o

EUROPEAN MEDICINES AGENCY

SCIENCE MEDICINES HEALTH

EMA/638140/2015

EMEA/H/C/003822

EPAR summary for the public

Ravicti

glycerol phenylbutyrate

This is a summary of the European public assessment report (EPAR) for Ravicti. It explains how the Agency assessed the medicine to recommend its authorisation in the EU and its conditions of use. It is not intended to provide practical advice on how to use Ravicti.

For practical information about using Ravicti, patients should read the package leaflet or contact their doctor or pharmacist.

What is Ravicti and what is it used for?

Ravicti is a medicine used long-term to manage urea-cycle disorders in adults and children from the age of two months, when the diseases cannot be managed by changes in their diet alone. Patients with urea cycle disorders are not able to get rid of waste nitrogen from the body because they lack some liver enzymes. In the body, waste nitrogen is turned into ammonia, which is harmful when it accumulates. Ravicti is used in patients who lack one or more of the following enzymes: carbamoyl phosphate synthase-I, ornithine carbamoyltransferase, argininosuccinate synthetase, argininosuccinate lyase, arginase I and ornithine translocase.

Ravicti contains the active substance glycerol phenylbutyrate.

Because the number of patients with urea cycle disorders is low, the diseases are considered 'rare', and Ravicti was designated an 'orphan medicine' (a medicine used in rare diseases) on 10 June 2010.

How is Ravicti used?

Ravicti is available as a liquid (1.1 g/ml) to be taken by mouth, or through a tube that goes from the nose to the stomach or through the belly into the stomach. It can only be obtained with a prescription and should be prescribed by a doctor who has experience in treating patients with urea-cycle disorders.

30 Churchill Place • Canary Wharf • London E14 5EU • United Kingdom Telephone +44 (0)20 3660 6000 Facsimile +44 (0)20 3660 5555 Send a question via our website www.ema.europa.eu/contact

© European Medicines Agency, 2015. Reproduction is authorised provided the source is acknowledged.

Since proteins are a source of nitrogen, Ravicti must be used together with a special low-protein diet to reduce the intake of nitrogen, and sometimes with dietary supplements (depending on the daily protein intake needed for growth and development).

The daily dose of Ravicti depends on the patient's diet, height and weight. During treatment, regular blood tests are needed to adjust the daily dose. The total daily dose of Ravicti should be divided into equal amounts and given with each meal. For further information, see the summary of product characteristics (also part of the EPAR).

Ravicti may be a life-long treatment unless the patient has a successful liver transplant.

How does Ravicti work?

The active substance in Ravicti, glycerol phenylbutyrate, is converted to phenylacetate in the body. Phenylacetate attaches to the amino acid glutamine found in proteins, which contains nitrogen, to form a substance that can be removed from the body by the kidneys. This allows the levels of nitrogen in the body to decrease, reducing the amount of ammonia produced.

What benefits of Ravicti have been shown in studies?

Ravicti has been compared with sodium phenylbutyrate (another medicine used to treat urea cycle disorders) in a study involving 88 adults with urea cycle disorders. The main measure of effectiveness was the change in the blood level of ammonia after 4 weeks of treatment. The study showed that Ravicti was at least as effective as the comparator in controlling the blood level of ammonia: the estimated average ammonia level was approximately 866 micromoles per litre in patients treated with Ravicti, compared with approximately 977 micromoles per litre in patients treated with sodium phenylbutyrate. Additional data from supportive studies showed a similar effect of Ravicti in children from 2 months of age.

What are the risks associated with Ravicti?

The most common side effects with Ravicti (which may affect more than 5 in 100 people) are diarrhoea, flatulence (passing gas), headache, decreased appetite, vomiting, tiredness, feeling sick and abnormal skin odour.

Ravicti must not be used for the treatment of acute hyperammonaemia (sudden rise of blood ammonia levels). For the full list of all side effects and restrictions with Ravicti, see the package leaflet.

Why is Ravicti approved?

The Agency's Committee for Medicinal Products for Human Use (CHMP) decided that the benefits of Ravicti are greater than its risks and recommended that it be approved for use in the EU.

Ravicti was shown to be effective in reducing the blood level of ammonia in patients with urea cycle disorders. Ravicti is a sustained-release medicine, meaning the active substance is released evenly during the day. Therefore, the removal of waste nitrogen also occurs evenly and this results in a better control of blood ammonia levels throughout the day. For this same reason Ravicti must not be used to treat acute hyperammonaemia as more rapidly acting treatments are needed in these cases.

Additionally, the Committee considered that since Ravicti is available as a liquid this could make the medicine more palatable especially for children, compared with other medicines available as granules to be added to food; the liquid formulation also facilitates its administration via tube to patients unable to swallow because of neurological problems.

Ravicti

EMA/638140/2015    Page 2/3

The side effects of Ravicti affected mainly the gut and were considered manageable. However, further data on the long-term safety of Ravicti are awaited.

What measures are being taken to ensure the safe and effective use of Ravicti?

A risk management plan has been developed to ensure that Ravicti is used as safely as possible. Based on this plan, safety information has been included in the summary of product characteristics and the package leaflet for Ravicti, including the appropriate precautions to be followed by healthcare professionals and patients.

In addition, the company that markets Ravicti will set up a registry of patients to obtain further information on the long-term benefits and safety of the medicine.

Further information can be found in the summary of the risk management plan.

Other information about Ravicti

The European Commission granted a marketing authorisation valid throughout the European Union for Ravicti on 27 November 2015

The full EPAR and risk management plan summary for Ravicti can be found on the Agency's website: ema.europa.eu/Find medicine/Human medicines/European public assessment reports. For more information about treatment with Ravicti, read the package leaflet (also part of the EPAR) or contact your doctor or pharmacist.

The summaries of the opinions of the Committee for Orphan Medicinal Products for Ravicti can be found on the Agency's website:

•    carbamoyl phosphate-synthase-1 deficiency;

•    ornithine carbamoyltransferase deficiency;

•    citrullinaemia type 1;

•    argininosuccinic aciduria;

•    hyperargininaemia;

•    ornithine translocase deficiency (hvperornithinaemia-hvperammonaemia homocitrullinuria (HHH) syndrome).

This summary was last updated in 12-2015.

Ravicti

EMA/638140/2015