Source: Marketing Authorisation Holder Revision Year: 2022 Publisher: Viatris Pty Ltd, Level 1, 30 The Bond, 30-34 Hickson Road, Millers Point NSW 2000, www.viatris.com.au, Phone: 1800 274 276
Fluvoxamine has two isomeric forms: an E isomer which is pharmacologically active, and a Z isomer which is non-active. LUVOX tablets contain only the E isomer.
The mechanism of action of fluvoxamine is believed to be related to its ability to selectively inhibit presynaptic reuptake of serotonin, and thus increase the serotonin concentrations within the synaptic cleft. This is accompanied by minimal interference with the noradrenergic and dopaminergic processes.
Unlike tricyclic antidepressants, fluvoxamine has limited affinity for alpha adrenergic, beta adrenergic, histaminergic, muscarinic, dopaminergic or serotoninergic receptors. Antagonism of these post-synaptic receptors are believed to be associated with some of the cardiovascular, anticholinergic and sedative effects of classical tricyclic antidepressant drugs.
Dose-dependent decreases in rapid eye movement (REM) sleep and increased REM latency were found with fluvoxamine. These effects are similar to those of other antidepressant drugs.
In depression, the efficacy of fluvoxamine was established in 15 three-way trials in which fluvoxamine (≥100 mg/day) was compared with both placebo and a tricyclic antidepressant (imipramine ≥150 mg/day or desipramine, ≥100 mg/day) generally over a period of 6 weeks and using HAM-D, CGI severity and MADRS as the main efficacy criteria. Of these studies, seven showed conclusive results: four were positive for both fluvoxamine and active reference therapy, whereas the other three studies showed only efficacy for active reference therapy. In a pooled analysis of the results of all these studies, both fluvoxamine (n=837) and active reference therapy (n=779) were found to be more effective than placebo (n=837). HAM-D improvements (LOCF) after 6 weeks were 39.1%, 41.9% and 33.9%, respectively. In these studies, the effective dose range for fluvoxamine was determined to lie between 100 mg and 300 mg per day. Using various definitions of response based on HAM-D or CGI criteria, there were no statistically significant differences in response rates between fluvoxamine and active reference therapy. Statistical analyses of the data did not reveal any patient features (such as age, sex, race etc.) which predict treatment response to fluvoxamine.
A study of depressed outpatients who had responded to fluvoxamine (MADRS 10) during an initial 26-week open treatment phase (n=204) and were then double-blind randomised to continuation on fluvoxamine (100 mg/day) or placebo for 1 year demonstrated a significantly lower relapse rate for fluvoxamine (13%) compared to those on placebo (35%).
Adult OCD Studies: The effectiveness of fluvoxamine in the treatment of Obsessive Compulsive Disorder (OCD) was demonstrated in two 10-week placebo-controlled studies (Studies 1 and 2). The results of two 10-week clomipramine-controlled studies (Studies 3 and 4) support the effectiveness of fluvoxamine in the treatment of OCD.
Studies 1 and 2 were flexible dose double-blind parallel group, multicentre studies in which patients with moderate to severe OCD received fluvoxamine in doses up to 300 mg/day or placebo. 157 patients received fluvoxamine versus 158 patients who received placebo. Improvements from baseline in Yale-Brown Obsessive Compulsive Disorder (Y-BOCS) and NIMH-OC scores and the CGI improvement score were significantly greater in fluvoxamine-treated patients. In these studies, the overall response rates were 36% for fluvoxamine and 12% for placebo, and the effective dosage range for fluvoxamine was between 100 mg and 300 mg daily. In open extension studies, efficacy in OCD was demonstrated to be maintained in a total of 72 patients treated for a total of 46 weeks or more.
Studies 3 and 4 were flexible dose double-blind parallel group multicentre studies comparing fluvoxamine (100-300 mg/day) with clomipramine (100 mg-250 mg/day). 69 patients received fluvoxamine versus 76 patients who received clomipramine. Fluvoxamine and clomipramine were equally efficacious on the YBOCS, NIMH-OC and CGI improvement scores.
Paediatric OCD Study: The effectiveness of fluvoxamine for the treatment of OCD was also demonstrated in a 10-week multicentre, parallel group, placebo-controlled study in a paediatric outpatient population (children and adolescents, ages 8-17) followed by an open-label extension of up to two years.
In the double-blind phase of the study, patients were titrated to a total daily fluvoxamine dose of approximately 100 mg/day over the first two weeks of the trial, following which the dose was adjusted within a range of 50-200 mg/day (on a b.i.d. schedule) on the basis of response and tolerance. All patients had moderate to severe OCD (DSM-III-R) with mean baseline ratings on the Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS), total score of 24. Patients receiving fluvoxamine maleate experienced mean reductions of approximately 6 units on the CY-BOCS total score, compared to a 3 unit reduction for placebo patients.
The following table provides the outcome classification by treatment group on the Global Improvement item of the Clinical Global Impression (CGI) scale for the paediatric study.
| OUTCOME CLASSIFICATION (%) ON CGI-GLOBAL IMPROVEMENT ITEM FOR COMPLETERS IN PAEDIATRIC STUDY | ||
|---|---|---|
| Outcome Classification | Fluvoxamine (N=38) | Placebo (N=36) |
| Very Much Improved | 21% | 11% |
| Much Improved | 18% | 17% |
| Minimally Improved | 37% | 22% |
| No change | 16% | 44% |
| Worse | 8% | 6% |
Post hoc exploratory analyses for gender effects on outcomes did not suggest any differential responsiveness on the basis of gender. Further exploratory analyses revealed a prominent treatment effect in the 8-11 age group and essentially no effect in the 12-17 age group. The reason for the difference in these results is unknown. However, follow up data from the open extension of the study showed a further improvement as demonstrated by a decrease of an additional 3 to 6 units on the CY-BOCS in young, as well as adolescent, patients. This improvement was sustained over a one-year period in 54 of the 98 patients who completed the one-year extension and in 12 of the 22 patients who completed the two-year extension.
Fluvoxamine is almost completely absorbed following oral administration. The absolute bioavailability is 53% (90% confidence interval: 44-62%). Absorption is unaffected by the presence of food.
Maximum plasma levels occur within 3-8 hours of dosing. Steady state levels are usually achieved within one week. The mean plasma half-life is approximately 12-13 hours after a single dose and approximately 22 hours following repeated dosing. In vitro binding of fluvoxamine to human plasma proteins is 80%, and the volume of distribution is estimated to be 20 L/kg.
The pharmacokinetics of fluvoxamine is linear between single oral doses of 25-100 mg. During multiple dosing in the range of 100-300 mg per day, the higher doses produced disproportionally higher plasma concentrations than predicted from data obtained with the lower dose.
Fluvoxamine undergoes extensive hepatic transformation, mainly via oxidative demethylation, into at least 9 metabolites. Less than 4% of the dose is excreted in the urine as unchanged parent compound, while approximately 94% of the dose is recovered in the urine as metabolites. The two principal metabolites exhibit negligible pharmacological activity. In view of the structures of the other metabolites, it is not expected that the other metabolites would be pharmacologically active.
The pharmacokinetics of fluvoxamine in patients with renal dysfunction do not appear to differ significantly from those in healthy, young volunteers. The area under the plasma concentration-time curve (AUC) and halflife were greater, however, in patients with liver dysfunction. Patients suffering from renal or hepatic insufficiency should be carefully monitored when treated with fluvoxamine. Upward dose titration should be carried out more slowly in this patient population.
The multiple-dose pharmacokinetics of fluvoxamine was determined in male and female children (ages 6-11) and adolescents (ages 12-17). The clearance of fluvoxamine in children was approximately half that observed in adolescents. AUC and Cmax in children were 1.5 to 2.7-fold higher than that in adolescents. As in adults, both children and adolescents exhibited non-linear multi-dose pharmacokinetics. Female children showed significantly lower clearance values and higher AUC(0-12) and Cmax compared to male children and, therefore, lower doses of LUVOX may produce therapeutic benefit. No gender differences were observed in adolescents. Body weight adjusted mean clearance at a dose of 300 mg/day was approximately 50% higher in adolescents compared to adults in previous studies.
No evidence of mutagenicity or chromosomal damage was observed in vitro. An in vivo test for chromosomal damage in mice (micronucleus test) gave no clear evidence of clastogenic activity.
In animal studies, there was no evidence of carcinogenic activity when fluvoxamine was given to rats at dietary doses up to 211 mg/kg/day for 30 months (approximately 2-5 times the maximum human exposure, based on plasma AUC), or to hamsters at about the same dose level for 112 weeks (male) and 85 weeks (female) (approximately two thirds the maximum human exposure, based on plasma AUC).
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