Canagliflozin

Canagliflozin is an orally active inhibitor of the sodium-glucose co-transporter 2 (SGLT2). This transporter, found in the proximal renal tubules, is responsible for most of the reabsorption of filtered glucose from the tubular lumen. People with diabetes have been shown to reabsorb more glucose in the kidney, which may help to keep blood glucose persistently high.

Mechanism of Action

• Urinary glucose excretion: by inhibiting SGLT2, canagliflozin reduces the reabsorption of filtered glucose and lowers the renal threshold for glucose (RTG). Urinary glucose excretion rises, which lowers plasma glucose through a mechanism that does not depend on insulin.
• Osmotic diuresis and weight: the extra glucose in the urine acts as an osmotic diuretic, which reduces systolic blood pressure, and the loss of calories reduces body weight.
• Beta-cell function: improved beta-cell function (HOMA beta-cell) and a better insulin secretion response to a mixed meal were seen in clinical studies.
• Intestinal SGLT1: before meals, the 300 mg dose lowered the post-meal glucose rise more than 100 mg did. This may be partly due to local inhibition of intestinal SGLT1, which canagliflozin inhibits only weakly, by transiently high concentrations in the gut before absorption. No glucose malabsorption has been shown.

Pharmacokinetics

• Absorption: rapid, with peak concentrations 1 to 2 hours after dosing (median) and a mean absolute oral bioavailability of about 65%. Peak concentration and AUC rise in proportion to the dose from 50 to 300 mg. Steady state is reached after 4 to 5 days of once-daily dosing, with up to 36% accumulation in plasma. A high-fat meal has no effect, but taking the tablet before the first meal of the day is recommended because it can reduce the post-meal glucose rise by delaying intestinal glucose absorption.
• Distribution: the mean steady-state volume of distribution after an intravenous infusion was 83.5 L, indicating extensive tissue distribution. About 99% is bound to plasma proteins, mainly albumin, independent of concentration and not meaningfully altered by renal or hepatic impairment.
• Metabolism: mainly O-glucuronidation, by UGT1A9 and UGT2B4, to two inactive O-glucuronide metabolites. Oxidative metabolism by CYP3A4 is minimal (about 7%).
• Elimination: apparent terminal half-life 10.6 hours with 100 mg and 13.1 hours with 300 mg. After a radiolabelled dose, DrugBank reports about 41.5% of the dose in faeces as unchanged drug, 7.0% as a hydroxylated metabolite and 3.2% as an O-glucuronide, and about 33% in urine, mainly as O-glucuronides, with less than 1% unchanged. Renal clearance was 1.30–1.55 mL/min and systemic clearance about 192 mL/min after an intravenous dose.
• Special populations: the glucose-lowering effect depends on renal function. It is reduced in moderate renal impairment and likely absent in severe impairment (see Administration and Dosage).

Canagliflozin is indicated for 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 because of intolerance or contraindications.
• In addition to other medicinal products: for the treatment of diabetes.

The SmPC points to its sections 4.4, 4.5 and 5.1 for study results on combinations of therapy, glycaemic control, and cardiovascular and renal events. Canagliflozin is also marketed in a fixed-dose combination with metformin (Vokanamet), which has its own SmPC.

• Hypersensitivity to canagliflozin or to any of the excipients.

The SmPC draws on 22,645 adults with type 2 diabetes in 15 double-blind controlled studies (13,278 treated with canagliflozin) and on post-marketing use. The most commonly reported reactions were hypoglycaemia in combination with insulin or a sulphonylurea, vulvovaginal candidiasis, urinary tract infection, and polyuria or pollakiuria (frequent urination). Reactions that led to discontinuation in at least 0.5% of treated patients were vulvovaginal candidiasis (0.7% of women) and balanitis or balanoposthitis (0.5% of men).

Very common (≥1/10): vulvovaginal candidiasis; hypoglycaemia in combination with insulin or a sulphonylurea.

Common (≥1/100 to <1/10): balanitis or balanoposthitis, urinary tract infection (pyelonephritis and urosepsis have been reported after marketing), constipation, thirst (including dry mouth and polydipsia), nausea, polyuria or pollakiuria, dyslipidaemia, increased haematocrit.

Uncommon (≥1/1,000 to <1/100): dehydration, postural dizziness, syncope, hypotension, orthostatic hypotension, photosensitivity, rash, urticaria, bone fracture, renal failure (mainly in the context of volume depletion), increased blood creatinine, urea, potassium and phosphate, and lower limb amputations (mainly of the toe and midfoot), especially in patients at high risk of heart disease.

Rare (≥1/10,000 to <1/1,000): anaphylactic reaction, diabetic ketoacidosis, angioedema.

Not known: necrotising fasciitis of the perineum (Fournier’s gangrene).

Genital mycotic infections were frequent: vulvovaginal candidiasis occurred in 10.4% and 11.4% of women on 100 mg and 300 mg versus 3.2% on placebo, mostly in the first four months. Hypoglycaemia was about 4% in all groups, including placebo, when canagliflozin was used alone or added to metformin; added to insulin it occurred in 49.3% (100 mg), 48.2% (300 mg) and 36.8% (placebo) of adults. In 171 children aged 10 years and older (84 on canagliflozin), reactions were comparable with those in adults; headache, nasopharyngitis, urinary tract infection and vomiting were more frequent than with placebo, and none of the events were severe or serious.

• Diuretics: canagliflozin may add to their effect and increase the risk of dehydration and hypotension; it is not recommended with loop diuretics.
• Insulin and insulin secretagogues (such as sulphonylureas): they can cause hypoglycaemia, so a lower dose of insulin or the secretagogue may be needed.
• Enzyme inducers (St John’s wort, rifampicin, barbiturates, phenytoin, carbamazepine, ritonavir, efavirenz): they may lower canagliflozin exposure; rifampicin reduced the AUC by 51% and the peak concentration by 28%, which may reduce efficacy. Glycaemic control should be monitored. If an inducer must be given, the dose may be raised to 300 mg once daily in patients who tolerate 100 mg, have eGFR or creatinine clearance of at least 60 and need more control; at eGFR 45 to below 60, other glucose-lowering therapy should be considered.
• Bile acid sequestrants (colestyramine): may reduce canagliflozin exposure. Take canagliflozin at least 1 hour before or 4–6 hours after them.
• Digoxin and other cardiac glycosides: canagliflozin 300 mg raised digoxin AUC by 20% and peak concentration by 36%, probably through P-glycoprotein inhibition. Monitor appropriately.
• Lithium: SGLT2 inhibitors may lower serum lithium concentrations, so monitor lithium more closely, especially when starting and when doses change.
• Dabigatran: its concentrations may rise; watch for signs of bleeding or anaemia.
• Statins and BCRP substrates: simvastatin exposure rose by 12% (not clinically relevant), but increased exposure cannot be excluded for BCRP substrates such as rosuvastatin and some anti-cancer medicines.
• No relevant interaction: metformin, hydrochlorothiazide, oral contraceptives, ciclosporin and probenecid did not alter canagliflozin exposure; canagliflozin had no clinically relevant effect on metformin, oral contraceptives, glibenclamide, paracetamol, hydrochlorothiazide or warfarin. Interaction studies were done only in adults.
• Laboratory tests: canagliflozin makes 1,5-anhydroglucitol assays unreliable for judging glycaemic control.
• Alcohol: excess alcohol may promote ketoacidosis (DrugBank), and alcohol abuse is among the factors that raise the risk in the SmPC.

Canagliflozin is taken orally once a day, preferably before the first meal of the day, and the tablets are swallowed whole. If the patient is volume depleted, this should be corrected before starting.

Recommended Dose

• Starting dose: 100 mg once daily.
• Increase to 300 mg once daily: in patients who tolerate 100 mg, have an eGFR of at least 60 mL/min/1.73 m² or a creatinine clearance of at least 60 mL/min, and need tighter glycaemic control. Take care when increasing the dose in patients aged 75 years or older, those with known cardiovascular disease, or others for whom the initial diuresis poses a risk.
• Add-on to insulin or an insulin secretagogue (such as a sulphonylurea): a lower dose of insulin or the secretagogue may be considered to reduce the risk of hypoglycaemia.
• Diabetic kidney disease as add-on to standard of care (for example ACE inhibitors or angiotensin receptor blockers): 100 mg once daily.

Dose by Kidney Function

• eGFR or creatinine clearance of 60 or above: start at 100 mg; increase to 300 mg if tolerated and more glycaemic control is needed.
• 30 to below 60: use 100 mg.
• Below 30: patients already taking canagliflozin continue 100 mg (until dialysis or kidney transplantation); it should not be started. See the footnotes of Table 1 in the SmPC.
• Glycaemic efficacy is reduced in moderate and likely absent in severe renal impairment, so other glucose-lowering medicines should be considered if more control is needed.

Special Populations

• Elderly: renal function and the risk of volume depletion should be taken into account.
• Hepatic impairment: no adjustment in mild or moderate impairment. Not studied in severe impairment, so not recommended.
• Children and adolescents: from 10 years, no dose adjustment; in children weighing below 50 kg, caution when increasing to 300 mg because safety data are limited. Safety and effectiveness below 10 years have not been established.

Missed Dose

Take the missed dose as soon as it is remembered. A double dose must not be taken on the same day.

Diabetic Ketoacidosis

Rare cases of diabetic ketoacidosis (DKA), including life-threatening and fatal cases, have been reported with SGLT2 inhibitors. Several presented atypically, with blood glucose only moderately raised (below 14 mmol/L, 250 mg/dL), so DKA must be considered if there are non-specific symptoms such as nausea, vomiting, anorexia, abdominal pain, excessive thirst, difficulty breathing, confusion, or unusual fatigue or sleepiness, whatever the glucose level. If DKA is suspected, canagliflozin is stopped immediately.

• Treatment is interrupted in patients hospitalised for acute serious illness, and withheld for an appropriate number of days before major surgery or other procedures with prolonged fasting. Blood ketones are preferred to urine ketones for monitoring.
• Higher-risk patients include those with low beta-cell reserve (low C-peptide, latent autoimmune diabetes in adults, history of pancreatitis), restricted food intake or severe dehydration, reduced insulin doses, or increased insulin needs from acute illness, surgery or alcohol abuse. Risk also appears higher in moderate to severe renal impairment requiring insulin.
• Restarting after DKA on an SGLT2 inhibitor is not recommended unless another clear cause is found and resolved. Canagliflozin must not be used in type 1 diabetes.

Kidney Function and Volume Depletion

• Renal function is checked before starting, at least yearly, and before starting medicines that may reduce it. An initial fall in eGFR is seen and then levels off.
• In adults with eGFR below 60 mL/min/1.73 m² or creatinine clearance below 60 mL/min, volume-depletion reactions, raised potassium and larger rises in creatinine and urea were more frequent, particularly at 300 mg, so the dose is limited to 100 mg.
• The osmotic diuresis can lower blood volume and blood pressure, most often in the first three months. Caution applies in known cardiovascular disease, eGFR below 60, antihypertensive treatment with a history of hypotension, diuretic use and age 65 or over. Canagliflozin is not recommended with loop diuretics or in volume depletion, for example during gastrointestinal illness; during such illness, volume status, renal function and electrolytes are monitored and a temporary interruption may be considered.

Lower Limb Amputations

In long-term studies in adults with established cardiovascular disease or at least two risk factors, lower limb amputation (mainly of the toe and midfoot) was more frequent with canagliflozin than with placebo (0.63 versus 0.34 events per 100 patient-years). No difference was seen with 100 mg in a study of adults with diabetic kidney disease. Before starting, factors that may raise the risk are considered; higher-risk patients are monitored, and all are advised on routine foot care and adequate hydration. Stopping canagliflozin may be considered if a skin ulcer, infection, osteomyelitis or gangrene of the leg or foot develops.

Fournier’s Gangrene

Necrotising fasciitis of the perineum is a rare but serious, potentially life-threatening event that needs urgent surgery and antibiotics. Patients should seek medical attention for pain, tenderness, redness or swelling of the genital or perineal area with fever or malaise. If it is suspected, canagliflozin is stopped and treatment started promptly.

Genital and Urinary Tract Infections

Vulvovaginal candidiasis and balanitis or balanoposthitis (mostly in uncircumcised men, sometimes leading to phimosis or circumcision) are more likely in people with a past genital mycotic infection; most were treated with topical antifungals while canagliflozin continued. Complicated urinary tract infections, including pyelonephritis and urosepsis, have been reported after marketing; temporary interruption should be considered.

Other Precautions

• Haematocrit: it rises with treatment, so patients with an already raised haematocrit need careful monitoring.
• Elderly: patients aged 75 or over had more volume-depletion reactions and larger falls in eGFR.
• Cardiac failure: experience in NYHA class III is limited and there is none in class IV.
• Urine tests: patients taking canagliflozin test positive for glucose in urine.

Pregnancy, Breastfeeding and Fertility

• Pregnancy: there are no data in pregnant women and animal studies showed reproductive toxicity. Canagliflozin should not be used in pregnancy, and treatment is stopped when pregnancy is detected.
• Breastfeeding: it is unknown whether canagliflozin passes into human milk, animal data show excretion in milk, and a risk to newborns and infants cannot be excluded. It should not be used during breastfeeding.
• Fertility: the effect on fertility in humans has not been studied; animal studies showed no effect.

Lactose and Sodium

The tablets contain lactose (39.26 mg in the 100 mg tablet, 117.78 mg in the 300 mg tablet). Patients with rare hereditary galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take them. Each tablet contains less than 1 mmol sodium (23 mg).

Effect on Driving

Canagliflozin has no or negligible influence on the ability to drive and use machines. Patients should be alerted to the risk of hypoglycaemia when it is added to insulin or an insulin secretagogue, and to volume-depletion reactions such as postural dizziness.

Invokana tablets need no special storage conditions. They are supplied in PVC/aluminium perforated unit-dose blisters in packs of 10 x 1, 30 x 1, 90 x 1 and 100 x 1 tablets; not all pack sizes may be marketed. Keep out of the sight and reach of children.

3 years. Do not use after the expiry date on the pack.

Prescription only (Rx). Canagliflozin tablets are taken at home by the patient, so they are supplied to the patient or to the treating clinic on prescription. No cold chain is needed.