit time-dependent pharmacokinetics and accumulated in plasma up to 36% following multiple doses of 100 mg and 300 mg.

Absorption

The mean absolute oral bioavailability of canagliflozin is approximately 65%. Co-administration of a high-fat meal with canagliflozin had no effect on the pharmacokinetics of canagliflozin; therefore, INVOKANA may be taken with or without food. However, based on the potential to reduce postprandial plasma glucose excursions due to delayed intestinal glucose absorption, it is recommended that INVOKANA be taken before the first meal of the day [see DOSAGE AND ADMINISTRATION].

Distribution

The mean steady-state volume of distribution of canagliflozin following a single intravenous infusion in healthy subjects was 119 L, suggesting extensive tissue distribution. Canagliflozin is extensively bound to proteins in plasma (99%), mainly to albumin. Protein binding is independent of canagliflozin plasma concentrations. Plasma protein binding is not meaningfully altered in patients with renal or hepatic impairment.

Metabolism

O-glucuronidation is the major metabolic elimination pathway for canagliflozin, which is mainly glucuronidated by UGT1A9 and UGT2B4 to two inactive O-glucuronide metabolites.

CYP3A4-mediated (oxidative) metabolism of canagliflozin is minimal (approximately 7%) in humans.

Excretion

Following administration of a single oral [14C]canagliflozin dose to healthy subjects, 41.5%, 7.0%, and 3.2% of the administered radioactive dose was recovered in feces as canagliflozin, a hydroxylated metabolite, and an O-glucuronide metabolite, respectively. Enterohepatic circulation of canagliflozin was negligible.

Approximately 33% of the administered radioactive dose was excreted in urine, mainly as O-glucuronide metabolites (30.5%). Less than 1% of the dose was excreted as unchanged canagliflozin in urine. Renal clearance of canagliflozin 100 mg and 300 mg doses ranged from 1.30 to 1.55 mL/min.

Mean systemic clearance of canagliflozin was approximately 192 mL/min in healthy subjects following intravenous administration.

Specific Populations

Renal Impairment

A single-dose, open-label study evaluated the pharmacokinetics of canagliflozin 200 mg in subjects with varying degrees of renal impairment (classified using the MDRD-eGFR formula) compared to healthy subjects.

Renal impairment did not affect the Cmax of canagliflozin. Compared to healthy subjects (N=3; eGFR greater than or equal to 90 mL/min/1.73 m²), plasma AUC of canagliflozin was increased by approximately 15%, 29%, and 53% in subjects with mild (N=10), moderate (N=9), and severe (N=10) renal impairment, respectively, (eGFR 60 to less than 90, 30 to less than 60 and 15 to less than 30 mL/min/1.73 m² , respectively), but was similar for ESRD (N=8) subjects and healthy subjects.

Increases in canagliflozin AUC of this magnitude are not considered clinically relevant. The pharmacodynamic response to canagliflozin declines with increasing severity of renal impairment [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS].

Canagliflozin was negligibly removed by hemodialysis.

Hepatic Impairment

Relative to subjects with normal hepatic function, the geometric mean ratios for Cmax and AUC∞ of canagliflozin were 107% and 110%, respectively, in subjects with Child-Pugh class A (mild hepatic impairment) and 96% and 111%, respectively, in subjects with Child-Pugh class B (moderate hepatic impairment) following administration of a single 300 mg dose of canagliflozin.

These differences are not considered to be clinically meaningful. There is no clinical experience in patients with Child-Pugh class C (severe) hepatic impairment [see Use In Specific Populations].

Pharmacokinetics Effects of Age, Body Mass Index (BMI)/Weight, Gender and Race

Based on the population PK analysis with data collected from 1526 subjects, age, body mass index (BMI)/weight, gender, and race do not have a clinically meaningful effect on pharmacokinetics of canagliflozin [see Use in Specific Populations].

Pediatric

Studies characterizing the pharmacokinetics of canagliflozin in pediatric patients have not been conducted.

Drug Interaction Studies

In Vitro Assessment of Drug Interactions

Canagliflozin did not induce CYP450 enzyme expression (3A4, 2C9, 2C19, 2B6, and 1A2) in cultured human hepatocytes. Canagliflozin did not inhibit the CYP450 isoenzymes (1A2, 2A6, 2C19, 2D6, or 2E1) and weakly inhibited CYP2B6, CYP2C8, CYP2C9, and CYP3A4 based on in vitro studies with human hepatic microsomes. Canagliflozin is a weak inhibitor of P-gp.

Canagliflozin is also a substrate of drug transporters P-glycoprotein (P-gp) and MRP2.

In Vivo Assessment of Drug Interactions

Table 5: Effect of Co-Administered Drugs on Systemic Exposures of Canagliflozin

Co-Administered Drug Dose of Co-Administered Drug* Dose of Canagliflozin* Geometric Mean Ratio (Ratio With/Without Co-Administered Drug) No Effect=1.0
AUC† (90% CI) Cmax (90% CI)
See DRUG INTERACTIONS for the clinical relevance of the following:
Rifampin 600 mg QD for 8 days 300 mg 0.49 (0.44; 0.54) 0.72 (0.61; 0.84)
No dose adjustments of INVOKANA required for the following:
Cyclosporine 400 mg 300 mg QD for 8 days 1.23 (1.19; 1.27) 1.01 (0.91; 1.11)
Ethinyl estradiol and levonorgestrel 0.03 mg ethinyl estradiol and 0.15 mg levonorgestrel 200 mg QD for 6 days 0.91 (0.88; 0.94) 0.92 (0.84; 0.99)
Hydrochlorothiazide 25 mg QD for 35 days 300 mg QD for 7 days 1.12 (1.08; 1.17) 1.15 (1.06; 1.25)
Metformin 2,000 mg 300 mg QD for 8 days 1.10 (1.05; 1.15) 1.05 (0.96; 1.16)
Probenecid 500 mg BID for 3 days 300 mg QD for 17 days 1.21 (1.16; 1.25) 1.13 (1.00; 1.28)
* Single dose unless otherwise noted
† AUCinf for drugs given as a single dose and AUC24h for drugs given as multiple doses QD = once daily; BID = twice daily

Table 6: Effect of Canagliflozin on Systemic Exposure of Co-Administered Drugs

Co- Administered Drug Dose of CoAdministered Drug* Dose of Canagliflozin* Geometric Mean Ratio (Ratio With/Without Co-Administered Drug) No Effect = 1.0
  AUC†
(90% CI)
Cmax
(90% CI)
See DRUG INTERACTIONS for the clinical relevance of the following:
Digoxin 0.5 mg QD first day followed by 0.25 mg QD for 6 days 300 mg QD for 7 days digoxin 1.20
(1.12; 1.28)
1.36
(1.21; 1.53)
No dose adjustments of co-administered drug required for the following:
Acetaminophen 1,000 mg 300 mg BID for 25 days acetaminophen 1.06‡(0.98; 1.14) 1.00
(0.92; 1.09)
Ethinyl estradiol and levonorgestrel 0.03 mg ethinyl estradiol and 0.15 mg levonorgestrel 200 mg QD for 6 days ethinyl estradiol 1.07
(0.99; 1.15)
1.22
(1.10; 1.35)
levonorgestrel 1.06
(1.00; 1.13)
1.22
(1.11; 1.35)
Glyburide 1.25 mg 200 mg QD for 6 days glyburide 1.02
(0.98; 1.07)
0.93
(0.85; 1.01)
3 -cis-hydroxy-glyburide 1.01
(0.96; 1.07)
0.99
(0.91; 1.08)
4-trans-hydroxy- glyburide 1.03
(0.97; 1.09)
0.96
(0.88; 1.04)
Hydrochloro- thiazide 25 mg QD for 35 days 300 mg QD for 7 days hydrochlorothiazide 0.99
(0.95; 1.04)
0.94
(0.87; 1.01)
Metformin 2,000 mg 300 mg QD for 8 days metformin 1.20
(1.08; 1.34)
1.06
(0.93; 1.20)
Simvastatin 40 mg 300 mg QD for 7 days simvastatin 1.12
(0.94; 1.33)
1.09
(0.91; 1.31)
simvastatin acid 1.18
(1.03; 1.35)
1.26
(1.10; 1.45)
Warfarin 30 mg 300 mg QD for 12 days (R)-warfarin 1.01
(0.96; 1.06)
1.03
(0.94; 1.13)
(S)-warfarin 1.06
(1.00; 1.12)
1.01
(0.90; 1.13)
INR 1.00
(0.98; 1.03)
1.05
(0.99; 1.12)
* Single dose unless otherwise noted
† AUCinf for drugs given as a single dose and AUC24h for drugs given as multiple doses
‡ AUC0-12h
QD = once daily; BID = twice daily; INR = International Normalized Ratio

Animal Toxicology And/Or Pharmacology

In a juvenile toxicity study in which canagliflozin was dosed directly to young rats from postnatal day (PND) 21 until PND 90 at doses of 4, 20, 65, or 100 mg/kg, increased kidney weights and a dose-related increase in the incidence and severity renal pelvic and renal tubular dilatation were reported at all dose levels. Exposure at the lowest dose tested was greater than or equal to 0.5 times the maximum clinical dose of 300 mg. The renal pelvic dilatations observed in juvenile animals did not fully reverse within the 1-month recovery period. Similar effects on the developing kidney were not seen when canagliflozin was administered to pregnant rats or rabbits during the period of organogenesis or during a study in which maternal rats were dosed from gestation day (GD) 6 through PND 21 and pups were indirectly exposed in utero and throughout lactation.

In embryo-fetal development studies in rats and rabbits, canagliflozin was administered for intervals coinciding with the first trimester period of non-renal organogenesis in humans.

No developmental toxicities were observed at any dose tested other than a slight increase in the number of fetuses with reduced ossification at a dose that was associated with maternal toxicity and that is approximately 19 times the human exposure to canagliflozin at the 300 mg clinical dose.

Clinical Studies

INVOKANA (canagliflozin) has been studied as monotherapy, in combination with metformin, sulfonylurea, metformin and sulfonylurea, metformin and a thiazolidinedione (i.e., pioglitazone), and in combination with insulin (with or without other antihyperglycemic agents). The efficacy of INVOKANA was compared to a dipeptidyl peptidase-4 (DPP-4) inhibitor (sitagliptin) and a sulfonylurea (glimepiride). INVOKANA was also evaluated in adults 55 to 80 years of age and patients with moderate renal impairment.

In patients with type 2 diabetes, treatment with INVOKANA produced clinically and statistically significant improvements in HbA1C compared to placebo. Reductions in HbA1C were observed across subgroups including age, gender, race, and baseline body mass index (BMI).

Monotherapy

A total of 584 patients with type 2 diabetes inadequately controlled on diet and exercise participated in a 26-week, double-blind, placebo-controlled study to evaluate the efficacy and safety of INVOKANA. The mean age was 55 years, 44% of patients were men, and the mean baseline eGFR was 87 mL/min/1.73 m². Patients taking other antihyperglycemic agents (N=281) discontinued the agent and underwent an 8-week washout followed by a 2-week, single-blind, placebo run-in period. Patients not taking oral antihyperglycemic agents (N=303) entered the 2-week, single-blind, placebo run-in period directly. After the placebo run-in period, patients were randomized to INVOKANA 100 mg, INVOKANA 300 mg, or placebo, administered once daily for 26 weeks.

At the end of treatment, INVOKANA 100 mg and 300 mg once daily resulted in a statistically significant improvement in HbA1C (p < 0.001 for both doses) compared to placebo. INVOKANA 100 mg and 300 mg once daily also resulted in a greater proportion of patients achieving an HbA1C less than 7%, in significant reduction in fasting plasma glucose (FPG), in improved postprandial glucose (PPG), and in percent body weight reduction compared to placebo (see Table 7). Statistically significant (p < 0.001 for both doses) mean changes from baseline in systolic blood pressure relative to placebo were -3.7 mmHg and -5.4 mmHg with INVOKANA 100 mg and 300 mg, respectively.

Table 7: Results from 26-Week Placebo-Controlled Clinical Study with INVOKANA as Monotherapy*

Efficacy Parameter Placebo
(N=192)
INVOKANA100 mg
(N=195)
INVOKANA300 mg
(N=197)
HbA1C (%)
  Baseline (mean) 7.97 8.06 8.01
  Change from baseline (adjusted mean) 0.14 -0.77 -1.03
  Difference from placebo (adjusted mean) (95%CI) † -0.91* (-1.09, -0.73) -1.16* (-1.34, -0.99)
Percent of Patients Achieving HbA1C < 7% 21 45* 62*
Fasting Plasma Glucose (mg/dL)
  Baseline (mean) 166 172 173
  Change from baseline (adjusted mean) 8 -27 -35
  Difference from placebo (adjusted mean) (95%CI) † -36‡ (-42, -29) -43* (-50, -37)
2-hour Postprandial Glucose (mg/dL)
  Baseline (mean) 229 250 254
  Change from baseline (adjusted mean) 5 -43 -59
  Difference from placebo (adjusted mean) (95%CI) † -48* (-59.1, -37.0) -64* (-75.0, -52.9)
Body Weight
  Baseline (mean) in kg 87.5 85.9 86.9
  % change from baseline (adjusted mean) -0.6 -2.8 -3.9
  Difference from placebo (adjusted mean) (95%CI) † -2.2* (-2.9, -1.6) -3.3* (-4.0, -2.6)
* Intent-to-treat population using last observation in study prior to glycemic rescue therapy
† Least squares mean adjusted for baseline value and stratification factors
‡ p < 0.001

Combination Therapy

Add-on Combination Therapy With Metformin

A total of 1284 patients with type 2 diabetes inadequately controlled on metformin monotherapy (greater than or equal to 2,000 mg/day, or at least 1,500 mg/day if higher dose not tolerated) participated in a 26-week, double-blind, placebo-and active-controlled study to evaluate the efficacy and safety of INVOKANA in combination with metformin. The mean age was 55 years, 47% of patients were men, and the mean baseline eGFR was 89 mL/min/1.73 m² . Patients already on the required metformin dose (N=1009) were randomized after completing a 2-week, single-blind, placebo run-in period. Patients taking less than the required metformin dose or patients on metformin in combination with another antihyperglycemic agent (N=275) were switched to metformin monotherapy (at doses described above) for at least 8 weeks before entering the 2-week, single-blind, placebo run-in. After the placebo run-in period, patients were randomized to INVOKANA 100 mg, INVOKANA 300 mg, sitagliptin 100 mg, or placebo, administered once daily as add-on therapy to metformin.

At the end of treatment, INVOKANA 100 mg and 300 mg once daily resulted in a statistically significant improvement in HbA1C (p < 0.001 for both doses) compared to placebo when added to metformin. INVOKANA 100 mg and 300 mg once daily also resulted in a greater proportion of patients achieving an HbA1C less than 7%, in significant reduction in fasting plasma glucose (FPG), in improved postprandial glucose (PPG), and in percent body weight reduction compared to placebo when added to metformin (see Table 8). Statistically significant (p < 0.001 for both doses) mean changes from baseline in systolic blood pressure relative to placebo were -5.4 mmHg and -6.6 mmHg with INVOKANA 100 mg and 300 mg, respectively.

Table 8: Results from 26-Week Placebo-Controlled Clinical Study of INVOKANA in Combination with Metformin*

Efficacy Parameter Placebo + Metformin
(N=183)
INVOKANA 100 mg + Metformin
(N=368)
INVOKANA 300 mg + Metformin
(N=367)
HbAlC (%)
  Baseline (mean) 7.96 7.94 7.95
  Change from baseline (adjusted mean) -0.17 -0.79 -0.94
  Difference from placebo (adjusted mean) (95% CI) † -0.62‡ (-0.76, -0.48) -0.77‡ (-0.91, -0.64)
  Percent of patients achieving HbAlC < 7% 30 46‡ 58‡
Fasting Plasma Glucose (mg/dL)
  Baseline (mean) 164 169 173
  Change from baseline (adjusted mean) 2 -27 -38
  Difference from placebo (adjusted mean) (95% CI)† -30‡ (-36, -24) -40‡ (-46, -34)
2-hour Postprandial Glucose (mg/dL)
  Baseline (mean) 249 258 262
  Change from baseline (adjusted mean) -10 -48 -57
  Difference from placebo (adjusted mean) (95%CI)† -38‡ (-49, -27) -47‡ (-58, -36)
Body Weight
  Baseline (mean) in kg 86.7 88.7 85.4
  % change from baseline (adjusted mean) -1.2 -3.7 -4.2
  Difference from placebo (adjusted mean) (95% CI)† -2.5‡ (-3.1, -1.9) -2.9‡ (-3.5, -2.3)
* Intent-to-treat population using last observation in study prior to glycemic rescue therapy
† Least squares mean adjusted for baseline value and stratification factors
‡ p < 0.001

INVOKANA Compared to Glimepiride, Both as Add-on Combination With Metformin

A total of 1450 patients with type 2 diabetes inadequately controlled on metformin monotherapy (greater than or equal to 2,000 mg/day, or at least 1,500 mg/day if higher dose not tolerated) participated in a 52-week, double-blind, active-controlled study to evaluate the efficacy and safety of INVOKANA in combination with metformin.

The mean age was 56 years, 52% of patients were men, and the mean baseline eGFR was 90 mL/min/1.73 m² . Patients tolerating maximally required metformin dose (N=928) were randomized after completing a 2-week, single-blind, placebo run-in period. Other patients (N=522) were switched to metformin monotherapy (at doses described above) for at least 10 weeks, then completed a 2-week single-blind run-in period. After the 2-week run-in period, patients were randomized to INVOKANA 100 mg, INVOKANA 300 mg, or glimepiride (titration allowed throughout the 52-week study to 6 or 8 mg), administered once daily as add-on therapy to metformin.

As shown in Table 9 and Figure 1, at the end of treatment, INVOKANA 100 mg provided similar reductions in HbA1C from baseline compared to glimepiride when added to metformin therapy. INVOKANA 300 mg provided a greater reduction from baseline in HbA1C compared to glimepiride, and the relative treatment difference was -0.12% (95% CI: -0.22; -0.02). As shown in Table 9, treatment with INVOKANA 100 mg and 300 mg daily provided greater improvements in percent body weight change, relative to glimepiride.

Table 9: Results from 52-Week Clinical Study Comparing INVOKANA to Glimepiride in Combination with Metformin*

Efficacy Parameter INVOKANA 100 mg + Metformin
(N=483)
INVOKANA 300 mg + Metformin
(N=485)
Glimepiride(titrated) + Metformin
(N=482)
HbA1C (%)
  Baseline (mean) 7.78 7.79 7.83
  Change from baseline (adjusted mean) -0.82 -0.93 -0.81
  Difference from glimepiride (adjusted mean) (95% CI) † -0.01‡ (-0.11; 0.09) -0.12‡ (-0.22; -0.02)
  Percent of patients achieving HbA1C < 7% 54 60 56
Fasting Plasma Glucose (mg/dL)
  Baseline (mean) 165 164 166
  Change from baseline (adjusted mean) -24 -28 -18
  Difference from glimepiride (adjusted mean)(95% CI)† -6 (-10; -2) -9 (-13; -5)
Body Weight
  Baseline (mean) in kg 86.8 86.6 86.6
  % change from baseline (adjusted mean) -4.2 -4.7 1.0
  Difference from glimepiride (adjusted mean) (95% CI)† -5 2§ (-5.7; -4.7) -5 7§ (-6.2; -5.1)
* Intent-to-treat population using last observation in study prior to glycemic rescue therapy
† Least squares mean adjusted for baseline value and stratification factors
‡ INVOKANA + metformin is considered non-inferior to glimepiride + metformin because the upper limit of this confidence interval is less than the pre-specified non-inferiority margin of < 0.3%.
§p < 0.001

Figure 1: Mean HbA1C Change at Each Time Point (Completers) and at Week 52 Using Last Observation Carried Forward (mITT Population)

Mean HbA1C Change at Each Time Point - Illustration

Add-on Combination Therapy With Sulfonylurea

A total of 127 patients with type 2 diabetes inadequately controlled on sulfonylurea monotherapy participated in an 18-week, double-blind, placebo-controlled sub-study to evaluate the efficacy and safety of INVOKANA in combination with sulfonylurea. The mean age was 65 years, 57% of patients were men, and the mean baseline eGFR was 69 mL/min/1.73 m². Patients treated with sulfonylurea monotherapy on a stable protocol-specified dose (greater than or equal to 50% maximal dose) for at least 10 weeks completed a 2-week, single-blind, placebo run-in period. After the run-in period, patients with inadequate glycemic control were randomized to INVOKANA 100 mg, INVOKANA 300 mg, or placebo, administered once daily as add-on to sulfonylurea.

As shown in Table 10, at the end of treatment, INVOKANA 100 mg and 300 mg daily provided statistically significant (p < 0.001 for both doses) improvements in HbA1C relative to placebo when added to sulfonylurea. INVOKANA 300 mg once daily compared to placebo resulted in a greater proportion of patients achieving an HbA1C less than 7%, (33% vs 5%), greater reductions in fasting plasma glucose (-36 mg/dL vs +12 mg/dL), and greater percent body weight reduction (-2.0% vs -0.2%).

Table 10: Results from 18-Week Placebo-Controlled Clinical Study of INVOKANA in Combination with Sulfonylurea*

Efficacy Parameter Placebo + Sulfonylurea
(N=45)
INVOKANA 100 mg + Sulfonylurea
(N=42)
INVOKANA 300 mg + Sulfonylurea
(N=40)
HbA1C (%)
  Baseline (mean) 8.49 8.29 8.28
  Change from baseline (adjusted mean) 0.04 -0.70 -0.79
  Difference from placebo (adjusted mean) (95% CI)† -0.74‡ (-1.15, -0.33) -0.83‡ (-1.24, -0.41)
* Intent-to-treat population using last observation in study prior to glycemic rescue therapy
† Least squares mean adjusted for baseline value
‡ p < 0.001

Add-on Combination Therapy With Metformin and Sulfonylurea

A total of 469 patients with type 2 diabetes inadequately controlled on the combination of metformin (greater than or equal to 2,000 mg/day or at least 1,500 mg/day if higher dose not tolerated) and sulfonylurea (maximal or near-maximal effective dose) participated in a 26-week, double-blind, placebo-controlled study to evaluate the efficacy and safety of INVOKANA in combination with metformin and sulfonylurea. The mean age was 57 years, 51% of patients were men, and the mean baseline eGFR was 89 mL/min/1.73 m². Patients already on the protocol-specified doses of metformin and sulfonylurea (N=372) entered a 2-week, single-blind, placebo run-in period. Other patients (N=97) were required to be on a stable protocol-specified dose of metformin and sulfonylurea for at least 8 weeks before entering the 2-week run-in period. Following the run-in period, patients were randomized to INVOKANA 100 mg, INVOKANA 300 mg, or placebo, administered once daily as add-on to metformin and sulfonylurea.

At the end of treatment, INVOKANA 100 mg and 300 mg once daily resulted in a statistically significant improvement in HbA1C (p < 0.001 for both doses) compared to placebo when added to metformin and sulfonylurea. INVOKANA 100 mg and 300 mg once daily also resulted in a greater proportion of patients achieving an HbA1C less than 7%, in a significant reduction in fasting plasma glucose (FPG), and in percent body weight reduction compared to placebo when added to metformin and sulfonylurea (see Table 11).

Table 11: Results from 26-Week Placebo-Controlled Clinical Study of INVOKANA in Combination with Metformin and Sulfonylurea*

Efficacy Parameter Placebo + Metformin and Sulfonylurea
(N=156)
INVOKANA 100 mg + Metformin and Sulfonylurea
(N=157)
INVOKANA 300 mg + Metformin and Sulfonylurea
(N=156)
HbA1C (%)
  Baseline (mean) 8.12 8.13 8.13
  Change from baseline (adjusted mean) -0.13 -0.85 -1.06
  Difference from placebo (adjusted mean) (95%CI)† -0.71‡ (-0.90; -0.52) -0.92‡ (-1.11; -0.73)
  Percent of patients achieving A1C < 7% 18 43‡ 57‡
Fasting Plasma Glucose (mg/dL) 
  Baseline (mean) 170 173 168
  Change from baseline (adjusted mean) 4 -18 -31
  Difference from placebo (adjusted mean) (95%CI)† -22‡ (-31 , -13) -35‡ (-44,- 25)
Body Weight
  Baseline (mean) in kg 90.8 93.5 93.5
  % change from baseline (adjusted mean) -0.7 -2.1 -2.6
  Difference from placebo (adjusted mean) (95%CI)† -1.4‡ (-2.1;-0.7) -2.0‡ (-2.7;-1.3)
* Intent-to-treat population using last observation in study prior to glycemic rescue therapy
† Least squares mean adjusted for baseline value and stratification factors
‡ p < 0.001

INVOKANA Compared to Sitagliptin, Both as Add-on Combination Therapy With Metformin and Sulfonylurea

A total of 755 patients with type 2 diabetes inadequately controlled on the combination of metformin (greater than or equal to 2,000 mg/day or at least 1,500 mg/day if higher dose not tolerated) and sulfonylurea (near-maximal or maximal effective dose) participated in a 52-week, double-blind, active-controlled study to compare the efficacy and safety of INVOKANA 300 mg versus sitagliptin 100 mg in combination with metformin and sulfonylurea. The mean age was 57 years, 56% of patients were men, and the mean baseline eGFR was 88 mL/min/1.73 m² . Patients already on protocol-specified doses of metformin and sulfonylurea (N=716) entered a 2-week single-blind, placebo run-in period. Other patients (N=39) were required to be on a stable protocol-specified dose of metformin and sulfonylurea for at least 8 weeks before entering the 2-week run-in period. Following the run-in period, patients were randomized to INVOKANA 300 mg or sitagliptin 100 mg as add-on to metformin and sulfonylurea.

As shown in Table 12 and Figure 2, at the end of treatment, INVOKANA 300 mg provided greater HbA1C reduction compared to sitagliptin 100 mg when added to metformin and sulfonylurea (p < 0.05). INVOKANA 300 mg resulted in a mean percent change in body weight from baseline of -2.5% compared to +0.3% with sitagliptin 100 mg. A mean change in systolic blood pressure from baseline of -5.06 mmHg was observed with INVOKANA 300 mg compared to +0.85 mmHg with sitagliptin 100 mg.

Table 12: Results from 52-Week Clinical Study Comparing INVOKANA to Sitagliptin in Combination with Metformin and Sulfonylurea*

Efficacy Parameter INVOKANA 300 mg + Metformin and Sulfonylurea
(N=377)
Sitagliptin 100 mg + Metformin and Sulfonylurea
(N=378)
HbAlC (%)
  Baseline (mean) 8.12 8.13
  Change from baseline (adjusted mean) -1.03 -0.66
  Difference from sitagliptin (adjusted mean) (95% CI)† -0.37‡ (-0.50; -0.25)
  Percent of patients achieving HbAlC < 7% 48 35
Fasting Plasma Glucose (mg/dL)
  Baseline (mean) 170 164
  Change from baseline (adjusted mean) -30 -6
  Difference from sitagliptin (adjusted mean) (95% CI)† -24 (-30; -18)
Body Weight
  Baseline (mean) in kg 87.6 89.6
  % change from baseline (adjusted mean) -2.5 0.3
  Difference from sitagliptin (adjusted mean) (95% CI) † -2.8§ (-3.3; -2.2)
* Intent-to-treat population using last observation in study prior to glycemic rescue therapy
† Least squares mean adjusted for baseline value and stratification factors
‡ INVOKANA + metformin + sulfonylurea is considered non-inferior to sitagliptin + metformin + sulfonylurea because the upper limit of this confidence interval is less than the pre-specified non-inferiority margin of < 0.3%.
§p < 0.001

Figure 2: Mean HbA1C Change at Each Time Point (Completers) and at Week 52 Using Last Observation Carried Forward (mITT Population)

Mean HbA1C Change at Each Time Point - Illustration

Add-on Combination Therapy With Metformin and Pioglitazone

A total of 342 patients with type 2 diabetes inadequately controlled on the combination of metformin (greater than or equal to 2,000 mg/day or at least 1,500 mg/day if higher dose not tolerated) and pioglitazone (30 or 45 mg/day) participated in a 26-week, double-blind, placebo-controlled study to evaluate the efficacy and safety of INVOKANA in combination with metformin and pioglitazone. The mean age was 57 years, 63% of patients were men, and the mean baseline eGFR was 86 mL/min/1.73 m². Patients already on protocol-specified doses of metformin and pioglitazone (N=163) entered a 2-week, single-blind, placebo run-in period. Other patients (N=181) were required to be on stable protocol-specified doses of metformin and pioglitazone for at least 8 weeks before entering the 2-week run-in period. Following the run-in period, patients were randomized to INVOKANA 100 mg, INVOKANA 300 mg, or placebo, administered once daily as add-on to metformin and pioglitazone.

At the of end of treatment, INVOKANA 100 mg and 300 mg once daily resulted in a statistically significant improvement in HbA1C (p < 0.001 for both doses) compared to placebo when added to metformin and pioglitazone. INVOKANA 100 mg and 300 mg once daily also resulted in a greater proportion of patients achieving an HbA1C less than 7%, in significant reduction in fasting plasma glucose (FPG) and in percent body weight reduction compared to placebo when added to metformin and pioglitazone (see Table 13). Statistically significant (p < 0.05 for both doses) mean changes from baseline in systolic blood pressure relative to placebo were -4.1 mmHg and -3.5 mmHg with INVOKANA 100 mg and 300 mg, respectively.

Table 13: Results from 26-Week Placebo-Controlled Clinical Study of INVOKANA in Combination with Metformin and Pioglitazone*

Efficacy Parameter Placebo + Metformin and Pioglitazone
(N=115)
INVOKANA 100 mg + Metformin and Pioglitazone
(N=113)
INVOKANA 300 mg + Metformin and Pioglitazone
(N=114)
HbA1C (%)
  Baseline (mean) 8.00 7.99 7.84
  Change from baseline (adjusted mean) -0.26 -0.89 -1.03
  Difference from placebo (adjusted mean) (95% CI) † -0.62‡ (-0.81; -0.44) -0.76‡ (-0.95; -0.58)
  Percent of patients achieving HbA1C < 7% 33 47‡ 64‡
Fasting Plasma Glucose (mg/dL)
  Baseline (mean) 164 169 164
  Change from baseline (adjusted mean) 3 -27 -33
  Difference from placebo (adjusted mean) (95% CI) † -29‡ (-37; -22) -36‡ (-43; -28)
Body Weight
  Baseline (mean) in kg 94.0 94.2 94.4
  % change from baseline (adjusted mean) -0.1 -2.8 -3.8
  Difference from placebo (adjusted mean) (95% CI)† -2.7‡ (-3.6; -1.8) -3.7‡ (-4.6; -2.8)
* Intent-to-treat population using last observation in study prior to glycemic rescue therapy
† Least squares mean adjusted for baseline value and stratification factors
‡ p < 0.001

Add-On Combination Therapy With Insulin (With or Without Other Antihyperglycemic Agents)

A total of 1718 patients with type 2 diabetes inadequately controlled on insulin greater than or equal to 30 units/day or insulin in combination with other antihyperglycemic agents participated in an 18-week, double-blind, placebo-controlled substudy of a cardiovascular study to evaluate the efficacy and safety of INVOKANA in combination with insulin. The mean age was 63 years, 66% of patients were men, and the mean baseline eGFR was 75 mL/min/1.73 m². Patients on basal, bolus, or basal/bolus insulin for at least 10 weeks entered a 2-week, single-blind, placebo run-in period. Approximately 70% of patients were on a background basal/bolus insulin regimen. After the run-in period, patients were randomized to INVOKANA 100 mg, INVOKANA 300 mg, or placebo, administered once daily as add-on to insulin. The mean daily insulin dose at baseline was 83 units, which was similar across treatment groups.

At the of end of treatment, INVOKANA 100 mg and 300 mg once daily resulted in a statistically significant improvement in HbA1C (p < 0.001 for both doses) compared to placebo when added to insulin. INVOKANA 100 mg and 300 mg once daily also resulted in a greater proportion of patients achieving an HbA1C less than 7%, in significant reductions in fasting plasma glucose (FPG), and in percent body weight reductions compared to placebo (see Table 14). Statistically significant (p < 0.001 for both doses) mean changes from baseline in systolic blood pressure relative to placebo were -2.6 mmHg and -4.4 mmHg with INVOKANA 100 mg and 300 mg, respectively.

Table 14: Results from 18-Week Placebo-Controlled Clinical Study of INVOKANA in Combination with Insulin ≥ 30 Units/Day (With or Without Other Oral Antihyperglycemic Agents)*

Efficacy Parameter Placebo + Insulin
(N=565)
INVOKANA 100 mg + Insulin
(N=566)
INVOKANA 300 mg + Insulin
(N=587)
HbA1C (%)
  Baseline (mean) 8.20 8.33 8.27
  Change from baseline (adjusted mean) 0.01 -0.63 -0.72
  Difference from placebo (adjusted mean) (95% CI) † -0.65‡ (-0.73, -0.56) -0.73‡ (-0.82, -0.65)
  Percent of patients achieving HbAlC < 7% 8 20‡ 25‡
Fasting Plasma Glucose (mg/dL)
  Baseline 169 170 168
  Change from baseline (adjusted mean) 4 -19 -25
  Difference from placebo (adjusted mean)(97.5% CI) † -23‡ (-29, -16) -29‡ (-35,-23)
Body Weight
  Baseline (mean) in kg 97.7 96.9 96.7
  % change from baseline (adjusted mean) 0.1 -1.8 -2.3
  Difference from placebo (adjusted mean) (97.5% CI) † -1.9‡ (-2.2, -1.5) -2.4‡ (-2.8, -2.0)
* Intent-to-treat population using last observation in study prior to glycemic rescue therapy
† Least squares mean adjusted for baseline value and stratification factors
‡ p < 0.001

Studies in Special Populations

Adults 55 to 80 Years of Age

A total of 714 older patients with type 2 diabetes inadequately controlled on current diabetes therapy (either diet and exercise alone or in combination with oral or parenteral agents) participated in a 26-week, double-blind, placebo-controlled study to evaluate the efficacy and safety of INVOKANA in combination with current diabetes treatment. The mean age was 64 years, 55% of patients were men, and the mean baseline eGFR was 77 mL/min/1.73 m² . Patients were randomized to the addition of INVOKANA 100 mg, INVOKANA 300 mg, or placebo, administered once daily. At the end of treatment, INVOKANA provided statistically significant improvements from baseline relative to placebo in HbA1C (p < 0.001 for both doses) of -0.57% (95% CI: -0.71; -0.44) for INVOKANA 100 mg and -0.70% (95% CI: -0.84; -0.57) for INVOKANA 300 mg. Statistically significant (p < 0.001 for both doses) reductions from baseline in fasting plasma glucose (FPG) and body weight were also observed in this study relative to placebo [see Use In Specific Populations].

Moderate Renal Impairment

A total of 269 patients with type 2 diabetes and a baseline eGFR of 30 mL/min/1.73 m² to less than 50 mL/min/1.73 m² inadequately controlled on current diabetes therapy participated in a 26-week, double-blind, placebo-controlled clinical study to evaluate the efficacy and safety of INVOKANA in combination with current diabetes treatment (diet or antihyperglycemic agent therapy, with 95% of patients on insulin and/or sulfonylurea). The mean age was 68 years, 61% of patients were men, and the mean baseline eGFR was 39 mL/min/1.73 m² . Patients were randomized to the addition of INVOKANA 100 mg, INVOKANA 300 mg, or placebo, administered once daily.

At the end of treatment, INVOKANA 100 mg and INVOKANA 300 mg daily provided greater reductions in HbA1C relative to placebo (-0.30% [95% CI: -0.53; -0.07] and -0.40%, [95% CI: -0.64; -0.17], respectively) [see WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS, and Use in Specific Populations].

Last reviewed on RxList: 5/29/2014
This monograph has been modified to include the generic and brand name in many instances.

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