Drug Action
Reversibly inhibits sodium-glucose co- transporter 2 (SGLT2) in the renal proximal convoluted tubule to reduce glucose reabsorption and increase urinary glucose excretion.
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Drug reference
Reversibly inhibits sodium-glucose co- transporter 2 (SGLT2) in the renal proximal convoluted tubule to reduce glucose reabsorption and increase urinary glucose excretion.
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Type 2 diabetes mellitus as monotherapy (if metformin inappropriate) | Type 2 diabetes mellitus in combination with insulin or other antidiabetic drugs (if existing treatment fails to achieve adequate glycaemic control) ▶BY MOUTH ▶Adult: 100 mg once daily; increased if tolerated to 300 mg once daily if required, dose to be taken preferably before breakfast
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DUE TO INTERACTIONS ▶Manufacturer advises increase dose if tolerated to 300 mg once daily with concurrent use of rifampicin. ▶Dose of concomitant insulin or drugs that stimulate insulin secretion may need to be reduced.
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Ketoacidosis
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Elderly (risk of volume depletion). elevated haematocrit. heart failure (limited experience). hypotension. risk of volume depletion CAUTIONS, FURTHER INFORMATION ▶Volume depletion Correct hypovolaemia before starting treatment.
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NICE decisions ▶Canagliflozin, dapagliflozin and empagliflozin as monotherapies for treating type 2 diabetes (May 2016) NICE TA390 Canagliflozin (Invokana ®) as monotherapy is recommended as an option for treating type 2 diabetes in adults for whom metformin is contra-indicated or not tolerated and when diet and exercise alone do not provide adequate glycaemic control, only if a dipeptidyl peptidase- 4 (DPP-4) inhibitor would otherwise be prescribed, and a sulfonylurea or pioglitazone is not appropriate. Patients currently receiving canagliflozin whose disease does not meet the above criteria should be able to continue treatment until they and their NHS clinician consider it appropriate to stop. www.nice.org.uk/guidance/ta390 ▶Canagliflozin in combination therapy for treating type 2 diabetes (June 2014) NICE TA315 Canagliflozin (Invokana ®) in a dual therapy regimen in combination with metformin is recommended for the treatment of type 2 diabetes, only if a sulfonylurea is contra-indicated or not tolerated, or the patient has a significant risk of hypoglycaemia. Canagliflozin in a triple therapy regimen is an option for the treatment of type 2 diabetes in combination with metformin and a sulfonylurea, or metformin and a thiazolidinedione. Canagliflozin in combination with insulin (alone or with other antidiabetic drugs) is an option for the treatment of type 2 diabetes. Patients currently receiving canagliflozin in a dual or triple therapy regimen that is not recommended according to the above criteria should have the option to continue treatment until they and their NHS clinician consider it appropriate to stop. www.nice.org.uk/guidance/ta315
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MHRA/CHM ADVICE (UPDATED APRIL 2016): RISK OF DIABETIC KETOACIDOSIS WITH SODIUM-GLUCOSE CO-TRANSPORTER 2 (SGLT2) INHIBITORS (CANAGLIFLOZIN, DAPAGLIFLOZIN OR EMPAGLIFLOZIN) A review by the European Medicines Agency has concluded that serious, life-threatening, and fatal cases of diabetic ketoacidosis (DKA) have been reported rarely in patients taking an SGLT2 inhibitor. In several cases, the presentation of DKA was atypical with patients having only moderately elevated blood glucose levels, and some of them occurred during off-label use. To minimise the risk of such effects when treating patients with a SGLT2 inhibitor, the European Medicines Agency has issued the following advice: . inform patients of the signs and symptoms of DKA, (including rapid weight loss, nausea or vomiting, abdominal pain, fast and deep breathing, sleepiness, a sweet smell to the breath, a sweet or metallic taste in the mouth, or a different odour to urine or sweat), and advise them to seek immediate medical advice if they develop any of these . test for raised ketones in patients with signs and symptoms of DKA, even if plasma glucose levels are near-normal . use canagliflozin with caution in patients with risk factors for DKA, (including a low beta cell reserve, conditions leading to restricted food intake or severe dehydration, sudden reduction in insulin, increased insulin requirements due to acute illness, surgery or alcohol abuse), and discuss these risk factors with patients . discontinue treatment if DKA is suspected or diagnosed . do not restart treatment with any SGLT2 inhibitor in patients who experienced DKA during use, unless another cause for DKA was identified and resolved . interrupt SGLT2 inhibitor treatment in patients who are hospitalised for major surgery or acute serious illnesses; treatment may be restarted once the patient’s condition has stabilised MHRA/CHM ADVICE: SGLT2 INHIBITORS: MONITOR KETONES IN BLOOD DURING TREATMENT INTERRUPTION FOR SURGICAL PROCEDURES OR ACUTE SERIOUS MEDICAL ILLNESS (MARCH 2020) New recommendations have been issued following a European review of peri-operative diabetic ketoacidosis in patients taking SGLT2 inhibitors. Healthcare professionals are advised to monitor ketone levels during SGLT2 inhibitor treatment interruption in patients who have been hospitalised for major surgery or acute serious illness—measurement of blood ketone levels is preferred to urine. Treatment may be restarted once ketone levels are normal and the patient’s condition has stabilised. MHRA/CHM ADVICE (UPDATED MARCH 2017): INCREASED RISK OF LOWER-LIMB AMPUTATION (MAINLY TOES) Canagliflozin may increase the risk of lower-limb amputation (mainly toes) in patients with type 2 diabetes. Preventive foot care is important for all patients with diabetes. The MHRA has issued the following advice while clinical trials are ongoing: . consider stopping canagliflozin if a patient develops a significant lower limb complication (e.g. skin ulcer, osteomyelitis, or gangrene) . carefully monitor patients who have risk factors for amputation (e.g. previous amputations, existing peripheral vascular disease, or neuropathy) . monitor all patients for signs and symptoms of water or salt loss; ensure patients stay sufficiently hydrated to prevent volume depletion in line with the manufacturer’s recommendations . advise patients to stay well hydrated, carry out routine preventive foot care, and seek medical advice promptly if they develop skin ulceration, discolouration, or new pain or tenderness . start treatment for foot problems (e.g. ulceration, infection, or new pain or tenderness) as early as possible . continue to follow standard treatment guidelines for routine preventive foot care for people with diabetes. MHRA/CHM ADVICE: SGLT2 INHIBITORS: REPORTS OF FOURNIER’S GANGRENE (NECROTISING FASCIITIS OF THE GENITALIA OR PERINEUM) (FEBRUARY 2019) Fournier’s gangrene, a rare but serious and potentially life-threatening infection, has been associated with the use of sodium-glucose co-transporter 2 (SGLT2) inhibitors. If Fournier’s gangrene is suspected, stop the SGLT2 inhibitor and urgently start treatment (including antibiotics and surgical debridement). Patients should be advised to seek urgent medical attention if they experience severe pain, tenderness, erythema, or swelling in the genital or perineal area, accompanied by fever or malaise—urogenital infection or perineal abscess may precede necrotising fasciitis.
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→Appendix 1: canagliflozin
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▶Common or very common Balanoposthitis. constipation. dyslipidaemia. hypoglycaemia (in combination with insulin or sulfonylurea). increased risk of infection. nausea. thirst. urinary disorders. urosepsis ▶Uncommon Dehydration. dizziness postural. hypotension . lower limb amputations. renal failure. skin reactions. syncope ▶Rare or very rare Anaphylactic reaction. angioedema. diabetic ketoacidosis (discontinue immediately) ▶Frequency not known Fournier’s gangrene (discontinue and initiate treatment promptly) SIDE-EFFECTS, FURTHER INFORMATION Consider interrupting treatment if volume depletion occurs.
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Avoid—toxicity in animal studies.
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Avoid—present in milk in animal studies.
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Manufacturer advises avoid in severe impairment—no information available.
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Avoid initiation if eGFR less than 60 mL/minute/1.73 m2. Avoid if eGFR less than 45 mL/minute/1.73 m2. Dose adjustments Reduce dose to 100 mg once daily if eGFR falls persistently below 60 mL/minute/1.73 m2 and Endocrine system existing canagliflozin treatment tolerated. Monitoring Monitor renal function at least twice a year in moderate impairment.
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Determine renal function before treatment and at least annually thereafter, and before initiation of concomitant drugs that reduce renal function and periodically thereafter.
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There can be variation in the licensing of different medicines containing the same drug. Tablet ▶Invokana (Napp Pharmaceuticals Ltd) Canagliflozin (as Canagliflozin hemihydrate) 100 mg Invokana 100mg tablets | 30 tablet P £39.20 DT = £39.20 Canagliflozin (as Canagliflozin hemihydrate) 300 mg Invokana 300mg tablets | 30 tablet P £39.20 DT = £39.20
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Patients should be advised to report symptoms of volume depletion including postural hypotension and dizziness. Patients should be informed of the signs and symptoms of diabetic ketoacidosis, see MHRA advice.
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100 mg once daily; increased if tolerated to
First-line fragment. Read the complete Indications and Dose section above.
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