Diacerein-containing medicines for oral administration

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Summary

 

Restrictions to the use of diacerein-containing medicines

Restrictions intended to limit risks of severe diarrhoea and effects on the liver

On 19 March 2014, the Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh)1 endorsed recommendations to restrict the use of diacerein-containing medicines in order to manage the risks of severe diarrhoea and effects on the liver.

Due to the risks associated with severe diarrhoea, diacerein is no longer recommended in patients aged 65 years and above. It is also advised that patients start treatment on half the normal dose (i.e. 50 mg daily instead of 100 mg) and should stop taking diacerein if diarrhoea occurs.

In addition, diacerein-containing medicines must now not be used in any patient with liver disease or a history of liver disease, and doctors should be monitoring their patients for early signs of liver problems.

Doctors should also note that, based on available data, the use of diacerein is to be limited to treating symptoms of osteoarthritis affecting the hip or knee. Treatment should only be started by doctors experienced in treating osteoarthritis.

These recommendations are based on the review of the benefits and risks of diacerein conducted by the EMA’s Pharmacovigilance and Risk Assessment Committee (PRAC) and follow concerns raised by the French medicines agency (ANSM) about diacerein’s gastro-intestinal and liver effects. The CMDh endorsed the PRAC’s final recommendations to address these concerns and ensure that diacerein’s benefits continue to outweigh its known risks.

As the CMDh position on diacerein was adopted by majority vote, it was sent to the European Commission which endorsed it and issued a final legally binding decision valid throughout the European Union (EU) on 4 September 2014.


1The CMDh is a medicines regulatory body representing the European Union (EU) Member States.

Information to patients

Diacerein is a medicine used to treat joint diseases such as osteoarthritis (swelling and pain in the joints). Following an EU-wide review of diacerein, its use has been restricted in order to minimise the risks of severe diarrhoea and liver problems.

Patients are advised of the following:

  • Diacerein should only be used for treating symptoms of osteoarthritis affecting the hip or knee.
  • If you have diarrhoea while taking diacerein, stop taking your medicine and contact your doctor to discuss which other treatments you can take.
  • If you are taking diacerein and you are 65 years or above, contact your doctor to discuss your treatment.
  • You should not take diacerein if you have or have had liver problems. Your doctor will monitor your liver function on a regular basis and advise about the symptoms of liver problems (such as pruritus (itching) and jaundice). Contact your doctor if you have symptoms of liver problems.
  • If you have any questions about your treatment, please contact your doctor or pharmacist.
Information to healthcare professionals
  • Due to the risks associated with severe diarrhoea:
    • it is advisable to start treatment with half the normal dose (i.e. 50 mg per day) for the first 2 to 4 weeks, after which the recommended dose is 50 mg twice a day.
    • treatment should be stopped if diarrhoea occurs.
    • diacerein is not recommended in patients aged 65 years or above.
  • Diacerein must not be used in any patient with liver disease or a history of liver disease. Doctors should be monitoring their patients for early signs of liver problems and advising them how to recognise early symptoms.
  • Diacerein should only be used to treat symptoms of osteoarthritis of the hip or knee and it is not recommended for rapidly progressive hip osteoarthritis.
  • Treatment should only be started by doctors experienced in treating osteoarthritis.

The recommendations are based on a review of available data on the efficacy and safety of diacerein. Efficacy in the symptomatic treatment of osteoarthritis of the hip or knee was shown in published studies where diacerein was superior to placebo in relieving pain1-5. The first beneficial effects of diacerein in these studies were seen after 2 to 4 weeks of continuous use.

With regard to safety, loose stools or diarrhoea were the most frequently reported adverse events in clinical studies with diacerein at a dose of 100 mg per day. The proportion of patients with diarrhoea in clinical trials ranged from 0% to 54.4%. In the majority of cases diacerein-induced diarrhoea started in the first weeks of treatment.

Elevated serum liver enzymes and cases of symptomatic acute hepatic injury have been reported in the post-marketing phase with diacerein. In clinical studies, around 0.5% of patients on diacerein had some kind of liver reaction, with most cases being mild, reversible increases in serum transaminases. The proportion of patients who develop drug-induced liver injury following treatment with diacerein is estimated to be 0.03%.

References

  1. Lequesne M, Berdah L, Gérentes I. Efficacy and Safety of Diacerein for the treatment of Knee and Hip Osteoarthritis [Efficacité et tolérance de la diacerhéine dans le traitment de la gonarthrose et de la coxarthrose]. La Revue du Praticien 1998;48:S31-S35
  2. Pavelka K, Trc T, Karpas K, Vítek P, Sedlacková M, Vlasáková V, Böhmová J, Rovenský J. The Efficacy and Safety of Diacerein in the Treatment of Painful Osteoarthritis of the Knee. Arthritis & Rheumatism 2007;56:4055-4064.
  3. Singh K, Sharma R, Rai J. Diacerein as adjuvant to diclofenac sodium in osteoarthritis knee. International Journal of Rheumatic Diseases 2012;15(1):69-77.
  4. Pelletier JP, Yaron M, Haraoui B, Cohen P, Nahir M A, Choquette D, et al. Efficacy and Safety of Diacerein in Osteoarthritis of the Knee. Arthritis and Rheumatism 2000;43(10):2339-2348.
  5. Nguyen M, Dougados M, Berdah L, Amor B. Diacerhein in the treatment of osteoarthritis of the hip. Arthritis Rheum. 1994 Apr;37(4):529-36.
More about the medicine

Diacerein is a slow-acting medicine of the class ‘anthraquinones’ used to treat joint diseases such as osteoarthritis (swelling and pain in the joints).It works by blocking the actions of interleukin‑1 beta, a protein involved in the inflammation and destruction of cartilage that play a role in the development of symptoms of degenerative joint diseases such as osteoarthritis.

Diacerein-containing medicines are taken by mouth and are currently authorised in the following EU Member States: Austria, Czech Republic, France, Greece, Italy, Portugal, Slovakia and Spain.

More about the procedure

The review of diacerein-containing medicines was initiated on 29 November 2012 at the request of the French medicines agency under Article 31 of Directive 2001/83/EC.

The review of diacerein was conducted by the Pharmacovigilance Risk Assessment Committee (PRAC). In November 2013, the PRAC initially recommended the suspension of the marketing authorisations for diacerein-containing medicines. However, following re-examination, the PRAC considered additional proposals to manage diacerein’s risks and was satisfied that with new restrictions diacerein’s benefits would outweigh its risks.

The PRAC’s final recommendations were sent to the Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh), which endorsed the recommendations and adopted a position by majority vote.

The CMDh position was sent to the European Commission which endorsed it and issued an EU-wide legally binding decision on 4 September 2014.

Name Language First published Last updated
Diacerein Article-31 referral - Restrictions to the use of diacerein-containing medicines BG = bălgarski 2014-09-19  
Diacerein Article-31 referral - Restrictions to the use of diacerein-containing medicines ES = español 2014-09-19  
Diacerein Article-31 referral - Restrictions to the use of diacerein-containing medicines CS = čeština 2014-09-19  
Diacerein Article-31 referral - Restrictions to the use of diacerein-containing medicines DA = dansk 2014-09-19  
Diacerein Article-31 referral - Restrictions to the use of diacerein-containing medicines DE = Deutsch 2014-09-19  
Diacerein Article-31 referral - Restrictions to the use of diacerein-containing medicines ET = eesti keel 2014-09-19  
Diacerein Article-31 referral - Restrictions to the use of diacerein-containing medicines EL = elliniká 2014-09-19  
Diacerein Article-31 referral - Restrictions to the use of diacerein-containing medicines EN = English 2014-09-19  
Diacerein Article-31 referral - Restrictions to the use of diacerein-containing medicines FR = français 2014-09-19  
Diacerein Article-31 referral - Restrictions to the use of diacerein-containing medicines IT = italiano 2014-09-19  
Diacerein Article-31 referral - Restrictions to the use of diacerein-containing medicines LV = latviešu valoda 2014-09-19  
Diacerein Article-31 referral - Restrictions to the use of diacerein-containing medicines LT = lietuvių kalba 2014-09-19  
Diacerein Article-31 referral - Restrictions to the use of diacerein-containing medicines HU = magyar 2014-09-19  
Diacerein Article-31 referral - Restrictions to the use of diacerein-containing medicines MT = Malti 2014-09-19  
Diacerein Article-31 referral - Restrictions to the use of diacerein-containing medicines NL = Nederlands 2014-09-19  
Diacerein Article-31 referral - Restrictions to the use of diacerein-containing medicines PL = polski 2014-09-19  
Diacerein Article-31 referral - Restrictions to the use of diacerein-containing medicines PT = português 2014-09-19  
Diacerein Article-31 referral - Restrictions to the use of diacerein-containing medicines RO = română 2014-09-19  
Diacerein Article-31 referral - Restrictions to the use of diacerein-containing medicines SK = slovenčina 2014-09-19  
Diacerein Article-31 referral - Restrictions to the use of diacerein-containing medicines SL = slovenščina 2014-09-19  
Diacerein Article-31 referral - Restrictions to the use of diacerein-containing medicines FI = suomi 2014-09-19  
Diacerein Article-31 referral - Restrictions to the use of diacerein-containing medicines SV = svenska 2014-09-19  
Diacerein Article-31 referral - Restrictions to the use of diacerein-containing medicines HR = Hrvatski 2014-09-19  

Key facts

About this medicine

Approved nameDiacerein-containing medicines for oral administration
International non-proprietary name (INN) or common name

diacerein

Associated namesZondar
Class-

About this procedure

Current statusEuropean Commission final decision
Reference numberEMEA/H/A-31/1349
TypeArticle 31 referrals

This type of referral is triggered when the interest of the Community is involved, following concerns relating to the quality, safety or efficacy of a medicine or a class of medicines.

Decision making modelPRAC-CMDh
Authorisation modelNationally authorised product(s)

Key dates and outcomes

Procedure start date29/11/2012
PRAC recommendation date06/03/2014
EC decision date04/09/2014
OutcomeVariation

All documents

Procedure started

Name Language First published Last updated
Diacerein Article-31 referral - PRAC list of questions HR = Hrvatski 2012-11-30 2013-03-11
Diacerein Article-31 referral - Annex I HR = Hrvatski 2012-11-30  
Diacerein Article-31 referral - Notification HR = Hrvatski 2012-11-30  
Diacerein Article-31 referral - Timetable for the procedure HR = Hrvatski 2012-11-30 2014-01-17
Diacerein Article-31 referral - Review started HR = Hrvatski 2012-11-30  

Recommendation provided by Pharmacovigilance Risk Assessment Committee

Name Language First published Last updated
PRAC re-examines diacerein and recommends that it remain available with restrictions HR = Hrvatski 2014-03-07  
PRAC recommends suspension of diacerein-containing medicines HR = Hrvatski 2013-11-08 2013-12-06

Position provided by CMDh

Name Language First published Last updated
CMDh endorses recommendations to restrict the use of diacerein-containing medicines HR = Hrvatski 2014-03-21  
Diacerein Article-31 referral - Annex III HR = Hrvatski 2014-03-21  

European Commission final decision

Name Language First published Last updated
Diacerein Article-31 referral - PRAC assessment report HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex III HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex III HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex III HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex III HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex III HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex III HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex III HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex III HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex III HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex III HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex III HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex III HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex III HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex III HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex III HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex III HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex III HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex III HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex III HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex III HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex III HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex III HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex III HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Restrictions to the use of diacerein-containing medicines HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Restrictions to the use of diacerein-containing medicines HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Restrictions to the use of diacerein-containing medicines HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Restrictions to the use of diacerein-containing medicines HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Restrictions to the use of diacerein-containing medicines HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Restrictions to the use of diacerein-containing medicines HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Restrictions to the use of diacerein-containing medicines HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Restrictions to the use of diacerein-containing medicines HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Restrictions to the use of diacerein-containing medicines HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Restrictions to the use of diacerein-containing medicines HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Restrictions to the use of diacerein-containing medicines HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Restrictions to the use of diacerein-containing medicines HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Restrictions to the use of diacerein-containing medicines HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Restrictions to the use of diacerein-containing medicines HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Restrictions to the use of diacerein-containing medicines HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Restrictions to the use of diacerein-containing medicines HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Restrictions to the use of diacerein-containing medicines HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Restrictions to the use of diacerein-containing medicines HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Restrictions to the use of diacerein-containing medicines HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Restrictions to the use of diacerein-containing medicines HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Restrictions to the use of diacerein-containing medicines HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Restrictions to the use of diacerein-containing medicines HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Restrictions to the use of diacerein-containing medicines HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex I HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex I HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex I HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex I HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex I HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex I HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex I HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex I HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex I HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex I HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex I HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex I HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex I HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex I HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex I HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex I HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex I HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex I HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex I HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex I HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex I HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex I HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex I HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - CMDh divergent position HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex II HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex II HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex II HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex II HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex II HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex II HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex II HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex II HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex II HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex II HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex II HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex II HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex II HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex II HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex II HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex II HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex II HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex II HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex II HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex II HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex II HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex II HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex II HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex IV HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex IV HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex IV HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex IV HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex IV HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex IV HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex IV HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex IV HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex IV HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex IV HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex IV HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex IV HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex IV HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex IV HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex IV HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex IV HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex IV HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex IV HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex IV HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex IV HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex IV HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex IV HR = Hrvatski 2014-09-19  
Diacerein Article-31 referral - Annex IV HR = Hrvatski 2014-09-19  

Document description:

  • Annex I - List of the medicines affected by the referral
  • Annex II - Scientific conclusions of the Committee for Medicinal Products for Human Use (CHMP) or Coordination Group for Mutual Recognition and Decentralised Procedures - Human (CMDh)
  • Annex III - Changes to the summary of product characteristics, labelling or package leaflet - available when the CHMP or CMDh recommends changes to the product information. Also includes conditions for lifting of suspensions, if applicable
  • Annex IV - Conditions of the marketing authorisation - available when the CHMP or CMDh recommends other measures to be taken for the marketing authorisation such as safety measures or additional studies
  • Notification - A letter from a Member State, the European Commission or a marketing-authorisation holder requesting the initiation of a referral procedure
  • Rationale for triggering - Background provided by the party triggering the referral explaining the issues leading to the initiation of the procedure
  • PRAC list of questions - Questions agreed by the PRAC requesting further information to evaluate the issues identified
  • PRAC timetable - Timeframe agreed by the PRAC to receive information, assess the issues and adopt a recommendation
  • PRAC / CHMP / CMDh assessment report - The assessment and conclusions of the PRAC and CHMP or CMDh on the issues investigated

Current status:
European Commission final decision

More information on Diacerein