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EUROPEAN MEDICINES AGENCY

SCIENCE MEDICINES HEALTH

EMA/633676/2014

EMEA/H/C/000915

EPAR summary for the public

Valdoxan

agomelatine

This is a summary of the European public assessment report (EPAR) for Valdoxan. 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 Valdoxan.

What is Valdoxan?

Valdoxan is a medicine that contains the active substance agomelatine. It is available as tablets (25 mg).

What is Valdoxan used for?

Valdoxan is used to treat major depression in adults. Major depression is a condition in which patients have mood disturbances that interfere with their everyday life. Symptoms often include deep sadness, feelings of worthlessness, loss of interest in favourite activities, sleep disturbances, a feeling of being slowed down, feelings of anxiety and changes in weight.

The medicine can only be obtained with a prescription.

How is Valdoxan used?

The recommended dose of Valdoxan is one tablet once a day, taken at bedtime. If there is no improvement in symptoms after two weeks, the doctor may increase the dose to two tablets taken together at bedtime. Patients with depression should be treated for at least six months to make sure that they are free of symptoms.

The patient's liver function should be checked with blood tests before starting treatment and when the dose is increased, followed by further tests around three, six, 12 and 24 weeks later. Treatment should not be started or should be stopped in patients with abnormal liver enzyme levels in the blood (more

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than three times the normal level). Treatment should be discontinued immediately if the patient develops symptoms or signs of potential liver injury.

For further information, see the package leaflet.

How does Valdoxan work?

The active substance in Valdoxan, agomelatine, is an antidepressant. It works in two ways, by stimulating the MT1 and MT2 receptors, which are normally activated by melatonin, and also by blocking the 5-HT_2C receptors, which are normally activated by the neurotransmitter 5-hydroxytryptamine (also called serotonin). This is thought to lead to increases in the levels of dopamine and noradrenaline between nerve cells in the areas of the brain that are involved in the control of mood. This is believed to help relieve the symptoms of depression. Valdoxan might also help to normalise the patient's sleep patterns.

How has Valdoxan been studied?

Valdoxan has been compared with placebo (a dummy treatment) in five main short-term studies involving a total of 1,893 adults with major depression. Three of these studies included some patients treated with other antidepressants, either fluoxetine or paroxetine, as an 'active comparator'. The active comparator groups were included to check that the study was able to measure the effectiveness of medicines in treating depression. The main measure of effectiveness in these five studies was the change in symptoms after six weeks, as measured on a standard scale for depression called the Hamilton Depression Rating Scale (HAM D). The company also presented the results of a further study comparing Valdoxan with sertraline (another antidepressant).

Two other main studies compared the ability of Valdoxan and placebo to prevent symptoms returning in 706 patients whose depression had already been controlled with Valdoxan. The main measure of effectiveness was the number of patients whose symptoms returned during 24 to 26 weeks of treatment.

What benefit has Valdoxan shown during the studies?

In the short-term studies, Valdoxan was seen to be more effective than placebo in the two studies where no active comparator was used. In the other three studies, which did include an active comparator, there were no differences in scores between the patients taking Valdoxan and those taking placebo. However, no effect of fluoxetine or paroxetine was seen in two of these studies, making the results difficult to interpret. The additional study showed that agomelatine was more effective than sertraline, with a difference in HAM D scores of 1.68 after six weeks.

In the first of the long-term studies, there was no difference between Valdoxan and placebo in preventing symptoms from returning during 26 weeks of treatment. However, the second study showed that symptoms returned in 21% of the patients taking Valdoxan over 24 weeks (34 out of 165), compared with 41% of the patients taking placebo (72 out of 174).

As the effects of Valdoxan have not been established in patients aged 75 years or above, Valdoxan is not recommended in this age group.

What is the risk associated with Valdoxan?

The most common side effects with Valdoxan (seen in between 1 and 10 patients in 100) are headache, dizziness, somnolence (sleepiness), insomnia (difficulty sleeping), migraine, nausea (feeling sick), diarrhoea, constipation, abdominal pain (stomach ache), vomiting, hyperhidrosis (excessive sweating), back pain, fatigue (tiredness), increases in liver enzymes and anxiety. Most side effects were mild or moderate in intensity, happened within the first two weeks of treatment and were temporary. For the full list of all side effects reported with Valdoxan, see the package leaflet.

Valdoxan must not be used in patients who have problems with their liver, such as cirrhosis (scarring of the liver) or active liver disease, nor in patients whose level of transaminases (liver enzymes) in the blood is more than three times the normal level. It must also not be used in patients who are taking medicines that slow down the breakdown of Valdoxan in the body, such as fluvoxamine (another antidepressant) and ciprofloxacin (an antibiotic). For the full list of restrictions, see the package leaflet.

Why has Valdoxan been approved?

The CHMP noted that Valdoxan's benefits in terms of treating depression might be lower than seen with other antidepressants. However, since the medicine has a different mode of action, few side effects and a different safety profile to existing antidepressants, the Committee concluded that Valdoxan could be a valuable treatment for some patients as long as their liver function is tested frequently. Therefore, the CHMP decided that Valdoxan's benefits are greater than its risks and recommended that it be given marketing authorisation.

What measures are being taken to ensure the safe use of Valdoxan?

A risk management plan has been developed to ensure that Valdoxan 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 Valdoxan, including the appropriate precautions to be followed by healthcare professionals and patients.

In addition, the company that makes Valdoxan will supply educational material for doctors prescribing Valdoxan. This material explains the safety of the medicine, its interactions with other medicines, and includes guidance on the monitoring of liver function and management of possible symptoms of liver problems. A patient booklet will also be distributed to all patients who are prescribed Valdoxan so that they are aware of the risk to the liver, the importance of monitoring liver function and the signs of liver problems to look out for.

Other information about Valdoxan

The European Commission granted a marketing authorisation valid throughout the European Union for Valdoxan on 19 February 2009.

The full EPAR for Valdoxan 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 Valdoxan read the package leaflet (also part of the EPAR) or contact your doctor or pharmacist.

This summary was last updated in 11-2014.

Valdoxan

EMA/633676/2014

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