Ranitidine-containing medicinal products - referral

Current status

European Commission final decision

Overview

EMA confirms recommendation to suspend all ranitidine medicines in the EU

On 17 September 2020, EMA’s human medicines committee (CHMP) confirmed its recommendation to suspend all ranitidine medicines in the EU due to the presence of low levels of an impurity called N-nitrosodimethylamine (NDMA). This follows a re-examination of CHMP’s April 2020 opinion, which was requested by one of the companies marketing ranitidine medicines.

NDMA is classified as a probable human carcinogen (a substance that could cause cancer) based on animal studies. It is present in some foods and water supplies and is not expected to cause harm when ingested at very low levels.

Available safety data do not show that ranitidine increases the risk of cancer, and any possible risk is likely to be very low. However, NDMA has been found in several ranitidine medicines above levels considered acceptable, and there are unresolved questions about the source of this impurity.

There is some evidence that NDMA may form from the degradation of ranitidine itself with increasing levels seen over its shelf life. It is not clear if NDMA can also be formed from ranitidine inside the body. Some studies suggest that it can, while others do not. Given the uncertainties, the CHMP has recommended in April 2020 a precautionary suspension of these medicines in the EU.

Ranitidine medicines are used for reducing stomach acid in patients with conditions such as heartburn and stomach ulcers. Alternatives are available and patients should contact their healthcare professionals for advice about which medicine to take.

Following the re-examination, the CHMP maintained the conditions for lifting the suspension of the medicines, including requirements for companies to provide more data on the possible formation of NDMA from ranitidine inside the body. The formation of NDMA in the body is expected to be very low following a single low dose of ranitidine given by injection or infusion (drip). Therefore, the CHMP slightly amended the conditions for lifting the suspension for those ranitidine medicines that are given by injection or infusion as a single, low dose.

Many ranitidine medicines have not been available in the EU for several months. This is because national authorities have recalled them as a precaution while the EMA review was ongoing.

Since 2018 NDMA and similar compounds known as nitrosamines have been detected in several medicines. EU regulators have acted to identify possible sources of the impurities and set strict requirements for manufacturers.

EMA is continuing to work with national authorities, EDQM,¹ the European Commission and international partners to make sure effective measures are taken to prevent the presence of these impurities in medicines. 

¹The European Directorate for the Quality of Medicines & HealthCare

Information for patients

• Ranitidine medicines are suspended in the EU as a precaution because of the presence at low levels of an impurity called NDMA.
• Alternative medicines are available to reduce stomach acid. If you have been prescribed ranitidine, your doctor will advise you on an alternative.
• Contact your doctor or pharmacist if you have any questions about which alternative to take.

Information for healthcare professionals

• Ranitidine medicines are suspended in the EU due to the presence of NDMA impurities.
• Available clinical and epidemiological data do not show that ranitidine increases the risk of cancer. However, NDMA has been found in several ranitidine medicines above levels considered acceptable.
• Although the exact source of the impurity in ranitidine is yet to be determined, it is possible that NDMA forms from the degradation of ranitidine even under normal storage conditions. Some studies indicated that ranitidine may cause endogenous NDMA formation by degradation or metabolism in the gastro-intestinal tract, but other studies did not.
• While ranitidine medicines are unavailable, patients should be advised on alternative medicines.
• Healthcare professionals should advise patients who have been taking ranitidine, with or without a prescription, on how to treat or manage conditions such as heartburn and gastric ulcers.

More about the medicine

Ranitidine belongs to a class of medicines known as H2 (histamine-2) blockers, which work by blocking histamine receptors in the stomach and reducing the production of stomach acid.

It is used to treat and prevent conditions such as heartburn and stomach ulcers. Ranitidine-containing medicines have been authorised at national level for about 30 years and are available as tablets, syrups and injectable formulations.

More about the procedure

The review of ranitidine was initiated on 12 September 2019 at the request of the European Commission, under Article 31 of Directive 2001/83/EC.

The review was carried out by the Committee for Medicinal Products for Human Use (CHMP), responsible for questions concerning medicines for human use, which adopted its initial opinion in April 2020. Following a re-examination of the opinion, requested by one of the companies concerned, the CHMP made amendments to its recommendation. The final CHMP opinion was forwarded to the European Commission, which issued a final legally binding decision applicable in all EU Member States on 24 November 2020.

Ranitidine Article-31 referral - EMA confirms recommendation to suspend all ranitidine medicines in the EU

Reference Number: EMA/666097/2020Summary:

EMA’s human medicines committee (CHMP) has confirmed its recommendation to suspend all ranitidine medicines in the EU due to the presence of low levels of an impurity called N-nitrosodimethylamine (NDMA).

Key facts

About this medicine

• Approved name:
  Ranitidine-containing medicinal products
• International non-proprietary name (INN) or common name:
  ranitidine

About this procedure

• Current status:
  European Commission final decision
• Reference number:
  EMEA/H/A-31/1491
• 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.

• Authorisation model:
  Nationally authorised product(s)
• Decision making model:
  CHMP-EC

Key dates and outcomes

• CHMP opinion date:
  17/09/2020
• EC decision date:
  24/11/2020

All documents

Procedure started

Ranitidine Article-31 referral - EMA to review ranitidine medicines following detection of NDMA

Reference Number: EMA/503622/2019

Ranitidine Article-31 referral - Notification

Ranitidine Article-31 referral - Timetable for the procedure

Reference Number: EMA/CHMP/506572/2019 Rev. 3

Ranitidine Article-31 referral - CHMP list of questions

Reference Number: EMA/CHMP/506572/2019

Opinion provided by Committee for Medicinal Products for human Use

Ranitidine Article-31 referral - Suspension of ranitidine medicines in the EU

AdoptedReference Number: EMA/231394/2020. Rev.1

European Commission final decision

Ranitidine Article-31 referral - Assessment report

AdoptedReference Number: EMA/599846/2020 Corr.1

Ranitidine Article-31 referral - Annex III

Ranitidine Article-31 referral - Annex II

Ranitidine Article-31 referral - Annex I

Ranitidine Article-31 referral - EMA confirms recommendation to suspend all ranitidine medicines in the EU

Reference Number: EMA/666097/2020Summary:

EMA’s human medicines committee (CHMP) has confirmed its recommendation to suspend all ranitidine medicines in the EU due to the presence of low levels of an impurity called N-nitrosodimethylamine (NDMA).

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.