Agomelatine (Valdoxan) – New contraindication

Agomelatine (Valdoxan) – New contraindication and a reminder of the importance of liver function monitoring

Agomelatine* is a melatonergic agonist indicated in the treatment of major depressive episodes in adults, which has been authorised for use across the EU since February 2009. Agomelatine exerts its pharmacological effect by agonist activity at the melatonin MT1 and MT2 receptors, and antagonism at the serotonin 5-HT_2C receptor, thereby increasing levels of dopamine and noradrenaline in areas of the brain involved in mood control.

A risk of hepatic adverse effects has been known to be associated with agomelatine since it was first authorised and the product information has included warnings about these risks and the requirement for regular monitoring of liver function tests during treatment with agomelatine. Since then, cases of liver injury, including hepatic failure, elevations of liver enzymes exceeding 10 times the upper limit of normal, hepatitis and jaundice have been reported in patients treated with agomelatine. The majority of these abnormalities occurred during the first months of treatment and the pattern of liver damage appears mainly hepatocellular. When agomelatine was discontinued, the serum transaminases usually returned to normal levels. In December 2012, the IMB highlighted the risk of hepatotoxicity in its Drug Safety Newsletter (51^st edition) as well as in MIMS Ireland (November 2012 issue), and emphasised the importance of liver function monitoring.

As further cases of severe hepatic adverse reactions have been reported the product information is being further updated to contraindicate the use of agomelatine in patients with transaminases exceeding three times the upper limit of normal. Prescribers are again reminded of the existing warnings and the need for liver function monitoring.

Prescribers should also be aware of updates to the product information concerning use in the elderly. Whilst the efficacy and safety of agomelatine (25-50mg/day) have been established in patients < 75 years, no significant effect has been identified in patients 75 years or older. Therefore, considering the lack of significant benefit in very elderly patients (≥75 years) and the vulnerability of this age group, agomelatine should not be used in patients aged 75 years or older.

Advice for Healthcare Professionals

• Do not prescribe agomelatine in the following situations:

-          in patients with hepatic impairment i.e. cirrhosis or active liver disease,

-          in patients with transaminases exceeding 3 times the upper limit of normal,

-          in patients aged 75 years and over (no significant benefit has been documented in this group).

• Caution should be exercised when prescribing agomelatine for patients with risk factors for hepatic injury e.g. obesity/overweight/non-alcoholic fatty liver disease, diabetes, substantial alcohol intake or use of concomitant medicines associated with risk of hepatic injury.
• Liver function tests (LFTs) should be monitored in all patients receiving agomelatine as follows and agomelatine treatment should be discontinued if a patient presents with symptoms or signs of liver injury:

- at initiation of treatment,

- periodically at 3 weeks, 6 weeks (end of acute phase), 12 weeks, 24 weeks (end of maintenance phase) and thereafter,

- when increasing the dose of agomelatine at the same time intervals that apply to initiation of treatment,

- whenever clinically indicated.

• Any patient who develops increased serum transaminases should have their LFTs repeated within 48 hours.
• Patients should be informed of the symptoms of potential liver injury, and should be advised to stop taking agomelatine immediately and to seek urgent medical advice if these symptoms appear.
• Any suspected adverse reactions associated with use of agomelatine should continue to be reported to the IMB in the usual way.

*Product information for agomelatine is available at www.imb.ie