Reboxetine
Encyclopedia
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, including unpublished data, published data on reboxetine overestimated the benefit of reboxetine versus placebo by up to 115% and reboxetine versus SSRIs by up to 23%, and also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 enantiomer
s, the (R,R)-(–)- and (S,S)-(+)-isomer.
(NRI); it does not inhibit the reuptake of serotonin
.
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):
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.
isoenzyme.
The primary metabolite of reboxetine is O-desethylreboxetine, and there are also three minor metabolites—Phenol A, Phenol B, and UK1, Phenol B being the most minor.
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.
, 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
.
Antidepressant
An antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. According to Gelder, Mayou &*Geddes people with a depressive illness will experience a therapeutic effect to their mood;...
for use in the treatment of clinical depression
Clinical depression
Major depressive disorder is a mental disorder characterized by an all-encompassing low mood accompanied by low self-esteem, and by loss of interest or pleasure in normally enjoyable activities...
, panic disorder
Panic disorder
Panic disorder is an anxiety disorder characterized by recurring severe panic attacks. It may also include significant behavioral change lasting at least a month and of ongoing worry about the implications or concern about having other attacks. The latter are called anticipatory attacks...
and ADD/ADHD, developed by Pharmacia (now Pfizer
Pfizer
Pfizer, Inc. is an American multinational pharmaceutical corporation. The company is based in New York City, New York with its research headquarters in Groton, Connecticut, United States...
). 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
Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen
IQWiG, the Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen , is a German agency responsible for assessing the quality and efficiency of medical treatments, including drugs, non-drug interventions , diagnostic and screening methods, and treatment and disease management...
, 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
Chirality (chemistry)
A chiral molecule is a type of molecule that lacks an internal plane of symmetry and thus has a non-superimposable mirror image. The feature that is most often the cause of chirality in molecules is the presence of an asymmetric carbon atom....
. 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 enantiomer
Enantiomer
In chemistry, an enantiomer is one of two stereoisomers that are mirror images of each other that are non-superposable , much as one's left and right hands are the same except for opposite orientation. It can be clearly understood if you try to place your hands one over the other without...
s, the (R,R)-(–)- and (S,S)-(+)-isomer.
Mode of action
Unlike most antidepressants on the market, reboxetine is a norepinephrine reuptake inhibitorNorepinephrine reuptake inhibitor
A norepinephrine reuptake inhibitor or adrenergic reuptake inhibitor , is a type of drug which acts as a reuptake inhibitor for the neurotransmitters norepinephrine and epinephrine by blocking the action of the norepinephrine transporter...
(NRI); it does not inhibit the reuptake of serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
.
Side effects
Common side effectsAdverse drug reaction
An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...
of reboxetine include: dry mouth, constipation
Constipation
Constipation refers to bowel movements that are infrequent or hard to pass. Constipation is a common cause of painful defecation...
, headache, drowsiness, dizziness, excessive sweating and insomnia
Insomnia
Insomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...
. 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 CYP3A4CYP3A4
Cytochrome P450 3A4 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. As a result, CYP3A4 is present in...
isoenzyme.
The primary metabolite of reboxetine is O-desethylreboxetine, and there are also three minor metabolites—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 papaverinePapaverine
Papaverine is an opium alkaloid antispasmodic drug, used primarily in the treatment of visceral spasm, vasospasm , and occasionally in the treatment of erectile dysfunction...
and ketoconazole
Ketoconazole
Ketoconazole is a synthetic antifungal drug used to prevent and treat fungal skin infections, especially in immunocompromised patients such as those with AIDS or those on chemotherapy. Ketoconazole is sold commercially as an anti-dandruff shampoo, topical cream, and oral tablet.Ketoconazole is...
.
According to Weiss et al., reboxetine is an intermediate-level inhibitor of P-glycoprotein
P-glycoprotein
P-glycoprotein 1 also known as multidrug resistance protein 1 or ATP-binding cassette sub-family B member 1 or cluster of differentiation 243 is a glycoprotein that in humans is encoded by the ABCB1 gene...
, which gives it the potential to interact with ciclosporin
Ciclosporin
Ciclosporin , cyclosporine , cyclosporin , or cyclosporin A is an immunosuppressant drug widely used in post-allogeneic organ transplant to reduce the activity of the immune system, and therefore the risk of organ rejection...
, tacrolimus
Tacrolimus
Tacrolimus is an immunosuppressive drug that is mainly used after allogeneic organ transplant to reduce the activity of the patient's immune system and so lower the risk of organ rejection...
, paroxetine
Paroxetine
Paroxetine is an SSRI antidepressant. Marketing of the drug began in 1992 by the pharmaceutical company SmithKline Beecham, now GlaxoSmithKline...
, sertraline
Sertraline
Sertraline hydrochloride is an antidepressant of the selective serotonin reuptake inhibitor class. It was introduced to the market by Pfizer in 1991. Sertraline is primarily used to treat major depression in adult outpatients as well as obsessive–compulsive, panic, and social anxiety disorders in...
, quinidine
Quinidine
Quinidine is a pharmaceutical agent that acts as a class I antiarrhythmic agent in the heart. It is a stereoisomer of quinine, originally derived from the bark of the cinchona tree.-Mechanism:...
, fluoxetine
Fluoxetine
Fluoxetine is an antidepressant of the selective serotonin reuptake inhibitor class. It is manufactured and marketed by Eli Lilly and Company...
, fluvoxamine
Fluvoxamine
Fluvoxamine is an antidepressant which functions as a selective serotonin reuptake inhibitor . Fluvoxamine was first approved by the U.S. Food and Drug Administration in 1993 for the treatment of obsessive compulsive disorder . Fluvoxamine CR is approved to treat social anxiety disorder...
.
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 ItalyItaly
Italy , officially the Italian Republic languages]] under the European Charter for Regional or Minority Languages. In each of these, Italy's official name is as follows:;;;;;;;;), is a unitary parliamentary republic in South-Central Europe. To the north it borders France, Switzerland, Austria and...
, Germany
Germany
Germany , officially the Federal Republic of Germany , is a federal parliamentary republic in Europe. The country consists of 16 states while the capital and largest city is Berlin. Germany covers an area of 357,021 km2 and has a largely temperate seasonal climate...
and the United Kingdom
United Kingdom
The United Kingdom of Great Britain and Northern IrelandIn the United Kingdom and Dependencies, other languages have been officially recognised as legitimate autochthonous languages under the European Charter for Regional or Minority Languages...
. In May 2007, however, the Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
declined Pharmacia's license application for the American market. Therefore it is yet to be available in the United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
.