Summary Basis of Decision for Invokana

Clinical Pharmacology

Canagliflozin, the medicinal ingredient in Invokana, is an orally-active inhibitor of sodium-glucose co-transporter 2 (SGLT2). Canagliflozin acts by inhibiting SGLT2 which results in reducing reabsorption of filtered glucose in the kidney and thereby increases excretion of the glucose through the urine.

Pharmacokinetics

The pharmacokinetics of canagliflozin were comparable between healthy subjects and in patients with type 2 diabetes, with up to 36% accumulation in diabetic patients following multiple doses of 100 mg and 300 mg. The mean absolute oral bioavailability of canagliflozin is approximately 65%. O-glucuronidation is the major metabolic elimination pathway and 33% of a radioactive dose is excreted in urine.

Intrinsic Factors and Special populations

A starting dose of 100 mg canagliflozin is recommended in all patients, which, if tolerated, may be increased to 300 mg, if necessary for glycemic control. No dose adjustment of canagliflozin is necessary based on intrinsic factors such as gender, race/ethnicity, genetic polymorphism (UGT1A9), body mass index, mild and moderate renal or hepatic impairment. Canagliflozin is not recommended in patients with severe renal or hepatic impairment, end stage renal disease or dialysis patients.

Drug-Drug Interactions

Uridine diphosphate glucuronosyl transferase (UGT), cytochrome P450 3A4 enzyme (CYP3A4), and P-glycoprotein (P-gp) inducer (rifampin) decreased canagliflozin exposure with reduced efficacy/clinical benefit and hence require increased dosage from 100 to 300 mg. Canagliflozin increased the exposure of P-gp substrate digoxin by 20% and hence digoxin monitoring is required. Canagliflozin pharmacokinetics was not altered when co-administered with UGT inhibitor (probenecid), CYP3A4/P-gp inhibitor (cyclosporine). Canagliflozin did not alter the pharmacokinetics of CYP3A4 substrates (simvastatin,ethinyl estradiol and levonorgestrel), CYP2C9 substrates (glyburide and warfarin), OCT2 substrate (metformin) and hydrochlorthiazide.

For further details, please refer to the Invokana Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Invokana was evaluated primarily based on nine Phase III double-blind, placebo- and/or active-controlled studies:

• One placebo-controlled study (DIA3005) which evaluated the use of Invokana as a monotherapy. This study included a separate non-placebo controlled substudy to investigate the efficacy and safety of Invokana in subjects with more severe hyperglycemia [Hemoglobin A1c (HbA1C) >10 and ≤12%].
• Five placebo- or active-controlled studies which investigated Invokana as an add-on therapy with other antihyperglycemic agents: two studies (DIA3006 and DIA3009) with metformin only; two studies (DIA3002 and DIA3015) with metformin and sulfonylurea, and one study (DIA3012) with metformin and pioglitazone.
• Two placebo-controlled studies (DIA3010 and DIA3004) which investigated Invokana as an add-on to the standard diabetes treatment regimen, one study conducted in older patients, and one study conducted in patients with moderate renal impairment, respectively.
• One ongoing cardiovascular study (DIA3008) conducted in patients with type 2 diabetes; safety analyses were conducted that investigated Invokana as add-on therapy with a sulfonylurea and as add-on therapy with insulin.

Across these studies, subjects enrolled had a history of type 2 diabetes which was inadequately controlled; either through diet and exercise and/or with the add-on of various background antihyperglycemic regimens. A total of 10,285 subjects received at least one dose of study drug. Enrolled subjects had a baseline HbA1c level of ≥7% and ≤10.5% [≤10% for the DIA3005 (Main Study), and ≤9.5% for Study DIA3009]. The majority of patients were in the 55-60 year age range, with the exception of studies DIA3010 (older patient study), DIA3004 (moderate renal impairment study) and DIA3008 (cardiovascular risk study), where most subjects were in the 60-69 year age range. Most subjects were obese, with a baseline body mass index (BMI) ≥30 kg/m².

In all studies/substudies to support the efficacy of Invokana, the primary efficacy endpoint chosen to evaluate the effect of Invokana on glycemic control included a decrease in HbA1c levels in the groups receiving Invokana (100 mg or 300 mg once daily), relative to the comparator group (placebo and/or active control). The main difference among the studies was the primary assessment time point. Most studies evaluated the primary efficacy endpoint at week 26, however, the 2 active-controlled studies, DIA3009 (add-on to metformin, active comparator glimepiride) and DIA3015 (add-on to metformin and sulfonylurea, active comparator sitagliptin) had a primary assessment time point of 52 weeks. In addition, the two DIA3008 [CANagliflozin cardioVascular Assessment Study (CANVAS)] substudies (add-on to insulin and add-on to sulfonylurea) had a primary assessment time point of 18 weeks.

Across studies, results demonstrated that when compared to placebo, Invokana was associated with clinically significant reductions in HbA1c, with the exception of subjects with moderate renal impairment. Overall, study results showed, in a broad range of subjects and treatment backgrounds, placebo-adjusted decreases in HbA1c at 18 or 26 weeks ranging from -0.54% to -0.91% and -0.63% to -1.16% for the 100 mg dose and 300 mg dose respectively. Furthermore, results from two 52 week studies (DIA3009 and DIA3015), which compared Invokana to the active comparators glimepiride and sitagliptin showed that the reductions in HbA1c continued to be demonstrated with minimal attenuation of the glycemic response over a 52 week period.

As for subjects with moderate renal impairment, efficacy was shown to be substantially reduced. This noted lack of efficacy is consistent with the known mechanism of action of Invokana, where Invokana's efficacy is dependent on the estimated Glomerular Filtration Rate (eGFR). Furthermore, subjects with decreased eGFRs did demonstrate an increased incidence of adverse events with use of Invokana. As such, Health Canada requested from the sponsor to provide further data in order to better assess the benefit-risk ratio in this subject population (see Clinical Safety section).

Results of secondary efficacy endpoints, including; fasting blood glucose levels, proportions of subjects achieving HbA1c target levels, and post-prandial glucose levels, further supported the results noted with that of the primary endpoint. Also observed was an associated dose-related decrease in body weight and systolic blood pressure with prolonged use of Invokana therapy.

For more information, refer to the Invokana Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The safety profile of Invokana was evaluated based primarily on nine Phase III, double-blind, placebo-controlled studies which were previously described in the Clinical Efficacy section. A total of 10,285 subjects with type 2 diabetes were enrolled which included 3,139 subjects treated with Invokana 100 mg and 3,506 subjects treated with Invokana 300 mg.

The primary assessment of safety and tolerability was conducted in a pooled analysis [Number of patients (N = 2,313)] of four 26-week placebo-controlled clinical studies (monotherapy and add-on therapy with metformin, metformin and sulfonylurea, and metformin and pioglitazone). The most commonly reported adverse reactions during treatment (≥5%) were; vulvovaginal candidiasis, urinary tract infection (UTI), and polyuria or pollakiuria. Adverse reactions leading to discontinuation of ≥0.5% of all Invokana-treated subjects were vulvovaginal candidiasis (0.7% of females) and balanitis or balanoposthitis (0.5% of males).

A total of eight serious adverse drug reactions were reported in the primary placebo-controlled safety population, including, five reports from subjects taking Invokana 100 mg daily (two urticaria, two UTI, and one nausea), two reports from subjects taking Invokana 300 mg daily (one UTI, one constipation) and one report from a subject in the placebo group (reduced intravascular volume). Of these serious adverse reactions, two led to discontinuation in the Invokana group (UTI and urticaria).

During review of the New Drug Submission for Invokana, several safety concerns were identified by Health Canada which led to the issuance of a Notice of Non-Compliance (NON) to the sponsor. These concerns included; observed or potential increased risks of venous thromboembolic (VTE) events, serious cardiovascular adverse events early in treatment, stroke, adverse events associated with peripheral vascular insufficiency, bone fractures, renal events, thyroid neoplasms, and a lack of efficacy observed in patients with moderate renal impairment. In response to the NON, the sponsor submitted updated clinical data to address these concerns. Further details are as follows:

Thromboembolic effects

An apparent increased risk of thromboembolic adverse events (in general) and VTE events were observed in Invokana treated subjects when compared to non-Invokana treated subjects. In regards to VTE events (deep venous thrombosis and pulmonary embolism), the dose-related numerical imbalance was particularly evident when VTE events with provoking factors were excluded; with incidence rates of 1.08, 1.55 and 0.44 events per 1,000 subject years for the Invokana 100 mg, 300 mg, and non-Invokana groups, respectively. Despite the apparent three-fold increased risk of non-provoked VTEs in Invokana treated subjects, the imbalance does not achieve statistical significance, owing to the relatively low incidence of events, with a calculated VTE risk attributable to Invokana 300 mg of roughly 1 in 900 subjects per year of treatment.

In regards to the observed numerical excess of VTE events seen in the Phase III studies, updated data provided by the sponsor (provided in response to the NON) nowshow no imbalance in total VTE events between Invokana and comparator treated subjects. The sponsor does however; acknowledge a possible safety concern regarding use of Invokana therapy and the associated effect on intravascular volume depletion and resulting hemoconcentration. Therefore, new text has been added to the Warnings and Precautions and Adverse Events sections of the Invokana Product Monograph which describe the hemoconcentration observed with use of Invokana therapy. The newly inserted wording places a strong emphasis regarding possible volume depletion and the recommended measures to take in an attempt to mitigate risk. This includes careful assessment and monitoring of volume status, and initiating correction of hypovolemia when necessary.

Peripheral vascular insufficiency

In the pool of eight clinical studies with 78 weeks of mean duration of exposure, skin ulcers occurred in 0.7%, 1.1%, and 1.5% of subjects and peripheral ischemia occurred in 0.1%, 0.4%, and 0.2% of subjects receiving a comparator, Invokana 100 mg, and Invokana 300 mg, respectively. An imbalance in these events generally were seen within the first 24 weeks of treatment and occurred in subjects with known or at high risk for atherosclerotic disease, longer duration of diabetes, presence of diabetic complications, and diuretic use.

Data were also examined regarding non-traumatic lower limb amputations, almost all of which were attributed to ischemic and/or infectious complications. Twice as many events were seen in Invokana treated subjects than in non-Invokana subjects, with amputations occurring at a rate of 3.6 per 1,000 patient-years in Invokana treated subjects compared to 1.8 per 1,000 patient-years in the non-Invokana subjects. Amputations were too infrequent for the results to achieve statistical significance; however, amputations had an apparent observed risk attributable to Invokana treatment of approximately one case per 480 patients treated for one year. New text was therefore inserted in the Adverse Reactions section of the Invokana Product Monograph in order to inform the prescriber of the increased risk of adverse events consistent with peripheral ischemia induced by Invokana. The new text added to the Invokana Product Monograph is aimed at minimizing intravascular volume depletion and the resulting hemoconcentration, thereby possibly reducing the risk of exacerbation of peripheral ischemia.

Cardiovascular safety

Imbalances in Major Adverse Cardiac Events (MACE)

An imbalance in MACE events suggestive of increased risk with Invokana was evident in the first 30 days upon initiating Invokana treatment. Thus, in the first 30 days of treatment 13 subjects in the Invokana treatment group suffered a stroke, myocardial infarction, hospitalization for unstable angina, or cardiovascular death, compared to one subject in the placebo group, who suffered a myocardial infarction. The number of subjects contributing to this early imbalance in MACE endpoints is small, and certainly vulnerable to chance. In addition, the sponsor contends that the single event reported in the non-Invokana group is fewer than would be predicted. However, clinically significant hemodynamic changes are seen with Invokana which are evident and/or peak within the first few weeks of treatment [for example (e.g.) decreases in systolic blood pressure (BP), decreases in eGFR, and osmotic diuresis-related events]. This raises the possibility that hemodynamic effects (volume depletion, hemoconcentration) may precipitate early adverse cardiovascular events, particularly amongst susceptible subjects. Consistent with this possibility is the fact that all but one early event in the Invokana group occurred in high risk patients from CANVAS. However, insufficient data are available regarding hemodynamic measures such as BP with a close temporal relationship to the adverse events to be able to evaluate such a relationship.

Cardiovascular effects of Invokana-induced increased low-density lipoprotein-cholesterol (LDL-C) levels

Invokana treatment is associated with a dose-related increase in low density lipoprotein cholesterol averaging 0.11 mmol/L and 0.21 mmol/L for Invokana 100 mg and 300 mg, respectively. Numerically smaller increases in high density lipoprotein were observed. The long-term cardiovascular effects of this increase in the low density lipoprotein cholesterol are unknown. However, data from the Cholesterol Treatment Trialists' Collaboration suggest that the 0.21 mmol/L increase in low density lipoprotein cholesterol seen with Invokana 300 mg might be expected to translate into an increase in risk of major cardiovascular events of about 4-5% annually.

Results from a meta-analysis of the Phase III studies showed a trend suggesting a greater risk of stroke in Invokana-treated subjects, with an observed hazard ratio, compared to non-Invokana subjects of 1.29 [95% confidence interval (CI): 0.726, 2.289]. In contrast, hazard ratios for the combined MACE endpoints, as well as the other individual MACE components (cardiovascular death, myocardial infarction and unstable angina) were all less than one, as was the hazard ratio for hospitalization for congestive heart failure. To further address this safety concern, the sponsor has committed to completing a post-market safety study, "CANVAS-R", to provide additional data in regards to both short and longer-term cardiovascular safety. When combined with the ongoing Study DIA3008 (CANVAS), it is expected that, by study completion in 2017, safety data will be available for approximately 10,000 high cardiovascular risk subjects over roughly 30,000 patient-years of study drug exposure.

Bone safety

A statistically significant increase in upper limb fractures was observed with Invokana treatment, with bone fracture events reported in 0.79% of subjects in the combined Invokana treatment group, compared to 0.37% of subjects in the non-Invokana group. Furthermore, treatment with Invokana was also shown to be associated with more frequent falls, most likely due to induced volume depletion. In contrast, updated data provided by the sponsor failed to show a consistent detrimental effect on bone density with use of Invokana therapy. As a risk minimization measure, text has been added in the Adverse Reactions section of the Invokana Product Monograph to describe the increased risk of both falls and fractures associated with Invokana use. The revisions to the Product Monograph are intended to minimize the risks of volume depletion in Invokana treated patients and are considered an appropriate measure to minimize fall and bone fracture risk.

Renal effects

The originally proposed indication for use of Invokana in patients with moderate renal impairment (eGFR ≥30 mL/min/1.73m² and <60 mL/min/1.73m²) was not considered adequately supported. Efficacy of Invokana is substantially diminished in subjects with moderate renal impairment, while adverse events (particularly renal adverse events and decreases in laboratory indices of renal function) are substantially increased as renal function decreases. Accordingly, a contraindication was inserted in the Invokana Product Monograph to administering Invokana in patients with an eGFR <45 mL/min/1.73 m². The prescriber is therefore advised that Invokana should not be initiated in subjects with an eGFR <60 mL/min/1.73 m². In addition, renal function and volume status should be monitored regularly, and Invokana should be discontinued if eGFR falls below 45 mL/min/1.73 m².

Thyroid Neoplasms

There were eight reports of thyroid neoplasms in Invokana treated subjects compared to one subject in the non-Invokana group (randomization was approximately 2:1 for Invokana: non-Invokana subjects). In the more comprehensive and updated data provided by the sponsor in the response to the NON, there were nine Invokana subjects diagnosed with a thyroid neoplasm, compared to three non-Invokana treated subjects. This renders the result in incidence rates of 0.95 cases/1,000 patient-years (PY) for pooled Invokana treated subjects compared to 0.64/1,000 PY for the non-Invokana treated subjects, with the difference failing to achieve statistical significance. Eight of the nine subjects in the Invokana groups were diagnosed as having a thyroid nodule or nodules, and one 46-year old male in the 100 mg Invokana group was diagnosed as having papillary thyroid carcinoma. Considering the small number of cases, as well as the lack of any effects of Invokana on thyroid structure or function in the non-clinical studies, concerns regarding an increased risk of thyroid neoplasms with Invokana are not considered substantiated, based on the available data.

Safety Conclusion

The safety concerns regarding Invokana have been adequately described in the Invokana Product Monograph, and appropriate recommendations for risk mitigation have been included. Thus, when considering the efficacy results observed in the nine Phase III studies when compared to the possible safety risks, overall the benefit-risk assessment of Invokana is considered favourable. Appropriate warnings and precautions are in place in the approved Invokana Product Monograph to capture the identified safety concerns.

For more information, refer to the Invokana Product Monograph, approved by Health Canada and available through the Drug Product Database.