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Safety & Tolerability

Prescribers should consult the summary of product characteristics in relation to any adverse reactions

Invokana is generally well tolerated 1,2

Cases of Diabetic Ketoacidosis (DKA) (≥1/10,000 to <1/1,000), Lower Limb Amputation (≥1/1,000 to <1/100) and Fournier’s Gangrene (unknown frequency) have been reported. See the SmPC for further details. 1

Invokana as monotherapy or as add-on to MET, MET + SU or MET + PIO.

Diabetic ketoacidosis – Frequency rare (≥ 1/10,000 to < 1/1,000)

  • Rare cases of diabetic ketoacidosis (DKA) including life threatening and fatal cases, have been reported with SGLT2 inhibitors, including Invokana. If DKA is suspected or diagnosed, treatment with Invokana 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 Invokana may be restarted once when the ketone values are normal and the patient’s condition has stabilised.

Signal for increased risk of lower limb amputation (LLA) – Frequency uncommon (≥1/1000 to <1/100)

  • A small increased risk of LLA was seen in the Invokana treatment group vs the placebo group in the CANVAS Programme. 3
  • This risk equates to an additional 0.29 amputations per 100 years of patient treatment vs placebo, 3 but has not been seen anywhere else across the 12 completed Phase III or IV canagliflozin clinical trials, which included more than 8,100 type 2 diabetes patients with low CV risk, nor in a real world evidence study in a more general population of patients with type 2 diabetes. 4-6

  • In patients with established CV disease there was significant increased risk of below-knee amputation in patients taking any SGLT-2 inhibitor versus non SGLT2-inhibitors.7 A review committee investigated the potential risk of LLA and concluded that all patients taking an SGLT2 inhibitor should be counselled about preventative footcare, as the underlying mechanism has not been established. Subsequently a warning of the potential increased risk of LLA (mostly affecting the toes) has been added to the SmPC for all SGLT2-inhibitors, highlighting the importance of routine preventative foot care. 6

Necrotising fasciitis of the perineum (Fournier’s gangrene) – Frequency not known and cannot be estimated from the available data

  • 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 necrotizing fasciitis. If Fournier’s gangrene is suspected, Invokana should be discontinued and prompt treatment (including antibiotics and surgical debridement) should be instituted.

Date of preparation: November 2019 | Job code: UK/INV-18087d

References
  1. Reference 9
  2. Usiskin K et al. Post grad Med 2014;126(3):16-34
  3. Neal B et al. N Engl J Med 2017;377:644-57.DOI:10.1056/NEJMoa1611925
  4. Yuan z et al. Diabetes Obes Metab 2017; DOI:10.1111/dom.13115
  5. Reference 7
  6. Reference 8
  7. Udell JA et al. Circulation 2018;137:1450-59