Numeta G13%E and Numeta G16%E emulsion for infusion - referral

Current status

CMDh final position

Overview

Numeta G13%E to be suspended and new risk minimisation measures to be introduced for Numeta G16%E

The Coordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh), a medicines regulatory body representing the European Union (EU) Member States, has endorsed by consensus the recommendation to suspend the marketing authorisation of Numeta G13%E because of a risk of hypermagnesaemia (high blood levels of magnesium). Numeta G13%E, which is given into a vein to premature babies to provide nutritional support (intravenous nutrition or parenteral nutrition), will remain suspended until a reformulated preparation is made available.

For another nutrition preparation given into a vein, Numeta G16%E, used in full-term newborns and children up to two years, the CMDh agreed that the benefit-risk balance remains positive, provided that healthcare professionals monitor their patients' blood magnesium levels before giving the preparation and at appropriate intervals thereafter in accordance with routine clinical practice and the clinical needs of the individual patient. In patients whose blood magnesium levels are elevated or signs of hypermagnesaemia are identified, Numeta G16%E should be stopped or the infusion rate reduced.

Numeta preparations are given to provide nutritional support in children who cannot be fed by mouth or with a feeding tube. They contain nutrients such as glucose (sugar), lipids (fats), amino acids and other important substances including magnesium.

Hypermagnesaemia is a serious condition and symptoms may include weakness, nausea and vomiting, breathing difficulties, hypotension (low blood pressure) and arrhythmias (irregular heart beat).

The review of Numeta G13%E and Numeta G16%E was carried out by the the European Medicines Agency's Pharmacovigilance Risk Assessment Committee (PRAC) following several reports of hypermagnesaemia (without clinical symptoms) in preterm infants. As a precautionary measure, the manufacturer decided to voluntarily recall Numeta G13%E in the EU. The PRAC assessed the available data on the risk of hypermagnesaemia with Numeta G13%E and Numeta G16%E preparations from clinical studies, post-marketing reports and the published literature and considered available treatment guidelines. Stakeholders were also invited to submit any relevant information to support the assessment, and the Agency's Paediatric Committee (PDCO) was consulted for advice.

Having considered available guidelines and relevant literature and considering the magnesium content of Numeta, the PRAC concluded that the administration of Numeta G13%E could lead to a higher risk of hypermagnesaemia. In addition, the PRAC noted that this risk is further increased in premature newborns because their kidneys are immature and less able to clear the body of magnesium. The PRAC also noted the difficulty in identifying symptoms of hypermagnesaemia in premature newborns, which means that hypermagnesaemia may not be detected until it causes serious complications.

For Numeta G16%E, the PRAC concluded that although the magnesium content may result in a magnesium intake that is slightly higher than suggested in some guidelines, the proposed measures, including updating the product information and a further study, are sufficient to ensure the safe use of this product. The product information should be revised accordingly and healthcare professionals should be informed in writing of the potential risk of hypermagnesaemia, which is increased in patients with impaired kidney function and those whose mothers were receiving supplemental magnesium before delivery, and of the measures to be taken to minimise this risk. In addition, the PRAC recommended a study be carried out to further evaluate blood magnesium levels observed in term newborn infants and children up to two years of age following use of Numeta G16%E.

As the PRAC recommendations were endorsed by consensus by the CMDh, they will now be implemented directly in all Member States, according to an agreed timetable.

Information to parents and carers

• Because of the risk of hypermagnesaemia (high blood levels of magnesium), the nutrition preparation Numeta G13%E has been suspended until a reformulated preparation is made available. Numeta G13%E is given into a vein to provide nutritional support in premature babies who cannot be fed by mouth or with a feeding tube.
• The nutrition preparation Numeta G16%E can continue to be used in full-term newborns and children up to two years, however the doctor will monitor the levels of magnesium in the child's blood before giving the preparation and at appropriate intervals thereafter. The doctor will stop giving Numeta G16%E if magnesium levels are high, or will give Numeta at a slower rate.
• Severe hypermagnesaemia is rare but can have adverse clinical consequences. Doctors will monitor newborns and children who are receiving Numeta G16%E for symptoms of hypermagnesaemia such as weakness, nausea and vomiting, breathing difficulties, hypotension (low blood pressure) and arrhythmias (irregular heart beat).
• Parents who have any questions or concerns should speak to the treating doctor or other healthcare professional.

Information to healthcare professionals

For Numeta G13%E:

• Following several reports of hypermagnesaemia in preterm infants, the nutrition preparation Numeta G13%E has been suspended until a reformulated preparation is made available. While Numeta G13%E is suspended, healthcare professionals should use alternative nutrition solutions, which may include authorised standardised or individually prepared solutions.

For Numeta G16%E:

• The benefit-risk balance of the nutrition preparation Numeta G16%E, used in full-term newborns and children up to two years, remains positive. However, healthcare professionals should be aware of the potential risk for hypermagnesaemia. This risk is increased in patients with reduced renal function, and in newborn infants of mothers who were receiving supplemental magnesium prior to delivery.
• When giving Numeta G16%E, doctors should monitor serum magnesium levels, along with other electrolyte levels at baseline and at appropriate intervals thereafter. This should be done in accordance with routine clinical practice and the clinical needs of the individual patient.
• Doctors should also monitor patients for signs and symptoms of hypermagnesaemia such as nausea, vomiting and flushing, generalised weakness, respiratory failure, hypotension and arrhythmias. Clinical signs may not be identifiable unless hypermagnesaemia is severe.
• In case of hypermagnesaemia, the infusion of Numeta G16%E should be stopped or infusion rate reduced and alternative fluids, nutrition and electrolytes prescribed as deemed clinically appropriate.

Further information about the EU-wide safety review:

• The company marketing Numeta identified 14 case reports of hypermagnesaemia with Numeta G13%E. Magnesium levels mainly ranged from 1.025 mmol/l to > 1.5 mmol/l and no clinical signs or symptoms were reported for any of the cases.
• The appropriate parenteral magnesium intake in preterm infants is uncertain. However, widely recognised guidelines^1,2 recommend a parenteral magnesium intake of 0.15-0.25 mmol/kg/day. The maximum total licensed amount of magnesium that can be delivered to preterm infants using Numeta G13%E is 0.55 mmol/kg/day, which is above this recommended intake.
• The company identified one case of hypermagnesaemia associated with Numeta G16%E. This report was confounded by the fact that additional magnesium may have been given.
• The maximum total amount of magnesium that can be delivered to term infants using Numeta G16%E according to its product information is 0.3 mmol/kg/day. Although this is within the recommendations reported in the literature as a whole, it is slightly more than suggested by some recognised guidelines^1,2,3 (0.15-0.25 mmol/kg/day and 0.2 mmol/kg/day for term infant to one year of age, 0.15-0.25 mmol/kg/day and 0.1 mmol/kg/day for children from one year to two years of age).

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References:

1. Canada T, Crill C, Guenter P. American Society for Parenteral and Enteral Nutrition parenteral nutrition handbook. Silver Spring,Maryland: American Society for Parenteral and Enteral Nutrition. 2009; 167.
2. Mirtallo J., Canada T., Johnson D., Kumpf V., Petersen C., Sacks G., Seres D., Guenter P, Task Force for the Revision of Safe Practices for Parenteral Nutrition. Safe practices for parenteral nutrition. JPEN J Parenter Enteral Nutr 2004; 28(6):S39-S70.
3. Koletzko B., Goulet O., Hunt J., Krohn K., Shamir R. Guidelines on paediatric parenteral nutrition of the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and the European Society for Clinical Nutrition and Metabolism (ESPEN), supported by the European Society of Paediatric Research (ESPR). J Pediatric Gastroenterology Nutrition 2005; 41: S1-S87.

More about the medicine

Numeta G13%E and Numeta G16%E (glucose, lipids, aminoacids and electrolytes) are parenteral nutrition solutions. Parenteral nutrition is the providing of nutrients and fluids through a vein in patients who cannot be fed by mouth or by enteral nutrition (the use of a feeding tube passed directly into the gut). Parenteral nutrition is necessary in premature neonates and in some full-term babies in order to prevent complications such as growth retardation and breathing complications and to promote the normal development of the brain.

Numeta G13%E and Numeta G16%E have been authorised since 2011 via national procedures in the following Member States: Austria, Belgium, the Czech Republic, Denmark, Finland, France, Germany, Greece, Ireland, Italy, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Spain, Sweden and the United Kingdom.

More about the procedure

The review of Numeta G13%E and Numeta G16%E was initiated on 13 June 2013 at the request of Sweden, under Article 107i of Directive 2001/83/EC, also known as the urgent Union procedure.

The review was conducted by the Pharmacovigilance Risk Assessment Committee (PRAC). As the review only covers nationally authorised medicines, the PRAC recommendation was forwarded to the Coordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh), which adopted a final position. The CMDh is a medicines regulatory body representing the EU Member States.

Numeta G13%E to be suspended and new risk-minimisation measures to be introduced for Numeta G16%E

Reference Number: EMA/564255/2013

Key facts

About this medicine

• Approved name:
  Numeta G13%E and Numeta G16%E emulsion for infusion
• Class:
  -

About this procedure

• Current status:
  CMDh final position
• Reference number:
  EMEA/H/A-107i/1373
• Type:
  Article 107i procedures

  This type of procedure is triggered when a Member State or the European Commission consider that urgent action is necessary because of a safety issue. Situations that fall under this procedure include consideration for suspension or revocation of the marketing authorisation for a medicine, the prohibition of supply of a medicine or major changes to the marketing authorisation such as deletion of indications, reduction of the recommended dose or new contraindications. The procedure is also applicable in case of a safety issue with a class of medicines.

• Authorisation model:
  Nationally authorised product(s)
• Decision making model:
  PRAC-CMDh

Key dates and outcomes

• Procedure start date:
  13/06/2013
• PRAC recommendation date:
  05/09/2013
• CHMP opinion date:
  18/09/2013
• Outcome:
  Suspension

Data submission

The Agency invites all stakeholders (e.g. healthcare professionals, patients' organisations and the general public) to submit data relevant to this procedure. This is in accordance with Article 107j(1) of Directive 2001/83/EC.

The following requirements apply for data to be considered:

• Submissions must be accompanied by the submission form below, with all fields completed. The form must be used with Adobe Reader X+ or Adobe Acrobat X+:
  Numeta Article-107i procedure - Stakeholders' submission form

• Data submitted should make reference to the Pharmacovigilance Risk Assessment Committee (PRAC) questions:Numeta Article-107i procedure - PRAC list of questions to be addressed by the stakeholders

• The submission of all data should take place by 1 July 2013.

Submitting data

Send the completed form electronically to the stakeholders' submission inbox ([e-mail]). Specify the name of the medicine in the subject line of the e-mail.

The size of the submission file should not exceed 25 MB. If your attempt to send your data package to the dedicated e-mail address is unsuccessful, please use alternative submission means.

It is of the utmost importance that data are provided promptly, to avoid undermining the safety review. Due to the urgent nature of the procedure, you are strongly advised to submit your data in English.

Protection of personal data

Personal data submitted are subject to data-protection rules as established by Regulation (EC) 45/2001. They will be treated in accordance with the

.

 

Treatment and publication of data

Data submitted will be received and recorded by the Agency.

The Agency will prepare a list of all submissions received, which will be published as an annex to the PRAC assessment report for transparency purposes and public awareness.

Please note that all data submitted in the context of this procedure may be shared and disclosed in the public domain.

All documents

Procedure started

Numeta Article-107i procedure - PRAC list of questions to be addressed by the stakeholders

Reference Number: EMA/PRAC/366917/2013

Numeta Article-107i procedure - Stakeholders' submission form

Numeta Article-107i procedure - Notification

Numeta Article-107i procedure - Annex I

Numeta Article-107i procedure - PRAC list of questions

Numeta Article-107i procedure - Rationale for triggering

Numeta Article-107i procedure - Review started

Numeta Article-107i procedure - Timetable for the procedure

Recommendation provided by Pharmacovigilance Risk Assessment Committee

Numeta Article-107i procedure - PRAC assessment report

AdoptedReference Number: EMA/587344/2013

Numeta Article-107i procedure - PRAC recommends suspension and reformulation for Numeta G13%E and risk minimisation measures for Numeta G16%E

Reference Number: EMA/531101/2013

Position provided by CMDh

Numeta Article-107i procedure - Annex V

Reference Number: EMEA/H/A-107i/1373

Numeta Article-107i procedure - Annex VI

Reference Number: EMEA/H/A-107i/1373

Numeta Article-107i procedure - Annex III

Reference Number: EMEA/H/A-107i/1373

Numeta Article-107i procedure - Annex II

Reference Number: EMEA/H/A-107i/1373

Numeta Article-107i procedure - Annex I

Reference Number: EMEA/H/A-107i/1373

Numeta Article-107i procedure - Annex IV

Reference Number: EMEA/H/A-107i/1373

Numeta G13%E to be suspended and new risk-minimisation measures to be introduced for Numeta G16%E

Reference Number: EMA/564255/2013

Numeta Article-107i procedure - Amendments to relevant sections of the summary of product characteristics and package leaflet

Numeta G13%E to be suspended and new risk-minimisation measures to be introduced for Numeta G16%E

Reference Number: EMA/564255/2013

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.