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.
For the full list of excipients, see section 6.1.
Film-coated tablet (tablet).
- 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 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. In patients tolerating canagliflozin 100 mg once daily who have an eGFR ≥ 60 mL/min/1.73 m2 or CrCl ≥ 60 mL/min and need tighter glycaemic control, the dose can be increased to 300 mg once daily orally (see below and section 4.4).
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 (see section 4.4). In patients with evidence of volume depletion, correcting this condition prior to initiation of canagliflozin is recommended (see section 4.4).
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 (see sections 4.5 and 4.8).
Elderly (≥ 65 years old)
Renal function and risk of volume depletion should be taken into account (see section 4.4).
Patients with 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 (see sections 4.4, 4.8, 5.1, and 5.2).
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 (see sections 4.4 and 5.2).
Patients with 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 (see section 5.2).
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.
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
General
Invokana has not been studied in patients with type 1 diabetes and is therefore not recommended for use in these patients.
Invokana should not be used for the treatment of diabetic ketoacidosis as it is not effective in this setting.
Use in patients with 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 (see section 4.2).
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 (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 and canagliflozin should not be used in patients with an eGFR < 45 mL/min/1.73 m2 or CrCl < 45 mL/min (see section 4.2). 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 (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
- 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 (see section 5.1). 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 (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 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) (see sections 4.2 and 4.8).
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 (see section 4.8).
Patients should be advised to report symptoms of volume depletion. Canagliflozin is not recommended for use in patients receiving loop diuretics (see section 4.5) 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.
Elevated haematocrit
Haematocrit increase was observed with canagliflozin treatment (see section 4.8); 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 (see sections 4.2 and 4.8).
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 (see section 4.8). 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.
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, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.
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 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 (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 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 Cmax 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 Cmax of simvastatin and an 18% increase in AUC and a 26% increase in Cmax 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 (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.
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).
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 (see sections 4.2, 4.4 and 4.8).
Summary of the safety profile
The safety of canagliflozin was eva luated 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) (see sections 4.2 and 4.4).
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 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).
Table 1: Frequency of adverse reactions (MedDRA) in placebo-controlled studiesa
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System organ class
Frequency
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Adverse reaction
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Metabolism and nutrition disorders
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very common
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Hypoglycaemia in combination with insulin or sulphonylurea
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uncommon
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Dehydration*
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Nervous system disorders
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uncommon
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Dizziness postural*, Syncope*
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Vascular disorders
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