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Clinical Pharmacokinetics of Fluvoxamine

Clinical Pharmacokinetics volume 27, pages 175–190 (1994)Cite this article

Summary

Fluvoxamine is a selective inhibitor of serotonin reuptake that is widely used in the management of depression.

Following oral administration, the drug is absorbed efficiently from the gastrointestinal tract. Peak plasma concentrations are usually observed within 2 to 8 hours postdose for capsules and film-coated tablets and within 4 to 12 hours for enteric-coated tablets. Despite complete absorption, oral bioavailability may be incomplete probably because of first-pass metabolism. Approximately 77% of fluvoxamine is plasma protein bound.

Only negligible amounts of fluvoxamine are excreted unchanged in urine. The drug is extensively biotransformed, mostly by oxidation, and at least 11 different metabolites have been detected in human urine. None of the metabolites is known to possess significant pharmacological activity.

Following administration of single doses, fluvoxamine shows a biphasic elimination with a mean terminal elimination half-life of about 15 to 20 hours. Steady-state plasma fluvoxamine concentrations are achieved 5 to 10 days after initiation of therapy and are 30 to 50% higher than those predicted from single-dose data. Preliminary data also suggest that plasma drug concentrations may increase non-linearly with increasing daily dosage. The relationship between plasma fluvoxamine concentration and clinical response has not been clearly defined.

Fluvoxamine pharmacokinetics are substantially unaltered in the elderly, whereas higher plasma drug concentrations (relative to dose) are observed in patients with alcoholic cirrhosis of the liver. Fluvoxamine inhibits oxidative drug metabolising enzymes and, therefore, causes a number of clinically significant drug interactions. Drugs whose metabolic elimination is impaired by fluvoxamine include tricyclic antidepressants, alprazolam, bromazepam, diazepam, theophylline, phenazone (antipyrine), propranolol, warfarin, methadone and carbamazepine.

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References

  1. Palmer KJ, Benfield P. Fluvoxamine. An overview of its pharmacological properties and therapeutic potential in non-depressive disorders. CNS Drugs 1994; 1: 57–87

    Article  CAS  Google Scholar 

  2. Benfield P, Ward A. Fluvoxamine: A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in depressive illness. Drugs 1986; 32: 313–34

    PubMed  Article  CAS  Google Scholar 

  3. De Jonghe F, Swinkels JA. The safety of antidepressants. Drugs 1992; 43 Suppl. 2: 40–7

    PubMed  Article  Google Scholar 

  4. Kasper S, Fuger J, Moller H-J. Comparative efficacy of antidepressants. Drugs 1992; 43 Suppl. 2: 11–23

    PubMed  Article  Google Scholar 

  5. Wilde MI, Plosker JL, Benfield P. Fluvoxamine. An updated review of its pharmacology, and therapeutic use in depressive illness. Drugs 1993; 46: 895–924

    PubMed  Article  CAS  Google Scholar 

  6. Wagner W, Plekkenpol B, Gray TE, et al. Safety database of fluvoxamine: Analysis and report. Pharmacopsychiatry 1993; 26 (Suppl): 10–6

    PubMed  Article  Google Scholar 

  7. Van Harten J. Comparative pharmacokinetics of selective serotonin re-uptake inhibitors. Clin Pharmacokinet 1993; 24: 203–20

    PubMed  Article  Google Scholar 

  8. Ruijten HM, De Bree H, Borst JM, et al. Fluvoxamine: Metabolic fate in animals. Drug Metab Disp 1984; 12: 82–92

    CAS  Google Scholar 

  9. Hurst HE, Jones DR, Jarboe CH, et al. Determination of clovoxamine concentration in human plasma by electron capture gas chromatography. Clin Chem 1981; 27: 1210–2

    PubMed  CAS  Google Scholar 

  10. Dawling S, Ward N, Essex EG, et al. Rapid measurement of basic drugs in blood applied to clinical and forensic toxicology. Ann Clin Biochem 1990; 27: 473–7

    PubMed  CAS  Google Scholar 

  11. De Jong GJ. The use of a pre-column for the direct high-performance liquid Chromatographic determination of the antidepressants fluvoxamine and clovoxamine in plasma. J Chromatogr 1980; 183: 203–11

    PubMed  Article  Google Scholar 

  12. De Jong GJ, Zeeman J. The potential of pre-columns to improve detection properties in high-performance liquid chromatography. Chromatographia 1982; 15: 453–8

    Article  Google Scholar 

  13. Schweitzer C, Spahn H, Mutschier E. Fluorimetric determination of fluvoxamine or clovoxamine in human plasma after thin-layer Chromatographic or high-performance liquid Chromatographic separation. J Chromatogr 1986; 382: 405–11

    PubMed  Article  CAS  Google Scholar 

  14. Foglia JP, Birder LA, Perel JM. Determination of fluvoxamine in human plasma by high-performance liquid chromatography with ultraviolet detection. J Chromatogr 1989; 495: 295–302

    PubMed  Article  CAS  Google Scholar 

  15. Van der Meersch-Mougeot V, Diquet B. Sensitive one-step extraction procedure for column liquid Chromatographic determination of fluvoxamine in human and rat plasma. J Chromatogr 1991; 567: 441–9

    PubMed  Article  Google Scholar 

  16. Hartter S, Wetzel H, Hiemke C. Automated determination of fluvoxamine in human plasma by column switching high-performance liquid chromatography. Clin Chem 1992; 38: 2082–6

    PubMed  CAS  Google Scholar 

  17. Hartter S, Wetzel H, Hammes E, et al. Inhibition of antidepressant demethylation and hydroxylation by fluvoxamine in depressed patients. Psychopharmacology 1993; 110: 303–8

    Article  Google Scholar 

  18. De Bree H, Van der Schoot JB, Post LC. Fluvoxamine maleate: Disposition in man. Eur J Drug Metab Pharmacokinet 1983; 8: 175–9

    Article  Google Scholar 

  19. De Vries MH, Raghoebar M, Mathlener IS, et al. Single and multiple oral dose fluvoxamine kinetics in young and elderly subjects. Ther Drug Monit 1992; 14: 493–8

    PubMed  Article  Google Scholar 

  20. Van Harten J, Duchiers J, Devissaguet J-P, et al. Pharmacokinetics of fluvoxamine maleate in patients with liver cirrhosis after single-dose oral administration. Clin Pharmacokinet 1993; 24: 177–82

    PubMed  Article  Google Scholar 

  21. De Vries MH, Van Harten J, Van Bemmel P, et al. Pharmacokinetics of fluvoxamine maleate after increasing single oral doses in healthy subjects. Biopharm Drug Dispos 1993; 14: 291–6

    PubMed  Article  Google Scholar 

  22. Van Harten J, Van Bemmel P, Dobrinska MR, et al. Bioavailability of fluvoxamine given with and without food. Biopharm Drug Dispos 1991; 12: 571–557

    PubMed  Article  Google Scholar 

  23. Perucca E. Routes of drug administration. Med Int 1992; 101: 4229–34

    Google Scholar 

  24. Claassen V. Review of the animal pharmacology and pharmacokinetics of fluvoxamine. Br J Clin Pharmacol 1983; 15 (3 Suppl.): 349S–55S

    PubMed  Article  Google Scholar 

  25. Overmars, H, Scherpenisse PM, Post LC. Fluvoxamine maleate: metabolism in man. Eur J Drug Metab Pharmacokinet 1983; 8: 269–280

    PubMed  Article  CAS  Google Scholar 

  26. Lemoine A, Gautier JC, Azoulay D, et al. The major pathway of imipramine metabolism is catalyzed by cytochromes P-450 1A2 and P-450 3A4 in human liver. Mol Pharmacol 1993; 43: 827–32

    PubMed  CAS  Google Scholar 

  27. Skjelbo E, Brosen K, Hallas J, et al. The mephenytoin oxidation polymorphism is partially responsible for the N-demethylation of imipramine. Clin Pharmacol Ther 1991; 49: 18–23

    PubMed  Article  CAS  Google Scholar 

  28. Brosen K, Skielbo E, Rasmussen BB, et al. Fluvoxamine is a potent inhibitor of cytochrome P4501A2. Biochem Pharmacol 1993; 45: 1211–4

    PubMed  Article  CAS  Google Scholar 

  29. Crewe HK, Lennard MS, Tucker GT, et al. The effect of selective serotonin re-uptake inhibitors on cytochrome P4502D6 (CYP2D6) activity in human liver microsomes. Br J Clin Pharmacol 1992; 34: 262–5

    PubMed  Article  CAS  Google Scholar 

  30. Otton SV, Dafang W, Joffe RT, et al. Inhibition by fluoxetine of cytochrome P4502D6 activity. Clin Pharmacol Ther 1993; 53: 401–9

    PubMed  Article  CAS  Google Scholar 

  31. Bouquet S, Vandel S, Bertschy G, et al. Pharmacokinetics of fluoxetine and fluvoxamine in depressed patients: Personal results. Clin Neuropharmacol 1992; 15 (1 Suppl.): 82–83A

    Article  Google Scholar 

  32. Van Harten J, Stevens LA, Raghoebar M, et al. Fluvoxamine does not interact with alcohol or potentiate alcohol-related impairment of cognitive function. Clin Pharmacol Ther 1992; 52: 427–35

    PubMed  Article  Google Scholar 

  33. Raghoebar M, Roseboom H. Kinetics of fluvoxamine in special populations. Poster presented at the Symposium on Variability in Pharmacokinetics and Drug Response. Gothenburg, October 3–5 1988

  34. Wright S, Dawling S, Ashford JJ. Excretion of fluvoxamine in breast milk. Br J Clin Pharmacol 1991; 31: 209

    PubMed  Article  CAS  Google Scholar 

  35. Murphy JM, Waller MB, Gatto GJ. Monoamine uptake inhibitors attenuate ethanol intake in alcohol preferring (P) rats. Alcohol 1985; 2: 349–52

    PubMed  Article  CAS  Google Scholar 

  36. Naranjo CA, Sellers EM. Serotonin uptake inhibitors attenuate ethanol intake in problem drinkers. Recent Dev Alcohol 1989; 7: 255–266

    PubMed  CAS  Google Scholar 

  37. Kasper S, Dotsch M, Vieira A. Plasma levels of fluvoxamine and maprotiline and clinical response in major depression. Pharmacopsychiatry 1992; 25: 106

    Google Scholar 

  38. Kasper S, Dotsch M, Kick H, et al. Plasma concentrations of fluvoxamine and maprotiline in major depression: Implications of therapeutic efficacy and side effects. Eur Neuropsychopharmacol 1993; 3: 13–21

    PubMed  Article  CAS  Google Scholar 

  39. Foglia JP, Perel JM, Nathan RS, et al. Therapeutic drug monitoring (TDM) of fluvoxamine, a selective antidepressant. Clin Chem 1990; 36: 1043

    Google Scholar 

  40. Nathan RS, Perel JM, Pollock BG, et al. The role of neuropharmacologic selectivity in antidepressant action: Fluvoxamine versus desipramine. J Clin Psychiatry 1990; 51: 367–72

    PubMed  CAS  Google Scholar 

  41. Hartter S, Hiemke C. Determination of fluvoxamine in human plasma by HPLC-analysis including direct injection of plasma and column switching [abstract]. Pharmacopsychiatry 1992; 25: 103

    Google Scholar 

  42. Nelson JC, Mazure CM, Bowers MB, et al. A preliminary, open study of the combination of fluoxetine and desipramine for rapid treatment of major depression. Arch Gen Psychiatry 1991; 48: 303–737

    PubMed  Article  CAS  Google Scholar 

  43. Wetzel H, Hartter S, Szegedi A, et al. Fluvoxamine comedication to tricyclic antidepressants: metabolic interactions, clinical efficiency and side effects [abstract]. Pharmacopsychiatry 1993; 26: 211

    Google Scholar 

  44. Bertschy G, Vandel S, Vandel B, et al. Fluvoxamine-tricyclic antidepressant interaction. An accidental finding. Eur J Clin Pharmacol 1991; 40: 119–20

    PubMed  Article  CAS  Google Scholar 

  45. Hartter S, Szegedi A, Wetzel H, et al. Differential interactions of fluvoxamine and paroxetine with the metabolism of tricyclic antidepressants [abstract]. Pharmacopsychiatry 1993: 26: 156

    Google Scholar 

  46. Spina E, Campo GM, Avenoso A, et al. Interaction between fluvoxamine and imipramine/desipramine in four patients. Ther Drug Monit 1992; 14: 194–6

    PubMed  Article  CAS  Google Scholar 

  47. Spina E, Pollicino AM, Avenoso A, et al. Effect of fluvoxamine on the pharmacokinetics of imipramine and desipramine in healthy subjects. Ther Drug Monit 1993; 15: 243–6

    PubMed  Article  CAS  Google Scholar 

  48. Spina E, Pollicino AM, Avenoso A, et al. Fluvoxamine-induced alterations in plasma concentrations of imipramine and desipramine in depressed patients. Int J Clin Pharmacol Res 1993; 13: 167–71

    PubMed  CAS  Google Scholar 

  49. Seifritz E, Holsboer-Trachsler E, Hemmeter U, et al. Increased trimipramine plasma levels during fluvoxamine comedication. Pharmacopsychiatry 1993; 26: 195

    Article  Google Scholar 

  50. Skjelbo E, Brosen K. Inhibitors of imipramine metabolism by human liver microsomes. Br J Clin Pharmacol 1992; 34: 256–61

    PubMed  Article  CAS  Google Scholar 

  51. Hendrickx B, Floris M. A controlled pilot study of the combination of fluvoxamine and lithium. Curr Ther Res 1991; 49: 106–10

    Google Scholar 

  52. Evans M, Marwick P. Fluvoxamine and lithium: An unusual interaction. Br J Psych 1990; 156: 286

    Article  CAS  Google Scholar 

  53. Boyer WF, Feighner JP. Pharmacokinetics and drug interactions. In: Feighner JP, Boyer WF, editors. Selective serotonin re-uptake inhibitors. Chichester: John Wiley & Sons, 1991: 81–8

    Google Scholar 

  54. Stimmel GL, Skowron DM, Chameides WA. Focus on fluvoxamine: A serotonin reuptake inhibitor for major and obsessive compulsive disorder. Hospital Formulary 1991; 26: 635–43

    Google Scholar 

  55. Perucca E, Gatti G, Cipolla G, et al. Inhibition of diazepam metabolism by fluvoxamine: a pharmacokinetic study in normal volunteers. Clin Pharmacol Ther. In press

  56. Van Harten J, Holland RL, Wesnes K, et al. Kinetic and dynamic interaction study between fluvoxamine and benzodiazepines. Poster presented at the II Jerusalem Conference on Pharmaceutical Sciences and Clinical Pharmacology; May 24–29 1992; Jerusalem

  57. Van Harten J, Holland RL, Wesnes K. Influence of multiple-dose administration of fluvoxamine on the pharmacokinetics of the benzodiazepines bromazepam and lorazepam: a randomized, cross-over study [abstract]. Eur Neuropsychopharmacol 1992; 2: 381

    Article  Google Scholar 

  58. Fleishaker JC, Hulst LK. Effect of fluvoxamine on the pharmacokinetics and pharmacodynamics of alprazolam in healthy volunteers. Pharm Res 1992; 9 Suppl: S292

    Article  Google Scholar 

  59. Fritze J, Unsorg B, Lanczik M. Interaction between carbamazepine and fluvoxamine. Acta Psychiatr Scand 1991; 84: 583–584

    PubMed  Article  CAS  Google Scholar 

  60. Bonnet P, Vandel S, Nezelof S, et al. Carbamazepine, fluvoxamine: Is there a pharmacokinetic interaction? Therapie 1992; 47: 165

    PubMed  CAS  Google Scholar 

  61. Martinelli V, Bocchetta A, Palmas AM, et al. An interaction between carbamazepine and fluvoxamine. Br J Clin Pharmacol 1993; 36: 615

    PubMed  Article  CAS  Google Scholar 

  62. Spina E, Avenoso A, Pollicino AM, et al. Carbamazepine coadministration with fluoxetine or fluvoxamine. Ther Drug Monit 1993c; 15: 247–50

    PubMed  Article  CAS  Google Scholar 

  63. Diot P, Jonville AP, Gerard F, et al. Possible interaction entre theophylline et fluvoxamine. Therapie 1991; 46: 170–71

    PubMed  CAS  Google Scholar 

  64. Sperber AD. Toxic interaction between fluvoxamine and sustained release theophylline in an 11-year-old boy. Drug Saf 1991; 6: 460–2

    PubMed  Article  CAS  Google Scholar 

  65. Thomson AH, McGovern EM, Bennie P, et al. Interaction between fluvoxamine and theophylline. Pharm J 1992; 249: 137

    Google Scholar 

  66. Campbell ME, Grant DM, Inaba T, et al. Biotransformation of caffeine, paraxanthine, theophylline and theobromine by polycyclic aromatic hydrocarbon-inducible cytochrome(s) P-450 in human liver microsomes. Drug Metab Dispos 1987; 15: 237–48

    PubMed  CAS  Google Scholar 

  67. Ochs HR, Greenblatt DJ, Verburg-Ochs B, et al. Chronic treatment with fluvoxamine, clovoxamine, and placebo: Interaction with digoxin and effects on sleep and alertness. J Clin Pharmacol 1989; 29: 91–5

    PubMed  CAS  Google Scholar 

  68. Bertshy G, Baumann P, Eap CB, et al. Probable metabolic interaction between methadone and fluvoxamine in addict patients. Ther Drug Monit 1994; 16: 42–5

    Article  Google Scholar 

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Affiliations

  1. Clinical Pharmacology Unit, Department of Internal Medicine and Therapeutics, University of Pavia, Piazza Botta 10, 27100, Pavia, Italy

    Emilio Perucca & Giuliana Gatti

  2. Institute of Pharmacology, University of Messina, Messina, Italy

    Edoardo Spina

Authors
  1. Emilio Perucca
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  2. Giuliana Gatti
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  3. Edoardo Spina
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Perucca, E., Gatti, G. & Spina, E. Clinical Pharmacokinetics of Fluvoxamine. Clin. Pharmacokinet. 27, 175–190 (1994). https://doi.org/10.2165/00003088-199427030-00002

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Keywords

  • Adis International Limited
  • Theophylline
  • Fluvoxamine
  • Plasma Drug Concentration
  • Maprotiline