Calcitonin - referral

Current status

European Commission final decision

Overview

On 19 July 2012, the European Medicines Agency (EMA) completed a review of the benefits and risks of calcitonin-containing medicines, concluding that there was evidence of a small increased risk of cancer with long-term use of these medicines. The Agency's Committee for Medicinal Products for Human Use (CHMP) recommended that they should only be authorised for short-term use in Paget's disease, acute bone loss due to sudden immobilisation and hypercalcaemia caused by cancer. The Committee also concluded that the benefits of calcitonin-containing medicines did not outweigh their risks in the treatment of osteoporosis and that they should no longer be used for this condition.

After a re-examination, the Committee confirmed its recommendation on 15 November 2012.

What is calcitonin?

Calcitonin is a hormone that increases the amount of calcium in the bones and lowers the calcium level in the blood.

Calcitonin, manufactured in the laboratory, is used in medicines to treat or prevent conditions that involve the loss of calcium from the bones. It has been used in the European Union (EU) for the treatment of osteoporosis (a disease that makes bones fragile), Paget's disease (a bone disease that involves bone remodelling and can cause deformity), and hypercalcaemia (increased blood calcium) caused by cancer. It is also used to prevent acute bone loss due to sudden immobilisation such as in patients with recent osteoporotic fractures.

Calcitonin-containing medicines have been available in the EU as solutions for injection or infusion (drip into a vein) since 1973, and as a nasal spray since 1987. They are currently marketed in most EU countries.

Why were calcitonin-containing medicines reviewed?

This review was initiated following preliminary findings from two studies of an unlicensed oral calcitonin medicine, which pointed to a possible association with prostate cancer. These findings were made available to EU national authorities in November 2010.

A possible association between calcitonin and prostate cancer was first investigated by the United Kingdom (UK) medicines regulatory agency in 2004, but a causal association could not be established with the evidence available at the time. The issue was also investigated in 2009 and 2010 by the EMA's Pharmacovigilance Working Party (PhVWP), but there was insufficient evidence at the time for any regulatory action

Following the receipt of the data from the studies on the unlicensed oral medicine, the UK medicines agency asked the CHMP to carry out a full assessment of the benefit-risk balance of calcitonin-containing medicines and to issue an opinion on whether their marketing authorisations should be maintained, varied, suspended or withdrawn across the EU.

Which data has the CHMP reviewed?

In addition to the two studies of the unlicensed oral calcitonin medicine, the CHMP reviewed available data on the benefits and risks of calcitonin-containing medicines provided by the companies that market these medicines as well as data from the scientific literature and from third parties. The CHMP also reviewed post-marketing safety data, randomised controlled studies and experimental cancer studies.

What are the conclusions of the CHMP?

The CHMP noted that the available data suggest that a higher proportion of patients treated with calcitonin for long periods of time may develop cancer of various types, compared with patients taking placebo. Although the cancer rates reported in the studies were low, the increase in cancer rates seen with calcitonin varied between 0.7% in studies with the oral formulation to 2.4% in the studies with the nasal formulation. Taking into account the limited benefit of calcitonin when used to treat post-menopausal osteoporosis to reduce the risk of vertebral fractures, the CHMP concluded that the benefits of calcitonin did not outweigh the risks in this condition. As the nasal spray is only used in osteoporosis, the CHMP recommended that this formulation should no longer be used.

The benefit-risk balance remains positive only for the following uses:

• treatment of Paget's disease for patients who cannot be treated with alternative treatments;
• prevention of acute bone loss due to sudden immobilisation such as in patients with recent osteoporotic fractures;
• treatment of hypercalcaemia caused by cancer.

However, the CHMP recommended that even for these uses, calcitonin treatment should be given for the shortest possible time using the smallest effective dose. The Committee maintained its recommendations after re-examination.

What are the recommendations for patients?

• Calcitonin will no longer be used for the treatment of osteoporosis. Patients being treated for osteoporosis with calcitonin nasal sprays or other formulations are advised to speak to their doctor at a routine appointment, who will recommend suitable alternative treatment.
• Patients receiving injectable calcitonin who have any questions should speak to their doctor or pharmacist.

What are the recommendations for prescribers?

• Prescribers should note that calcitonin should no longer be used for the treatment of osteoporosis.
• Calcitonin will only be available as a solution for injection and infusion, and should only be used for:
  • prevention of acute bone loss due to sudden immobilisation, with a recommended treatment period of two weeks and a maximum treatment period of four weeks;
  • Paget's disease, restricted to patients who do not respond to alternative treatments or for whom such treatments are not suitable, and with treatment normally limited to three months (longer treatment and periodic retreatment may be considered taking into account the benefits and risks);
  • hypercalcaemia caused by cancer.
• Treatment with calcitonin should be limited to the shortest possible time using the smallest effective dose.

The European Commission issued a decision on 13 February 2013.

Questions and answers on the review of calcitonin-containing medicines - Outcome of a procedure under Article 31 of Directive 2001/83/EC

Key facts

About this medicine

• Approved name:
  Calcitonin
• International non-proprietary name (INN) or common name:
  calcitonin

About this procedure

• Current status:
  European Commission final decision
• Reference number:
  EMEA/H/A-31/1291
• 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:
  19/07/2012
• EC decision date:
  13/02/2013

All documents

Questions and answers on the review of calcitonin-containing medicines

Reference Number: EMA/476001/2012

Calcitonin: Product information as approved by the CHMP on 19 July 2012, pending endorsement by the European Commission

Opinion provided by Committee for Medicinal Products for human Use

Questions and answers on the review of calcitonin-containing medicines - Outcome of re-examination

Calcitonin: Product information as approved by the CHMP on 15 November 2012, pending endorsement by the European Commission

European Commission final decision

Calcitonin Article-31 referral - Annex I

Calcitonin Article-31 referral - Annex II

Calcitonin Article-31 referral - Annex III

Calcitonin Article-31 referral - Annex IV

Assessment report for calcitonin containing medicinal products

Adopted

Questions and answers on the review of calcitonin-containing medicines - Outcome of a procedure under Article 31 of Directive 2001/83/EC

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.