Invokana · 4.3 Contraindications · 1

HOS-096524 · has-adverse-reaction-information · PDF-Seite 10

Summary of the safety profile The safety of canagliflozin was evaluated in 22,645 adult patients with type 2 diabetes, including 13,278 patients treated with canagliflozin and 9,367 patients treated with comparator in 15 double-blind, controlled phase 3 and phase 4 clinical studies. A total of 10,134 adult patients were treated in two dedicated cardiovascular studies for a mean exposure duration of 149 weeks (223 weeks in CANVAS and 94 weeks in CANVAS-R), and 8,114 adult patients were treated in 12 double blind, controlled phase 3 and phase 4 clinical studies, for a mean exposure duration of 49 weeks. In a dedicated renal outcomes study, a total of 4,397 adult patients with type 2 diabetes and diabetic kidney disease had a mean exposure duration of 115 weeks. 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) in adults. 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 adult 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 (table 2) (see sections 4.2 and 4.4). Tabulated list of adverse reactions Adverse reactions in table 2 are based on the pooled analysis of the placebo- and active-controlled studies 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. 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). Table 2: Tabulated list of adverse reactions (MedDRA) from placebo-e an

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HOS-096520 · has-contraindication-information · PDF-Seite 4

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

HOS-096519 · has-indication-information · PDF-Seite 2

Invokana is indicated for the treatment of adults and children aged 10 years and older with insufficiently controlled type 2 diabetes mellitus as an adjunct to diet and exercise: - as monotherapy when metformin is considered inappropriate due to intolerance or contraindications - in addition to other medicinal products for the treatment of diabetes. For study results with respect to combination of therapies, effects on glycaemic control, cardiovascular and renal events, and the populations studied, see sections 4.4, 4.5 and 5.1. 2

HOS-096522 · has-interaction-information · PDF-Seite 8

Pharmacodynamic interactions Diuretics Canagliflozin may add to the effect of diuretics and may increase the risk of dehydration and hypotension (see section 4.4). 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 (see sections 4.2 and 4.8). 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 decrease the exposure to canagliflozin. Following co-administration of canagliflozin with rifampicin (an inducer of various active transporters and medicinal product-metabolising enzymes), 51% and 28% decreases in canagliflozin systemic exposure (AUC) and peak concentration (Cmax) 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 (see sections 4.2 and 4.4). 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 cont

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HOS-096523 · has-pregnancy-information · PDF-Seite 9

Pregnancy There are no data from the use of canagliflozin in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). 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 (see section 5.3). A risk to newborns/infants cannot be excluded. Canagliflozin should not be used during breast-feeding. 9 Fertility The effect of canagliflozin on fertility in humans has not been studied. No effects on fertility were observed in animal studies (see section 5.3).

HOS-096521 · has-warning-information · PDF-Seite 4

General Canagliflozin should not be used in patients with type 1 diabetes mellitus (see “Diabetic Ketoacidosis” in section 4.4). Renal impairment The efficacy of canagliflozin for glycaemic control 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 (see section 4.2). In adult 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 (see section 4.8). 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 (see section 4.2). Regardless of pretreatment eGFR, patients on canagliflozin experienced an initial fall in eGFR that thereafter attenuated over time (see sections 4.8 and 5.1). Monitoring of renal function is recommended as follows: - Prior to initiation of canagliflozin and at least annually, thereafter (see sections 4.2, 4.8, 5.1, and 5.2) - Prior to initiation of concomitant medicinal products that may reduce renal function and periodically thereafter. There is experience with canagliflozin for the treatment of diabetic kidney disease (eGFR ≥30 mL/min/1.73 m2) both with and without albuminuria in adult patients. While both groups of patients benefitted, patients with albuminuria may benefit more from treatment with canagliflozin. 4 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 (see section 5.1). In controlled clinical studies of canagliflozin in adults, 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 (see section 4.8). Caution should be exercised in patients for whom a canagliflozin-induced drop in blood pressure could pose a risk, such as patients with known

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