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Fluvoxamine

A Review of its Therapeutic Potential in the Management of Anxiety Disorders in Children and Adolescents

Paediatric Drugs volume 3, pages 763–781 (2001)Cite this article

Summary

Abstract

Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI) which may be used for the management of anxiety disorders in children and adolescents. Absorption of fluvoxamine was similar in adolescents to that in adults, which suggests that the maximum dosage of the drug for patients aged between 12 and 17 years can be as high as 300 mg/day. However, steady-state plasma fluoxetine concentrations were 2 to 3 times higher in children (aged between 6 and 11 years) than in adolescents; thus, the maximum fluvoxamine dosage recommended for children is 200 mg/day.

Fluvoxamine (50 to 300 mg/day) for 8 to 16 weeks significantly reduced symptoms of obsessive-compulsive disorder (OCD) [measured across multiple assessment scales] compared with placebo in a well controlled trial in paediatric patients (n = 120) or from baseline in noncomparative trials in adolescent (n = 20) or paediatric (n = 16) patients. Improvements with fluvoxamine (up to 200 mg/day) were observed for up to 1 year in 98 patients with OCD in a noncomparative trial. The drug (up to 250 or 300 mg/day) also improved symptoms of anxiety compared with placebo in an 8-week well controlled trial in 128 paediatric patients with social phobia, separation anxiety disorder or generalised anxiety disorder (GAD).

Fluvoxamine (50 to 300 mg/day) appears to be well tolerated in paediatric patients, with most adverse events with the drug (except abdominal discomfort, which occurred more often in patients receiving fluvoxamine) occurring with a similar incidence to those with placebo. The most common adverse events involved the central nervous system or gastrointestinal system. Most adverse events reported by paediatric patients with OCD were similar to those reported by adults.

In conclusion, fluvoxamine is generally well tolerated and has demonstrated short-term efficacy compared with placebo in the treatment of OCD, and social phobia, separation anxiety disorder or GAD in well controlled trials in paediatric patients. Reductions in symptoms of anxiety with fluvoxamine have been observed for up to 1 year in children and adolescents with OCD. However, there are currently no comparative trials of fluvoxamine with other pharmacological agents. In the absence of such trials, current consensus opinion recommends that when pharmacotherapy is indicated, fluvoxamine, like other SSRIs, can be used as first-line treatment for anxiety disorders, particularly OCD, in paediatric patients. However, direct comparisons are required to assess the relative efficacy and tolerability of pharmacological agents in order to make firm recommendations for the treatment of anxiety disorders in this patient group.

Pharmacodynamic Properties

Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI). It has little or no effect on other monoamine reuptake mechanisms or monoamine neuronal function, and has low affinity for serotonin receptors or receptors of other neurotransmitters.

The drug has demonstrated anxiolytic activity in animal models, and it reduced polydipsia in a rat model of obsessive-compulsive disorder (OCD). It has relatively few cardiovascular or anticholinergic effects, and appears to have negligible proconvulsant or sedative effects. In addition, fluvoxamine has minimal effects on psychomotor and cognitive function in humans.

Pharmacokinetic Properties

General properties: Fluvoxamine is almost completely absorbed from the gastrointestinal tract following oral administration, with an oral bioavailability of ≈50%. Maximum plasma concentrations (Cmax) of the drug are reached within 2 to 8 hours after administration. After therapeutic dosages in adults, fluvoxamine displays nonlinear pharmacokinetics, which are not affected by concomitant food intake.

The volume of distribution of fluvoxamine is 25 L/kg, but plasma protein binding (77%) is low compared with other SSRIs. Fluvoxamine undergoes extensive oxidative metabolism, although the specific hepatic cytochrome P450 (CYP) isoenzymes involved remain unidentified. Most of an oral dose of fluvoxamine is excreted in the urine with only 3% being excreted as unchanged drug.

Children and adolescents: Children aged between 6 and 11 years had higher values for bodyweight-corrected mean Cmax(14.8 vs 4.2 μg/L/kg) and area under the plasma concentration-time curve (AUC12h; 155.1 vs 43.9 μg/L/kg □h) than adolescents aged between 12 and 17 years after fluvoxamine 200 mg/day (given as 100mg twice daily up to steady-state). In contrast, Cmax (6.7 and 5.7 μg/L/kg, respectively) and AUC12h (69.6 and 59.4 μg/L/kg □h, respectively) values for adolescents were similar to those for adults after fluvoxamine 300 mg/day (given as 150mg twice daily up to steady state).

Cmax and AUC12h were significantly higher in female (28.1 μg/L/kg and 293.5 μg/L/kg □h, respectively; n = 3) than in male (9.1 μg/L/kg and 95.8 μg/L/kg □h, respectively; n = 7) children after fluvoxamine 200 mg/day, but there there were no gender differences in absorption kinetics in adolescent patients.

Preliminary data indicate that after multiple doses of fluvoxamine 25 to 100mg twice daily, mean steady-state clearance (CL) in children (aged between 6 and 11 years) was 40 to 65% lower than that observed in adolescents (aged between 12 and 17 years). In addition, CL after fluvoxamine 150mg twice daily was 54% higher in adolescents than in adults.

Relative to other SSRIs, fluvoxamine is a weak inhibitor of CYP2D6, a moderate inhibitor of CYP2C19 and CYP3A4 and a potent inhibitor of CYP1A2 in hepatic microsomes. The drug is therefore likely to inhibit the metabolism and prolong the elimination of CYP1A2 substrates and may impair the elimination of drugs metabolised by CYP3A4 and CYP2C19.

Therapeutic Trials

Obsessive-compulsive disorder: Oral administration of fluvoxamine (50 to 300 mg/day) for 8 to 16 weeks significantly reduced symptoms of OCD (measured across multiple assessment scales) compared with placebo in paediatric patients (aged between 8 and 17 years; n = 120) or from baseline in noncomparative trials in adolescents (aged between 13 and 18 years; n = 20) or paediatric patients (average age 14.8 years; n = 16). At 10 weeks, patients receiving fluvoxamine (50 to 200 mg/day) experienced significantly greater improvement in mean Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS) score than patients receiving placebo (6.0 vs 3.3 mean change from baseline, p = 0.033) in a randomised, double-blind trial. Significant improvement from baseline compared with placebo was also observed in the National Institute of Mental Health Global Obsessive Compulsive Scale (p = 0.026) and the Clinical Global Impression Scale (CGI) evaluated by the clinician, parent and patient (p < 0.05 for all three). In addition, at trial end, more patients receiving fluvoxamine (42 and 30%) than placebo (27 and 16%) were classified as responders (defined as a 25% reduction from baseline in the CY-BOCS score and much or very much improved on clinician CGI score, respectively), although these results were marginally nonsignificant (p = 0.065 and p = 0.078, respectively). Response rates were higher in children (aged between 8 and 12 years) than adolescents (aged between 13 and 17 years) in a post-hoc subgroup analysis.

Improvements with fluvoxamine (up to 200 mg/day) were observed for up to 1 year in 98 paediatric patients in a noncomparative long-term extension phase of the 10-week, placebo-controlled trial. Patients previously treated with placebo showed a marked improvement from baseline in CY-BOCS score (baseline 24.2, improvement 48%), and patients who had experienced an improvement in OCD symptoms with fluvoxamine during the short-term trial continued to show improvement in CY-BOCS score (from 16.8 to 14.1) with long-term treatment.

Social phobia, separation anxiety disorder and generalised anxiety disorder (GAD): Fluvoxamine (up to 250 mg/day in children aged <12 years and up to 300 mg/day in adolescents aged between 12 and 17 years) significantly reduced symptoms of anxiety (improvement on the Paediatric Anxiety Rating Scale of 52 vs 16%; p < 0.001) and increased response rates (score <4 on the CGI-Improvement scale, 76 vs 29%; p < 0.001) compared with placebo over 8 weeks of treatment in a randomised, double-blind trial involving 128 paediatric patients with social phobia, separation anxiety disorder or GAD.

Tolerability

Fluvoxamine (50 to 300 mg/day) appears to be well tolerated in short- or long-term trials involving paediatric patients (n = 98 to 128) aged between 6 and 17 years, with most adverse events with the drug (except abdominal discomfort in patients with social phobia, separation anxiety disorder or GAD) occurring with a similar incidence to those with placebo, and few patients withdrawing due to adverse events. There were no reported clinically significant abnormalities in laboratory parameters with short- or long-term treatment with fluvoxamine (up to 200 mg/day); however, abnormal vital signs (including weight gain, decreased systolic blood pressure, decreased diastolic blood pressure and weight loss) were reported with both placebo and fluvoxamine (50 to 200 mg/day) in a well controlled trial.

Obsessive-compulsive disorder: The adverse event profile for children and adolescents with OCD appears similar to that for adults, although several events (such as agitation, depression, dysmenorrhoea, flatulence, hyperkinesia and rash) appear to occur with a greater frequency in paediatric patients than in adults.

The incidence of adverse events (including headache, insomnia, infection, asthenia, abdominal pain, nausea, diarrhoea, dyspepsia, pharyngitis, agitation, hyperkinesia, rhinitis and somnolence) was similar with fluvoxamine (50 to 200 mg/day) to that with placebo in a 10-week, randomised, double-blind trial in paediatric patients (aged between 8 and 17 years) with OCD. Adverse events were generally transient. The adverse events profile with fluvoxamine (up to 200 mg/day) did not appear to differ with long-term (1-year) use in an extended noncomparative phase in 98 paediatric patients with OCD.

Social phobia, separation anxiety disorder and GAD: Significantly more patients with social phobia, separation anxiety disorder or GAD who were receiving fluvoxamine (up to 250 mg/day in children aged <12 years or up to 300 mg/day in adolescents aged between 12 and 17 years) than placebo experienced abdominal discomfort (49 vs 28%, p = 0.02) in a randomised, double-blind trial; there was also a trend towards a greater incidence of increased motor activity in patients receiving fluvoxamine than in those receiving placebo (27 vs 12%, p = 0.06). Other adverse events that occurred with an incidence of ≥10% in fluvoxamine or placebo recipients included headache (43 and 37%, respectively), drowsiness or sedation (21 and 15%), difficulty falling asleep (19 and 20%), nausea (19 and 14%), influenza or upper respiratory symptoms (19 and 11%), vomiting (19 and 9%), nasal congestion (17 and 18%), tiredness or fatigue (17 and 8%), muscle or joint pain (17 and 8%), sore throat (16 and 9%), decreased appetite (16 and 6%), diarrhoea (14 and 15%), coughing (10 and 14%) and skin irritation (10 and 14%).

Dosage and Administration

Dosage recommendations for oral fluvoxamine in paediatric patients with anxiety disorders are currently only available for the treatment of OCD. In this patient group, the recommended fluvoxamine starting dosage is 25mg administered as a single daily dose at bedtime. The maximum dosage in children (up to 11 years) should not exceed 200 mg/day and in adolescents should not exceed 300 mg/day. The dosage should be titrated in 25mg increments every 4 to 7 days (depending on tolerability) until maximum therapeutic benefit is achieved. Dosages >50 mg/day should be administered in 2 divided doses; if these are not equal, the larger dose should be administered at bedtime.

Fluvoxamine, like other SSRIs, has been associated with decreased appetite and fluctuations in body weight; the effects, if any, of long-term fluvoxamine use on growth, development and maturation of children and adolescents are unknown. Bodyweight and growth should be monitored regularly in patients treated with fluvoxamine for longer than 10 weeks.

Fluvoxamine is contraindicated in combination with a monoamine oxidase inhibitor (MAOI), and the drug should not be used within 14 days of discontinuing treatment with an MAOI. In addition, at least 2 weeks should be allowed between ceasing treatment with fluvoxamine and starting treatment with an MAOI. Furthermore, fluvoxamine should not be used in combination with some drugs metabolised by CYP3A4 (e.g. pimozide, cisapride, terfenadine or astemizole) or with diazepam, and fluvoxamine should be used with caution and/or appropriate monitoring implemented and dosage adjustments made when the drug is used in combination with other agents with which it may potentially interact (e.g. alprazolam, theophylline and warfarin).

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    Susan M. Cheer & David P. Figgitt

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  1. Susan M. Cheer
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Cheer, S.M., Figgitt, D.P. Fluvoxamine. Paediatr Drugs 3, 763–781 (2001). https://doi.org/10.2165/00128072-200103100-00004

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Keywords

  • Paediatric Patient
  • Anxiety Disorder
  • Selective Serotonin Reuptake Inhibitor
  • Fluvoxamine
  • Social Phobia