Cookie policy: This site uses cookies (small files stored on your computer) to simplify and improve your experience of this website. Cookies are small text files stored on the device you are using to access this website. For more information please take a look at our terms and conditions. Some parts of the site may not work properly if you choose not to accept cookies.

Join

Subscribe or Register

Existing user? Login

Adverse drug events

MHRA updates canagliflozin lower limb amputation warning

UK drug regulator has reminded health professionals of amputation risk associated with canaglifozin.

Toe amputee

Source: BSIP SA / Alamy Stock Photo

The MHRA and EMA used data from two ongoing clinical trials to inform their updates, the results of which show that canagliflozin potentially increases the risk of lower limb amputation

The Medicines and Healthcare products Regulatory Agency (MHRA), which regulates drugs and devices in the UK, has updated its advice concerning the increased risk of lower limb amputation associated with canaglifozin, a drug used to treat type 2 diabetes.

The move follows a recommendation from the European Medicines Agency (EMA), which evaluates medicinal products for use in Europe, that a warning about the possible risks of toe amputation should be added to the prescribing information for canagliflozin and other sodium-glucose co-transporter 2 (SGLT2) inhibitors.

The MHRA confirmed in a drug safety update on 22 March 2017 that the prescribing information for canagliflozin will also list lower limb amputation as an uncommon side effect (occurring in fewer than 10 patients per 1,000)[1]

The updates from the MHRA and EMA follow a review of data from two ongoing canagliflozin clinical trials, CANVAS and CANVAS-R, the results of which show that the SGLT2 inhibitor potentially increases the risk of lower limb amputation. According to trial data seen by the MHRA, 6 of the 243 British patients involved in the two trials have had to undergo amputations.

Once approved by the European Commission, the warning about an increased risk of amputation will be added to the summary of product characteristics and package leaflet for canagliflozin, as well as for two other SGLT2 products — dapagliflozin and empagliflozin.

These changes were recommended by the EMA’s Committee for Medicinal Products for Human Use at its meeting on 23 February 2017.

Preliminary data from the CANVAS study show that the incidence of lower limb amputation (mostly affecting the toes) was 7 in 1,000 patient-years with canagliflozin 100mg daily and 5 in 1,000 patient-years with canagliflozin 300mg daily. The amputation rate was 3 in 1,000 patient-years for patients who received a placebo.

In the CANVAS-R study, the incidence of lower limb amputation was 8 in 1,000 patient-years with canagliflozin, compared with 4 in 1,000 patient-years in the placebo group.

However, the EMA points out that the preliminary data are not final because the two studies are ongoing and that “no imbalances were seen in other studies”.

The EMA adds that the trials’ independent data monitoring committee — which has access to all unblinded outcome data and data on side effects — recommended in March 2016 that the two studies should continue and participants be informed of the risk.

The MHRA drug safety update points out that evidence does not show an increased risk for dapagliflozin and empagliflozin, but that the risk may be a class effect.

As such, the MHRA advises healthcare professionals to monitor patients receiving canagliflozin who have risk factors for amputation, such as poor control of diabetes and problems with the heart and blood vessels, and to consider stopping the drug if patients develop foot complications such as infection, skin ulcers, osteomyelitis or gangrene.

It also says patients receiving any SGLT2 inhibitor should be advised about the importance of routine preventive foot care and adequate hydration.

SGLT2 inhibitor-containing medicines that are marketed in the UK include: Invokana (canagliflozin; Janssen), Vokanamet (canagliflozin and metformin; Janssen), Forxiga (dapagliflozin; AstraZeneca), Xigduo (dapagliflozin and metformin; AstraZeneca), Jardiance (empagliflozin; Boehringer Ingelheim), and Synjardy (empagliflozin and metformin; Boehringer Ingelheim).

In a statement, Janssen, the sponsor of the CANVAS studies, says it is taking the amputation risk “very seriously” and has been “proactive in our approach to notifying healthcare professionals and the relevant regulatory bodies around the world about this information”.

The company adds that it followed the independent data monitoring committee’s advice that the CANVAS studies should continue towards their planned endpoint and that patients involved in the trial were informed about the potential risk and were free to withdraw from it at any time.

Janssen adds: “Importantly, the higher incidence seen within the CANVAS programme, which enrolled patients whose diabetes was not well controlled at the beginning of the studies and who also have a history of cardiovascular events or are deemed to be at a high risk for such events, was not observed across the other 12 completed phase III and phase IV clinical trials or in the post-marketing safety monitoring reports.”

The company says it remains confident that canagliflozin is an important treatment option for people with type 2 diabetes.

Citation: The Pharmaceutical Journal DOI: 10.1211/PJ.2017.20202509

Have your say

For commenting, please login or register as a user and agree to our Community Guidelines. You will be re-directed back to this page where you will have the ability to comment.

Recommended from Pharmaceutical Press

  • Paediatric Drug Handling

    Paediatric Drug Handling

    Written for new pharmaceutical scientists, this book provides a background in paediatric pharmacy and a comprehensive introduction to children's medication.

    £33.00Buy now
  • Physicochemical Principles of Pharmacy

    Physicochemical Principles of Pharmacy

    This established textbook covers every aspect of drug properties from the design of dosage forms to their delivery by all routes to sites of action in the body.

    £48.00Buy now
  • Introduction to Renal Therapeutics

    Introduction to Renal Therapeutics

    Introduction to Renal Therapeutics covers all aspects of drug use in renal failure. Shows the role of the pharmacist in patient care for chronic kidney disease.

    £38.00Buy now
  • FASTtrack: Pharmacology

    FASTtrack: Pharmacology

    FASTtrack: Pharmacology is a study guide providing an account of drug action, as well as dealing with molecular pharmacology at a more advanced level.

    £25.00Buy now
  • Drugs in Use

    Drugs in Use

    Optimise drug therapy for your patients. These case studies help you bridge the gap between theoretical medicines knowledge and practical applications.

    £43.00Buy now

Search an extensive range of the world’s most trusted resources

Powered by MedicinesComplete
  • Print
  • Share
  • Comment
  • Save
  • Print Friendly Version of this pagePrint Get a PDF version of this webpagePDF

Supplementary images

  • Toe amputee

Jobs you might like

Newsletter Sign-up

Want to keep up with the latest news, comment and CPD articles in pharmacy and science? Subscribe to our free alerts.