National PBM Drug Monograph

Canagliflozin Monograph

National PBM Drug Monograph

Canagliflozin (Invokana)

VHA Pharmacy Benefits Management Strategic Healthcare Group

Medical Advisory Panel and VISN Pharmacist Executives

The purpose of VACO PBM-SHG drug monographs is to provide a comprehensive drug review for making formulary decisions. These documents will be updated when new data warrant additional formulary discussion. Documents will be placed in the Archive section when the information is deemed to be no longer current.

EXECUTIVE SUMMARY

· Canagliflozin (CAN) is the first selective inhibitor of the sodium-glucose co-transporter 2 (SGLT2) to be marketed in the US. Inhibiting SGLT2 at the proximal renal tubule results in reduced reabsorption of filtered glucose and increases urinary glucose excretion. It is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes (T2DM). Canagliflozin has been studied as monotherapy or in combination with metformin (MET), sulfonylureas (SU), metformin +SU, metformin + pioglitazone (PIO), and insulin ± other oral agents.

· The recommended starting dose is 100mg taken once daily before the first meal of the day. If additional glycemic control is needed, the dose may be increased to 300mg once daily in patients who have an estimated GFR (eGFR) of ≥ 60mL/min/1.73m2. The dose of canagliflozin is limited to 100mg daily in patients with moderate renal impairment (eGFR 45 to <60mL/min/1.73m2). Canagliflozin should not be initiated in patients with an eGFR < 45mL/min/1.73m2. Assessment of renal function is recommended prior to initiating canagliflozin and periodically thereafter. Discontinue canagliflozin if eGFR is persistently eGFR < 45mL/min/1.73m2. Canagliflozin in contraindicated in severe renal impairment (eGFR < 30/min/1.73m2), end stage renal disease, or patients on dialysis.

· Duration of the phase 3 trials ranged from 26-52 weeks. Baseline hemoglobin A1c (A1C) was approximately 8.0%.

· For each of the 2 doses respectively the mean change in A1C when used as monotherapy was -0.8% and

-1.0%; as add-on therapy to metformin -0.8% and -0.9%; as add-on to SU -0.7% and -0.8%; as part of a 3-drug oral regimen (CAN+MET+SU or CAN+MET+PIO) -0.9% and -1.0%; as add-on to insulin (± other oral agents) -0.6% and -0.7%.

· In those studies with an active comparator, both canagliflozin 100mg and glimepiride (mean dose 5.6mg/day) reduced A1C by an average of 0.8%. In another study the average decrease for canagliflozin 300mg and sitagliptin 100mg was 1.0% and 0.7% respectively.

· Patients with moderately impaired renal function had a lesser A1C response (-0.33% and -0.44% for the 2 doses of canagliflozin).

· Due to urinary loss of glucose, use of canagliflozin resulted in weight loss from baseline with means ranging from -1.2% to -4.2% for the 100mg dose and -1.5% to -4.7% for the 300mg dose. Generally, the decrease was less when canagliflozin was combined with other agents known to cause weight gain.

· In general, the rate of hypoglycemia was low with canagliflozin monotherapy or in combination with metformin ± pioglitazone. In this pooled population, the incidence of hypoglycemia was 3.8%, 4.3%, and 2.2% for canagliflozin 100mg, 300mg, and placebo (PBO) respectively. In the comparator study of canagliflozin vs. glimepiride as add-on to metformin, hypoglycemia was reported in 5.6%, 4.9%, and 34.2% for canagliflozin 100mg, 300mg, and glimepiride groups respectively

· When combined with other drugs known to cause hypoglycemia such as insulin or SUs the incidence of hypoglycemia is greater with the addition of canagliflozin compared to the addition of placebo.

· The rate of hypoglycemia was similar for canagliflozin 300mg and sitagliptin when added-on to metformin+SU, (43.2 vs. 40.7% for any event).

· Canagliflozin is associated with an increased risk of urinary tract (UTI) and genital mycotic infections. The majority of cases of infection were considered mild-moderate in intensity. The treatment difference for UTI was 1.5% [95%CI 0.4, 2.6]. In those with renal impairment, the treatment difference for UTI was 0.8 [95%CI -2.4, 4.0]. The treatment difference for genital mycotic infections was 11.2% [95%CI 9.5, 12.9] for females and 6.7 [95%CI 5.6, 7.8] for males. Genital mycotic infection was more common in men and women who had prior history of infection and in uncircumcised men.

· Dose-related increases in low density lipoprotein cholesterol (LDL-C) occur with canagliflozin. The mean change in LDL-C relative to placebo in the pooled placebo-controlled dataset was 4.4mg/dl (CAN100) and 8.2mg/dl (CAN300). The respective changes in high density lipoprotein cholesterol (HDL-C) were 2.1mg/dL and 5.1mg/dL.

· The FDA-requires a meta-analysis of major cardiovascular adverse events (MACE). For the overall population the combined canagliflozin hazard ratio for all cardiovascular (CV) events was 0.91 [95% CI 0.68, 1.22]. Among the individual MACE components, nonfatal stroke was reported more often with canagliflozin vs. placebo/active comparator with a hazard ratio of 1.29 [95%CI 0.8, 2.09]. A large randomized, placebo-controlled, long-term cardiovascular safety trial is underway in patients with a prior history of or who are at risk for CV disease (CANVAS study 3008).

· Canagliflozin can cause osmotic diuresis due to increased urinary glucose. Adverse events related to osmotic diuresis (e.g., polyuria, urinary frequency, and thirst) and decreased intravascular volume (e.g., postural dizziness, orthostatic hypotension, etc.) were increased with canagliflozin versus comparator. The incidence is increased in older patients, those with eGFR <60mL/min/1.73m2, and concomitant loop diuretic use.

· Canagliflozin can cause a dose-related decrease in eGFR (defined as a >30% decrease from baseline). Patients with moderate renal impairment were more likely to experience a decrease in eGFR than those with normal renal function. The decrease in eGFR occurs early in treatment (week 3 or 6) and coincides with reduced intravascular volume due to osmotic diuresis that can occur at that time; however, it tends to trend towards baseline values by the end of study

In patients with baseline micro or macroalbuminuria, mean urine albumin/creatinine ratio decreased with

canagliflozin and increased with placebo/comparator.

· Hyperkalemia may occur with canagliflozin. Patients with moderate renal impairment who are taking medications that interfere with potassium excretion (e.g., potassium-sparing diuretics, ACEI, ARBs) are more likely to develop hyperkalemia.

· There was a dose-dependent decrease in systolic blood pressure with canagliflozin versus placebo or comparator. Mean changes across studies ranged from -0.1 to -6.1mmHg. Mean changes in diastolic blood pressure ranged from -1.2 to -3.2mmHg. Symptomatic hypotension may occur after initiation of canagliflozin particularly in patients with eGFR <60mL/min/1.73m2, elderly patients, those taking diuretics or medications that interfere with the renin-angiotensin-aldosterone system (e.g., ACEI, ARBs) or patients with low systolic blood pressure.

· The rate of bone fracture was 18.7, 17.6, and 14.2 events per 1000 patient-years for canagliflozin 100mg, 300mg and placebo/active comparator respectively. Upper extremity fractures were more common with canagliflozin than placebo/active comparator.

· The rate of acute or chronic pancreatitis per 1000 patient-years was 2.7, 0.9, and 0.9 for canagliflozin 100mg, 300mg and placebo/active comparator respectively.

· Pregnancy Category C; avoid canagliflozin during pregnancy, especially during the 2nd and 3rd trimesters. Because of potential serious adverse reactions to the nursing infant, a decision should be made to discontinue canagliflozin or nursing taking into account importance of the drug to the mother.

· Among the 3rd line oral agents (canagliflozin, pioglitazone, DPP-4 inhibitors) canagliflozin has the highest acquisition cost.

Introduction

Canagliflozin was approved March 2013 and is the first selective inhibitor of the sodium-glucose co-transporter 2 (SGLT2) to be marketed in the US.

Pharmacology

The kidney plays a major role in glucose homeostasis through glomerular filtration and reabsorption of glucose. Renal reabsorption of glucose is mediated by SGLT1 and SGLT2 within the proximal tubule. SGLT2 is expressed almost exclusively in the kidney and is responsible for the majority of glucose reabsorption. SGLT1 is primarily expressed along the brush border of the small intestine and is also located in the proximal tubule; it is mainly responsible for glucose absorption in the GI tract, but also accounts for approximately 10% of glucose reabsorption at the proximal renal tubule. Inhibiting SGLT2 decreases plasma glucose by increasing urinary glucose excretion.

The glycemic lowering effects of SGLT2 inhibitors is independent of insulin secretion by the pancreas; therefore, the efficacy is not expected to decline with progressive ẞ-cell failure.

Pharmacokinetics

Table 1: Pharmacokinetics of Canagliflozin

Absolute bioavailability / Approximately 65%
Time to maximum concentration / 1-2 hours
Terminal half-life / 11-13 hours
Volume of distribution / 119L (in healthy subjects after a single IV dose)
Protein binding / 99% (mainly albumin); protein binding is not meaningfully altered in patients with renal or hepatic impairment
Metabolism / Primarily via O-glucuronidation by UGT1A9 and UGT2B4 into 2 inactive metabolites
Metabolism via CYP3A4 is minimal (approximately 7%)
Elimination / · 41.5% (parent), 7% (hydroxylated metabolite), and 3.2% (O-glucuronide metabolite) recovered in feces
· 33% in urine mainly as O-glucuronide metabolite

Data obtained from product package insert

FDA approved indications

Canagliflozin is indicated as an adjunct to diet and exercise to improve glycemic control in patients with T2DM.

Canagliflozin has been studied as monotherapy or in combination with metformin, SUs, metformin +SU, metformin +PIO, and insulin ± other oral agents.

Current VA alternatives

None in the SGLT2 inhibitor class; other drugs for treatment of type 2 diabetes on the VANF include metformin, glipizide, glyburide, acarbose, NPH insulin, long-acting insulin analogs, regular insulin, and insulin aspart.

Dosing

· The dose of canagliflozin is limited to 100mg daily in patients with moderate renal impairment (eGFR 45 to <60mL/min/1.73m2).

· Canagliflozin should not be initiated in patients with an eGFR < 45mL/min/1.73m2.

· Assessment of renal function is recommended prior to initiating canagliflozin and periodically thereafter. Discontinue canagliflozin if eGFR is persistently eGFR < 45mL/min/1.73m2.

· No dosage adjustment is needed for patients with mild-moderate hepatic impairment. Canagliflozin has not been studied in patients with severe hepatic impairment and is therefore not recommended.

· If canagliflozin is administered with a UDP-Glucuronosyl Transferase (UGT) enzyme inducer (e.g., rifampin, phenytoin, phenobarbital, ritonavir), consider increasing the dosage to 300mg once daily in those with eGFR ≥ 60mL/min/1.73m2 and require additional glycemic control.

· Another antihyperglycemic agent should be used in patients with eGFR 45 to <60mL/min/1.73m2 receiving concurrent therapy with a UGT inducer.

Dosage form/strengths

Canagliflozin is available as a 100mg and 300mg film-coated tablet.

Efficacy

The Phase 3 clinical trial program for canagliflozin is comprised of 9 randomized, double-blind, controlled trials (n=10,285). At the time of this writing, 3 trials have been published (3005, 3004, and 3015). The data for the remaining trials were obtained from the FDA Advisory Committee briefing documents and product package insert. The duration of studies was 26 weeks (6 trials) or 52 weeks (2 trials). Study 3008 is a long-term cardiovascular safety study in patients with a prior history of or who are at risk for CV disease; 18-week substudy results were available for those receiving concomitant insulin or SU.

Glycemic Efficacy

Average baseline A1C and fasting blood glucose was approximately 8.0% and 170mg/dL respectively. Rescue therapy with another anti-glycemic agent was allowed (except study 3015) as defined by protocol (Table 2).

Canagliflozin significantly reduced A1C compared to placebo. The mean reduction in A1C with monotherapy or combination with metformin was approximately 0.8% and 0.9-1.0% with canagliflozin 100mg and 300mg respectively. When used as part of a triple oral therapy regimen, mean reduction in A1C was approximately 0.9% and 1.0% with the 100mg and 300mg doses respectively. There were 2 studies that had an active comparator arm. In study 3009, canagliflozin was found to be non-inferior to glimepiride. In study 3015, reduction in A1C was significantly greater with canagliflozin 300mg compared to sitagliptin 100mg. In study 3006 (extension), the mean reduction in A1C was the same for canagliflozin and sitagliptin. In the 18-week substudy, the A1C response when canagliflozin was used in combination with insulin was -0.63% and -0.72% and with SU was -0.7% and -0.79% for the 2 doses respectively.

In the monotherapy study (3005) a substudy was conducted in patients who had a baseline A1C of 10-12%. Only active drug (no placebo) was given. At week 26, the change in A1C was -2.13% and -2.56% respectively for canagliflozin 100mg and 300mg.

Studies 3010 and 3004 and were conducted in special T2DM populations. Study 3010 enrolled older subjects and study 3004 enrolled patients with stable stage 3 chronic kidney disease (eGFR 30-49 mL/min/1.73m2). In these trials, canagliflozin 100mg, 300mg or placebo was added to the patients’ ongoing diabetes medications. In the renal impairment study, mean reduction in A1C was -0.33 and

-0.44% for each canagliflozin dose. Urinary glucose excretion is proportional to GFR; therefore, it is not unexpected that a lesser response was seen in this population. The results for the older patient study were

-0.6% and -0.73% for the 2 doses.

Extension trials for 3006 (52-weeks total duration) and 3009 (104-weeks total duration) showed that glycemic efficacy is relatively well maintained in comparison to the parent trials.

In the placebo-controlled trials and comparator trial with glimepiride, fewer patients receiving canagliflozin required rescue therapy.

Two-hour post-prandial glucose (2-h PPG) was evaluated in studies 3005, 3006, and 3015. With monotherapy, the change in 2-h PPG was -43, -59, and 8mg/dL with canagliflozin 100mg, 300mg, and placebo respectively. When combined with metformin, the mean changes were -48, -57, and -10mg/dL respectively. In the triple therapy comparator study with sitagliptin, the mean change was -58.5 for canagliflozin 300mg and -39.9mg/dL for sitagliptin.

Table 2: Glycemic Efficacy and Change in Weight

Study / Duration / Patients / Treatment arms / Baseline A1C (%) / A1C (%) / A1C < 7% (%) / FPG (mg/dL) / Need for rescue (%) / Weight (%)
Stenlof
3005 / 26 weeks / Treatment naive / CAN100
CAN300
PBO / 8.06
8.01
7.97 / -0.77
-1.03
0.14 / 44.5
62.4
20.6 / -27.2
-35
8.3 / 3
2
23 / -2.8
-3.9
-0.6
3006 / 26 weeks / Inadequate control on MET / CAN 100 + MET
CAN 300 + MET
PBO + MET / 7.94
7.95
7.96 / -0.79
-0.94
-0.17 / 45.5
57.8
29.8 / -27.3
-37.8
2.5 / 2
<1
15 / -3.7
-4.2
-1.2
3009 / 52 weeks / Inadequate control on MET / CAN100 + MET
CAN300+ MET
GLIM + MET / 7.78
7.79
7.83 / -0.82
-0.93
-0.81 / 53.6
60.1
55.8 / -24.3
-27.5
-18.3 / 6.6
4.9
10.6 / -4.2
-4.7
1.0
3008
Sub-study / 18 weeks / Inadequate control on SU / CAN100+SU
CAN 300 +SU
PBO+ SU / 8.29
8.28
8.49 / -0.7
-0.79
0.04 / 25
33.3
5 / -25.4
-36.1
12 / 5
0
18 / -
-
-
3002 / 26 weeks / Inadequate control on MET+SU / CAN100+MET+SU
CAN 300 +MET+SU
PBO+MET+SU / 8.13
8.13
8.12 / -0.85
-1.06
-0.13 / 43.2
56.6
18 / -18.2
-30.5
4.1 / 1
2
13 / -2.1
-2.6
-0.7
Schernthaner 3015 / 52 weeks / Inadequate control on
MET +SU / CAN 300 +MET+SU
SIT 100+MET+SU / 8.12
8.13 / -1.03
-0.66 / 47.6
35.3 / -29.9
-5.9 / N/A / -2.5
0.3
3008
Sub-study / 18 weeks / Insulin ±AHA / CAN100+ INS ±AHA
CAN300 + INS ±AHA
PBO + INS ±AHA / 8.33
8.27
8.20 / -0.63
-0.72
0.01 / 19.8
24.7
7.7 / -18.6
-25
4 / 4
3
9 / -1.8
-2.3
0.1
3012 / 26 weeks / Inadequate control on MET+PIO / CAN100+MET+PIO
CAN300+MET+PIO
PBO+MET+PIO / 7.99
7.84
8.00 / -0.89
-1.03
-0.26 / 46.9
64.3
32.5 / -26.8
-33.2
2.5 / 1
0
12 / -2.8
-3.8
-0.1
Yale
3004 / 26 weeks / Moderate renal impairment
Add-on to AHA / CAN100 +AHA
CAN300 + AHA
PBO + AHA / 7.9
8.0
8.0 / -0.33
-0.44
-0.03 / 27.3
32.6
17.2 / -14.9
-11.7
0.49 / 4.4
3.3
14.3 / -1.2
-1.5
0.3
3010 / 26 weeks / Older pts.
Add on to AHA / CAN100 +AHA
CAN300 + AHA
PBO + AHA / 7.7 / -0.6
-0.73
-0.03 / 47.7
58.5
28 / -18.1
-20.3
7.4 / 2.1
0.4
10.9 / -2.3
-3.0
Diff. vs. PBO
Gonzalez
Extension
3006 / 52 weeks / Inadequate control on MET / CAN100+MET
CAN300+MET
SIT +MET
PBO+MET→SIT+MET / 7.9
8.0
7.9
NR / -0.73
-0.88
-0.73
NR / NR
NR
NR
NR / -26.2
-35.2
-17.7
NR / NR
NR
NR
NR / -3.8
-4.2
-1.3
NR
Cefalu
Extension
3009 / 104 weeks / Inadequate control on MET / CAN100 + MET
CAN300+ MET
GLIM + MET / 7.8
7.8
7.8 / -0.65
-0.74
-0.55 / 42.5
50.2
43.9 / -19.3
-22.5
-10.6 / NR
NR
NR / -4.1
-4.2
0.9

Data obtained from published clinical trials, FDA Advisory Committee briefing documents, 2013 ADA meeting and product package insert