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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 Dosage & Administration).
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 Adverse Reactions).
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 Dosage & Administration).
Regardless of pretreatment eGFR patients on canagliflozin experienced an initial fall in eGFR that thereafter attenuated over time (see Adverse Reactions and Pharmacology: Pharmacodynamics under Actions).
Monitoring of renal function is recommended as follows: Prior to initiation of canagliflozin and at least annually, thereafter (see Dosage & Administration, Adverse Reactions, Pharmacology: Pharmacodynamics and Pharmacokinetics under Actions).
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. While both groups of patients benefitted, patients with albuminuria may benefit more from treatment with canagliflozin.
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 Pharmacology: Pharmacodynamics under Actions). 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 Adverse Reactions).
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 Dosage & Administration and Adverse Reactions).
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 Adverse Reactions).
Patients should be advised to report symptoms of volume depletion. Canagliflozin is not recommended for use in patients receiving loop diuretics (see Interactions) 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. Risk of DKA appears to be higher in patients with moderately to severely decreased renal function who require insulin.
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. Monitoring of ketones is recommended in these patients. Measurement of blood ketone levels is preferred to urine. Treatment with canagliflozin may be restarted when the ketone values are normal and 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 studies suggest that DKA occurs with common frequency when patients with type 1 diabetes are treated with SGLT2 inhibitors.
Lower limb amputations: In long-term clinical studies of canagliflozin in patients with type 2 diabetes with establishedcardiovascular disease (CVD) or at least 2 risk factors for CVD, Invokana was associated with an increased risk of lower limb amputation versus placebo (0.63 vs 0.34 events per 100 patient-years, respectively), and this increase occurred primarily in the toe and midfoot (see section 4.8). In a long-term clinical study in patients with type 2 diabetes and diabetic kidney disease, no difference in lower limb amputation risk was observed in patients treated with canagliflozin 100 mg relative to placebo. In this study precautionary measures as outlined below were applied. As an underlying mechanism has not been established, risk factors, apart from general risk factors, for amputation are unknown.
Before initiating Invokana, consider factors in the patient history that may increase the risk foramputation. 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 Invokana in patients who develop events which may precede amputation such as lower-extremity skin ulcer, infection, osteomyelitis or gangrene.
Necrotising fasciitis of the perineum (Fournier's gangrene): Post-marketing cases of necrotising fasciitis of the perineum, (also known as Fournier's gangrene), have been reported in female and male patients taking SGLT2 inhibitors. This is a rare but serious and potentially life-threatening event that requires urgent surgical intervention and antibiotic treatment.
Patients should be advised to seek medical attention if they experience a combination of symptoms of pain, tenderness, erythema, or swelling in the genital or perineal area, with fever or malaise. Be aware that either uro-genital infection or perineal abscess may precede necrotising fasciitis. If Fournier's gangrene is suspected, Invokana should be discontinued and prompt treatment (including antibiotics and surgical debridement) should be instituted.
Elevated haematocrit: Haematocrit increase was observed with canagliflozin treatment (see Adverse Reactions); therefore, careful monitoring 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 Dosage & Administration and Adverse Reactions).
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 studies with canagliflozin (see Adverse Reactions). Male and female patients with a history of genital mycotic infections were more likely to develop an infection. Balanitis or balanoposthitis occured primarily in uncircumcised male patients which in some instances resulted in phimosis and/or circumcision. 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.
Urinary tract infections: Post-marketing cases of complicated urinary tract infections including pyelonephritis and urosepsis have been reported in patients treated with canagliflozin, frequently leading to treatment interruption. Temporary interruption of canagliflozin should be considered in patients with complicated urinary tract infections.
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 medicinal product.
Sodium: This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.
Effects on ability to drive and use machines: 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 Dosage & Administration, Precautions and Adverse Reactions).
