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Fluvoxamine chemical structure
Fluvoxamine

(E)-5-methoxy-1-[4-(trifluoromethyl)phenyl]pentan-1-one O-2-aminoethyl oxime
IUPAC name
CAS number
54739-18-3
ATC code

N06AB08

PubChem
5324346
DrugBank
DB00176
Chemical formula {{{chemical_formula}}}
Molecular weight 318.335
Bioavailability 77%
Metabolism Hepatic
Elimination half-life 15.6 hours
Excretion Renal
Pregnancy category C
Legal status {{{legal_status}}}
Routes of administration Oral


Fluvoxamine (brand name Luvox) is an antidepressant which functions as a selective serotonin reuptake inhibitor (SSRI). Fluvoxamine was first approved by the U.S. Food and Drug Administration (FDA) in 1993 for the treatment of obsessive compulsive disorder (OCD).[1] Fluvoxamine CR (controlled release) is approved to treat social anxiety disorder.[2] Fluvoxamine is also prescribed to treat major depressive disorder (MDD) and anxiety disorders, such as panic disorder and post-traumatic stress disorder (PTSD).[3]

Medical usesEdit

Fluvoxamine's primary use is the treatment of obsessive compulsive disorder (OCD). Fluvoxamine has been found to be useful in the treatment of major depressive disorder (MDD), and anxiety disorders such as panic disorder, social anxiety disorder, post-traumatic stress disorder (PTSD), and obsessive-compulsive spectrum disorders. Fluvoxamine is indicated for children and adolescents with OCD.[4]

Adverse effectsEdit

Side effects most commonly observed with fluvoxamine include nausea, vomiting, drowsiness, insomnia, 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.[5] Sexual side effects with fluvoxamine are less pronounced than with other SSRIs.[6]

PharmacologyEdit

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, with the sole exception of the σ1 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 inside the brain. Indeed, other SSRIs which also act as σ1 receptor agonists, such as sertraline and escitalopram (not verified but likely to be), display enhanced antidepressant efficacy.[7] 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).[8] In fact, the TCA opipramol, a σ1 receptor agonist without effects on the serotonin, dopamine, or norepinephrine systems, has considerable antidepressant and anxiolytic efficacy in its own right.

PharmacokineticsEdit

The oral bioavailability of fluvoxamine is 53%. The plasma protein binding is about 80%.[9]

MetabolismEdit

Fluvoxamine is strongly metabolized in the liver, mostly by the processes of oxidative demethylation (producing fluvoxamine acid and its N-acetyl analog) and deamination (producing fluvoxethanol). Only fluvoxamine acid has been shown to have SERT inhibitor activity, roughly 1-2 orders of magnitude less potent than the parent compound.[10]

Radio-labeled administration of a dose of fluvoxamine produced nine identifiable metabolites, constituting 85% of the absorbed dosage (thus 15% of the fluvoxamine remained unchanged). This isolate of metabolites was empirically proven to contain 60% fluvoxamine acid and its N-acetyl analog, and 10% fluvoxethanol, with the other six metabolites making up 30%.[10]

EliminationEdit

Fluvoxamine has the shortest serum half-life of all SSRIs, with a mean of 15.6 hours.[11]

Drug interactionsEdit

Fluvoxamine inhibits 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.[12] A recent warning has been published regarding potentially serious interaction with tizanidine, based on CYP1A2 metabolism.[13] The half-life of caffeine is significantly extended by the use of fluvoxamine, which can cause insomnia and irritability in coffee drinkers.

Fluvoxamine inhibits metabolism of diazepam and phenytoin via CYP2C19 and metabolism of aripiprazole, chlorpromazine, clozapine, haloperidol, olanzapine, perphenazine, risperidone, thioridazine and zuclopenthixol via CYP2D6 as well as of aripiprazole, clozapine, haloperidol, quetiapine and ziprasidone via CYP3A4.[14]

Fluvoxamine has low potential for the drug interactions which are based on inhibition of enzyme Cytochrome P450 CYP2D6, less than most other SSRIs.[15][16][17] Naturally the other SSRIs which are metabolized by CYP2D6 will have more CYP2D6-based interactions with TCAs, antiarrhythmics, B-blockers, phenytoin, opioids and neuroleptics.

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.[10][18]

SynthesisEdit

File:Luvox.jpg

600px

Fluvoxamine is one of only two SSRIs (along with alaproclate) to have a monocyclic structure.[19][20]

HistoryEdit

Fluvoxamine was developed by Solvay Pharmaceuticals and was the first non-TCA drug approved by the U.S. Food and Drug Administration (FDA) specifically for the treatment of OCD.[21] 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.[22] At the end of 1995, more than 10 million patients worldwide had been treated with fluvoxamine.[23] Fluvoxamine was the first SSRI to be registered for the treatment of obsessive compulsive disorder in children by the FDA in 1997.[24] Fluvoxamine was the first drug approved for the treatment of social anxiety disorder in Japan in 2005.[25]

In 1999, fluvoxamine came under great public scrutiny after it was discovered that 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.[26] Sales fell, and Solvay withdrew the medication from the U.S. market in 2002.[27] In 2007, Solvay re-introduced Luvox to the U.S. market, which is now manufactured by Palo Alto, California-based Jazz Pharmaceuticals, Inc., with a generic version of Luvox available from IVAX Pharmaceuticals, Inc. On February 28, 2008, the FDA approved a controlled-release formulation of fluvoxamine for Solvay Pharmaceuticals, to be marketed as Luvox CR.[28][29]

Society and cultureEdit

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 prior to his departure from the show.

One of two shooters at the Columbine High School massacre, Eric Harris, was taking Luvox. Some analysts, such as psychiatrist Peter Breggin, have argued that this medication may have contributed to Harris's actions. Breggin claimed that side-effects of these drugs include increased aggression, loss of remorse, depersonalization, and mania.

ReferencesEdit

  1. "FDA Advisory Committee Recommends Luvox (Fluvoxamine) Tablets for Obsessive Compulsive Disorder," PRNewswire, 10/18/93
  2. Stahl, S. Stahl's Essential Psychopharmacology: The Prescriber's Guide. Cambridge University Press. New York, NY. 2009. pp.215
  3. Karen J. McClellan, David P. Figgitt (Drugs October 2000). Fluvoxamine An Updated Review of its Use in the Management of Adults with Anxiety Disorders. Adis Drug Evaluation 60 (4): 925–954.
  4. (March 2005) US-FDA Fluvoxamine Product Insert.
  5. LUVOX® Consumer Medicine Information | Better Health Channel
  6. Hengeveld VW et al., Waldinger MD (1998). Effect of SSRI antidepressants on ***: a double blind, randomised, placebo-controlled study with fluoxetine, fluvoxamine, paroxetine and sertraline. Journal of Clinical Psychopharmacology 18 (4): 274–281.
  7. Hashimoto K et al., Narita N (1996). Interactions of selective reuptake inhibitors with subtypes of sigma receptor in rat brain. Eur J Pharmacol 307 (1): 117–9.
  8. C.Sandner, Carrasco JL (December 2005). Clinical effects of pharmacological variations in selective serotonin reuptake inhibitors: an overview. International Journal of Clinical Practice 59 (12): 1428–1434.
  9. Barr Laboratories Inc (2010). Fluvoxamine Official FDA information, side effects and uses. URL accessed on 2011-02-15.
  10. 10.0 10.1 10.2 Luvox Tablets (Fluvoxamine Maleate) Drug Information: Uses, Side Effects, Drug Interactions and Warnings at RxList. URL accessed on 2009-02-17.
  11. Center for Drug Evaluation and Research, (2000). Fluvoxamine Maleate Tablets. Application Number: 75901, Retrieved July 28, 2008, from http://web.archive.org/web/20061008155754/http://www.fda.gov/cder/foi/anda/2000/75901_Fluvoxamine%20Maleate_Prntlbl.pdf
  12. Kroom, Lisa A. (10-01-2007). Drug Interactions With Smoking. Am J Health-Syst Pharm. 64 (18): 1917–1921.
  13. Waknine, Yael Prescribers Warned of Tizanidine Drug Interactions. Medscape News. Medscape. URL accessed on 2008-02-01.
  14. Bondy, Brigitta, Illja Spellmann (2007). Pharmacogenetics of Antipsychotics: Useful For the Clinician?. Curr Opin Psychiatry 20 (1): 126–130.
  15. P., Baumann (1996). Pharmacokinetic-pharmacodynamic relationship of the Selective serotonin reuptake inhibitors. Clinical Pharmacokinetics 31 (6): 444–469.
  16. Gill HS, DeVane CL (1997). Clinical Pharmacokinetics of Fluvoxamine: applications to dosage regime design. Journal of Clinical Psychiatry 58 (Suppl 5): 7–14.
  17. DeVane, CL (1998). Translational pharmacokinetics: current issues with newer antidepressants. Depression and Anxiety 8 (Suppl 1): 64–70.
  18. Brain Elimination Half-Life of Fluvoxamine.
  19. A Wilkinson, M Courtney, A Westlind-Danielsson, G Hallnemo and K E Akerman (December). Alaproclate acts as a potent, reversible and noncompetitive antagonist of the NMDA receptor coupled ion flow. JPET 271 (3): 1314–1319.
  20. K L Nicholson and R L Balster (23 April). Evaluation of the phencyclidine-like discriminative stimulus effects of novel NMDA channel blockers in rats. Psychopharmacology.
  21. Pharmalot | BrainPhysics.com| Medications for OCD.
  22. Solvay Pharmaceuticals Australia | Luvox.
  23. (1999) . Fluvoxamine Product Monograph.
  24. Luvox Approved For Obsessive Compulsive Disorder in Children and Teens. Http://www.pslgroup.com/dg/2261a.htm.
  25. Solvay's Fluvoxamine maleate is first drug approved for the treatment of social anxiety disorder in Japan. Http://www.solvaypress.com/pressreleases/0,,33713-2-83,00.htm.
  26. includeonly>Pankratz, Howard. "Judge: Seal Columbine papers for 25 years", The Denver Post, January 26, 2007. Retrieved on 2008-03-03.
  27. Solvay Pharmaceuticals, Inc. Withdraws LUVOX. Http://www.solvaypharmaceuticals-us.com/newsroom/pressreleases/0,,14517-2-0,00.htm.
  28. 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). URL accessed on 2008-03-14.
  29. Luvox CR | Prescribing Info. URL accessed on 2008-02-21.


Antidepressants (ATC N06A) edit
Monoamine oxidase inhibitors (MAOI) Harmaline, Iproclozide, Iproniazid, Isocarboxazid, Nialamide, Phenelzine, Selegiline, Toloxatone, Tranylcypromine
Reversible inhibitor of monoamine oxidase A (RIMA) Brofaromine, Moclobemide
Dopamine reuptake inhibitor (DARI) Amineptine, Phenmetrazine, Vanoxerine, Modafinil
Norepinephrine-dopamine reuptake inhibitors Bupropion
Norepinephrine reuptake inhibitor (NRI) or (NARI) Atomoxetine, Maprotiline, Reboxetine, Viloxazine
Serotonin-norepinephrine reuptake inhibitor (SNRI) Duloxetine, Milnacipran, Venlafaxine
Selective serotonin reuptake inhibitor (SSRI) Alaproclate, Etoperidone, Citalopram, Escitalopram, Fluoxetine, Fluvoxamine, Paroxetine, Sertraline, Zimelidine
Selective serotonin reuptake enhancer (SSRE) Tianeptine
Tricyclic antidepressants (TCA) Amitriptyline, Amoxapine, Butriptyline, Clomipramine, Desipramine, Dibenzepin, Dothiepin, Doxepin, Imipramine, Iprindole, Lofepramine, Melitracen, Nortriptyline, Opipramol, Protriptyline, Trimipramine
Tetracyclic antidepressants Maprotiline, Mianserin, Nefazodone, Trazodone
Noradrenergic and specific serotonergic antidepressant (NaSSA) Mirtazapine

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