A signal is defined by WHO as reported information on a possible causal relationship between an adverse event and a drug, the relationship being unknown or incompletely documented previously. Usually more than a single report is required to generate a signal, depending upon the seriousness of the event and the quality of the information. A signal is a hypothesis together with data and arguments and it is important to note that a signal is not only uncertain but also preliminary in nature.
Agomelatine is a potent, non-selective melatonin receptor MT1 and MT2 agonist plus a neutral serotonergic 5-HT2C antagonist indicated for the treatment of major depressive episodes. Inhibition of the 5-HT2C receptor is held responsible for the direct antidepressant effect.
Agomelatine has been authorised in the European Union and other countries for the treatment of major depressive episodes. It has not been authorised in the USA.
Agomelatine is indicated for adults (over 18 years) because of the lack of data in paediatric populations. The recommended dose is 25 to 50 mg daily taken orally at bedtime.
A signal of increased blood pressure identified with Agomelatine from WHO global database of individual case safety reports (VigiBase).
Twenty-four reports have been observed in the WHO global database of individual case safety reports (ICSRs), VigiBase, for blood pressure increased (BPI) under agomelatine treatment.
Signal Detection method:
UMC Disproportionate Reporting: The Information Component (IC)
IC025 is negative (as of 27 June 2019), however, agomelatine is not used in the USA where BPI is more commonly reported overall, and in a disproportionality analysis adjusted for region of origin, the expected value is around 10, rendering a stronger statistical association which would be highlighted as disproportionally reported by IC analysis. This means that if its calculation is restricted to the rest of the world (non-US reports), the IC025 is positive. Moreover, taking the high number of positive dechallenges in the analysed ICSRs into account (where labelled adverse effects of agomelatine abated together with the BPI) and the positive (in one case double) rechallenges, they strongly suggest a positive causal relationship.
Signal Validation details:
The adverse events occurred between December 2012 and November 2017. The ICSRs originated from eight countries: Germany (15 cases), Austria (2), Switzerland (2), and Australia, the Czech Republic, Portugal, South Africa, and Turkey (one each). They were spontaneous reports except 2 cases which came from clinical studies. The reporters were physicians with the exception of 2 cases from non-health-care professionals, one from pharmacist, two from other health-care professionals, and for one case the reporter was unknown.
In 3 cases the outcome was not reported, otherwise, except in 2 cases, the patients recovered. In the reports agomelatine was the only suspected drug, except one case where all those administered except esomeprazole were reported as suspected.
- The cases were analysed first to exclude those where the concomitant medication could cause BPI/hypertension. The European product information of the concomitant drugs (European Medicines Agency webpage or the MRI product index) revealed that, in addition to typical antidepressants (trazodone, paroxetine, venlafaxine, sertraline and clomipramine), pregabalin (used, among others, in cases of generalised anxiety) and ezetimibe (primary hypercholesterinaemia) have hypertension labelled as an adverse effect.
- During the next “filtering”, more cases were excluded: 3 cases where one and a half months, two years and nine months agomelatine treatment before the onset of BPI, one case due to poor reporting, one case according to its narrative, the agomelatine treatment was maintained but the patient’s BP improved, one case where onset of BPI reported on the day of the agomelatine administration, then the treatment was continued with no further data, one case was a suicide attempt, and one case as the patient had an underlying hypertension and, according to the narrative, a reduction of the antihypertensive treatment was made at the time of agomelatine initiation. Thus, only 12 ICSRs remained for detailed analysis.
- Well-controlled arterial hypertension/hypertension as one of the patients’ underlying diseases was reported in 4 cases.
- The reported time to onset of the increased blood pressure was a few hours in one case, three days in another, about seven days in 2 cases, while general statements (such as ”after introduction” or “initiation”, ”since she took it”) indicated that the time to onset seemed to be short. In one case BPI happened “after the dose was increased from 25 mg to 50 mg”.
- In nine cases positive dechallenge (plus in one case reaction abated for dose reduction) while in two cases positive rechallenge were reported.
- It should also be stressed that labelled adverse effects of agomelatine (e.g. migraine, nausea, sweats, anxiety, restlessness, insomnia, dizziness and blurred vision), if they occurred in the analysed cases, also abated at the same time as BPI did. In one case increased heart rate abated together with BPI while the outcome of other events labelled for agomelatine (tiredness, somnolence and headache) was not reported.
- Further search involved with MedDRA term hypertension where 17 reports for hypertension following agomelatine administration were found in VigiBase (13 October 2019). In six of them no concomitant medication was reported and in six other cases, although there was concomitant medication, agomelatine was reported as the only suspect drug. (Only two of these latter six cases also reported concomitant medications which have hypertension as a labelled ADR, i.e. allopurinol and sertraline.) In four cases positive dechallenge also occurred. The time to onset, when it could be identified from the reports, varied from “same day” (three cases) to two days (two cases), and around two weeks (two cases) up to one month or longer (seven cases). Labelled adverse effects of agomelatine occurred and abated together with the hypertension in ten cases.
Literature and labelling search details:
Hypertension/BPI is not listed in the European Summary of Product Characteristics of agomelatine. Furthermore, it states that “agomelatine had neutral effect on heart rate and blood pressure in clinical trials”. (There were clinical trials where hypertension was reported in the agomelatine arm. Its frequency was found to be 1.2% but because of the limited number of the subjects involved and the lack of a placebo arm in this trial, the causality could not be established.)
It is also well-known that people suffering from depression are more likely than the others to develop hypertension.
Experiments have suggested that agomelatine prevents rather than causes hypertension. Moreover, in 2014, the Uppsala Monitoring Centre published a signal on hypotension occurring under agomelatine treatment. In response to the signal the marketing authorisation holder accepted that 5- HT2C/5-HT2B antagonists could induce an antihypertensive effect in animals and/or humans with hypertension, while it did not endorse it as a clinically relevant safety concern.
Melatonin, structurally closely related to agomelatine but binding to the MT receptors exclusively is used for sleep disorders such as short-term primary insomnia or to decrease jet- lag. It is interesting that clinical studies revealed that its use at night an hour before sleep appeared to lower BP. (There is some debate about its mechanism: is it based on serotonin antagonism by melatonin or is it because the subjects had fuller, better quality sleep?) On the other hand, melatonin has hypertension as a labelled adverse effect with a frequency of “uncommon” (that means 0.1 to 1.0%).
It is also well-known that some medicines that usually lower blood pressure may paradoxically increase blood pressure. There are drugs (such as pregabalin, indicated, among others, to generalised anxiety disorders) that have labelled adverse reactions both hypo- and hypertension with the same frequency.
References:
https://www.who.int/publications-detail/who-pharmaceuticals-newsletter-978-92-4-000568-6
European Medicines Agency: Summary of Product Characteristics for agomelatine (Valdoxan). Available from:https://www.ema.europa.eu/en/documents/pro duct-information/valdoxan-epar-product- information_en.pdf. Accessed: 29 May 2019.
Uppsala Monitoring Centre. Agomelatine and Hypertension. WHO Pharm. Newsletter 2014(4): 13-17.
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