Fluvoxamine extended-release formulation was FDA-approved to treat generalized social anxiety disorder (GSAD) and obsessive-compulsive disorder (OCD) because it demonstrated efficacy in reducing anxiety symptoms of these disorders in 3 clinical trials. The new formulation may benefit patients unable to tolerate the existing immediate-release form.
Clinical implications
Like other selective serotonin reuptake inhibitors (SSRIs), fluvoxamine alleviates symptoms of GSAD and OCD. The extended-release formulation allows the medication to be administered once daily (Table 1) and, according to the manufacturer, may reduce side effects and improve tolerability.
Many clinicians have prescribed immediate-release fluvoxamine once daily, and the efficacy and tolerability of the immediate- and extended-release formulations have not been compared in head-to-head trials. In addition, no studies have examined the efficacy of extended-release fluvoxamine in treating other psychiatric conditions.
Table 1
Extended-release fluvoxamine: Fast facts
| Brand name: Luvox CR |
| Class: Selective serotonin reuptake inhibitor |
| Indication: Generalized social anxiety disorder and obsessive-compulsive disorder |
| Approval date: February 29, 2008 |
| Availability date: March 2008 |
| Manufacturer: Jazz Pharmaceuticals |
| Dosing forms: 100 mg and 150 mg extended-release capsules |
| Recommended dose: Starting dose: 100 mg/d. Titrate in 50-mg/week increments until maximum therapeutic benefit is achieved. Maximum recommended dose: 300 mg/d |
How it works
Decreased serotonin levels are associated with GSAD and OCD. Fluvoxamine’s therapeutic effect is thought to be mediated through its specific serotonin reuptake inhibition in the CNS.1
The drug acts primarily on serotonin 2C receptors, with no reported significant affinity for histaminergic, adrenergic, muscarinic, or dopaminergic receptors.1 Fluvoxamine’s 1-sigma receptor antagonism is unique among SSRIs, and researchers have suggested that this may make fluvoxamine more effective than other SSRIs in treating anxious or delusional depression.2
The extended-release formulation uses a spheroidal oral drug absorption system, a proprietary technology that limits peak-to-trough variance for 24 hours.1 The manufacturer postulates that decreased plasma concentration variability will improve fluvoxamine’s tolerability.1
Pharmacokinetics
In a single-dose crossover study of 28 healthy subjects, the mean maximum concentration of drug (Cmax) for extended-release fluvoxamine was 38% lower than that of the immediate-release formulation, which may reduce the risk of adverse effects.1 Its relative bioavailability was 84%, and mean plasma half-life was 16.3 hours in male and female volunteers.1
Fluvoxamine is extensively metabolized in the liver, primarily through oxidative demethylation and deamination.1 Nine metabolites constitute 85% of the urinary excretion product; the main metabolite is fluvoxamine acid.1 Approximately 2% of fluvoxamine is excreted unchanged in urine. Administering extended-release fluvoxamine capsules with food does not appear to affect the drug’s absorption.1
Fluvoxamine is a potent inhibitor of the cytochrome P450 (CYP) 1A2 isoenzyme and also is believed to significantly inhibit CYP3A4, CYP2C9, CYP3A4, and CYP2C19. It is a relatively weak inhibitor of CYP2D6.1
Efficacy
The FDA based its approval of extended-release fluvoxamine on data from 3 clinical trials with positive outcomes: 2 for GSAD and 1 for OCD (Table 2).1,3-6
GSAD trials. In the first GSAD study—a randomized, double-blind, placebo-controlled, multicenter trial of 300 subjects with GSAD—participants were randomly assigned to receive extended-release fluvoxamine or placebo for 12 weeks.3 The extended-release fluvoxamine group started at 100 mg administered at night, with dosages titrated at 50 mg/week based on efficacy and tolerability to a maximum of 300 mg/d.1 Subjects in the extended-release fluvoxamine group demonstrated a statistically significant change in Liebowitz Social Anxiety Scale (LSAS) scores from baseline compared with those receiving placebo (P=0.02). Researchers observed similar results in secondary measures.
In an extension of this study, 112 subjects who demonstrated at least minimal improvement from extended-release fluvoxamine by week 12 continued the same dosing regimen for an additional 12 weeks. Investigators found the drug’s beneficial effects persisted to 24 weeks, although the magnitude of the effect decreased.4
A separate study using the same dosing regimen enrolled 279 adult patients in a 12-week, multicenter, randomized, placebo-controlled trial.5 The fluvoxamine-treated group showed statistically and clinically significant improvement:
- by week 4 on the LSAS and the Clinical Global Impression-Improvement (CGI-I) scale
- by week 6 on the Sheehan Disability Scale, Clinical Global Impression-Severity scale (CGI-S) and Patient Global Impression of Improvement (PGI) scale.5
OCD trial. Hollander et al6 conducted a 12-week, double-blind, placebo-controlled, flexible-dose, parallel multicenter trial of 253 adult patients with OCD.6 Compared with those receiving placebo, subjects treated with extended-release fluvoxamine, 100 to 300 mg/d, showed a statistically significant decrease in score on the Yale-Brown Obsessive Compulsive Scale (P=0.001).6 Analysis of the CGIS and CGI-I also revealed statistically significant improvement compared with placebo. The effect appeared to begin at week 2.