View source for Fluvoxamine

{{distinguish|Fluoxetine}}
{{Drugbox| Watchedfields = changed
| verifiedrevid = 312930285
|
|IUPAC_name = (''E'')-5-methoxy-1-[4-(trifluoromethyl)phenyl]pentan-1-one ''O''-2-aminoethyl oxime
| image = Fluvoxamine structure.svg
| width = 180px
| CASNo_Ref = {{cascite}}
| CAS_number=54739-18-3
| ChemSpiderID = 4481878
| ATC_prefix=N06
| ATC_suffix=AB08
| ATC_supplemental=
| PubChem=5324346
| DrugBank=APRD00425
| C=15 | H=21 | F=3 | N=2 | O=2
| molecular_weight = 318.335
| bioavailability= 77%
| metabolism = [[Hepatic]]
| elimination_half-life= 15.6 hours
| excretion = [[Renal]]
| pregnancy_category = C
| legal_US = Rx-only
| legal_AU = S4
| routes_of_administration= Oral
}}
'''Fluvoxamine''' (brand name '''Luvox''', earlier also '''Fevarin''') is an [[antidepressant]] which functions as a [[selective serotonin reuptake inhibitor]] (SSRI). Fluvoxamine was first approved by the [[Food and Drug Administration (United States)|U.S. Food and Drug Administration]] (FDA) in 1993 for the treatment of [[obsessive compulsive disorder]] (OCD).<ref>[http://www.toddlertime.com/med/luvox.htm ToddlerTime.com | What is Luvox?]</ref> Fluvoxamine CR (controlled release) is approved to treat [[social anxiety disorder]].<ref name="Stahl, S. Stahl's Essential Psychopharmacology 2009. pp.215">Stahl, S. Stahl's Essential Psychopharmacology: The Prescriber's Guide. Cambridge University Press. New York, NY. 2009. pp.215</ref> Fluvoxamine is also prescribed to treat [[major depressive disorder|major depression]] and [[anxiety disorders]], such as [[generalized anxiety disorder]] (GAD), [[panic disorder]], and [[post-traumatic stress disorder]] (PTSD).<ref>{{cite journal | first = David P. Figgitt | last = Karen J. McClellan | date = Drugs October 2000 | title = Fluvoxamine An Updated Review of its Use in the Management of Adults with Anxiety Disorders | journal = Adis Drug Evaluation | volume = 60 | issue = 4 | pages = 925–954}}</ref>

==History==
Fluvoxamine was developed by [[Solvay (company)|Solvay Pharmaceuticals]] and was the first non-[[tricyclic antidepressant|TCA]] drug approved by the U.S. Food and Drug Administration (FDA) specifically for the treatment of OCD.<ref>[http://www.brainphysics.com/medications.php Pharmalot | BrainPhysics.com| Medications for OCD]</ref> It was one of the first SSRI antidepressants to be launched (1984 in Switzerland), and following its FDA approval in 1993, it was launched in the U.S. in December 1994, Australia in February 1999 and Japan in June 1999.<ref>[http://www.solvay.com.au/default.asp?page=therapeutic+areas/neuroscience/ Solvay Pharmaceuticals Australia | Luvox]</ref> 

At the end of 1995, more than 10 million patients worldwide had been treated with fluvoxamine.<ref>{{cite journal | first = | last =  | year = 1999 | title = | journal = Fluvoxamine Product Monograph | volume = | issue = | pages = }}</ref> 

Fluvoxamine was the first SSRI to be registered for the treatment of obsessive compulsive disorder in children by the FDA in 1997.<ref>{{cite journal | first = | last =  | date =  | title = Luvox Approved For Obsessive Compulsive Disorder in Children and Teens | journal = Http://www.pslgroup.com/dg/2261a.htm | volume = | issue = | pages = }}</ref>

Fluvoxamine was the first drug approved for the treatment of social anxiety disorder in Japan in 2005.<ref>{{cite journal | first = | last =  | date = | title = Solvay’s Fluvoxamine maleate is first drug approved for the treatment of social anxiety disorder in Japan | journal = Http://www.solvaypress.com/pressreleases/0,,33713-2-83,00.htm | volume = | issue = | pages = }}</ref>

In 1999, fluvoxamine came under great public scrutiny after it was discovered that [[Eric Harris and Dylan Klebold|Eric Harris]], one of the two teenage shooters involved in the [[Columbine High School massacre]], had been taking the drug. Many immediately pointed fingers at fluvoxamine and its manufacturer Solvay Pharmaceuticals.<ref name="DenverPost">{{cite news |url=http://www.denverpost.com/golf/ci_5094436 |title=Judge: Seal Columbine papers for 25 years |accessdate=2008-03-03 |date=January 26, 2007 |format= |work=The Denver Post}}</ref> Sales fell, and Solvay withdrew the medication from the U.S. market in 2002.<ref>{{cite journal | first = | last =  | date = | title =Solvay Pharmaceuticals, Inc. Withdraws LUVOX  | journal = Http://www.solvaypharmaceuticals-us.com/newsroom/pressreleases/0,,14517-2-0,00.htm | volume = | issue = | pages = }}</ref>

In 2007, Solvay re-introduced Luvox to the U.S., which is now manufactured by Palo Alto, California-based Jazz Pharmaceuticals, Inc. A generic version of Luvox is available from [[IVAX Pharmaceuticals]], Inc.

On February 28, 2008, the FDA approved a controlled-release formulation of fluvoxamine, to be marketed as '''Luvox CR'''.<ref>{{cite web |url=http://www.jazzpharma.com/news.php?id=59 |title=Jazz Pharmaceuticals press release, February 28, 2008 – FDA APPROVES LUVOX CR (FLUVOXAMINE MALEATE) EXTENDED-RELEASE CAPSULES FOR THE TREATMENT OF SOCIAL ANXIETY DISORDER (SAD) AND OBSESSIVE COMPULSIVE DISORDER (OCD)  |accessdate=2008-03-14 |format= |work= }}</ref><ref>{{ cite web |title=Luvox CR | Prescribing Info |url=http://www.luvoxcr.com/LUVOX-CR-PI.pdf |accessdate=2008-02-21}}</ref>

==Indications==
Fluvoxamine is widely prescribed to treat major depressive disorder, and anxiety disorders such as obsessive compulsive disorder (OCD), generalized anxiety disorder (GAD), panic disorder, social phobia, and post-traumatic stress disorder (PTSD). Fluvoxamine is indicated for children and adolescents with OCD,<ref>{{cite journal | first = | last = | month = March | year = 2005 | title = US-FDA Fluvoxamine Product Insert | journal = | volume = | issue = | pages = }}</ref> and the CR form is also indicated for [[social anxiety disorder]].<ref name="Stahl, S. Stahl's Essential Psychopharmacology 2009. pp.215"/>

==Unapproved/off-label/investigational==
Fluvoxamine may help in the treatment of [[Irritable Bowel Syndrome]].<ref>{{cite journal | first = et al. | last = Emmanuel | year = 1997 | title = Treatment of Irritable Bowel Syndrome with Fluvoxamine | journal = Am J Psychiatry | volume = 154 | issue = 5| pages = 711–712 | pmid = 9137135 | last2 = Lydiard | first2 = RB | last3 = Crawford | first3 = M}}</ref>

==Side effects==
[[File:Luvox.jpg|250px|thumb|right|Luvox 100 mg scored tablets ([[Australia|AU]])]]
[[Adverse effect (medicine)|Side effects]] most commonly observed with fluvoxamine include nausea, vomiting, drowsiness, difficulty sleeping, dizziness, nervousness, feeling anxious, dry mouth, abdominal pain, constipation, diarrhea, heart burn, loss of appetite, muscle weakness, pins and needles, abnormal taste, headache, faster heart beat, sweating, weight gain, weight loss or unusual bruising. Other side effects which are observed more frequently in children include abnormal thoughts or behaviour, cough, increased period pain, nose bleeds, increased restlessness, infection and sinusitis.<ref>[http://www.betterhealth.vic.gov.au/BHCV2/bhcmed.nsf/pages/smcluvox/$File/smcluvox.pdf Better Health Channel | Consumer Medicine Information]</ref><ref>[http://www.mydr.com.au/medicines/cmis/luvox-tablets myDr | Consumer Medicine Information]</ref>

Sexual side effects with fluvoxamine are less pronounced than with other SSRIs.<ref>{{cite journal | first = Waldinger MD | last = Hengeveld VW et al. | last2 = Hengeveld | year = 1998 | first2 = MW | last3 = Zwinderman | first3 = AH | last4 = Olivier | first4 = B | title = Effect of SSRI antidepressants on ejaculation: a double blind, randomised, placebo-controlled study with fluoxetine, fluvoxamine, paroxetine and sertraline | journal = Journal of Clinical Psychopharmacology | volume = 18 | pmid = 9690692 | issue = 4| pages = 274–281 | doi = 10.1097/00004714-199808000-00004}}</ref><ref>{{cite journal| last = Riley| first = A.
  | authorlink = | coauthors =  R.T. Segraves| title = Treatment of Premature Ejaculation| journal = Int J. Clin Pract.| volume = 60| issue = 6| pages = 694–697| publisher = Blackwell Publishing| location = | year = 2006| pmid = 16805755| url = http://www.medscape.com/viewarticle/533889_print| doi = 10.1111/j.1368-5031.2006.00818.x| id = | accessdate = 2008-02-01}}</ref><ref>http://www.ncbi.nlm.nih.gov/pubmed/19440080</ref>

==Pharmacology==
Fluvoxamine is a potent and selective [[serotonin reuptake inhibitor]] with approximately 100-fold affinity for the [[serotonin transporter]] over the [[norepinephrine transporter]]. It has negligible affinity for the [[dopamine transporter]] or any other [[receptor (biochemistry)|receptor]], with the sole exception of the [[sigma-1 receptor|σ<sub>1</sub> receptor]]. It behaves as a potent [[agonist]] at this receptor and has the highest affinity of any SSRI for doing so. This may contribute to its antidepressant and anxiolytic effects. Indeed, other SSRIs which also act as [[sigma-1 receptor|σ<sub>1</sub> receptor]] agonists, such as [[sertraline]] and [[escitalopram]] (not verified but likely to be), display enhanced antidepressant efficacy.<ref>{{cite journal | first = Narita N | last = Hashimoto K et al. | year = 1996 | title = Interactions of selective reuptake inhibitors with subtypes of sigma receptor in rat brain | journal = Eur J Pharmacol| volume = 307 | issue = 1| pages = 117–9 | doi = 10.1016/0014-2999(96)00254-3 | pmid = 8831113 | last2 = Hashimoto | first2 = K | last3 = Tomitaka | first3 = S | last4 = Minabe | first4 = Y}}</ref> suggesting that it may have particular benefits in the treatment of depressed patients who show features of anxiety/stress and for whom memory impairment is particularly undesirable (such as in depressed elderly patients, and also in treating psychotic depression).<ref>{{cite journal | first = Carrasco JL | last = C.Sandner | month = December | year = 2005 | title = Clinical effects of pharmacological variations in selective serotonin reuptake inhibitors: an overview | journal = International Journal of Clinical Practice | volume = 59 | issue = 12 | pages = 1428–1434 | doi = 10.1111/j.1368-5031.2005.00681.x | pmid = 16351675 | last2 = Sandner | first2 = C}}</ref> In fact, the TCA [[opipramol]], a σ<sub>1</sub> receptor agonist without effects on the serotonin, dopamine, or norepinephrine systems, has considerable antidepressant and efficacy in its own right.

==Pharmacokinetics==
===Absorption===
The oral absorption of fluvoxamine is equal to or more than 94%.

===Distribution===
The plasma protein binding is only about 76%.

===Metabolism===
Fluvoxamine is strongly metabolized in the liver, mostly by the processes of oxidative demethylation(1) and deaminiation(2), which, respectively, create the three metabolites: fluvoxamine acid(by mechanism 1), it's N-acytylated analog(1), fluvoxethanol(2), of which only the first has been shown to have an affinity as a SERT inhibitor, roughly 100% - 200%, or 1-2 orders of magnitude, less potent than the active parent compound.<ref name="Rxlist Data">{{ cite web |title=Luvox Tablets (Fluvoxamine Maleate) Drug Information: Uses, Side Effects, Drug Interactions and Warnings at RxList |url=http://www.rxlist.com/luvox-drug.htm |accessdate=2009-02-17 }}</ref>

Radio-labeled administration of a dose of fluvoxamine produced nine identifiable metabolites, constituting 85% of the absorbed dosage. Of this base parent-metabolic percentage, 60% of the isolate was empirically proven to be fluvoxamine acid, and it's N-acytylated analog, 10% fluvoxethanol, logically deducible is that the additional 15% consisted of the remaining six identified metabolites of the parent compound.<ref name="Rxlist Data" />

===Elimination===
Fluvoxamine has the shortest [[half-life]] of all SSRIs; its mean [[Blood serum|serum]] half-life is 15.6 hours.<ref>Center for Drug Evaluation and Research, (2000). Fluvoxamine Maleate Tablets. Application Number: 75901, Retrieved July 28, 2008, from http://www.fda.gov/cder/foi/anda/2000/75901_Fluvoxamine%20Maleate_Prntlbl.pdf</ref>

==Drug interactions==
Fluvoxamine has a low potential for the [[drug interaction]]s which are based on inhibition of enzyme [[Cytochrome P450]] [[CYP2D6]]. Fluvoxamine shows the least interaction of the SSRIs, in regard to this specific enzyme.<ref>{{cite journal | first = Baumann | last = P. | year = 1996 | title = Pharmacokinetic-pharmacodynamic relationship of the Selective serotonin reuptake inhibitors | journal = Clinical Pharmacokinetics | volume = 31 | issue = 6| pages = 444–469 | doi = 10.2165/00003088-199631060-00004 | pmid = 8968657}}</ref><ref>{{cite journal | first = DeVane CL | last = Gill HS | year = 1997 | title = Clinical Pharmacokinetics of Fluvoxamine: applications to dosage regime design | journal = Journal of Clinical Psychiatric | volume = 58 | issue = Suppl 5 | pages = 7–14}}</ref><ref>{{cite journal | first =  CL | last = DeVane| year = 1998 | title = Translational pharmacokinetics: current issues with newer antidepressants | journal = Depression and Anxiety | volume = 8 | issue = Suppl 1 | pages = 64–70 | doi = 10.1002/(SICI)1520-6394(1998)8:1+<64::AID-DA10>3.0.CO;2-S | pmid =  9809216}}</ref>
Naturally the other SSRIs which are metabolized by CYP2D6 will have more CYP2D6-based interactions with [[tricyclic antidepressant|TCAs]], [[antiarrhythmics]], [[B-blockers]], [[phenytoin]], [[opioids]] and [[neuroleptics]].

Fluvoxamine does, however, inhibit cytochrome P450 enzyme [[CYP1A2]], which metabolises [[agomelatine]], [[caffeine]], [[clozapine]], [[haloperidol]], [[phenacetin]], [[tacrine]], [[theophylline]], and [[olanzapine]]. These substances can cause increased serum levels when administered together with fluvoxamine. Of major concern is the fact that the [[polycyclic aromatic hydrocarbons]] found in [[tobacco smoke]] are potent inducers of CYP1A2 so that smokers may require significant modification of medication dosage.<ref>{{cite journal| last = Kroom| first = Lisa A.| authorlink = | coauthors = | title = Drug Interactions With Smoking| journal = Am J Health-Syst Pharm.| volume = 64| issue = 18| pages = 1917–1921| publisher = American Society of Health-System Pharmacists| location = Medscape| date = 10-01-2007| url = http://www.medscape.com/viewarticle/562754_print| doi = 10.2146/ajhp060414| id = | accessdate = 2008-01-31| pmid = 17823102}}</ref> A recent warning has been published regarding potentially serious interaction with [[tizanidine]], based on CYP1A2 metabolism.<ref>{{cite web| last = Waknine| first = Yael| authorlink = | coauthors = | title = Prescribers Warned of Tizanidine Drug Interactions| work = Medscape News| publisher = Medscape| date = April 13, 2007| url = http://www.medscape.com/viewarticle/555194_print| format = | doi = | accessdate = 2008-02-01}}</ref>

Fluvoxamine inhibits metabolism of [[diazepam]] and [[phenytoin]] via [[CYP2C19]] and metabolism of [[aripiprazole]], [[chlorpromazine]], [[clozapine]], [[haloperidol]], [[olanzapine]], [[perphenazine]], [[risperidone]], [[thioridazine]] and [[zuclopenthixol]] via [[Cytochrome P450|CYP2D6]] as well as of [[aripiprazole]], [[clozapine]], [[haloperidol]], [[quetiapine]], [[risperidone]] and [[ziprasidone]] via [[Cytochrome P450|CYP3A4]].<ref>{{cite journal| last = Bondy| first = Brigitta| authorlink = 
  | coauthors = Illja Spellmann| title = Pharmacogenetics of Antipsychotics: Useful For the Clinician?
  | journal = Curr Opin Psychiatry| volume = 20| issue = 1| pages = 126–130| publisher = Lippincott Williams & Wilkins| location = Medscape| year = 2007| url = http://www.medscape.com/viewarticle/552100_print| doi = 10.1097/YCO.0b013e328017f69f
  | id = | accessdate = 2008-02-01| pmid = 17278909 }}</ref>

The plasma protein binding of fluvoxamine is about 77%. Drugs with low protein binding are less likely to displace other protein bound drugs, and therefore have a lower potential to cause protein binding-related drug interactions.

Fluvoxamine also inhibits [[CYP2C9]].<ref name="Rxlist Data" /><ref name="half-life">{{cite web |title=Brain Elimination Half-Life of Fluvoxamine |url=http://ajp.psychiatryonline.org/cgi/content/full/155/3/380 }}</ref>
<!--
==Appearance in popular culture==

The drug was given visibility in the American television series [[The Sopranos]] produced by [[HBO]], in the second season, episode 10. Dr. [[Jennifer Melfi]], the psychiatrist treating the character named [[Tony Soprano]], is prescribed Luvox by her own psychiatrist, to treat a strong inclination toward alcohol.

"Stuttering" John Melendez, formerly of The Howard Stern Show, had taken Luvox for a period of time before his departure from the show.
-->

==Chemistry==
Fluvoxamine is one of the few SSRIs to have a monocyclic structure.
[[File:Fluvoxamine rxn.png|500px]]<ref>A. Korkuczanski (1958). Przemysł chemiczny, 37, 162.</ref>

==See also==
*[[SSRI discontinuation syndrome]]
*[[Selective serotonin reuptake inhibitor]]

==References==
{{reflist|1}}

{{Antidepressants}}
{{Anxiolytics}}
{{Serotonergics}}

==External links==
* [http://www.drugs.com/cons/Fluvoxamine.html Drugs.com | Fluvoxamine]
* [http://www.rxlist.com/cgi/generic/fluvox.htm RxList.com | Fluvoxamine]

[[Category:Selective serotonin reuptake inhibitors]]
[[Category:Sigma agonists]]
[[Category:Oximes]]
[[Category:Ethers]]
[[Category:Organofluorides]]

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