Reboxetine ( Davedax, Edronax ) is a selective noradrenaline reuptake inhibitor antidepressant. It has been licensed in the UK since 1997 for the acute treatment of depressive illness or major depression, and for maintaining the clinical improvement in patients initially responding to treatment.
Reboxetine is also licensed as an antidepressant in Germany, and was assessed for efficacy and safety in 2010, along with two other antidepressants ( Mirtazapine and Bupropion ) by the German Institute for Quality and Efficiency in Health Care ( Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen [ IQWiG ] ). A meta-analysis presenting the main findings of the Institute’s assessment was published in the British Medical Journal in October 2010.
The paper generated significant public interest as the authors concluded from the data that the risks of Reboxetine in the treatment of depression outweighed the benefits. These conclusions raised concerns in other countries where Reboxetine was available, including in the UK.

The MHRA ( Medicines and Healthcare products Regulatory Agency ) and the European Pharmacovigilance Working Party therefore conducted their own review of Reboxetine efficacy and safety, and compared the results to the German analysis.

The European review of Reboxetine efficacy compared Reboxetine to placebo and examined response rates to treatment as an efficacy outcome in 11 placebo-controlled studies.
The German analysis had reviewed data from 13 differentially-controlled clinical studies of Reboxetine ( to either placebo alone; a selective serotonin re-uptake inhibitor [ SSRI ] alone; or both placebo and an SSRI ). This analysis also examined Reboxetine efficacy compared to placebo, but however excluded four of the 11 relevant placebo-controlled studies that were included in the European review.
Response rates were defined as the number of patients who showed a response to treatment, out of the total number of patients in the study. A response to treatment was defined as a greater than or equal to 50% reduction in the Hamilton Depression Rating Scale ( HDRS ) score from baseline to end of study.

For the assessment of Reboxetine safety, the European review examined adverse event data from 13 differentially-controlled clinical trials with Reboxetine ( either compared to placebo, another antidepressant, or both ).
The German analysis had also examined safety data from 13 differentially-controlled clinical trials with Reboxetine ( either compared to placebo, an SSRI, or both ).

Results of European review

Efficacy

The German analysis which assessed the results from seven placebo-controlled trials led the authors to conclude that there was no significant difference in response rates between patients receiving Reboxetine and those receiving placebo ( odds ratio, OR=1.24; p=0.07 ). However the European review, which assessed results from 11 placebo-controlled studies, showed that Reboxetine was statistically significantly more effective than placebo: OR 1.47; p=0<01). Despite the results from the European review showing statistical significance and the German analysis not showing significance, these two results are actually fairly similar. They both point to a small benefit of Reboxetine ( approximately 51% with Reboxetine compared to 44-46% with placebo [ 5-7% difference in response rates ]; lower bounds of confidence intervals: German analysis: 0.98; European review: 1.10 ).
It is questionable whether an overall meta-analysis is the most appropriate way to look at the data as the results were inconsistent between patient groups. The European review subsequently stratified the studies by baseline depression severity ( mild/moderate/severe ) measured using the Hamilton Depression Rating Scale, to examine whether there were any differences in treatment efficacy related to disease severity.
Patients in almost all of the studies had severe depression at baseline; the exceptions were studies 046 and 047 which included patients with a range of baseline severity. In both studies there was a consistent pattern with a substantial trend favouring placebo over Reboxetine in the mild and moderate patients, while the trend favoured Reboxetine in the severe patients, with a difference of about 8% in favour of Reboxetine. Therefore, Reboxetine was markedly more effective in patients with severe depression at baseline, compared to its efficacy in patients with mild or moderate depression. There was no evidence of any benefit for Reboxetine in mild/moderate patients.

General safety data

The German analysis looked at the safety data of eight placebo-controlled Reboxetine trials and found that Reboxetine was associated with higher event rates of patients with at least one adverse event ( OR=2.14 ) and a higher rate of discontinuations due to adverse events ( OR=2.21 ) than placebo.
Out of 13 treatment trials which compared Reboxetine with placebo, an SSRI, or both, there were 18 suicide related events: 6 associated with Reboxetine, 8 SSRI, 4 placebo. The only completed suicide was in the placebo group. There were no statistically significant differences between Reboxetine, SSRIs or placebo for the rate of serious adverse events or suicide-related adverse events.
There was no statistically significant differences between the Reboxetine or the SSRI treatment groups for reporting rates of greater than or equal to 1 non-serious adverse event, or rates of discontinuations due to non-serious adverse events ( OR=1.06; p=0.667 ).

The European review looked at data of 13 trials, for a total of 218 patients examined, which compared Reboxetine with placebo, another antidepressant; 173 adverse events were tabulated.
The most common adverse events occurring with the use of Reboxetine were: dry mouth ( n=67 ), nausea ( n=34 ), insomnia ( n=23 ), headache ( n=16 ), hypotension ( n=12 ), and increased sweating ( n=10 ). These adverse events were already known and are all listed in the product information for Reboxetine ( Summary of Product Characteristics [ SPC ] and Patient Information Leaflet [ PIL ] ). No new safety signals were identified.

Discussion

The European review of Reboxetine efficacy and safety data was triggered by the publication of a German data analysis in which Reboxetine was concluded to be overall, an ineffective and potentially harmful antidepressant. The German analysis calculated that efficacy for Reboxetine ( measured as response rates to treatment ) was not significantly different compared to placebo: OR=1.24; p=0.071. However this calculation was based on data from only seven out of a total 11 placebo-controlled Reboxetine studies.
The European review, which analysed data from all 11 placebo-controlled studies, showed that response rates for Reboxetine were statistically significantly higher than placebo: OR=1.47; p=0.01, providing evidence efficacy for Reboxetine.
The German analysis found that Reboxetine was inferior to placebo for safety measures; however the European review of all available data, which included all 11 placebo-controlled trials, did not identify any previously unrecognised safety concerns associated with Reboxetine, and confirmed the currently recognised side effect profile.

In conclusion, the European review provides evidence that Reboxetine is an effective medicine for patients with moderate or severe clinical depression, and that the balance of benefits and risks for Reboxetine in the treatment of depression remains positive.
It is questionable whether an overall meta-analysis is the most appropriate way to look at the data as the results were inconsistent between patient groups. Factors which may affect the magnitude of the Reboxetine treatment effect include:

a) Care setting - The early studies conducted between 1987-1991 predominantly included inpatients, while the later studies ( 1997-2000 ) were mainly in outpatients. Studies that were conducted in an inpatient setting consistently showed better efficacy results than studies conducted in outpatients, though favourable trends were still seen in the outpatient studies. Therefore, care setting may affect the magnitude of Reboxetine treatment effect, and it may be more effective in hospitalised patients. This could be because of differences in the type of patients likely to be hospitalised compared to those who are not, or because of the way patients are cared for in the hospital setting compared to outpatients. The four studies that were excluded by the German analysis were early studies which were mainly conducted between 1987-1991 in inpatients.

b) Baseline severity of depression - Baseline severity of depression also seemed to affect treatment effectiveness, and it is clear that greater Reboxetine efficacy compared to placebo was only demonstrated in patients with severe depression, not those with mild-moderate severity. This is in line with current clinical guidance, which already recommends that pharmacological treatment of depression is reserved for those with severe depression.

c) Safety - The selective noradrenaline reuptake inhibition of Reboxetine does confer a different risk profile than the SSRIs, with more well-recognised cardiac and urinary adverse reactions that are contained in the product information. Men in particular more frequently report more than one adverse event taking Reboxetine compared to Fluoxetine and these events tend to be urogenital as one would expect from the pharmacology of the drug. However, the European review of available safety data did not identify any previously unrecognised safety concerns associated with Reboxetine and the vast majority of adverse events presented in the clinical study reports are those that are labelled in the SPC and PIL for Reboxetine.

d) Premature discontinuations - Premature discontinuations were also generally lower for Reboxetine in the earlier studies than the later studies, which could also be a function of the hospital setting. Adverse events that cause a discontinuation for an out-patient may not cause discontinuation for a patient in hospital – the smaller number of withdrawals in the hospital setting would give Reboxetine a greater chance to show efficacy. There were consistently lower rates of discontinuation due to adverse events in the inpatient trials compared with outpatient trials, supporting the hypothesis that inpatients may tolerate adverse events in hospital better because of increased care and support, and are more likely to comply with medication given the level of supervision and monitoring provided in the hospital setting. The lower rates of treatment discontinuations due to adverse events coupled with the more favourable efficacy in hospital patients might lead us to form the opinion that perhaps Reboxetine is best placed restricted in use in a hospital setting only. To restrict the use of Reboxetine to patients in a hospital setting only however would prove an unjustifiable burden on the healthcare system and it is not considered necessary to admit patients already taking Reboxetine to hospital for the duration of treatment. For patients already receiving Reboxetine experiencing good clinical effect there is no reason to stop or switch medication from these data. There are no new safety concerns which would necessitate discontinuation of Reboxetine in patients with mild to moderate depression already receiving Reboxetine, if it is considered by their prescriber to be the most appropriate treatment.

Conclusions

Reboxetine is an effective antidepressant. A comprehensive European review of data has shown it has a clear clinical benefit. The results of the review stratified by baseline disease severity show that Reboxetine efficacy is greater in patients with severe depression and has not been shown in patients with mild/moderate disease, which is in line with current clinical guidance.
There are no safety data to suggest any change to the benefit-risk balance of Reboxetine. Overall, it is considered the balance of risks and benefits of Reboxetine remains favourable.

Source: MHRA, 2011

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