Reboxetine

Reboxetine is a drug marketed as an antidepressant for use in the treatment of clinical depression, panic disorder and ADD/ADHD, developed by Pharmacia (now Pfizer). Its mesylate (i.e. methanesulfonate) salt is sold under tradenames including Edronax, Norebox, Prolift, Solvex, Davedax or Vestra. It is approved for use in many European countries, but has not been approved for use in the United States because of a lack of proven efficacy.

According to a meta-analysis of 12 new-generation antidepressants, reboxetine was no more effective than placebo, was "significantly less" effective, and was less acceptable, than the other drugs in treating the acute-phase treatment of adults with unipolar major depression.

According to a systematic review and meta-analysis by IQWiG, including unpublished data, published data on reboxetine overestimated the benefit of reboxetine versus placebo by up to 115% and reboxetine versus SSRIs by up to 23%, and also underestimated harm, concluding that reboxetine was an ineffective and potentially harmful antidepressant. The study also showed that nearly three quarters of the data on patients who took part in trials of reboxetine were not published by Pfizer until now.

Reboxetine has two chiral centers. Thus, four stereoisomers may exist, the (R,R)-, (S,S)-, (R,S)-, and (S,R)-isomers. The active ingredient of reboxetine is a racemic mixture of two enantiomers, the (R,R)-(–)- and (S,S)-(+)-isomer.

Mode of action
Unlike most antidepressants on the market, reboxetine is a norepinephrine reuptake inhibitor (NRI); it does not inhibit the reuptake of serotonin.

Side effects
Common side effects of reboxetine include: dry mouth, constipation, headache, drowsiness, dizziness, excessive sweating and insomnia. Hypertension has been infrequently seen.

In 4 to 8% of all patients treated the medication has to be discontinued due to following reasons (percentages represent mean values):
 * insomnia 1.3%
 * excessive sweating 1.1%
 * vertigo/hypotension and paraesthesia 0.8%
 * dizziness, impotence, and other urological problems 0.5% each

Some other rare side effects include anxiety, loss of appetite, loss of libido, urinary retention in men, pain on ejaculation, increased orgasm intensity, and premature/quickened ejaculation.

Reboxetine is normally well tolerated. So far no attributable fatalities have been noted.

Metabolism
Both the (R,R)-(–) and (S,S)-(+)-enantiomers of reboxetine are predominantly metabolized by the CYP3A4 isoenzyme. The primary metabolite of reboxetine is O-desethylreboxetine, and there are also three minor metabolites&mdash;Phenol A, Phenol B, and UK1, Phenol B being the most minor.

Interactions with other medications
Because of its reliance on CYP3A4, reboxetine O-desethylation is markedly inhibited by papaverine and ketoconazole.

According to Weiss et al., reboxetine is an intermediate-level inhibitor of P-glycoprotein, which gives it the potential to interact with ciclosporin, tacrolimus, paroxetine, sertraline, quinidine, fluoxetine, fluvoxamine.

The potency and duration of the effects of benzodiazepines can be increased because reboxetine interferes with their excretion.

History
By mid-2007, reboxetine was licensed worldwide in over 50 countries, including Italy, Germany and the United Kingdom. In May 2007, however, the Food and Drug Administration declined Pharmacia's license application for the American market. Therefore it is yet to be available in the United States.