Valdoxan

Valdoxan

agomelatine

Manufacturer:

Servier

Distributor:

DKSH
Full Prescribing Info
Contents
Agomelatine.
Description
Each tablet also contains the following excipients: Lactose monohydrate, maize starch, povidone, sodium starch glycolate type A, stearic acid, magnesium stearate, anhydrous colloidal silica, hypromellose, yellow iron oxide (E172), glycerol, macrogol and titanium dioxide (E171). Printing Ink: Shellac, propylene glycol and indigotine (E132) aluminium lake.
Action
Pharmacotherapeutic Group: Other antidepressants. ATC Code: NO6AX22.
Pharmacology: Pharmacodynamics: Mechanism of Action: Agomelatine is a melatonergic agonist (MT1 and MT2 receptors) and 5-HT2C antagonist. Binding studies indicate that agomelatine has no effect on monoamine uptake and no affinity for α, β-adrenergic, histaminergic, cholinergic, dopaminergic and benzodiazepine receptors.
Agomelatine resynchronises circadian rhythms in animal models of circadian rhythm disruption. Agomelatine increases noradrenaline and dopamine release specifically in the frontal cortex and has no influence on the extracellular levels of serotonin.
Agomelatine has shown an antidepressant-like effect in animal models of depression (learned helplessness test, despair test, chronic mild stress) as well as in models with circadian rhythm desynchronisation and in models related to stress and anxiety.
In humans, Valdoxan has positive phase shifting properties; it induces a phase advance of sleep, body temperature decline and melatonin onset.
Clinical Efficacy and Safety: The efficacy and safety of Valdoxan in major depressive episodes have been studied in a clinical programme including 5800 patients of whom 3900 were treated with Valdoxan.
Six (6) placebo-controlled trials have been performed to investigate the short-term efficacy of Valdoxan in major depressive disorder: Two (2) flexible-dose studies and 4 fixed-dose studies. At the end of treatment (over 6 or 8 weeks), significant efficacy of agomelatine 25-50 mg was demonstrated in 3 of the 6 short-term double-blind placebo-controlled studies. Agomelatine failed to differentiate from placebo in 1 study where the active control fluoxetine showed assay sensitivity. In 2 other studies, it was not possible to draw any conclusions because the active controls, paroxetine and fluoxetine, failed to differentiate from placebo.
Efficacy was also observed in more severely depressed patients (baseline HAM-D ≥25) in all positive placebo-controlled studies.
Response rates were statistically significantly higher with Valdoxan compared with placebo.
The maintenance of antidepressant efficacy was demonstrated in a relapse prevention study. Patients responding to 8 or 10 weeks of acute treatment with open-label Valdoxan 25-50 mg once daily were randomised to either Valdoxan 25-50 mg once daily or placebo for further 6 months. Valdoxan 25-50 mg once daily demonstrated a statistically significant superiority compared to placebo (p=0.0001) on the primary outcome measure, the prevention of depressive relapse, as measured by time to relapse. The incidence of relapse during the 6 months double-blind follow-up period was 22% and 47% for Valdoxan and placebo, respectively.
Valdoxan does not alter daytime vigilance and memory in healthy volunteers. In depressed patients, treatment with Valdoxan 25 mg increased slow wave sleep without modification of rapid eye movement (REM) sleep amount or REM latency. Valdoxan 25 mg also induced an advance of the time of sleep onset and minimum heart rate. From the 1st week of treatment, onset and the quality of sleep were significantly improved without daytime clumsiness as assessed by patients.
In a specific sexual dysfunction comparative study with remitted depressed patients, there was a numerical trend (not statistically significant) towards less sexual emergent dysfunction than venlafaxine for sex effects scale (SEXFX) drive arousal or orgasm scores on Valdoxan. The pooled analysis of studies using the Arizona Sexual Experience Scale (ASEX) showed that Valdoxan was not associated with sexual dysfunction. In healthy volunteers, Valdoxan preserved sexual function in comparison with paroxetine.
Valdoxan had neutral effect on body weight, heart rate and blood pressure in clinical studies.
In a study designed to assess discontinuation symptoms by the Discontinuation Emergent Signs and Symptoms (DESS) checklist in patients with remitted depression, Valdoxan did not induce discontinuation syndrome after abrupt treatment cessation.
Valdoxan has no abuse potential as measured in healthy volunteer studies on a specific visual analogue scale or the Addiction Research Center Inventory (ARCI) 49 checklist.
Pharmacokinetics: Absorption and Bioavailability: Agomelatine is rapidly and well (≥80%) absorbed after oral administration. Absolute bioavailability is low (<5% at the therapeutic oral dose) and the interindividual variability is substantial. The bioavailability is increased in women compared to men. The bioavailability is increased by intake of oral contraceptives and reduced by smoking. The peak plasma concentration is reached within 1-2 hrs.
In the therapeutic dose range, agomelatine systemic exposure increases proportionally with dose. At higher doses, a saturation of the first-pass effect occurs.
Food intake (standard meal or high-fat meal) does not modify the bioavailability or the absorption rate. The variability is increased with high-fat food.
Distribution: Steady-state volume of distribution is about 35 L and plasma protein-binding is 95% irrespective of the concentration and is not modified with age and in patients with renal impairment but the free fraction is doubled in patients with hepatic impairment.
Biotransformation: Following oral administration, agomelatine is rapidly metabolised mainly via hepatic CYP1A2; CYP2C9 and CYP2C19 isoenzymes are also involved but with a low contribution.
The major metabolites, hydroxylated and demethylated agomelatine, are not active and are rapidly conjugated and eliminated in the urine.
Elimination: Elimination is rapid, the mean plasma half-life is between 1 and 2 hrs and the clearance is high (about 1100 mL/min) and essentially metabolic.
Excretion is mainly (80%) urinary and in the form of metabolites, whereas unchanged compound recovery in urine is negligible.
Kinetics is not modified after repeated administration.
Renal Impairment: No relevant modification of pharmacokinetic parameters in patients with severe renal impairment has been observed (n=8, single dose of 25 mg), but caution should be exercised in patients with severe or moderate renal impairment as only limited clinical data are available in these patients (see Dosage & Administration).
Hepatic Impairment: In a specific study involving cirrhotic patients with chronic mild (Child-Pugh type A) or moderate (Child-Pugh type B) liver impairment, exposure to agomelatine 25 mg was substantially increased (70 and 140 times, respectively), compared to matched volunteers (age, weight and smoking habit) with no liver failure (see Dosage & Administration, Contraindications and Precautions).
Ethnic Groups: There are no data on the influence of race on agomelatine pharmacokinetics.
Toxicology: Preclinical Safety Data: In mice, rats and monkeys, sedative effects were observed after single and repeated administration at high doses.
In rodents, a marked induction of CYP2B and a moderate induction of CYP1A and CYP3A were seen from 125 mg/kg/day whereas in monkeys, the induction was slight for CYP2B and CYP3A at 375 mg/kg/day. No hepatotoxicity was observed in rodents and monkeys in the repeat-dose toxicity studies.
Agomelatine passes into the placenta and foetuses of pregnant rats.
Reproduction studies in the rat and rabbit showed no effect of agomelatine on fertility, embryofoetal development and pre- and postnatal development.
A battery of in vitro and in vivo standard genotoxicity assays concludes to no mutagenic or clastogenic potential of agomelatine.
In carcinogenicity studies, agomelatine induced an increase in the incidence of liver tumours in the rat and mouse, at a dose at least 110-fold higher than the therapeutic dose. Liver tumours are most likely related to enzyme induction specific to rodents. The frequency of benign mammary fibroadenomas observed in the rat was increased with high exposures (60-fold the exposure at the therapeutic dose) but remains in the range of that of controls.
Safety pharmacology studies showed no effect of agomelatine on human Ether à-go-go Related Gene (hERG) current or on dog Purkinje cells action potential.
Agomelatine did not show proconvulsive properties at ip doses up to 128 mg/kg in mice and rats.
No effect of agomelatine on juvenile animals behavioural performances, visual and reproductive function were observed. There were mild non-dose dependent decreases in body weight related to the pharmacological properties and some minor effects on male reproductive tract without any impairment on reproductive performances.
Indications/Uses
Treatment of major depressive episodes in adults.
Dosage/Direction for Use
Recommended Dose: 25 mg once daily taken orally at bedtime. After 2 weeks of treatment, if there is no improvement of symptoms, the dose may be increased to 50 mg once daily ie, two 25-mg tablets, taken together at bedtime.
Patients with depression should be treated for a sufficient period of at least 6 months to ensure that they are free of symptoms.
Administration: Valdoxan tablets may be taken with or without food.
Overdosage
Symptoms: There is limited experience with agomelatine overdose. Experience with agomelatine in overdose has indicated that epigastralgia, somnolence, fatigue, agitation, anxiety, tension, dizziness, cyanosis or malaise have been reported.
One person having ingested 2450 mg agomelatine, recovered spontaneously without cardiovascular and biology abnormalities.
Management: No specific antidotes for agomelatine are known. Management of overdose should consist of treatment of clinical symptoms and routine monitoring. Medical follow-up in a specialised environment is recommended.
Contraindications
Hypersensitivity to agomelatine or to any of the excipients of Valdoxan.
Hepatic impairment (ie, cirrhosis or active liver disease) (see Precautions).
Concomitant use of potent CYP1A2 inhibitors (eg, fluvoxamine and ciprofloxacin) (see Interactions).
Special Precautions
Monitoring of Liver Function: Cases of liver injury, including hepatic failure, elevations of liver enzymes exceeding 10 times upper limit of normal, hepatitis and jaundice have been reported in patients treated with Valdoxan in the post-marketing setting (see Adverse Reactions). Most of them occurred during the 1st months of treatment. The pattern of liver damage was predominantly hepatocellular. When Valdoxan was discontinued in these patients, the serum transaminases usually returned to normal levels. Liver function tests should be performed in all patients: At initiation of treatment and then periodically after around 3 weeks, 6 weeks (end of acute phase), after around 12 and 24 weeks (end of maintenance phase) and thereafter when clinically indicated. When increasing the dosage, liver function tests should again be performed at the same frequency as when initiating treatment. Any patient who develops increased serum transaminases should have his/her liver function tests repeated within 48 hrs. Therapy should be discontinued if the increase in serum transaminases exceeds 3 times upper limit of normal and liver function tests should be performed regularly until serum transaminases return to normal.
If symptoms or signs of potential liver injury (eg, dark urine, light coloured stools, yellow skin/eyes, pain in the upper right belly, sustained new-onset and unexplained fatigue) are present, Valdoxan treatment should be discontinued immediately.
Caution should be exercised when Valdoxan is administered to patients with pre-treatment elevated transaminases (greater than the upper limit of the normal ranges and ≤3 times the upper limit of the normal range). Caution should be exercised when prescribing Valdoxan for patients with hepatic injury risk factors eg, obesity/overweight/non-alcoholic fatty liver disease, diabetes, substantial alcohol intake or concomitant medicinal products associated with risk of hepatic injury.
Bipolar Disorder/Mania/Hypomania: Valdoxan should be used with caution in patients with a history of bipolar disorder, mania or hypomania and should be discontinued if a patient develops manic symptoms (see Adverse Reactions).
Suicide/Suicidal Thoughts: Depression is associated with an increased risk of suicidal thoughts, self-harm and suicide (suicide-related events). This risk persists until significant remission occurs. As improvement may not occur during the first few weeks or more of treatments, patients should be closely monitored until such improvement occurs. It is general clinical experience that the risk of suicide may increase in the early stages of recovery.
Patients with a history of suicide-related events or those exhibiting a significant degree of suicidal ideation prior to commencement of treatment are known to be at greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment. A meta-analysis of placebo-controlled clinical trials of antidepressants in adult patients with psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo, in patients <25 years.
Close supervision of patients and in particular those at high risk should accompany treatment especially in early treatment and following dose changes. Patients (and caregivers of patients) should be alerted to the need to monitor for any clinical worsening, suicidal behaviour or thoughts and unusual changes in behaviour and to seek medical advice immediately if these symptoms are present.
Combination with CYP1A2 Inhibitors (see Contraindications and Interactions): Combination with potent CYP1A2 inhibitors is contraindicated. Caution should be exercised when prescribing Valdoxan with moderate CYP1A2 inhibitors (eg, propranolol, grepafloxacine, enoxacine) which may result in increased exposure of agomelatine.
Lactose Intolerance: Valdoxan contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take Valdoxan.
Renal Impairment: No relevant modification in agomelatine pharmacokinetic parameters in patients with severe renal impairment has been observed. However, only limited clinical data on the use of Valdoxan in depressed patients with severe or moderate renal impairment with major depressive episodes are available. Therefore, caution should be exercised when prescribing Valdoxan to these patients.
Hepatic Impairment: Valdoxan is contraindicated in patients with hepatic impairment (see Contraindications, Precautions and Pharmacology: Pharmacokinetics under Actions).
Treatment Discontinuation: No dosage tapering is needed on treatment discontinuation.
Effects on the Ability to Drive or Operate Machinery: No studies on the effects on the ability to drive and use machines have been performed. However, considering that dizziness and somnolence are common adverse reactions, patients should be cautioned about their ability to drive a car or operate machinery.
Impairment of Fertility: Reproduction studies in the rat and the rabbit showed no effect of agomelatine on fertility (see Pharmacology: Toxicology under Actions).
Use in Pregnancy: There are no or limited amount of data (<300 pregnancy outcomes) from the use of agomelatine in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see Pharmacology: Toxicology under Actions). As a precautionary measure, it is preferable to avoid the use of Valdoxan during pregnancy.
Use in Lactation:
It is not known whether agomelatine/metabolites are excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of agomelatine/metabolites in milk (see Pharmacology: Toxicology under Actions). A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breastfeeding or to discontinue/abstain from Valdoxan therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.
Use in Children: Valdoxan is not recommended in the treatment of depression in patients <18 years since safety and efficacy of Valdoxan have not been established in this age group. In clinical trials among children and adolescents treated with other antidepressants, suicide-related behaviour (suicide attempt and suicidal thoughts), and hostility (predominantly aggression, oppositional behaviour and anger) were more frequently observed compared to those treated with placebo.
Use in the Elderly: Efficacy has not been clearly demonstrated in the elderly (≥65 years). Only limited clinical data are available on the use of Valdoxan in elderly patients ≥65 years with major depressive episodes. Therefore, caution should be exercised when prescribing Valdoxan to these patients. Elderly Patients with Dementia: Valdoxan should not be used for the treatment of major depressive episodes in elderly patients with dementia since the safety and efficacy of Valdoxan have not been established in these patients.
Use In Pregnancy & Lactation
Use in Pregnancy: There are no or limited amount of data (<300 pregnancy outcomes) from the use of agomelatine in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see Pharmacology: Toxicology under Actions). As a precautionary measure, it is preferable to avoid the use of Valdoxan during pregnancy.
Use in Lactation:
It is not known whether agomelatine/metabolites are excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of agomelatine/metabolites in milk (see Pharmacology: Toxicology under Actions). A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breastfeeding or to discontinue/abstain from Valdoxan therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.
Adverse Reactions
In clinical trials, over 7200 depressed patients have received Valdoxan.
Adverse reactions were usually mild or moderate and occurred within the first 2 weeks of treatment. The most common adverse reactions were nausea and dizziness.
These adverse reactions were usually transient and did not generally lead to cessation of therapy.
Depressed patients display a number of symptoms that are associated with the illness itself. It is therefore sometimes difficult to ascertain which symptoms are a result of the illness itself and which are a result of treatment with Valdoxan.
Adverse reactions are listed as follows using the following convention: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/10,000), not known (cannot be estimated from the available data). The frequencies have not been corrected for placebo.
Psychiatric Disorders: Common: Anxiety. Uncommon: Agitation and related symptoms* (eg, irritability and restlessness), aggression*, nightmares*, abnormal dreams*. Rare: Mania/hypomania*. These symptoms may also be due to the underlying disease (see Precautions). Hallucinations*. Frequency Not Known: Suicidal thoughts or behaviour (see Precautions).
Nervous System Disorders: Common: Headache, dizziness, somnolence, insomnia, migraine. Uncommon: Paraesthesia.
Eye Disorders: Uncommon: Blurred vision.
Gastrointestinal Disorders: Common: Nausea, diarrhoea, constipation, abdominal pain, vomiting*.
Hepatobiliary Disorders: Common: Increased ALAT and/or ASAT (in clinical trials, increases >3 times the upper limit of the normal range for ALAT and/or ASAT were seen in 1.4% of patients on agomelatine 25 mg daily and 2.5% on agomelatine 50 mg daily vs 0.6% on placebo). Rare: Hepatitis, increased γ-glutamyltransferase* (GGT) (>3 times the upper limit of the normal range), increased alkaline phosphatase* (>3 times the upper limit of the normal range), hepatic failure*, jaundice*.
Skin and Subcutaneous Tissue Disorders: Common: Hyperhidrosis. Uncommon: Eczema, pruritus*, urticaria*. Rare: Erythematous rash, face oedema and angioedema*.
Musculoskeletal and Connective Tissue Disorders: Common: Back pain.
General Disorders and Administration Site Conditions: Common: Fatigue.
Investigations: Rare: Increased and decreased weight*.
*Frequency estimated from clinical trials for adverse events detected from spontaneous report.
Drug Interactions
Potential Interactions Affecting Agomelatine: Agomelatine is metabolised mainly by cytochrome P-450 1A2 (CYP1A2) (90%) and by CYP2C9/19 (10%). Medicinal products 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 a 60-fold (range 12-412) increase of agomelatine exposure.
Consequently, co-administration of Valdoxan with potent CYP1A2 inhibitors (eg, fluvoxamine, ciprofloxacin) is contraindicated.
Combination of agomelatine with oestrogens (moderate CYP1A2 inhibitors) results in a several fold increased exposure of agomelatine. While there was no specific safety signal in the 800 patients treated in combination with oestrogens, caution should be exercised when prescribing agomelatine with other moderate CYP1A2 inhibitors (eg, propranolol, grepafloxacine, enoxacine) until more experience has been gained (see Precautions).
Rifampicin an inducer of all 3 cytochromes involved in the metabolism of agomelatine may decrease the bioavailability of agomelatine.
Smoking induces CYP1A2 and has been shown to decrease the bioavailability of agomelatine, especially in heavy smokers (≥15 cigarettes/day) (see Pharmacology: Pharmacokinetics under Actions).
Potential for Agomelatine to Affect Other Medicinal Products: In vivo, agomelatine does not induce CYP450 isoenzymes. Agomelatine inhibits neither CYP1A2 in vivo nor the other CYP450 in vitro. Therefore, agomelatine will not modify exposure to medicinal products metabolised by CYP450.
Medicinal Products Highly Bound to Plasma Protein: Agomelatine does not modify free concentrations of medicinal products highly bound to plasma proteins or vice versa.
Others: No evidence of pharmacokinetic or pharmacodynamic interaction with medicinal products which could be prescribed concomitantly with Valdoxan in the target population was found in phase I clinical trials: Benzodiazepines, lithium, paroxetine, fluconazole and theophylline.
Alcohol: The combination of Valdoxan and alcohol is not advisable.
Electroconvulsive Therapy (ECT): There is no experience of concurrent use of agomelatine with ECT. Animal studies have not shown proconvulsant properties (see Pharmacology: Toxicology under Actions). Therefore, clinical consequences of ECT concomitant treatment with Valdoxan are considered to be unlikely.
Paediatric Population: Interaction studies have only been performed in adults.
Storage
Store below 30°C.
Shelf-Life: 3 years.
MIMS Class
ATC Classification
N06AX22 - agomelatine ; Belongs to the class of other antidepressants.
Presentation/Packing
FC tab 25 mg (orange-yellow, oblong, with blue imprint of company logo on one side) x 28's.
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