Invokana

Invokana 100 mg film-coated tablets

Invokana 300 mg film-coated tablets

Invokana 100 mg film-coated tablets

Each tablet contains canagliflozin hemihydrate, equivalent to 100 mg canagliflozin.

Excipient(s) with known effect

Each tablet contains 39.2 mg lactose.

Each tablet contains less than 1 mmol sodium (23 mg), and is essentially sodium-free.

Invokana 300 mg film-coated tablets

Each tablet contains canagliflozin hemihydrate, equivalent to 300 mg canagliflozin.

Excipient(s) with known effect

Each tablet contains 117.78 mg lactose.

Each tablet contains less than 1 mmol sodium (23 mg), and is essentially sodium-free.

Film-coated tablet (tablet).

Invokana 100 mg film-coated tablets

The tablet is yellow, capsule-shaped, approximately 11 mm in length, immediate-release and film-coated, with “CFZ” on one side and “100” on the other side.

Invokana 300 mg film-coated tablets

The tablet is white, capsule-shaped, approximately 17 mm in length, immediate-release and film-coated, with “CFZ” on one side and “300” on the other side.

Invokana is indicated in adults aged 18 years and older with type 2 diabetes mellitus to improve glycaemic control as:

Monotherapy

When diet and exercise alone do not provide adequate glycaemic control in patients for whom the use of metformin is considered inappropriate due to intolerance or contraindications.

Add-on therapy

Add-on therapy with other glucose-lowering medicinal products including insulin, when these, together with diet and exercise, do not provide adequate glycaemic control (see sections 4.4, 4.5, and 5.1 for available data on different add-on therapies).

Posology

The recommended starting dose of canagliflozin is 100 mg once daily.).

Care should be taken when increasing the dose in patients > 75 years of age, patients with known cardiovascular disease, or other patients for whom the initial canagliflozin-induced diuresis poses a risk. In patients with evidence of volume depletion, correcting this condition prior to initiation of canagliflozin is recommended.

When canagliflozin is used as add-on therapy with insulin or an insulin secretagogue (e.g., sulphonylurea), a lower dose of insulin or the insulin secretagogue may be considered to reduce the risk of hypoglycaemia.

Elderly (> 65 years old)

Renal function and risk of volume depletion should be taken into account.

Renal impairment

For patients with an eGFR 60 mL/min/1.73 m² to < 90 mL/min/1.73 m² or CrCl 60 mL/min to < 90 mL/min, no dose adjustment is needed.

Canagliflozin should not be initiated in patients with an eGFR < 60 mL/min/1.73 m² or CrCl < 60 mL/min. In patients tolerating canagliflozin whose eGFR falls persistently below 60 mL/min/1.73 m² or CrCl 60 mL/min, the dose of canagliflozin should be adjusted to or maintained at 100 mg once daily. Canagliflozin should be discontinued when eGFR is persistently below 45 mL/min/1.73 m² or CrCl persistently below 45 mL/min.

Canagliflozin should also not be used in patients with end stage renal disease (ESRD) or in patients on dialysis as it is not expected to be effective in such populations.

Hepatic impairment

For patients with mild or moderate hepatic impairment, no dose adjustment is required.

Canagliflozin has not been studied in patients with severe hepatic impairment and is not recommended for use in these patients.

Paediatric population

The safety and efficacy of canagliflozin in children under 18 years of age have not yet been established. No data are available.

Method of administration

For oral use

Invokana should be taken orally once a day, preferably before the first meal of the day. Tablets should be swallowed whole.

If a dose is missed, it should be taken as soon as the patient remembers; however, a double dose should not be taken on the same day.

Renal impairment

The efficacy of canagliflozin is dependent on renal function, and efficacy is reduced in patients who have moderate renal impairment and likely absent in patients with severe renal impairment.

In patients with an eGFR < 60 mL/min/1.73 m² or CrCl < 60 mL/min, a higher incidence of adverse reactions associated with volume depletion (e.g., postural dizziness, orthostatic hypotension, hypotension) was reported, particularly with the 300 mg dose. In addition, in such patients more events of elevated potassium and greater increases in serum creatinine and blood urea nitrogen (BUN) were reported.

Therefore, the canagliflozin dose should be limited to 100 mg once daily in patients with eGFR < 60 mL/min/1.73 m² or CrCl < 60 mL/min and canagliflozin should not be used in patients with an eGFR < 45 mL/min/1.73 m² or CrCl < 45 mL/min. Canagliflozin has not been studied in severe renal impairment (eGFR < 30 mL/min/1.73 m² or CrCl < 30 mL/min) or ESRD.

Monitoring of renal function is recommended as follows:

- Prior to initiation of canagliflozin and at least annually, thereafter

- Prior to initiation of concomitant medicinal products that may reduce renal function and periodically thereafter

- For renal function approaching moderate renal impairment, at least 2 times to 4 times per year. If renal function falls persistently below eGFR 45 mL/min/1.73 m² or CrCl < 45 mL/min, canagliflozin treatment should be discontinued.

Use in patients at risk for adverse reactions related to volume depletion

Due to its mechanism of action, canagliflozin, by increasing urinary glucose excretion (UGE) induces an osmotic diuresis, which may reduce intravascular volume and decrease blood pressure. In controlled clinical studies of canagliflozin, increases in adverse reactions related to volume depletion (e.g., postural dizziness, orthostatic hypotension, or hypotension) were seen more commonly with the 300 mg dose and occurred most frequently in the first three months.

Caution should be exercised in patients for whom a canagliflozin-induced drop in blood pressure could pose a risk, such as patients with known cardiovascular disease, patients with an eGFR < 60 mL/min/1.73 m², patients on anti-hypertensive therapy with a history of hypotension, patients on diuretics, or elderly patients (> 65 years of age).

Due to volume depletion, generally small mean decreases in eGFR were seen within the first 6 weeks of treatment initiation with canagliflozin. In patients susceptible to greater reductions in intravascular volume as described above, larger decreases in eGFR (> 30%) were sometimes seen, which subsequently improved, and infrequently required interruption of treatment with canagliflozin.

Patients should be advised to report symptoms of volume depletion. Canagliflozin is not recommended for use in patients receiving loop diuretics or who are volume depleted, e.g., due to acute illness (such as gastrointestinal illness).

For patients receiving canagliflozin, in case of intercurrent conditions that may lead to volume depletion (such as a gastrointestinal illness), careful monitoring of volume status (e.g., physical examination, blood pressure measurements, laboratory tests including renal function tests), and serum electrolytes is recommended. Temporary interruption of treatment with canagliflozin may be considered for patients who develop volume depletion while on canagliflozin therapy until the condition is corrected. If interrupted, consideration should be given to more frequent glucose monitoring.

Diabetic ketoacidosis

Rare cases of diabetic ketoacidosis (DKA), including life-threatening and fatal cases, have been reported in patients treated with SGLT2 inhibitors, including canagliflozin. In a number of cases, the presentation of the condition was atypical with only moderately increased blood glucose values, below 14 mmol/l (250 mg/dL). It is not known if DKA is more likely to occur with higher doses of canagliflozin.

The risk of diabetic ketoacidosis must be considered in the event of non-specific symptoms such as nausea, vomiting, anorexia, abdominal pain, excessive thirst, difficulty breathing, confusion, unusual fatigue or sleepiness. Patients should be assessed for ketoacidosis immediately if these symptoms occur, regardless of blood glucose level.

In patients where DKA is suspected or diagnosed, treatment with canagliflozin should be discontinued immediately.

Treatment should be interrupted in patients who are hospitalised for major surgical procedures or acute serious medical illnesses. In both cases, treatment with canagliflozin may be restarted once the patient's condition has stabilised.

Before initiating canagliflozin, factors in the patient history that may predispose to ketoacidosis should be considered.

Patients who may be at higher risk of DKA include patients with a low beta-cell function reserve (e.g., type 2 diabetes patients with low C-peptide or latent autoimmune diabetes in adults (LADA) or patients with a history of pancreatitis), patients with conditions that lead to restricted food intake or severe dehydration, patients for whom insulin doses are reduced and patients with increased insulin requirements due to acute medical illness, surgery or alcohol abuse. SGLT2 inhibitors should be used with caution in these patients.

Restarting SGLT2 inhibitor treatment in patients with previous DKA while on SGLT2 inhibitor treatment is not recommended unless another clear precipitating factor is identified and resolved.

The safety and efficacy of canagliflozin in patients with type 1 diabetes have not been established and canagliflozin should not be used for treatment of patients with type 1 diabetes. Limited data from clinical trials suggest that DKA occurs with common frequency when patients with type 1 diabetes are treated with SGLT2 inhibitors.

Elevated haematocrit

Haematocrit increase was observed with canagliflozin treatment ; therefore, caution in patients with already elevated haematocrit is warranted.

Elderly (> 65 years old)

Elderly patients may be at a greater risk for volume depletion, are more likely to be treated with diuretics, and to have impaired renal function. In patients > 75 years of age, a higher incidence of adverse reactions associated with volume depletion (e.g., postural dizziness, orthostatic hypotension, hypotension) was reported. In addition, in such patients greater decreases in eGFR were reported.

Genital mycotic infections

Consistent with the mechanism of sodium glucose co-transporter 2 (SGLT2) inhibition with increased UGE, vulvovaginal candidiasis in females and balanitis or balanoposthitis in males were reported in clinical trials. Male and female patients with a history of genital mycotic infections were more likely to develop an infection. Balanitis or balanoposthitis occurred primarily in uncircumcised male patients. In rare instances, phimosis was reported and sometimes circumcision was performed. The majority of genital mycotic infections were treated with topical antifungal treatments, either prescribed by a healthcare professional or self-treated while continuing therapy with Invokana.

Lower limb amputations

In ongoing, long-term clinical studies of canagliflozin in type 2 diabetes patients with cardiovascular disease (CVD) or at high risk for CVD, an increase in cases of lower limb amputation (primarily of the toe) has been observed in patients treated with canagliflozin.

As an underlying mechanism has not been established, risk factors, apart from general risk factors, for amputation are unknown. However, as precautionary measures, consideration should be given to carefully monitoring patients with a higher risk for amputation events and counselling patients about the importance of routine preventative foot care and maintaining adequate hydration. Consideration may also be given to stopping treatment with canagliflozin in patients that develop events preceding amputation such as lower-extremity skin ulcer, infection, osteomyelitis or gangrene.

Cardiac failure

Experience in New York Heart Association (NYHA) class III is limited, and there is no experience in clinical studies with canagliflozin in NYHA class IV.

Urine laboratory assessments

Due to its mechanism of action, patients taking canagliflozin will test positive for glucose in their urine.

Lactose intolerance

The tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

Pharmacodynamic interactions

Diuretics

Canagliflozin may add to the effect of diuretics and may increase the risk of dehydration and hypotension.

Insulin and insulin secretagogues

Insulin and insulin secretagogues, such as sulphonylureas, can cause hypoglycaemia. Therefore, a lower dose of insulin or an insulin secretagogue may be required to reduce the risk of hypoglycaemia when used in combination with canagliflozin.

Pharmacokinetic interactions

Effects of other medicinal products on canagliflozin

The metabolism of canagliflozin is primarily via glucuronide conjugation mediated by UDP glucuronosyl transferase 1A9 (UGT1A9) and 2B4 (UGT2B4). Canagliflozin is transported by P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP).

Enzyme inducers (such as St. John's wort [Hypericum perforatum], rifampicin, barbiturates, phenytoin, carbamazepine, ritonavir, efavirenz) may give rise to decreased exposure of canagliflozin. Following co-administration of canagliflozin with rifampicin (an inducer of various active transporters and drug-metabolising enzymes), 51% and 28% decreases in canagliflozin systemic exposure (AUC) and peak concentration (C_max) were observed. These decreases in exposure to canagliflozin may decrease efficacy.

If a combined inducer of these UGT enzymes and transport proteins must be co-administered with canagliflozin, monitoring of glycaemic control to assess response to canagliflozin is appropriate. If an inducer of these UGT enzymes must be co-administered with canagliflozin, increasing the dose to 300 mg once daily may be considered if patients are currently tolerating canagliflozin 100 mg once daily, have an eGFR > 60 mL/min/1.73 m² or CrCl > 60 mL/min, and require additional glycaemic control. In patients with an eGFR 45 mL/min/1.73 m² to < 60 mL/min/1.73 m² or CrCl 45 mL/min to < 60 mL/min taking canagliflozin 100 mg who are receiving concurrent therapy with a UGT enzyme inducer and who require additional glycaemic control, other glucose-lowering therapies should be considered.

Cholestyramine may potentially reduce canagliflozin exposure. Dosing of canagliflozin should occur at least 1 hour before or 4-6 hours after administration of a bile acid sequestrant to minimise possible interference with their absorption.

Interaction studies suggest that the pharmacokinetics of canagliflozin are not altered by metformin, hydrochlorothiazide, oral contraceptives (ethinyl estradiol and levonorgestrol), ciclosporin, and/or probenecid.

Effects of canagliflozin on other medicinal products

Digoxin

The combination of canagliflozin 300 mg once daily for 7 days with a single dose of digoxin 0.5 mg followed by 0.25 mg daily for 6 days resulted in a 20% increase in AUC and a 36% increase in C_max of digoxin, probably due to inhibition of P-gp. Canagliflozin has been observed to inhibit P-gp in vitro. Patients taking digoxin or other cardiac glycosides (e.g., digitoxin) should be monitored appropriately.

Dabigatran

The effect of concomitant administration of canagliflozin (a weak P-gp inhibitor) on dabigatran etexilate (a P-gp substrate) has not been studied. As dabigatran concentrations may be increased in the presence of canagliflozin, monitoring (looking for signs of bleeding or anaemia) should be exercised when dabigatran is combined with canagliflozin.

Simvastatin

The combination of canagliflozin 300 mg once daily for 6 days with a single dose of simvastatin (CYP3A4 substrate) 40 mg resulted in a 12% increase in AUC and a 9% increase in C_max of simvastatin and an 18% increase in AUC and a 26% increase in C_max of simvastatin acid. The increases in simvastatin and simvastatin acid exposures are not considered clinically relevant.

Inhibition of BCRP by canagliflozin cannot be excluded at an intestinal level and increased exposure may therefore occur for medicinal products transported by BCRP, e.g. certain statins like rosuvastatin and some anti-cancer medicinal products.

In interaction studies, canagliflozin at steady-state had no clinically relevant effect on the pharmacokinetics of metformin, oral contraceptives (ethinyl estradiol and levonorgestrol), glibenclamide, paracetamol, hydrochlorothiazide, or warfarin.

Drug/Laboratory test interference

1,5-AG assay

Increases in urinary glucose excretion with Invokana can falsely lower 1,5-anhydroglucitol (1,5-AG) levels and make measurements of 1,5-AG unreliable in assessing glycemic control. Therefore, 1,5-AG assays should not be used for assessment of glycemic control in patients on canagliflozin. For further detail, it may be advisable to contact the specific manufacturer of the 1,5-AG assay.

Pregnancy

There are no data from the use of canagliflozin in pregnant women. Studies in animals have shown reproductive toxicity.

Canagliflozin should not be used during pregnancy. When pregnancy is detected, treatment with canagliflozin should be discontinued.

Breast-feeding

It is unknown whether canagliflozin and/or its metabolites are excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of canagliflozin/metabolites in milk, as well as pharmacologically mediated effects in breast-feeding offspring and juvenile rats exposed to canagliflozin. A risk to newborns/infants cannot be excluded. Canagliflozin should not be used during breast-feeding.

Fertility

The effect of canagliflozin on fertility in humans has not been studied. No effects on fertility were observed in animal studies.

Canagliflozin has no or negligible influence on the ability to drive and use machines. However, patients should be alerted to the risk of hypoglycaemia when canagliflozin is used as add-on therapy with insulin or an insulin secretagogue, and to the elevated risk of adverse reactions related to volume depletion, such as postural dizziness.

Summary of the safety profile

The safety of canagliflozin was evaluated in 10,285 patients with type 2 diabetes, including 3,139 patients treated with canagliflozin 100 mg and 3,506 patients treated with canagliflozin 300 mg, who received medicinal product in nine double-blind, controlled phase 3 clinical studies.

The primary assessment of safety and tolerability was conducted in a pooled analysis (n = 2,313) of four 26-week placebo-controlled clinical studies (monotherapy and add-on therapy with metformin, metformin and a sulphonylurea, and metformin and pioglitazone). The most commonly reported adverse reactions during treatment were hypoglycaemia in combination with insulin or a sulphonylurea, vulvovaginal candidiasis, urinary tract infection, and polyuria or pollakiuria (i.e., urinary frequency). Adverse reactions leading to discontinuation of > 0.5% of all canagliflozin-treated patients in these studies were vulvovaginal candidiasis (0.7% of female patients) and balanitis or balanoposthitis (0.5% of male patients). Additional safety analyses (including long-term data) from data across the entire canagliflozin programme (placebo- and active-controlled studies) were conducted to assess reported adverse reactions in order to identify adverse reactions (see table 1).

Tabulated list of adverse reactions

Adverse reactions in table 1 are based on the pooled analysis of the four 26-week placebo-controlled studies (n = 2,313) described above. Adverse reactions reported from world-wide postmarketing use of canagliflozin are also included in this tabulation. Adverse reactions listed below are classified according to frequency and system organ class (SOC). Frequency categories are defined according to the following convention: very common (> 1/10), common (> 1/100 to < 1/10), uncommon (> 1/1,000 to < 1/100), rare (> 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data).

Description of selected adverse reactions

Adverse reactions related to volume depletion

In the pooled analysis of the four 26-week, placebo-controlled studies, the incidence of all adverse reactions related to volume depletion (e.g., postural dizziness, orthostatic hypotension, hypotension, dehydration, and syncope) was 1.2% for canagliflozin 100 mg, 1.3% for canagliflozin 300 mg, and 1.1% for placebo. The incidence with canagliflozin treatment in the two active-controlled studies was similar to comparators.

In the dedicated cardiovascular study, where patients were generally older with a higher rate of diabetes complications, the incidences of adverse reactions related to volume depletion were 2.8% with canagliflozin 100 mg, 4.6% with canagliflozin 300 mg, and 1.9% with placebo.

To assess risk factors for these adverse reactions, a larger pooled analysis (N = 9,439) of patients from eight controlled phase 3 studies including both doses of canagliflozin was conducted. In this pooled analysis, patients on loop diuretics, patients with a baseline eGFR 30 mL/min/1.73 m² to < 60 mL/min/1.73 m², and patients > 75 years of age had generally higher incidences of these adverse reactions. For patients on loop diuretics, the incidences were 3.2% on canagliflozin 100 mg and 8.8% on canagliflozin 300 mg compared to 4.7% in the control group. For patients with a baseline eGFR 30 mL/min/1.73 m² to < 60 mL/min/1.73 m², the incidences were 4.8% on canagliflozin 100 mg and 8.1% on canagliflozin 300 mg compared to 2.6% in the control group. In patients > 75 years of age, the incidences were 4.9% on canagliflozin 100 mg and 8.7% on canagliflozin 300 mg compared to 2.6% in the control group.

In the dedicated cardiovascular study and the larger pooled analysis, discontinuations due to adverse reactions related to volume depletion and serious adverse reactions related to volume depletion were not increased with canagliflozin.

Hypoglycaemia in add-on therapy with insulin or insulin secretagogues

The frequency of hypoglycaemia was low (approximately 4%) among treatment groups, including placebo, when used as monotherapy or as an add-on to metformin. When canagliflozin was added to insulin therapy, hypoglycaemia was observed in 49.3%, 48.2%, and 36.8% of patients treated with canagliflozin 100 mg, canagliflozin 300 mg, and placebo, respectively, and severe hypoglycaemia occurred in 1.8%, 2.7%, and 2.5% of patients treated with canagliflozin 100 mg, canagliflozin 300 mg, and placebo, respectively. When canagliflozin was added to a sulphonylurea therapy, hypoglycaemia was observed in 4.1%, 12.5%, and 5.8% of patients treated with canagliflozin 100 mg, canagliflozin 300 mg, and placebo, respectively.

Genital mycotic infections

Vulvovaginal candidiasis (including vulvovaginitis and vulvovaginal mycotic infection) was reported in 10.4% and 11.4% of female patients treated with canagliflozin 100 mg and canagliflozin 300 mg, respectively, compared to 3.2% in placebo-treated female patients. Most reports of vulvovaginal candidiasis occurred during the first four months of treatment with canagliflozin. Among female patients taking canagliflozin, 2.3% experienced more than one infection. Overall, 0.7% of all female patients discontinued canagliflozin due to vulvovaginal candidiasis.

Candidal balanitis or balanoposthitis was reported in 4.2% and 3.7% of male patients treated with canagliflozin 100 mg and canagliflozin 300 mg, respectively, compared to 0.6% in placebo-treated male patients. Among male patients taking canagliflozin, 0.9% had more than one infection. Overall, 0.5% of male patients discontinued canagliflozin due to candidial balanitis or balanoposthitis. In rare instances, phimosis was reported and sometimes circumcision was performed.

Urinary tract infections

Urinary tract infections were more frequently reported for canagliflozin 100 mg and 300 mg (5.9% versus 4.3%, respectively) compared to 4.0% with placebo. Most infections were mild to moderate with no increase in the occurrence of serious adverse reactions. Subjects responded to standard treatments while continuing canagliflozin treatment.

Bone fracture

In a cardiovascular study of 4,327 patients with known or at high risk for cardiovascular disease, the incidence rates of bone fracture were 1.6, 1.6, and 1.1 per 100 patient years of exposure to canagliflozin 100 mg, canagliflozin 300 mg, and placebo, respectively, with the fracture imbalance initially occurring within the first 26 weeks of therapy. In other type 2 diabetes studies with canagliflozin, which enrolled a general diabetes population of approximately 5,800 patients, no difference in fracture risk was observed relative to control. After 104 weeks of treatment, canagliflozin did not adversely affect bone mineral density.

Special populations

Elderly (> 65 years old)

In a pooled analysis of eight placebo-controlled and active-controlled studies, the safety profile in elderly patients was generally consistent with younger patients. Patients > 75 years of age had a higher incidence of adverse reactions related to volume depletion (such as postural dizziness, orthostatic hypotension, hypotension) with incidences of 4.9%, 8.7%, and 2.6% on canagliflozin 100 mg, canagliflozin 300 mg, and in the control group, respectively. Decreases in eGFR (-3.6% and -5.2%) were reported with canagliflozin 100 mg and canagliflozin 300 mg, respectively, compared to the control group (-3.0%).

Renal impairment (eGFR < 60 mL/min/1.73 m² or CrCl < 60 mL/min)

Patients with a baseline eGFR < 60 mL/min/1.73 m² or CrCl < 60 mL/min had a higher incidence of adverse reactions associated with volume depletion (e.g., postural dizziness, orthostatic hypotension, hypotension) with incidences of 4.7%, 8.1%, and 1.5% on canagliflozin 100 mg, canagliflozin 300 mg, and placebo, respectively.

The overall incidence of elevated serum potassium was higher in patients with moderate renal impairment with incidences of 7.5%, 12.3%, and 8.1% on canagliflozin 100 mg, canagliflozin 300 mg, and placebo, respectively. In general, elevations were transient and did not require specific treatment.

Increases in serum creatinine of 10-11% and BUN of approximately 12% were observed with both doses of canagliflozin. The proportion of patients with larger decreases in eGFR (> 30%) at any time during treatment was 9.3%, 12.2%, and 4.9% with canagliflozin 100 mg, canagliflozin 300 mg, and placebo, respectively. At study endpoint, 3.0% of patients treated with canagliflozin 100 mg, 4.0% with canagliflozin 300 mg, and 3.3% with placebo had such decreases.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search MHRA Yellow Card in Google Play or Apple App store.

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hrpa.ie

E-mail: [email protected]

Single doses up to 1,600 mg of canagliflozin in healthy subjects and canagliflozin 300 mg twice daily for 12 weeks in patients with type 2 diabetes were generally well-tolerated.

Therapy

In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute clinical measures if required. Canagliflozin was negligibly removed during a 4-hour haemodialysis session. Canagliflozin is not expected to be dialysable by peritoneal dialysis.

Pharmacotherapeutic group: Drugs used in diabetes, other blood glucose lowering drugs, excluding insulins. ATC code: A10BK02.

Mechanism of action

The SGLT2 transporter, expressed in the proximal renal tubules, is responsible for the majority of the reabsorption of filtered glucose from the tubular lumen. Patients with diabetes have been shown to have elevated renal glucose reabsorption which may contribute to persistent elevated blood glucose concentrations. Canagliflozin is an orally-active inhibitor of SGLT2. By inhibiting SGLT2, canagliflozin reduces reabsorption of filtered glucose and lowers the renal threshold for glucose (RT_G), and thereby increases UGE, lowering elevated plasma glucose concentrations by this insulin-independent mechanism in patients with type 2 diabetes. The increased UGE with SGLT2 inhibition also translates to an osmotic diuresis, with the diuretic effect leading to a reduction in systolic blood pressure; the increase in UGE results in a loss of calories and therefore a reduction in body weight, as has been demonstrated in studies of patients with type 2 diabetes.

Canagliflozin's action to increase UGE directly lowering plasma glucose is independent of insulin. Improvement in homeostasis model assessment for beta-cell function (HOMA beta-cell) and improved beta-cell insulin secretion response to a mixed-meal challenge has been observed in clinical studies with canagliflozin.

In phase 3 studies, pre-meal administration of canagliflozin 300 mg provided a greater reduction in postprandial glucose excursion than observed with the 100 mg dose. This effect at the 300 mg dose of canagliflozin may, in part, be due to local inhibition of intestinal SGLT1 (an important intestinal glucose transporter) related to transient high concentrations of canagliflozin in the intestinal lumen prior to medicinal product absorption (canagliflozin is a low potency inhibitor of the SGLT1 transporter). Studies have shown no glucose malabsorption with canagliflozin.

Pharmacodynamic effects

Following single and multiple oral doses of canagliflozin to patients with type 2 diabetes, dose-dependent decreases in RT_G and increases in UGE were observed. From a starting value of RT_G of approximately 13 mmol/L, maximal suppression of 24-hour mean RT_G was seen with the 300 mg daily dose to approximately 4 mmol/L to 5 mmol/L in patients with type 2 diabetes in phase 1 studies, suggesting a low risk for treatment-induced hypoglycaemia. The reductions in RT_G led to increased UGE in subjects with type 2 diabetes treated with either 100 mg or 300 mg of canagliflozin ranging from 77 g/day to 119 g/day across the phase 1 studies; the UGE observed translates to a loss of 308 kcal/day to 476 kcal/day. The reductions in RT_G and increases in UGE were sustained over a 26-week dosing period in patients with type 2 diabetes. Moderate increases (generally < 400 mL to 500 mL) in daily urine volume were seen that attenuated over several days of dosing. Urinary uric acid excretion was transiently increased by canagliflozin (increased by 19% compared to baseline on day 1 and then attenuating to 6% on day 2 and 1% on day 13). This was accompanied by a sustained reduction in serum uric acid concentration of approximately 20%.

In a single-dose study in patients with type 2 diabetes, treatment with 300 mg before a mixed meal delayed intestinal glucose absorption and reduced postprandial glucose through both a renal and a non-renal mechanism.

Clinical efficacy and safety

A total of 10,501 patients with type 2 diabetes participated in ten double-blind, controlled clinical efficacy and safety studies conducted to evaluate the effects of Invokana on glycaemic control. The racial distribution was 72% White, 16% Asian, 5% Black, and 8% other groups. 17% of patients were Hispanic. 58% of patients were male. Patients had an overall mean age of 59.5 years (range 21 years to 96 years), with 3,135 patients > 65 years of age and 513 patients > 75 years of age. 58% of patients had a body mass index (BMI) > 30 kg/m². In the clinical development programme, 1,085 patients with a baseline eGFR 30 mL/min/1.73 m² to < 60 mL/min/1.73 m² were evaluated.

Placebo-controlled studies

Canagliflozin was studied as monotherapy, dual therapy with metformin, dual therapy with a sulphonylurea, triple therapy with metformin and a sulphonylurea, triple therapy with metformin and pioglitazone, and as an add-on therapy with insulin (table 2). In general, canagliflozin produced clinically and statistically significant (p < 0.001) results relative to placebo in glycaemic control, including HbA_1c, the percentage of patients achieving HbA_1c < 7%, change from baseline fasting plasma glucose (FPG), and 2-hour postprandial glucose (PPG). In addition, reductions in body weight and systolic blood pressure relative to placebo were observed.

Furthermore, canagliflozin was studied as triple therapy with metformin and sitagliptin and dosed with a titration regimen, using a starting dose of 100 mg and titrated to 300 mg as early as week 6 in patients requiring additional glycaemic control who had appropriate eGFR and were tolerating canagliflozin 100 mg (table 2). Canagliflozin dosed with a titration regimen produced clinically and statistically significant (p < 0.001) results relative to placebo in glycaemic control, including HbA1c and change from baseline fasting plasma glucose (FPG), and a statistically significant (p < 0.01) improvement in the percentage of patients achieving HbA1c < 7%. In addition, reductions in body weight and systolic blood pressure relative to placebo were observed.

In addition to the studies presented above, glycaemic efficacy results observed in an 18-week dual therapy sub-study with a sulphonylurea and a 26-week triple therapy study with metformin and pioglitazone were generally comparable with those observed in other studies.

Active-controlled studies

Canagliflozin was compared to glimepiride as dual therapy with metformin and compared to sitagliptin as triple therapy with metformin and a sulphonylurea (table 3). Canagliflozin 100 mg as dual therapy with metformin produced similar reductions in HbA_1c from baseline and 300 mg produced superior (p < 0.05) reductions in HbA_1c compared to glimepiride, thus demonstrating non-inferiority. A lower proportion of patients treated with canagliflozin 100 mg (5.6%) and canagliflozin 300 mg (4.9%) experienced at least one episode/event of hypoglycaemia over 52 weeks of treatment compared to the group treated with glimepiride (34.2%). In a study comparing canagliflozin 300 mg to sitagliptin 100 mg in triple therapy with metformin and a sulphonylurea, canagliflozin demonstrated non-inferior (p < 0.05) and superior (p < 0.05) reduction in HbA_1c relative to sitagliptin. The incidence of hypoglycaemia episodes/events with canagliflozin 300 mg and sitagliptin 100 mg was 40.7% and 43.2%, respectively. Significant improvements in body weight and reductions in systolic blood pressure compared to both glimepiride and sitagliptin were also observed.

Canagliflozin as initial combination therapy with metformin

Canagliflozin was evaluated in combination with metformin as initial combination therapy in patients with type 2 diabetes failing diet and exercise. Canagliflozin 100 mg and canagliflozin 300 mg in combination with metformin XR resulted in a statistically significant greater improvement in HbA_1C compared to their respective canagliflozin doses (100 mg and 300 mg) alone or metformin XR alone (table 4).

Special populations

In three studies conducted in special populations (older patients, patients with an eGFR of 30 mL/min/1.73 m² to < 50 mL/min/1.73 m² and patients with or at high risk for cardiovascular disease), canagliflozin was added to patients' current stable diabetes treatments (diet, monotherapy, or combination therapy).

Older patients

A total of 714 patients > 55 years of age to ≤ 80 years of age (227 patients 65 years of age to < 75 years of age and 46 patients 75 years of age to ≤ 80 years of age) with inadequate glycaemic control on current diabetes treatment (glucose-lowering medicinal products and/or diet and exercise) participated in a double-blind, placebo-controlled study over 26 weeks. Statistically significant (p < 0.001) changes from baseline HbA_1c relative to placebo of -0.57% and -0.70% were observed for 100 mg and 300 mg, respectively.

Patients with eGFR 45 mL/min/1.73 m² to < 60 mL/min/1.73 m²

In a pooled analysis of patients (N = 721) with a baseline eGFR 45 mL/min/1.73 m² to < 60 mL/min/1.73 m², canagliflozin provided clinically meaningful reduction in HbA_1c compared to placebo, with -0.47% for canagliflozin 100 mg

The pharmacokinetics of canagliflozin are essentially similar in healthy subjects and patients with type 2 diabetes. After single-dose oral administration of 100 mg and 300 mg in healthy subjects, canagliflozin was rapidly absorbed, with peak plasma concentrations (median T_max) occurring 1 hour to 2 hours post-dose. Plasma C_max and AUC of canagliflozin increased in a dose-proportional manner from 50 mg to 300 mg. The apparent terminal half-life (t_1/2) (expressed as mean ± standard deviation) was 10.6 ± 2.13 hours and 13.1 ± 3.28 hours for the 100 mg and 300 mg doses, respectively. Steady-state was reached after 4 days 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.

Distribution

The mean steady-state volume of distribution of canagliflozin following a single intravenous infusion in healthy subjects was 83.5 litres, 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.

Biotransformation

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.

In in vitro studies, canagliflozin neither inhibited cytochrome P450 CYP1A2,CYP2A6, CYP2C19, CYP2D6, or CYP2E1, CYP2B6, CYP2C8, CYP2C9, nor induced CYP1A2, CYP2C19, CYP2B6, CYP3A4 at higher than therapeutic concentrations. No clinically relevant effect on CYP3A4 was observed in vivo.

Elimination

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 faeces 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 mL/min to 1.55 mL/min.

Canagliflozin is a low-clearance substance, with a mean systemic clearance of approximately 192 mL/min in healthy subjects following intravenous administration.

Special 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 CrCl based on the Cockroft-Gault equation) compared to healthy subjects. The study included 8 subjects with normal renal function (CrCl > 80 mL/min), 8 subjects with mild renal impairment (CrCl 50 mL/min to < 80 mL/min), 8 subjects with moderate renal impairment (CrCl 30 mL/min to < 50 mL/min), and 8 subjects with severe renal impairment (CrCl < 30 mL/min) as well as 8 subjects with ESRD on haemodialysis.

The C_max of canagliflozin was moderately increased by 13%, 29%, and 29% in subjects with mild, moderate, and severe renal failure, respectively, but not in subjects on haemodialysis. Compared to healthy subjects, plasma AUC of canagliflozin was increased by approximately 17%, 63%, and 50% in subjects with mild, moderate, and severe renal impairment, respectively, but was similar for ESRD subjects and healthy subjects.

Canagliflozin was negligibly removed by haemodialysis.

Hepatic impairment

Relative to subjects with normal hepatic function, the geometric mean ratios for C_max 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.

Elderly (> 65 years old)

Age had no clinically meaningful effect on the pharmacokinetics of canagliflozin based on a population pharmacokinetic analysis.

Paediatric population

A paediatric Phase 1 study examined the pharmacokinetics and pharmacodynamics of canagliflozin in children and adolescents > 10 to < 18 years of age with type 2 diabetes mellitus. The observed pharmacokinetic and pharmacodynamic responses were consistent with those found in adult subjects.

Other special populations

Pharmacogenetics

Both UGT1A9 and UGT2B4 are subject to genetic polymorphism. In a pooled analysis of clinical data, increases in canagliflozin AUC of 26% were observed in UGT1A9*1/*3 carriers and 18% in UGT2B4*2/*2 carriers. These increases in canagliflozin exposure are not expected to be clinically relevant. The effect of being homozygote (UGT1A9*3/*3, frequency < 0.1%) is probably more marked, but has not been investigated.

Gender, race/ethnicity, or body mass index had no clinically meaningful effect on the pharmacokinetics of canagliflozin based on a population pharmacokinetic analysis.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, and genotoxicity.

Canagliflozin showed no effects on fertility and early embryonic development in the rat at exposures up to 19 times the human exposure at the maximum recommended human dose (MRHD).

In an embryo-foetal development study in rats, ossification delays of metatarsal bones were observed at systemic exposures 73 times and 19 times higher than the clinical exposures at the 100 mg and 300 mg doses. It is unknown whether ossification delays can be attributed to effects of canagliflozin on calcium homeostasis observed in adult rats. Ossification delays were also observed for the combination of canagliflozin and metformin, which were more prominent than for metformin alone at canagliflozin exposures 43 times and 12 times higher than clinical exposures at 100 mg and 300 mg doses.

In a pre- and postnatal development study, canagliflozin administered to female rats from gestation day 6 to lactation day 20 resulted in decreased body weights in male and female offspring at maternally toxic doses > 30 mg/kg/day (exposures > 5.9 times the human exposure to canagliflozin at the MHRD). Maternal toxicity was limited to decreased body weight gain.

A study in juvenile rats administered canagliflozin from day 1 through day 90 postnatal did not show increased sensitivity compared to effects observed in adults rats. However, dilatation of the renal pelvis was noticed with a No Observed Effect Level (NOEL) at exposures 2.4 times and 0.6 times the clinical exposures at 100 mg and 300 mg doses, respectively, and did not fully reverse within the approximately 1-month recovery period. Persistent renal findings in juvenile rats can most likely be attributed to reduced ability of the developing rat kidney to handle canagliflozin-increased urine volumes, as functional maturation of the rat kidney continues through 6 weeks of age.

Canagliflozin did not increase the incidence of tumours in male and female mice in a 2-year study at doses of 10, 30, and 100 mg/kg. The highest dose of 100 mg/kg provided up to 14 times the clinical dose of 300 mg based on AUC exposure. Canagliflozin increased the incidence of testicular Leydig cell tumours in male rats at all doses tested (10, 30, and 100 mg/kg); the lowest dose of 10 mg/kg is approximately 1.5 times the clinical dose of 300 mg based on AUC exposure. The higher doses of canagliflozin (100 mg/kg) in male and female rats increased the incidence of pheochromocytomas and renal tubular tumours. Based on AUC exposure, the NOEL of 30 mg/kg/day for pheochromocytomas and renal tubular tumours is approximately 4.5 times the exposure at the daily clinical dose of 300 mg. Based on preclinical and clinical mechanistic studies, Leydig cell tumours, renal tubule tumours, and pheochromocytomas are considered to be rat-specific. Canagliflozin-induced renal tubule tumours and pheochromocytomas in rats appear to be caused by carbohydrate malabsorption as a consequence of intestinal SGLT1 inhibitory activity of canagliflozin in the gut of rats; mechanistic clinical studies have not demonstrated carbohydrate malabsorption in humans at canagliflozin doses of up to 2-times the maximum recommended clinical dose. The Leydig cell tumours are associated with an increase in luteinizing hormone (LH), which is a known mechanism of Leydig cell tumour formation in rats. In a 12-week clinical study, unstimulated LH did not increase in male patients treated with canagliflozin.

Tablet core

Lactose anhydrous

Microcrystalline cellulose

Hydroxypropylcellulose

Croscarmellose sodium

Magnesium stearate

Film-coating

Invokana 100 mg film-coated tablets

Polyvinyl alcohol

Titanium dioxide (E171)

Macrogol 3350

Talc

Iron oxide yellow (E172)

Invokana 300 mg film-coated tablets

Polyvinyl alcohol

Titanium dioxide (E171)

Macrogol 3350

Talc

Not applicable.

2 years.

This medicinal product does not require any special storage conditions.

Polyvinyl chloride/Aluminum (PVC/Alu) perforated unit dose blister.

Pack sizes of 10 x 1, 30 x 1, 90 x 1, and 100 x 1 film-coated tablets.

Not all pack sizes may be marketed.

No special requirements.

Janssen-Cilag International NV

Turnhoutseweg 30

B-2340 Beerse

Belgium

Invokana 100 mg film-coated tablets

EU/1/13/884/001 (10 tablets)

EU/1/13/884/002 (30 tablets)

EU/1/13/884/003 (90 tablets)

EU/1/13/884/004 (100 tablets)

Invokana 300 mg film-coated tablets

EU/1/13/884/005 (10 tablets)

EU/1/13/884/006 (30 tablets)

EU/1/13/884/007 (90 tablets)

EU/1/13/884/008 (100 tablets)

Date of first authorisation: 15 November 2013

15 March 2018