Pharmacopsychiatry 2002; 35(3): 101-108
DOI: 10.1055/s-2002-31522
Original Paper
© Georg Thieme Verlag Stuttgart · New York

Fluvoxamine: Safety Profile in Extensive
Post-Marketing Surveillance

R.  Buchberger, W.  Wagner
  • 1Global Drug Safety and Surveillance, Solvay Pharmaceuticals, Hannover, Germany
Further Information

Publication History

Publication Date:
23 May 2002 (online)

The safety profile of the selective serotonin reuptake inhibitor, fluvoxamine, has been assessed in clinical and post-marketing studies. Post-marketing surveillance provides the opportunity to assess a drug's safety in every day clinical conditions in a much greater patient population than in clinical trials and therefore serves as a useful tool to detect signals for adverse effects with an incidence of less than 1 : 10,000. The safety profile of fluvoxamine was evaluated based on data from 17 years of global post-marketing surveillance in an estimated 28 million patients exposed to fluvoxamine. A total of 6,658 adverse drug reaction reports received from world-wide sources were reviewed and analysed. Post-marketing surveillance data confirmed the favourable safety profile already observed in clinical and post-marketing studies. A remarkably low level of suicidality, switch to mania, and sexual dysfunction was found. Serotonin syndrome appeared to be a very rare complication of fluvoxamine treatment. No signals for drug interactions unknown so far were identified. Withdrawal symptoms were observed in everyday clinical conditions, which were generally mild and resolved spontaneously. However, no cases suggestive for drug dependence have been reported. In conclusion, the data presented underlined that fluvoxamine offers a safe and well-tolerated option in the treatment of depression and obsessive-compulsive disorder.

References

  • 1 Angst J. Sexual problems in healthy and depressed persons.  Int Clin Psychopharmacol. 1998;  13 (6) S1-S4
  • 2 Banki C M. Prophylactic potential of selective reuptake inhibitors in suicidal patients.  Int Clin Psychopharmacol. 1995;  9 (4) 61-65
  • 3 Barefoot J C, Schroll M. Symptoms of depression, acute myocardial infarction, and total mortality in a community sample.  Circulation. 1996;  93 1976-1980
  • 4 Baumann P. Pharmacokinetic-pharmacodynamic relationship of the selective serotonin reuptake inhibitors.  Clin Pharmacokinet. 1996;  31 444-469
  • 5 Benazzi F. SSRI discontinuation syndrome related to fluvoxamine (letter).  J Psychiat Neurosci. 1998;  23 94
  • 6 Berlin C S. Fluoxetine withdrawal symptoms (letter).  J Clin Psychiatry. 1996;  57 93-94
  • 7 Bertschy G, Eap C B, Powell K, Baumann P. Fluoxetine addition to methadone in addicts: pharmacokinetic aspects.  Ther Drug Mon. 1996;  18 570-572
  • 8 Bryois C, Ferrero F. Mania induced by citalopram (letter).  Arch Gen Psychiatry. 1994;  51 664-665
  • 9 Burrai C, Bocchetta A, del Zompo M. Mania and fluvoxamine (letter).  Am J Psychiatry. 1991;  148 1263-1264
  • 10 Carrillo J A, Ramos S I, Herraiz A G, Llerena A, Agundez J A, Berecz R, Duran M, Benitez J. Pharmacokinetic interaction of fluvoxamine and thioridazine in schizophrenic patients.  J Clin Psychopharmacol. 1999;  19 494-499
  • 11 Christensen R C. Paroxetine-induced psychotic mania (letter).  Am J Psychiatry. 1995;  152 1399-1400
  • 12 Code of Federal Regulations .Title 21, Chapter 1. Food and Drug Administration, Department of Health and Human Services. Part 312.32. IND Safety Reports 1999: revised 1 April
  • 13 Coding Symbols for Thesaurus of Adverse Reaction Terms. Rockville, Maryland USA; FDA Center for Drug Evaluation and Research 1989
  • 14 Bankowski Z, Bruppacher R, Crusius I, Gallagher J, Kremer G, Venulet J (eds) Reporting adverse drug reactions. Definitions of terms and criteria for their use. Council for International Organizations of Medical Sciences (CIOMS) 1999
  • 15 CPMP Position Paper on SSRIs and Dependency/Withdrawal Reactions. EMEA/CPMP/2775/99
  • 16 Daniel W A. The influence of SSRIs on the pharmacokinetics of thioridazine and its metabolites: in vivo and in vitro studies.  Exp Toxic Pathol. 1991;  51 309-314
  • 17 DeVane C L. Differential pharmacology of newer antidepressants.  J Clin Psychiatry. 1998;  59 (20) 85-93
  • 18 Downs J, Ward J, Farmer R. Preoccupation with suicide in patients treated with fluoxetine (letter, comment).  Am J Psychiatry. 1991;  148 1090-1091
  • 19 Eap C B, Bertschy G, Powell K, Baumann P. Fluvoxamine and fluoxetine do not interact in the same way with the metabolism of the enantiomers of methadone.  J Clin Psychopharmacol. 2000;  17 113-117
  • 20 Ebert D, Albert R, May A, Merz A, Murata H, Stosiek I, Zahner B. The serotonin syndrome and psychosis-like side effects of fluvoxamine in clinical use - an estimation of incidence.  Eur Neuropsychopharmacol. 1997;  7 71-74
  • 21 Edwards J G, Inman W HW, Wilton L, Pearce G L. Prescription-event monitoring of 10401 patients treated with fluvoxamine.  Br J Psychiatry. 1994;  164 387-395
  • 22 EMEA Human Medicines Evaluation Unit. Notice to Marketing Authorisation Holders .Pharmacovigilance Guidelines (CPMP/PhVWP/108/99 corr.). London; 1999: 29 January
  • 23 Fava G A, Grandi S. Withdrawal syndromes after paroxetine and sertraline discontinuation (letter).  J Clin Psychopharmacol. 1995;  15 374-375
  • 24 Feder R. Fluoxetine-induced mania (letter).  J Clin Psychiatry. 1990;  51 524-525
  • 25 Fernando A T, Schwader P. A case of citalopram withdrawal (letter).  J Clin Psychopharmacol. 2000;  20 581-582
  • 26 Fleishaker J C, Hulst L K. A pharmacokinetic and pharmacodynamic evaluation of the combined administration of alprazolam and fluovoxamine.  Eur J Clin Pharmacol. 1994;  46 35-39
  • 27 Frank A, Anderson C, Rubinstein D. Frequency of sexual dysfunction in “normal” couples.  N Engl J Med. 1978;  299 111-115
  • 28 Ghaziuddin M. Mania induced by sertraline in a prepubertal child (letter).  Am J Psychiatry. 1994;  151 944
  • 29 Gillman P K. Serotonin syndrome: history and risk.  Fundam Clin Pharmacol. 1998;  12 482-491
  • 30 Goodman W K, Ward H, Kablinger A, Murphy T. Fluvoxamine in the treatment of obsessive-compulsive disorder and related conditions.  J Clin Psychiatry. 1997;  58 (5) 32-49
  • 31 Hartmann K, Koller-Doser A, Kuhn M. Postmarketing Safety Information: How useful are spontaneous reports?.  Pharmacoepidemiol Drug Safety. 1999;  8 65-71
  • 32 Hegerl U, Bottlender R, Gallinat J, Kuss H J, Ackenheil M, Möller H J. The serotonin syndrome scale: first results on validity.  Eur Arch Psychiatry Clin Neurosci. 1998;  248 96-103
  • 33 Hemeryck A, De Vriendt C, Belpaire F M. Inhibition of CYP2C9 by selective serotonin reuptake inhibitors: in vitro studies with tolbutamide and (S)-warfarin using human liver microsomes.  Eur J Pharmacol. 1999;  54 947-951
  • 34 Hewer W, Rost W, Gattaz W F. Cardiovascular effects of fluvoxamine and maprotiline in depressed patients.  Eur Arch Psychiatry Clin Neurosci. 1995;  246 1-6
  • 35 Hochberg H M, Kanter D, Houser V P. Electrocardiographic findings during extended clinical trials of fluvoxamine in depression: one years experience.  Pharmacopsychiatry. 1995;  28 253-256
  • 36 Howland R H. Induction of mania with serotonin reuptake inhibitors.  J Clin Psychopharmacol. 1996;  16 425-427
  • 37 ICH Harmonised Tripartite Guideline .Clinical Safety Data Management: Periodic Safety Update Reports for Marketed Drugs. Recommended for adoption at Step 4 of the ICH process on November 6th, 1996. 
  • 38 ICH Harmonised Tripartite Guideline .Definitions and Standards for Expedited Reporting. Recommended for adoption at Step 4 of the ICH process on October 27th, 1994. 
  • 39 Jeppesen U, Gram L F, Vistisen K, Loft S, Poulsen H E, Brosen K. Dose-dependent inhibition of CYP1A2, CYP2C19 and CYP2D6 by citalopram, fluoxetine and paroxetine.  Eur J Clin Pharmacol. 1996;  51 73-78
  • 40 Jeppesen U, Rasmussen B B, Brosen K. Fluvoxamine inhibitis the CYP2C19-catalysed bioactivation of chloroguanide.  Clin Pharmacol Ther. 1997;  62 (3) 279-286
  • 41 Kasper S, Schindler S, Neumeister A. Risk of suicide in depression and its implication for psychopharmacological treatment.  Int Clin Psychopharmacol. 1996;  11 71-79
  • 42 Laird L K, Lydiard R B, Morton W A, Steele T E, Kellner C, Thompson N M, Ballender J C. Cardiovascular effects of imipramine, fluvoxamine and placebo in depressed outpatients.  J Clin Psychiatry. 1993;  54 224-228
  • 43 Lejoyeux M, Rouillon F, Ades J. Prospective evaluation of the serotonin syndrome in depressed inpatients treated with clomipramine.  Acta Psychiatr Scand. 1993;  88 369-371
  • 44 Lesperance F, Frasure-Smith N. Depression in patients with cardiac disease: a practical review.  J Psychosom Res. 2000;  48 379-391
  • 45 Letizia C, Kapik B, Flanders W D. Suicidal risk during controlled clinical investigations of fluvoxamine.  J Clin Psychiatry. 1996;  57 415-421
  • 46 LoCurto M J. The serotonin syndrome.  Emerg Med Clin N Am. 1997;  15 665-675
  • 47 Louie A K, Lannon R A, Ajari L J. Withdrawal reaction after sertraline discontinuation (letter).  Am J Psychiatry. 1994;  151 450-451
  • 48 Lu M L, Lane H Y, Chen K P, Su M H, Chang W H. Fluvoxamine reduces the clozapine dosage needed in refractory schizophrenic patients.  J Clin Psychiatry. 2000;  61 594-599
  • 49 Martin R M, Mann R D, Hands D E, Tomlin M, Emerson A. Design of a pilot prospective cohort study of adverse events monitored by hospital pharmacists.  Int J Pharmaceut Med. 1999;  13 11-16
  • 50 Martin T G. Serotonin syndrome.  Ann Emerg Med. 1996;  28 520-526
  • 51 Medicines Control Agency, Committee on Safety of Medicines .In focus: Selective Serotonin Reuptake Inhibitors. Current problems in Pharmacovigilance. September 2000 26: 11-12
  • 52 Mesdjian E, Seree E, Charvet B, Mirrione A, Bourgarel R V, Desobry A, Barra Y. Metabolism of carbamazepine by CYP3A6: a model for in vitro drug interactions studies.  Life Sci. 1999;  64 827-835
  • 53 Montejo-Gonzales A L, Llorca G, Izquierdo J A, Ledesma A, Bousono M. SSRI-induced sexual dysfunction: Fluoxetine, paroxetine, sertraline, and fluvoxamine in a prospective, multicenter, and descriptive clinical study of 344 patients.  J Sex Marital Therapy. 1997;  23 (3) 176-194
  • 54 Montgomery S A. Suicide and antidepressants.  Drugs. 1992;  43 (2) 24-31
  • 55 Musselman D L, Evans D L, Nemeroff C B. The relationship of depression to cardiovascular disease: epidemiology, biology, and treatment.  Arch Gen Psychiatry. 1998;  55 580-592
  • 56 Nafziger A N. et al . Incidence of sexual dysfunction in healthy volunteers on fluvoxamine therapy.  J Clin Psychiatry. 1999;  60 (3) 187-190
  • 57 Nathan S G. The epidemiology of DSM-III psychosexual dysfunctions.  J Sex Mar Therap. 1986;  12 267-282
  • 58 Nemeroff C B, Musselman D L, Evans D L. Depression and cardiac disease.  Depr Anxiety. 1998;  8 (1) 71-79
  • 59 Oldroyd J. Paroxetine-induced mania (letter).  J Am Acad Child Adolesc Psychiatry. 1997;  36 721-722
  • 60 Ottevanger E A. Fluvoxamine activity profile with special emphasis on the effect on suicidal ideation.  Eur J Clin Res. 1991;  1 47-54
  • 61 Pacheco L, Malo P, Aragues E, Etxebeste M. More cases of paroxetine withdrawal syndrome (letter).  Br J Psychiatry. 1996;  169 384
  • 62 Pan L P, Wijnant P, De Vriendt C, Rosseel M T, Belpaire F M. Characterization of the cytochrome P450 isoenzymes involved in the in vitro N-dealkylation of haloperidol.  Br J Clin Pharmacol. 1997;  44 557-564
  • 63 Pataki C S. Mood disorders and suicide in children and adolescents. In: Saddock BJ, Saddock VA (eds) Comprehensive Textbook of Psychiatry. 7th Edition. Lippincott; Williams & Wilkins 2000: 2740-2757
  • 64 Peet M. Induction of mania with selective serotonin reuptake inhibitors and tricyclic antidepressants.  Brit J Psychiatry. 1994;  165 835-836
  • 65 Prager G, Stollmaier W, Prager R. Sicherheit und Verträglichkeit von Fluvoxamin bei kardialen Risikopatienten (Safety and tolerability of fluvoxamine in cardiovascular risk patients, German).  Tw Neurology Psychiatric. 1991;  5 548-562
  • 66 Preskorn S H. Clinically relevant pharmacology of selective serotonin reuptake inhibitors. An overview with emphasis on pharmacokinetics and effects on oxidative drug metabolism.  Clin Pharmacokinet. 1997;  32 (1) 1-21
  • 67 Price J S, Waller P C, Wood S M, MacKay A V. A comparison of the postmarketing safety of four selective serotonin reuptake inhibitors including the investigation of symptoms occurring on withdrawal.  Brit J Clin Pharmacol. 1996;  42 757-763
  • 68 Rechlin T. The effect of amitriptyline, doxepin, fluvoxamine and paroxetine treatment on heart rate variability.  J Clin Psychopharmacol. 1994;  14 392-395
  • 69 Rothschild A J. Sexual side effects of antidepressants.  J Clin Psychiatry. 2000;  61 (11) 28-36
  • 70 Schatzberg A, Haddad P, Kaplan E M, Lejoyeux M, Rosenbaum J F, Young A H, Zajecka J. Serotonin re-uptake inhibitor discontinuation syndrome: a hypothetical definition. Discontinuation consensus panel.  J Clin Psychiatry. 1997;  58 5-10
  • 71 Schmider J, Greenblatt D J, von Moltke L L, Karsov D, Shader R I. Inhibition of CYP2C9 by selective serotonin reuptake inhibitors in vitro: Studies of phenytoin parahydroxylation.  Br J Clin Pharmacol. 1997;  44 495-498
  • 72 Schmidtke A, Bille-Brahe U, DeLeo D, Kerkhof A, Bjerke T, Crepet P. et al . Attempted suicide in Europe: rates, trends and sociodemographic characteristics of suicide attempters during the period 1989 - 1992. Results of the WHO/EURO multicentre study on parasuicide.  Acta Psychiatr Scand. 1996;  93 327-338
  • 73 Someya T, Suzuki Y, Shimoda K, Hirokane G, Morita S, Yokono A, Inoue Y, Takahashi S. The effect of cytochrome P450 2D6 genotypes on haloperidol metabolism: a preliminary study in a psychiatric population.  Psychiatry Clin Neurosci. 1999;  53 593-597
  • 74 Sporer K A. The serotonin syndrome.  Drug Safety. 1995;  13 94-104
  • 75 Sternbach H. The serotonin syndrome.  Am J Psychiatry. 1991;  148 705-713
  • 76 Stoll A L, Mayer P V, Kolbrener M, Goldstein E, Suplit B, Lucier J, Cohen B M, Tohen M. Antidepressant-associated mania: a controlled comparison with spontaneous mania.  Am J Psychiatry. 1994;  151 1642-1645
  • 77 Strik J JMH, Honig A, Lousberg R, Cheriex E C, Van Praag H M. Cardiac side-effects of two selective serotonin reuptake inhibitors in middle-aged and elderly depressed patients.  Int Clin Psychopharmacol. 1998;  13 263-267
  • 78 Szabadi E. Fluvoxamine withdrawal syndrome.  Br J Psychiat. 1992;  160 283-284
  • 79 Teicher M H, Glod C, Cole J O. Emergence of intense suicidal preoccupation durin fluoxetine treatment.  Am J Psychiat. 1990;  147 207-210
  • 80 Van Harten J. Overview of the pharmacokinetics of fluvoxamine.  Clin Pharmacokinet. 1995;  29 (1) 1-9
  • 81 Venkataraman S, Naylor M W, King C A. Mania associated with fluoxetine treatment in adolescents.  J Am Acad Child Adolesc Psychiatry. 1992;  31 276-281
  • 82 Wagner W, Vause E W. Fluvoxamine. A review of global drug-drug interaction data.  Clin Pharmacokinet. 1995;  29 (1) 26-32
  • 83 Wagner W, Zaborny B A, Gray T E. Fluvoxamine. A review of its safety profile in world-wide studies.  Int Clin Psychopharmacol. 1994;  9 223-227
  • 84 Waldinger M D, Hengeveld M W, Zwinderman A H. et al . Effect of SSRI antidepressants on ejaculation: a double-blind, randomised, placebo-controlled study with fluoxetine, fluvoxamine, paroxetine and sertraline.  J Clin Psychopharmacol. 1998;  18 274-281
  • 85 Ware M R. Fluvoxamine: a review of the controlled trials in depression.  J Clin Psychiatry. 1997;  58 (5) 15-23
  • 86 Wilde M, Plosker G L, Benfield P. Fluvoxamine. An updated review of its pharmacology and therapeutic use in depressive illness.  Drugs. 1993;  46 895-924
  • 87 Wilson W H, Higano H, Papadatos Y, Kelwala S, Ban T A. A double-blind placebo-controlled study to compare the autonomic effects of fluvoxamine with those of amitriptyline and doxepin in healthy volunteers.  Brit J Clin Pharmacol. 1983;  15 385S-392S

Dr. Robert Buchberger

Solvay Pharmaceuticals GmbH

Hans-Böckler-Allee 20

30173 Hannover

Germany