Bisphosphonates - referral

Current status

European Commission final decision

Overview

The European Medicines Agency has completed a review of bisphosphonate-containing medicines at the request of the United Kingdom and the European Commission, following reports of an increased risk of atypical stress fractures of the femur associated with these medicines. The Agency's Committee for Medicinal Products for Human Use (CHMP) has concluded that the benefits of bisphosphonates continue to outweigh their risks but that warnings of the risk of atypical femoral fractures should be added to the prescribing information for all bisphosphonate-containing medicines in the European Union (EU).

What are bisphosphonates?

Bisphosphonates are medicines that are used to treat and prevent bone disorders. They have been authorised in the EU since the early 1990s for hypercalcaemia (high levels of calcium in the blood) and the prevention of bone problems in patients with cancer. They have also been available since the mid 1990s for the treatment of osteoporosis (a disease that makes bones fragile) and Paget's disease (a disease involving bone growth that causes bone deformity). They work by stopping the action of the osteoclasts, the cells that are involved in breaking the bone down.

Bisphosphonates include alendronic acid, clodronic acid, etidronic acid, ibandronic acid, neridronic acid, pamidronic acid, risedronic acid, tiludronic acid and zoledronic acid. They are available in the EU as tablets and as solutions for infusion (drip into a vein) under various trade names and as generic medicines.

Why were bisphosphonates reviewed?

In 2008, the CHMP's Pharmacovigilance Working Party (PhVWP) noted that alendronic acid was associated with an increased risk of atypical fracture of the femur (thigh bone) that developed with low or no trauma. As a result, a warning was added to the product information of alendronic acid-containing medicines across Europe. The PhVWP also concluded at the time that it was not possible to rule out the possibility that the effect could be a class effect (an effect common to all bisphosphonates), and decided to keep the issue under close review.

In April 2010, the PhVWP noted that further data from both the published literature and post-marketing reports were now available that suggested that atypical stress fractures of the femur may be a class effect. The working party concluded that there was a need to conduct a further review to determine if any regulatory action was necessary.

Consequently, on 20 September 2010, the UK Medicines Regulatory Agency asked the CHMP to issue an opinion on bisphosphonate-containing medicines and atypical stress fractures and on whether the marketing authorisation for these medicines should be maintained, varied, suspended or withdrawn across the EU. At the same time, the European Commission requested the CHMP to carry out the same assessment for the centrally authorised medicines.

Which data has the CHMP reviewed?

The CHMP has reviewed all case reports of stress fractures in patients treated with bisphosphonates, relevant data from the published literature and data provided by the companies that make bisphosphonates. The Committee has also looked at epidemiological studies (studies of the causes and distribution of diseases in the population).

What are the conclusions of the CHMP?

The Committee noted that the number of reports of atypical fractures of the femur in users of bisphosphonates had increased since the 2008 review. The CHMP also noted that these fractures had a distinct pattern on X-rays and may be related to bisphosphonate use, especially during long-term use in osteoporosis. The Committee agreed that this could be related to the mode of action of bisphosphonates, which could lead to a delay in the repair of naturally occurring stress fractures although the exact mechanism is not known.

Based on the evaluation of the currently available data and the scientific discussion within the Committee, the CHMP concluded that atypical femoral fractures are likely to be a class effect of bisphosphonates but that such fractures occur only rarely and the benefits of bisphosphonate-containing medicines continue to outweigh their risks. However, the product information should be amended to add a warning concerning this risk, and, for bisphosphonates used in osteoporosis, to advise doctors to periodically review treatment, in particular after five or more years of treatment.

The full changes made to the information to doctors and patients are available on the Agency's website.

What are the recommendations for prescribers and patients?

• Doctors who prescribe bisphosphonate-containing medicines should be aware that atypical fractures may occur rarely in the femur (thigh bone), especially after long term use. If an atypical fracture is suspected in one leg then the other leg should also be examined
• Doctors who are prescribing these medicines for the prevention or treatment of osteoporosis should regularly review the need for continued treatment, especially after five or more years of use.
• Patients who are taking bisphosphonate-containing medicines need to be aware of the risk of atypical fracture of the thigh bone. They should report to their doctor any pain, weakness or discomfort in the thigh or groin area, as this may be an indication of a possible fracture.
• Patients who have any questions should speak to their doctor or pharmacist.

The European Commission issued a decision on 13 July 2011.

Questions and answers on the review of bisphosphonates and atypical stress fractures

AdoptedReference Number: EMA/288359/2011 Rev. 1

Key facts

About this medicine

• Approved name:
  Bisphosphonates
• International non-proprietary name (INN) or common name:
  • alendronic acid
  • clodronic acid
  • etidronic acid
  • ibandronic acid
  • neridronic acid
  • pamidronic acid
  • risedronic acid
  • tiludronic acid
  • zoledronic acid
• Associated names:
  • Actonel
  • Aredia
  • Bonefos
  • Didronel
  • Fosamax
  • Nerixia
  • Skelid
• Class:
  Bisphosphonates

About this procedure

• Current status:
  European Commission final decision
• Reference number:
  EMA/288359/2011
• Type:
  Article 31 referrals

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

Key dates and outcomes

• CHMP opinion date:
  14/04/2011
• EC decision date:
  13/07/2011

All documents

Bisphosphonates - Article 31 referral - Annex I

Adopted

Bisphosphonates - Article 31 referral - Annex II

Adopted

Bisphosphonates - Article 31 referral - Annex IV

Adopted

Assessment report for bisphosphonates containing medicinal products

AdoptedReference Number: EMA/725125/2011

Bisphosphonates - Article 31 - changes to product information

Questions and answers on the review of bisphosphonates and atypical stress fractures

AdoptedReference Number: EMA/288359/2011 Rev. 1

Description of documents published

Please note that some of the listed documents apply only to certain procedures.

• Overview - lay-language summary of the stage of the procedure
• Notification – a letter from a Member State, the European Commission or the marketing authorisation holder requesting the initiation of the procedure
• Scientific background – further background information from the triggering Member State on the issues leading to the initiation of the procedure (if applicable)
• List of questions – questions agreed by the Committee requesting further information from the marketing authorisation holder(s) / applicant(s) to evaluate the issues identified
• Timetable for the procedure – agreed timeframe to respond to the list of questions, to assess the issues and to adopt a conclusion
• List of medicines concerned by the procedure – medicine(s) / active substance(s) concerned, and marketing authorisation holder(s) / applicant(s)
• List of questions to be addressed by the stakeholders – call for data to be submitted by stakeholders (e.g. healthcare professionals, patient organisations, individual patients) (if applicable)
• Stakeholder submission form – form to be used by stakeholders to submit data (if applicable)
• Scientific conclusions – scientific conclusions of the PRAC and/or CHMP and/or CMDh
• Assessment report – PRAC or CHMP assessment and conclusions on the issues investigated, including divergent positions (if applicable)
• Divergent positions – divergent positions of the CHMP or CMDh members for pharmacovigilance procedures (if applicable)
• Changes to the summary of product characteristics, labelling and package leaflet (amended sections or fully revised version) (if applicable)
• Condition(s) to the marketing authorisation(s) – condition(s) for the safe and effective use of the medicine(s) (if applicable)
• Condition for lifting the suspension – condition to be fulfilled for the suspension of the marketing authorisation(s) to be lifted (if applicable)
• Timetable for implementation of CMDh position – agreed timeframe to submit and finalise the variation(s) implementing the outcome of the procedure (if applicable)

Note that older documents may have different titles.