Published: 14 December 2018
Publications
MARC media release: Enlafax – Monitoring to Continue
Two separate Ministerial Expert Advisory Groups have concluded that a rise in adverse reaction reporting to a commonly prescribed antidepressant is not caused by medicine safety or quality concerns.
The Medicines Adverse Reactions Committee (MARC) and the Medicines Assessment Advisory Committee (MAAC) made their assessments following a brand switch for the antidepressant: venlafaxine. Both Committees recognised the public concern about Enlafax described in the adverse reaction reports. The MARC were pleased to see that the new online reporting tool for consumers was making it easier for consumers to report their experiences. The Committee found these reports very valuable, allowing them to understand consumers experiences and concerns.
Pharmac’s change to only fund Enlafax XR in September last year triggered a significant increase in reports of suspected adverse reactions to the Centre for Adverse Reactions Monitoring.
The Medicines Adverse Reactions Committee (MARC) - reconsidered the safety of venlafaxine at their meeting earlier this month.
Committee Chair Associate Professor David Reith said it was important to investigate if there was something significantly different about the adverse reaction reports for different brands of venlafaxine which should prompt further action.
He says the large number of reports are concerning, but not unexpected given the response to previous brand switches. The number of reports alone does not mean that there is a safety problem with the medicine. The numbers of reports can be explained by publicity encouraging reporting which may also prompt some loss of confidence in the medicines.
The group’s overall assessment is that the type of events being reported fit with the known adverse reaction profile for all medicines containing venlafaxine. Associate Professor Reith says the Committee understands that many people are undergoing some very distressing experiences. ‘We are very grateful that people have taken the time to report these to CARM. These reports have been thoroughly reviewed as we did when similar reactions were reported to Efexor XR.’
Associate Professor Reith says we have good data on the adverse reactions caused by specific medicines regardless of whether they are originals or copies.
The group were reassured that Medsafe had taken seriously the increase in reports of suicidality and in an exploratory analysis had found no change in the number of people needing hospitalisation for mental health conditions while taking venlafaxine in the six months following the brand switch.
The group’s assessment was that the adverse reactions reported for Enlafax (or medicines containing the same active ingredient) were known or were related to the patient’s condition. Importantly the type of adverse reactions reported did not change with any change in brand.
As lack of choice may be an important factor behind the concerns related to Enlafax the Committee encourages Pharmac to promote its exemption option for the small number of patients unable to move on due to issues they attribute to the brand switch.
Associate Professor Richard Robson chair of the MAAC said, the Committee audited Medsafe’s evaluation of Enlafax and found it to be appropriate; no issues were identified with the evaluation of the product. We agreed that the bioequivalence studies for Enlafax show it is bioequivalent and therefore interchangeable with Efexor. In addition we considered that the manufacturing and testing of the medicine should result in a good quality medicine in line with international standards.
Associate Professor David Reith emphasised that anyone who is experiencing adverse effects from taking their medicine should go to their doctor and seek help as soon as possible.
BACKGROUND
The Medicines Adverse Reactions Committee (MARC) advises the Minister of Health on the safety of medicines. The Committee terms of reference, minutes and reports are published on the Medsafe website. https://medsafe.govt.nz/committees/marc.asp
The Medicines Assessment Advisory Committee (MAAC) provides advice to the Minister of Health on the benefits and risks of new medicines. Further information on this committee is available on the Medsafe website https://medsafe.govt.nz/committees/maac.asp
Enlafax is a generic medicine containing the active ingredient venlafaxine. Generic medicines are approved by Medsafe if they can show bioequivalence with the Innovator medicine. In this case Enlafax was shown to be absorbed to the same amount over the same time as Efexor. The study has been published on the Medsafe website. Enlafax has also been approved in other countries including Australia. https://medsafe.govt.nz/publications/OIA/27SeptRequestForBioequivalenceStudyForEnlafaxXR.pdf
The Centre for Adverse Reactions Monitoring (CARM) are contracted by Medsafe to collect reports of suspected adverse reactions to Medicines. The Centre informs Medsafe and the MARC of safety signals identified from these reports. Summaries of these reports can be found on the Medsafe website https://medsafe.govt.nz/projects/B1/ADRSearch.asp
CARM received four fatal reports for Efexor (the innovator) up to the end of 2010, one linked to suicide.
Adverse reaction reports for Efexor (innovator product) include, 25 cases where the patient required hospital treatment, 9 considered by CARM as life threatening – including four suicide attempts or suicidal tendency.
Adverse reaction reports for Enlafax include 25 reports are considered by CARM to be life threatening; one of persisting disability and 8 which required hospital treatment (received up to end of September 2018).
The data sheets provide information to healthcare professionals on who to prescribe medicines safely and the known side effects. Data sheets are published on the Medsafe website. The Efexor data sheet link: https://medsafe.govt.nz/profs/Datasheet/e/Efexorxrcap.pdf The Enlafax data sheet link: https://medsafe.govt.nz/profs/Datasheet/e/enlafaxXRcap.pdf
Both data sheets acknowledge the risk of worsening symptoms and suicide risk for patients:
The risk of suicide attempt is inherent in depression and may persist until significant remission occurs. The risk must be considered in all depressed patients.
Patients with depression may experience worsening of their depressive symptoms and/or the emergence of suicidality (suicidal ideation and behaviours) whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, all patients treated with venlafaxine should be monitored appropriately and observed closely for clinical worsening and suicidality, especially at the beginning of a course of treatment or at the time of dose changes, either increases or decreases.
Loss of placebo effect may explain some cases where reduced effect was reported. The placebo effect has been defined as a beneficial effect produced by a placebo drug or treatment, which cannot be attributed to the properties of the placebo itself, and must therefore be due to the patient's belief in that treatment. The magnitude of this effect in patients with persistent depressive disorder has been quantified in a meta-analysis as a therapeutic response rate in around 30%. The placebo response was greater when the patient had a reduced chance of being randomly assigned to placebo in a trial. [Meister R, Jansen A, Haerter M et al (2017) ‘Placebo and nocebo reactions in randomized trials of pharmacological treatments for persistent depressive disorder. A meta-regression analysis’ Journal of Affective Disorders 215: 288-298]
The nocebo effect is the opposite of the placebo effect.A nocebo effect describes a negative outcome based on beliefs of harm. The magnitude of this effect has been assessed in placebo controlled trials. A meta-analysis to quantify the effect in patients participating in clinical trials for depression has been published. In patients taking placebo the nocebo effect was so significant and severe that 4.5% of patients had to stop taking the placebo. [Mitsikostas D, Mantonakis L, Chalarakis N. (2014) ‘Nocebo in clinical trials for depression: A meta-analysis’ Psychiatry Research 215:82-86]
Enlafax has been approved in Australia https://www.tga.gov.au/artg/artg-id-143552
Reports of suspected adverse reactions are published on the TGA website https://www.tga.gov.au/database-adverse-event-notifications-daen
