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Fluvoxamine
Systematic (IUPAC) name
(Z)-5-methoxy-1-[4-(trifluoromethyl)phenyl]pentan-1-one O-2-aminoethyl oxime
Identifiers
CAS number 54739-18-3
ATC code N06AB08
PubChem 5324346
DrugBank APRD00425
ChemSpider 4481878
Chemical data
Formula C 15H21F3N2O2  
Mol. mass 318.335
Pharmacokinetic data
Bioavailability 77%
Metabolism Hepatic
Half life 15.6 hours
Excretion Renal
Therapeutic considerations
Pregnancy cat. C
Legal status Prescription Only (S4) (AU) -only (US)
Routes Oral
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Fluvoxamine (Luvox) is an antidepressant which functions as a selective serotonin reuptake inhibitor and is predominantly used to treat obsessive–compulsive disorder.

Contents

History

Fluvoxamine was one of the first of the SSRI antidepressants to be launched (1984, in Switzerland) and was developed by Solvay Pharmaceuticals. It was launched in the US in December 1994 and in Japan in June 1999. As of the end of 1995, more than 10 million patients worldwide have been treated with fluvoxamine.[1]

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.[2] Sales fell, and Solvay withdrew the medication from the U.S. market in 2002.[3]

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

Fluvoxamine was the first SSRI to be registered for the treatment of obsessive–compulsive disorder in children by FDA in 1997.[4]

Fluvoxamine was the first drug approved for the treatment of social anxiety disorder in Japan in 2005.[5]

On February 28, 2008, the US FDA approved a controlled-release formulation of fluvoxamine, to be marketed as Luvox CR.[6][7]

Indications

Fluvoxamine is widely prescribed to treat major depression, and anxiety disorders such as obsessive–compulsive disorder, Panic Disorder, Social Phobia, and Post-Traumatic Stress Disorder.[8]

Fluvoxamine is indicated for children and adolescents with OCD.[9]

Unapproved/off-label/investigational

Fluvoxamine may help in the treatment of Irritable Bowel Syndrome.[10] It also has been used with some success in the treatment of pedophilia.[11]

Side effects

Common side effects of fluvoxamine are: 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 observed more frequently in children are: abnormal thoughts or behaviour, cough, increased period pain, nose bleeds, increased restlessness, infection and sinusitis.[12][13]

Sexual side effects with fluvoxamine are rare, unlike other SSRIs.[14][15][16]

Chemistry

Luvox 100 mg scored tablets (AU)

Fluvoxamine is one of the few SSRIs to have a monocyclic structure.

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, with the sole exception of the sigma-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. Indeed, other SSRIs which also act as sigma-σ1 receptor agonists, such as sertraline and escitalopram (not verified but likely to be), display enhanced antidepressant efficacy.[17] 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).[18] In fact, the TCA opipramol, which is a selective sigma-σ1 receptor agonist, 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. [19]

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. [19]

Elimination

Fluvoxamine has the shortest half-life of all SSRIs; its mean serum half-life is 15.6 hours.[20]

Drug interactions

Fluvoxamine has a low potential for the drug interactions which are based on inhibition of enzyme Cytochrome P450 CYP2D6. Fluvoxamine shows the least interaction of the SSRIs, in regard to this specific enzyme.[21][22][23] Naturally the other SSRIs which are metabolized by CYP2D6 will have more CYP2D6-based interactions with TCAs, antiarrhythmics, B-blockers, phenytoin, opioids (eg. codeine, morphine, tramadol) and neuroleptics (eg. haloperidol, [risperidone).

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.[24] A recent warning has been published regarding potentially serious interaction with tizanidine, based on CYP1A2 metabolism.[25]

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, risperidone and ziprasidone via CYP3A4.[26]

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. [19] [27]

Notes

  1. ^ Fluvoxamine Product Monograph. 1999.  
  2. ^ "Judge: Seal Columbine papers for 25 years". The Denver Post. January 26, 2007. http://www.denverpost.com/golf/ci_5094436. Retrieved 2008-03-03.  
  3. ^ "Solvay Pharmaceuticals, Inc. Withdraws LUVOX". http://www.solvaypharmaceuticals-us.com/newsroom/pressreleases/0,,14517-2-0,00.htm.  
  4. ^ "Luvox Approved For Obsessive Compulsive Disorder in Children and Teens". Http://www.pslgroup.com/dg/2261a.htm.  
  5. ^ "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.  
  6. ^ "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)". http://www.jazzpharma.com/news.php?id=59. Retrieved 2008-03-14.  
  7. ^ "PDF-Prescribing Info". http://www.luvoxcr.com/LUVOX-CR-PI.pdf. Retrieved 2008-02-21.  
  8. ^ 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.  
  9. ^ US-FDA Fluvoxamine Product Insert. March 2005.  
  10. ^ Emmanuel, et al. (1997). "Treatment of Irritable Bowel Syndrome with Fluvoxamine". Am J Psychiatry 154: 711–712.  
  11. ^ Meg S Kaplan PhD, Richard B Krueger MD (January 2002). "Behavioral and psychopharmacological treatment of paraphilic and hypersexual disorders". Journal of Psychiatric Practice 8 (1): 21-32.  
  12. ^ Consumer Medicine Information
  13. ^ Consumer Medicine Information
  14. ^ Hengeveld VW et al., Waldinger MD (1998). "Effect of SSRI antidepressants on ejaculation: a double blind, randomised, placebo-controlled study with fluoxetine, fluvoxamine, paroxetine and sertraline". Journal of Clinical Psychopharmacology 18: 274–281. doi:10.1097/00004714-199808000-00004.  
  15. ^ Riley, A.; R.T. Segraves (2006). "Treatment of Premature Ejaculation". Int J. Clin Pract. (Blackwell Publishing) 60 (6): 694–697. doi:10.1111/j.1368-5031.2006.00818.x. http://www.medscape.com/viewarticle/533889_print. Retrieved 2008-02-01.  
  16. ^ http://www.ncbi.nlm.nih.gov/pubmed/19440080
  17. ^ Hashimoto K et al., Narita N (1996). "Interactions of selective reuptake inhibitors with subtypes of sigma receptor in rat brain". Eur J Pharmacol 307: 117–9. doi:10.1016/0014-2999(96)00254-3.  
  18. ^ 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. doi:10.1111/j.1368-5031.2005.00681.x.  
  19. ^ a b c "Luvox Tablets (Fluvoxamine Maleate) Drug Information: Uses, Side Effects, Drug Interactions and Warnings at RxList". http://www.rxlist.com/luvox-drug.htm. Retrieved 2009-02-17.  
  20. ^ 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
  21. ^ P., Baumann (1996). "Pharmacokinetic-pharmacodynamic relationship of the Selective serotonin reuptake inhibitors". Clinical Pharmacokinetics 31: 444–469. doi:10.2165/00003088-199631060-00004.  
  22. ^ Gill HS, DeVane CL (1997). "Clinical Pharmacokinetics of Fluvoxamine: applications to dosage regime design". Journal of Clinical Psychiatric 58 (Suppl 5): 7–14.  
  23. ^ DeVane, CL (1998). "Translational pharmacokinetics: current issues with newer antidepressants". Depression and Anxiety 8 (Suppl 1): 64–70. doi:10.1002/(SICI)1520-6394(1998)8:1+<64::AID-DA10>3.0.CO;2-S.  
  24. ^ Kroom, Lisa A. (10-01-2007). "Drug Interactions With Smoking". Am J Health-Syst Pharm. (Medscape: American Society of Health-System Pharmacists) 64 (18): 1917–1921. doi:10.2146/ajhp060414. http://www.medscape.com/viewarticle/562754_print. Retrieved 2008-01-31.  
  25. ^ Waknine, Yael (April 13, 2007). "Prescribers Warned of Tizanidine Drug Interactions". Medscape News. Medscape. http://www.medscape.com/viewarticle/555194_print. Retrieved 2008-02-01.  
  26. ^ Bondy, Brigitta; Illja Spellmann (2007). "Pharmacogenetics of Antipsychotics: Useful For the Clinician?". Curr Opin Psychiatry (Medscape: Lippincott Williams & Wilkins) 20 (1): 126–130. doi:10.1097/YCO.0b013e328017f69f. http://www.medscape.com/viewarticle/552100_print. Retrieved 2008-02-01.  
  27. ^ "Brain Elimination Half-Life of Fluvoxamine". http://ajp.psychiatryonline.org/cgi/content/full/155/3/380.  

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