Modified-released oral opioids - referral

Current status

European Commission final decision

Overview

Outcome of a procedure under Article 31 of Directive 2001/83/EC as amended

The European Medicines Agency has completed a review of the safety and effectiveness of modified-release oral opioid medicines of the WHO level III scale for the management of pain. The Agency's Committee for Medicinal Products for Human Use (CHMP) has concluded that the benefits of most of these medicines continue to outweigh their risks, but that warnings on the use of these medicines together with alcohol should be made consistent across the class.

However, for modified-release medicines that contain a 'polymethacrylate-triethylcitrate controlled release system', the Committee concluded that the marketing authorisations should be suspended. These suspensions will remain in force until the companies that make these medicines have reformulated them so that they are more stable in alcohol.

After re-examination, the Committee confirmed these recommendations on 18 November 2010.

What are modified-release oral medicines of the WHO level III scale for the management of pain?

Oral opioid medicines of the WHO level III scale for the management of pain are strong painkillers that are taken by mouth and used to treat intense pain that has not been controlled sufficiently with other medicines. They include morphine and the related medicines oxycodone and hydromorphone, all of which work by attaching to receptors in the brain and spinal cord to prevent pain. They are called 'WHO level III scale' medicines as they are on the highest step of the World Health Organization's three-step pain relief ladder. This ladder gives recommendations on the order in which painkillers of increasing strength should be used to control a patient's pain.

'Modified-release' forms of these medicines release the active substance slowly, often over many hours. This reduces the number of times a patient needs to take the medicine every day. Modified-release tablets and capsules are made by combining the active substance with other substances that break down slowly in the body or limit the active substance's release, such as cellulose-based substances and polymers. These are called 'controlled-release systems'.

There are over 500 different medicines belonging to the WHO level III scale group authorised in European Union (EU) Member States.

Why were these medicines reviewed?

These medicines were reviewed following concerns that alcohol might have an effect on the way they release the active substance in the body. Because some of the chemicals used in the controlled-release systems dissolve in alcohol, there is a theoretical possibility that taking these medicines together with alcohol may cause the active substance to be released too quickly. This is called 'dose dumping' and could put patients at risk of exposure to large doses of the opioid, leading to side effects such as respiratory depression (an inhibition of breathing).

Consequently, the European Commission asked the CHMP to carry out an assessment of the benefit-risk balance of these medicines, concentrating on their interaction with alcohol, 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?

The CHMP reviewed the results of laboratory studies looking at the way that controlled-release systems act when they are placed in solutions containing alcohol. They looked at seven different systems used with morphine, two used with hydromorphone and four used with oxycodone. The CHMP used the results of these studies to predict what would happen if these medicines were taken with alcohol. Some information was also available from studies in human volunteers.

The CHMP also took information from studies looking at the drinking habits of patients with severe pain into account. These included patients with late-stage cancer.

What are the conclusions of the CHMP?

The CHMP concluded that around half of the controlled-release systems tested showed a slight increase in the amount of active substance they released when placed in an alcohol solution, but that this effect was mild and would only have a minor effect on the release of the active substance.

However, for one of the controlled-release systems tested - once-daily capsules using a polymethacrylate-triethylcitrate coating to control the release of morphine - there was a significant interaction with alcohol. When these capsules were put into a 20% alcohol solution, 80% of the active substance was released within 15 minutes. This means that almost a full day's dose of morphine would be released all at once if a patient were to take the capsule with large drink of neat strong liquor, such as whisky or vodka.

The CHMP noted that the use of this medicine in combination with alcohol is already contra-indicated. However, studies looking at the drinking behaviour of patients with severe pain show that many patients drink alcohol while being treated with strong opioids.

Therefore, the CHMP concluded that modified-release opioids using the polymethacrylate-triethylcitrate controlled-release system are highly sensitive to alcohol and that there is a risk of dose dumping if patients drink alcohol while taking them. Therefore, the Committee recommended that the marketing authorisations for these medicines should be suspended until the companies that make these medicines have reformulated the medicines so that they are more stable in alcohol.

For all other medicines in this class, the Committee concluded that their benefits continue to outweigh their risks, and therefore recommended that their marketing authorisations be maintained.

However, the CHMP noted that all medicines in this class have the potential to interact with alcohol, such as increasing the opioids' sedative effects. Therefore, the Committee recommended that the warnings on this interaction be made consistent in the information for doctors and patients across all oral opioid medicines of the WHO level III scale.

The CHMP confirmed the above conclusions after re-examining its opinion. The Modified-release oral opioids - Article 31 referral - Annex III.

What are the recommendations for patients and prescribers?

• Prescribers of modified-release opioids and their patients should be aware of the potential interaction between these medicines and alcohol. They should take note of the restrictions and warnings for the medicines that they are using.
• Prescribers are reminded that there are a large number of modified-release opioids available in each Member State. They should consider switching patients currently taking opioids containing the polymethacrylate-triethylcitrate controlled-release system to alternatives while the suspension is in force.
• Patients who have any questions should speak to their doctor or pharmacist.

A European Commission decision on this opinion will be issued in due course.

Questions and answers on the review of modified-release oral opioid medicines of the WHO level III scale for the management of pain - Re-examination

Reference Number: EMA/728909/2010

Key facts

About this medicine

• Approved name:
  Modified-released oral opioids
• International non-proprietary name (INN) or common name:
  • hydromorphone
  • morphine
  • oxycodone
• Class:
  Opioids of the World Health Organization level III scale

About this procedure

• Current status:
  European Commission final decision
• Reference number:
  EMEA/H/A-31/001232
• 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:
  18/11/2010
• EC decision date:
  20/04/2011

All documents

Assessment Report for Authorised modified-release oral medicinal products of the WHO level III scale for the management of pain (intense sustained pain resistant to previous medications) (containing morphine, oxycodone, ...

AdoptedReference Number: EMA/355008/2011

Modified release oral opioids - Article 31 referral - Annex I

Adopted

Modified release oral opioids - Article 31 referral - Annex II

Adopted

Modified release oral opioids - Article 31 referral - Annex IV

Adopted

Modified-release oral opioids - Article 31 referral - Annex III

Questions and answers on the review of modified-release oral opioid medicines of the WHO level III scale for the management of pain - Initial

AdoptedReference Number: EMA/459105/2010

Questions and answers on the review of modified-release oral opioid medicines of the WHO level III scale for the management of pain - Re-examination

Reference Number: EMA/728909/2010

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.