Somatropin - referral

Current status

European Commission final decision

Overview

The European Medicines Agency has completed a review of the safety and effectiveness of somatropin-containing medicines, following the results of a French study which suggested an increased risk of mortality in patients treated with somatropin compared with the general population. The Agency's Committee for Medicinal Products for Human Use (CHMP) has concluded that the benefits of somatropin continue to outweigh its risks, but recommended changes to the product information to ensure that somatropin-containing medicines are used appropriately.

What is somatropin?

Somatropin is a copy of naturally occurring human growth hormone, produced by a method known as 'recombinant DNA technology'. Growth hormone promotes growth during childhood and adolescence, and also affects the way the body handles proteins, fats and carbohydrates.

Medicines containing somatropin are given by injection. They have been authorised in the EU since the 1980s through centralised or national procedures¹. The approved indications vary for the different somatropin-containing medicines: they may be used as hormone replacement therapy, and to correct short stature (height) in children with certain genetic diseases (Turner syndrome or Prader Willi syndrome), children who have long-standing kidney problems and children born small for their gestational age.

¹ The centrally authorised somatropin-containing medicines are NutropinAq, Omnitrope and Valtropin. The nationally authorised medicines are Genotropin, Humatrope, Maxomat, Norditropin, Saizen and Zomacton.

Why was somatropin reviewed?

In December 2010, the French medicines regulatory agency was made aware of preliminary results of a long-term population-based study in France of patients treated during childhood with somatropin-containing medicines. The study, called 'Santé Adulte GH Enfant' (SAGhE) study, was initiated in October 2007 and aimed at improving knowledge on the safety and appropriateness of somatropin treatment. It looked at data on 10,000 adults who started treatment between 1985 and 1996, using a mandatory national registry.

An analysis in approximately 7,000 of those patients who were treated for growth hormone deficiency and for gestational or idiopathic short stature showed a possible increased risk of mortality with somatropin compared with the general population. In particular, an increased risk of mortality due to bone tumours and cardiovascular events (such as bleeding in the brain) was seen. The risk appeared to be highest when doses higher than the ones approved were used.

Consequently, in December 2010 the French agency asked the CHMP to issue an opinion on the impact of these data on the benefit-risk balance of somatropin-containing medicines, 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 somatropin-containing medicines.

Which data has the CHMP reviewed?

The CHMP reviewed the available data on the safety of somatropin-containing medicines, including data from clinical trials, registries, and observational studies, as well as reports of side effects from post-marketing surveillance. The CHMP also looked into additional data from the unpublished French SAGhE study.

What are the conclusions of the CHMP?

The CHMP concluded that the French SAGhE study had significant methodological limitations and that the results could not be considered robust. After assessing all other available safety data on somatropin, the CHMP concluded that the potential signal of an increased risk of mortality seen in the French study is not corroborated by any other data, and that the benefit-risk balance of somatropincontaining medicines has not changed.

However, the Committee noted that the available data on the long-term effects of somatropin treatment are very limited. Further mortality data from the European SAGhE study will be available by the end of 2012, and the CHMP considered an analysis of these results to be essential to address any concerns raised by the French study.

Based on the evaluation of the currently available data and the scientific discussion within the Committee, the CHMP concluded that the benefit-risk balance of somatropin-containing medicines remains positive when used in the approved indications at the approved doses. However, to ensure that somatropin-containing medicines are used appropriately, the CHMP recommended that specific wording be included in the product information of all somatropin-containing medicines. In particular, the harmonised wording will emphasise that somatropin must not be used if there is any evidence of tumour activity, and that the maximum recommended daily dose should not be exceeded.

What are the recommendations for patients and healthcare professionals?

• Patients and healthcare professionals are reminded that the benefits of somatropin continue to outweigh its risks in the approved indications.
• Somatropin must not be used in patients with any evidence of tumour activity.
• The maximum recommended daily dose should not be exceeded.
• Patients or their carers who have any questions should speak to their doctor or pharmacist.

The European Commission issued a decision on 27 February 2012.

Questions and answers on the review of somatropin-containing medicines

Adopted Reference Number: EMA/966325/2011

Key facts

About this medicine

• Approved name:
  Somatropin
• International non-proprietary name (INN) or common name:
  somatropin
• Associated names:
  • Genotropin
  • Humatrope
  • Maxomat
  • Norditropin
  • Saizen
  • Zomacton

About this procedure

• Current status:
  European Commission final decision
• Reference number:
  EMEA/H/A-107/001287
• Type:
  Article 107 procedures (prior to July 2012)

  This type of procedure was triggered when a Member State varied, suspended or revoked the marketing authorisation for a medicine in its territory because of a safety issue. This procedure has been replaced by Article 107i.

Key dates and outcomes

• CHMP opinion date:
  15/12/2011
• EC decision date:
  27/02/2012

All documents

Somatropin - Article 107 referral - Assessment report

Adopted Reference Number: EMA/110423/2012

Somatropin - Article 107 referral - Annex I

Adopted

Somatropin - Article 107 referral - Annex II

Adopted

Somatropin - Article 107 referral - Annex III

Adopted

Somatropin - Article 107 referral - Annex IV

Adopted

Questions and answers on the review of somatropin-containing medicines

Adopted Reference Number: EMA/966325/2011

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.