Kuvan

sapropterin

This is a summary of the European public assessment report (EPAR) for Kuvan. It explains how the Committee for Medicinal Products for Human Use (CHMP) assessed the medicine to reach its opinion in favour of granting a marketing authorisation and its recommendations on the conditions of use for Kuvan.

What is Kuvan?

Kuvan is a medicine that contains the active substance sapropterin dihydrochloride. It is available as light yellow soluble tablets (100 mg).

What is Kuvan used for?

Kuvan is used to treat hyperphenylalaninaemia (HPA, high levels of phenylalanine in the blood) in patients with the genetic disorders phenylketonuria (PKU) or tetrahydrobiopterin (BH4) deficiency. Patients with these disorders cannot convert the amino acid phenylalanine (found in protein in the diet) into tyrosine (another amino acid). This causes a build-up of phenylalanine in the blood, which can lead to problems with the brain and nervous system.

Kuvan can be used in adults and children who have shown to respond adequately to the medicine. Kuvan is intended for use in children with HPA due to PKU who are at least four years old. Kuvan may be used in children of all ages with HPA due to BH4 deficiency.

Because the number of patients with HPA is low, the disease is considered ‘rare’, and Kuvan was designated an ‘orphan medicine’ (a medicine used in rare diseases) on 8 June 2004.

The medicine can only be obtained with a prescription.

How is Kuvan used?

Treatment with Kuvan must be started and supervised by a doctor who has experience in the treatment of PKU and BH4 deficiency. The amount of phenylalanine and protein in the patient’s diet needs to be monitored, to make sure that blood phenylalanine levels and nutritional balance are controlled. Kuvan is intended for long-term use.

The dose of Kuvan depends on the patient’s weight. Patients with PKU should start with 10 mg per kilogram body weight once a day and those with BH4 deficiency should start with 2 to 5 mg/kg once a day. After a week, the dose can be adjusted up to 20 mg/kg once a day if the patient has not responded to treatment. A satisfactory response is defined as a reduction in blood phenylalanine levels of at least 30% or to a level determined by the doctor. If this has been achieved after one month, the patient is classified as a ‘responder’ and can continue taking Kuvan.

Kuvan is taken with a meal at the same time every day, preferably in the morning. The tablets are dissolved in a glass of water before the patient drinks the solution. For some patients with BH4 deficiency, the dose may need to be divided into two or three doses over the course of the day to get the best effect.

How does Kuvan work?

The high levels of phenylalanine in the blood are due to a problem with the conversion of phenylalanine into tyrosine by the enzyme ‘phenylalanine hydroxylase’. Patients with PKU have defective versions of the enzyme, and patients with BH4 deficiency have low levels of BH4, a ‘cofactor’ that this enzyme needs to work properly. The active substance in Kuvan, sapropterin dihydrochloride, is a synthetic copy of BH4. In PKU, it works by enhancing the activity of the defective enzyme, and in BH4 deficiency it replaces the missing cofactor. This helps to restore the ability of the enzyme to convert phenylalanine into tyrosine, reducing phenylalanine levels in the blood.

How has Kuvan been studied?

For the treatment of patients with PKU, Kuvan has been studied in two main studies that compared Kuvan with placebo. All of the patients included in the studies had shown a response to an initial eight-day course of Kuvan but had a period of at least one week without the medicine before the studies started.

The first study involved 89 patients aged eight years or more who were not following a strict diet. The main measure of effectiveness was the reduction in blood phenylalanine levels over six weeks.

The second study involved 46 children aged between four and 12 years, who were on a diet with a controlled level of phenylalanine. From the third week of treatment, the diet was adjusted every two weeks based on blood phenylalanine levels. The main measure of effectiveness was the change in how much phenylalanine the children could eat while keeping blood phenylalanine at target levels. The study lasted for 10 weeks.

For the treatment of patients with BH4 deficiency, the company presented the results of three studies from the published literature with sapropterin dihydrochloride. One of these studies involved 16 patients who were treated for an average of 15.5 months.

What benefit has Kuvan shown during the studies?

For the treatment of PKU, Kuvan was more effective than placebo. In the first study, blood phenylalanine levels were around 867 ‘micromoles per litre’ at the start of the study. Normal levels are around 60 micromoles per litre in people without PKU. After six weeks, phenylalanine levels had fallen by 236 micromoles per litre in the patients taking Kuvan and had risen by 3 micromoles per litre in the patients taking placebo. In the second study, the children taking Kuvan could eat an average of 17.5 mg more phenylalanine per kilogram body weight every day after 10 weeks, compared with 3.3 mg more in the children taking placebo.

In the studies of patients with BH4 deficiency, patients showed an improvement in blood phenylalanine levels and other markers of the disease when they were taking sapropterin dihydrochloride.

What is the risk associated with Kuvan?

The most common side effects with Kuvan (seen in more than 1 patient in 10) are headache and rhinorrhoea (runny nose). For the full list of all side effects reported with Kuvan, see the package leaflet.

Kuvan should not be used in patients who may be hypersensitive (allergic) to sapropterin hydrochloride or any of the other ingredients.

Why has Kuvan been approved?

The CHMP decided that Kuvan’s benefits are greater than its risks and recommended that it be given marketing authorisation.

Other information about Kuvan

The European Commission granted a marketing authorisation valid throughout the European Union for Kuvan on 2 December 2008. The marketing authorisation holder is Merck Serono Europe Limited. The marketing authorisation is valid for five years, after which it can be renewed.

For more information about treatment with Kuvan, read the package leaflet (also part of the EPAR) or contact your doctor or pharmacist.

This EPAR was last updated on 25/06/2012 .

More detail is available in the summary of product characteristics

Product details

Publication details

Product information

16/12/2011  Kuvan -EMEA/H/C/000943 -II/0015

Contents

• Annex I - Summary of product characteristics
• Annex IIA - Manufacturing-authorisation holder responsible for batch release
• Annex IIB - Conditions of the marketing authorisation
• Annex IIIA - Labelling
• Annex IIIB - Package leaflet

Please note that the size of the above document can exceed 50 pages.

You are therefore advised to be selective about which sections or pages you wish to print.

Pharmacotherapeutic group

Other alimentary tract and metabolism products

Therapeutic indication

Kuvan is indicated for the treatment of hyperphenylalaninaemia (HPA) in adult and paediatric patients of 4 years of age and over with phenylketonuria (PKU) who have been shown to be responsive to such treatment (see section 4.2).

Kuvan is also indicated for the treatment of hyperphenylalaninaemia (HPA) in adult and paediatric patients with tetrahydrobiopterin (BH4) deficiency who have been shown to be responsive to such treatment (see section 4.2).

Changes since initial authorisation of medicine

Initial marketing-authorisation documents