Valdoxan (agomelatine) in the treatment of Major Depressive Episodes in Adults. Prescriber Guide Information for Healthcare Professionals

Transcription

1 Important information Do not discard! Valdoxan (agomelatine) in the treatment of Major Depressive Episodes in Adults Prescriber Guide Information for Healthcare Professionals Recommendations regarding: - Liver function monitoring - Interaction with potent CYP1A2 inhibitors Please refer to the Summary of Product Characteristics. Updated Prescribing Information can be found on the last page. Date of preparation : December 2014

2 Valdoxan overview Valdoxan was registered in Europe in February 2009 and is available in the UK since 2009 for the treatment of major depressive episodes in adults. Valdoxan and risk of hepatotoxicity Cases of liver injury*, including hepatic failure (some of which had a fatal outcome or resulted in liver transplantation), elevations of liver enzymes exceeding 10 times upper limit of normal, hepatitis and jaundice have been reported in patients treated with Valdoxan post-marketing. Most of them occurred during the first months of treatment. The pattern of liver damage is predominantly hepatocellular with a rise in serum transaminases which usually return to normal levels following cessation of Valdoxan. Patients with other hepatic risk factors appear to be more vulnerable. *Frequency: rare ( 1/10,000 to <1/1,000) Date of preparation : December 2014 Page 2 of 8

3 Recommendations for liver function monitoring Do not use Valdoxan in cases of - hepatic impairment (i.e. cirrhosis or active liver disease) - or transaminases > 3 X ULN (Upper Limit of Normal) Before starting treatment Carefully evaluate risk factors for hepatic injury e.g - obesity/overweight/non-alcoholic fatty liver disease - diabetes - substantial alcohol intake - concomitant medication associated with risk of hepatic injury Perform baseline liver function tests in every patient before starting treatment: - do not initiate treatment in patients with baseline values of ALT and/or AST > 3 X ULN - exercise caution in patients with baseline values of ALT and/or AST > ULN and 3 X ULN Perform transaminase tests (ALT/AST) in all patients Date of preparation : December 2014 Page 3 of 8

4 If the dose is increased, perform liver function tests at the same frequency as when initiating treatment. If a patient develops increased serum transaminases repeat his/her liver function tests within 48 hours. During treatment Discontinue Valdoxan treatment immediately if: - the patient develops symptoms or signs of potential liver injury (such as dark urine, light-coloured stools, yellow skin/eyes, right upper quadrant abdominal pain, sustained new-onset and unexplained fatigue) - the increase in serum transaminases exceeds 3X ULN Following discontinuation of Valdoxan therapy repeat liver function tests until serum transaminases return to normal. Inform your patients about: - the importance of liver function monitoring - the symptoms of potential liver injury As part of discussions with your patients, please ensure that you give him/her a Patient Alert Card that he/she needs to read and keep during the course of their treatment. The Patient Alert Card will help your patients to understand the recommendations to avoid liver side effects and keep track of his/her blood test appointments. Date of preparation : December 2014 Page 4 of 8

5 Summary of recommendations for liver function monitoring Finding ALT and/or AST increase < 3 X ULN ALT and/or AST increase > 3 X ULN Signs and symptoms of liver injury - dark urine - light coloured stools - yellow skin/eyes - right upper quadrant abdominal pain - sustained new-onset and unexplained fatigue Action needed Repeat the test within 48h Stop treatment immediately, repeat the blood tests until normalisation Stop treatment immediately, repeat the blood tests until normalisation Date of preparation : December 2014 Page 5 of 8

6 Interaction with potent CYP1A2 inhibitors Valdoxan is contraindicated with concomitant use of potent CYP1A2 inhibitors (e.g. fluvoxamine [Flaverin], ciprofloxacin [ciproxin]). Agomelatine is metabolised mainly by cytochrome P450 1A2 (CYP1A2) (90%) and by CYP2C9/19 (10%). Medicines that interact with these isoenzymes may decrease or increase the bioavailability of agomelatine. Fluvoxamine, a potent CYP1A2 and moderate CYP2C9 inhibitor, markedly inhibits the metabolism of agomelatine resulting in an increase in agomelatine exposure. In vivo, agomelatine does not induce CYP450 isoenzymes. Agomelatine inhibits neither CYP1A2 in vivo nor the other CYP450 in vitro. Therefore, Valdoxan is not expected to modify exposure to medicinal products metabolised by CYP450. For Further information Please contact the Medical Information Department of Servier in the UK. Tel: Medical.Information@uk.netgrs.com Servier Laboratories Ltd Wexham Springs Framewood Road Slough SL3 6PJ Date of preparation : December 2014 Page 6 of 8

7 Date of preparation : December 2014 Page 7 of 8

8 Prescribing Information VALDOXAN 25mg tablets Agomelatine Refer to the Summary of Product Characteristics (SPC) before prescribing. Presentation: Orange-yellow, oblong, film-coated tablets (with blue imprint of company logo on one side) containing 25mg of agomelatine. Indication: Treatment of major depressive episodes in adults. Dosage and Administration: Recommended daily dose is one 25 mg tablet taken orally at bedtime. After two weeks treatment, in the absence of symptom improvement, the dose may be increased to 50 mg once daily, taken as a single dose of two tablets at bedtime. Decision of dose increase has to be balanced with a higher risk of transaminases elevation. Any dose increase should be made on an individual patient benefit/risk basis and with strict respect of liver function test (LFT) monitoring. Perform LFTs in all patients before starting treatment. Do not initiate treatment if transaminases exceed 3 X upper limit of normal. Exercise caution before starting treatment and maintain close surveillance throughout treatment, especially if hepatic injury risk factors or concomitant medicinal products associated with risk of hepatic injury are present. Patients with depression should be treated for at least 6 months to ensure freedom from symptoms. Valdoxan may be taken with or without food. Children and adolescents below 18 years of age: Not recommended due to lack of data. Older people <75 years - safety and efficacy have been established; 75 years - No documented effect, therefore Valdoxan should not be used by patients in this age group. No dose adjustment required in relation to age. Patients with renal impairment: Caution in severe or moderate impairment due to limited clinical data. Patients with hepatic impairment: Contraindicated. Switching therapy from SSRI/SNRI antidepressant to agomelatine: Patients may experience discontinuation symptoms after cessation from an SSRI/ SNRI antidepressant. The SSRI/SNRI SPC should be consulted on how to withdraw the treatment to avoid this. Agomelatine can be started immediately while tapering the dosage of an SSRI/SNRI.Treatment discontinuation: No dosage tapering needed. Contraindications: Hypersensitivity to agomelatine or to excipients. Hepatic impairment or transaminases >3 X upper limit of normal. Concomitant potent CYP1A2 inhibitors i.e. fluvoxamine, ciprofloxacin. Precautions: Monitoring liver function: Perform baseline LFTs in all patients and do not initiate treatment in patients with baseline values of ALT and/or AST >3 X upper limit of normal. Perform LFTs before starting treatment or dosage increase and then again at approx. 3, 6, 12, 24 weeks after initiation or dosage increase, with further testing when clinically indicated. Repeat LFTs within 48 hours in any patient developing raised transaminases. Discontinue immediately if symptoms or signs of potential liver injury occur (such as dark urine, light coloured stools, yellow skin/eyes, right upper quadrant abdominal pain, sustained new-onset and unexplained fatigue). Discontinue if transaminases >3 X upper limit of normal and test regularly until they return to normal. Caution in patients with pre-treatment elevated transaminases (>upper limit of normal and 3 X upper limit of normal). Exercise caution in patients with hepatic injury risk factors e.g. obesity/overweight/non-alcoholic fatty liver disease, diabetes, substantial alcohol intake or concurrent treatment associated with risk of hepatic injury. Older people with dementia: Do not use. Patients with history of bipolar disorder, mania or hypomania: Use with caution and discontinue if patient develops manic symptoms. Suicide/suicidal thoughts: Close supervision should accompany initial drug therapy. Carefully monitor patients with a history of suicide-related events. Lactose intolerance: Valdoxan contains lactose patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. Pregnancy: As a precaution, not recommended. Breast-feeding: Discontinue breast-feeding if Valdoxan treatment essential. Interactions: Co-administration with potent CYP1A2 inhibitors e.g. fluvoxamine, ciprofloxacin, is contra-indicated. Agomelatine bioavailability reduced by rifampicin and smoking. No evidence of interactions between Valdoxan and the following: benzodiazepines, lithium, paroxetine, fluconazole or theophylline. As with all antidepressants, combining Valdoxan and alcohol is not advisable. There is no experience of concurrent use of Valdoxan with electroconvulsive therapy. Side effects: Adverse reactions were usually mild or moderate and occurred within first two weeks. Common: nausea, dizziness, headache, somnolence, insomnia, migraine, diarrhoea, constipation, abdominal pain, vomiting, hyperhidrosis, back pain, fatigue, anxiety, increases in AST and ALT. Uncommon: aggression, restless leg syndrome, tinnitus. Rare: mania/hypomania, hepatitis, increases in GGT and ALP, hepatic failure (exceptionally with fatal outcome or liver transplantation in patients with hepatic risk factors.), jaundice, facial oedema and angioedema. Frequency unknown: Suicidal thoughts or behaviour. Consult SPC for full list of side effects. NHS price: tablets. Legal Category: POM. Product Licence Number: EU/01/08/499/003. Further information: Servier Laboratories Ltd., Rowley, Wexham Springs, Slough SL3 6PJ Tel (01753) Date of Revision: November Adverse events should be reported. Reporting forms and information can be found at Adverse events should also be reported to Servier Laboratories Ltd. Tel (01753) Date of preparation : December 2014 Page 8 of 8