Fluvoxamine dosing

As of the date of this chapter (circa March, 2002), labeling changes regarding pediatric use have resulted from only two programs—the study of buspirone in pediatric GAD and a pharmacokinetic study of fluvoxamine in pediatric OCD (fluvoxamine already had a controlled clinical trial in pediatric patients). Two placebo-controlled trials with buspirone in pediatric GAD did not reveal a treatment effect, and this negative outcome is reflected in Buspar labeling. A pharmacokinetic study of fluvoxamine dosed at 100 mg bid in pediatric... 

Both fluvoxamine and sertraline are approved for the treatment of OCD in children and adolescents. Fluvoxamine was proven effective in a 10-week, double-blind, placebo-controlled trial in patients 8 to 17 years of age with OCD ( 149). Dosages in this study were adjusted to a total daily fluvoxamine dose of approximately 100 mg per day over the first 2 weeks using a balanced, twice-daily dosing schedule. After that, the dose was adjusted within a range of 50 to 200 mg per day based on clinical assessment of efficacy and tolerability. Fluvoxamine was superior to placebo on the Children s Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) at weeks 1 to 6 and week 10. However, the effect was mainly in the 8- to 11-year-old versus the 12- to 17-year-old age group. The significance of this age difference is not known. 

In another case report, a woman taking fluvoxamine became suicidal and had to be hospitalized (Bastani et al., 1996). In the hospital, the fluvoxamine dose was increased from 50 mg/day to 150 mg/day, whereupon her condition worsened and she began to experience auditory hallucinations. The fluvoxamine was discontinued, and she recovered within 24 hours, confirming that the medication had caused the depression and psychosis. 

Fluvoxamine has little inhibitory effect on CYP2D6 but is a potent inhibitor of CYP1A2 and CYP2C19. It also is a moderate inhibitor of CYP3A4, which is involved in the metabolism of haloperidol. When fluvoxamine (25, 75, and 150 mg/day, each for 2 weeks) was added to haloperidol in 12 patients with schizophrenia aged 22-59 years, plasma haloperidol concentrations rose dose-relatedly after fluvoxamine 25 mg/day haloperidol concentrations rose by about 20%, with additional 20% increases with each increment in fluvoxamine dose however, this was not associated with overt clinical toxicity (104). 

Yasui-Furukori N, Kondo T, Mihara K, Inoue Y, Kaneko S. Fluvoxamine dose-dependent interaction and the effects on negative symptoms in schizophrenia. Psychopharmacology 2004 171 223-7. 

Small D, Loghin C, Lucas R, Knadler MP, Zhang L, Chappell J, Bergstrom R, Callaghan JT. Pharmacokinetic evaluation of combined duloxetine and fluvoxamine dosing in CYP2D6 poor metabolizers. Clin Pharmacol Ther (2005) 77, P37. 

SSRIs Citalopram 10-30 mg fluoxetine 10-20 mg fluvoxamine 50 mg paroxetine 10-30 sertraline 25-150 mg all agents are given by mouth daily and can be dosed continuously or during the luteal phase only26 Sexual dysfunction (reduced libido, anorgasmia), insomnia sedation, hypersomnia, nausea, diarrhea... 

Quetiapine 3A4 2D6, 2C9 Carbamazepine and phenytoin topiramate prednisolone. Fluvoxamine fluoxetine sertraline (high dose) CYP3A4 substrates grapefruit juice. 

Alprazolam dose should be reduced by 50% if nefazodone (Serzone) or fluvoxamine is added. 

Fluvoxamine (Luvox). This is actually the oldest of the SSRIs. It is approved iu this couutry for the treatmeut of OCD but is also an effective treatment for major depression and many other anxiety disorders. It should be started at 50mg/day, and the effective dose range is from 100 to 300mg/day. Fluvoxamine is the only SSRI that must be takeu twice a day. The common side effects of fluvoxamine are comparable to other SSRIs. 

It may be fair to ask, Is this much ado about nothing Although test tube studies have shown that particular drugs interact, it is seldom that this causes problems for patients taking the medications. For example, the antidepressant fluvoxamine inhibits the enzyme that deactivates the antipsychotic haloperidol (Haldol). Does this mean that fluvoxamine and haloperidol cannot be taken together By no means. Although this would probably raise the blood level of haloperidol somewhat, the main effect if any would be that a smaller dose of haloperidol would be more effective. 

SSRls. SSRI antidepressants have also received considerable scrutiny in the treatment of OCD. Fluoxetine, fluvoxamine, paroxetine, and sertraline are all approved by the FDA for the treatment of OCD. Current studies suggest that each of these medications is more effective for OCD when administered at the higher end of the therapeutic dose range, that is, fluoxetine 60-80 mg/day, fluvoxamine 200-300 mg/ day, paroxetine 40-60 mg/day, and sertraline 150-200 mg/day. No controlled studies are yet available regarding the use of citalopram or escitalopram for OCD. Refer to Chapter 3 for more information regarding SSRl antidepressants. 

Another practical example of a pharmacokinetic drug interaction concerns the incidence of seizures in patients given a standard (300 mg/ day) dose of clozapine. Should the patient be given an SSRI antidepressant (such as fluoxetine, fluvoxamine, sertraline or paroxetine) concurrently then the clearance of clozapine could be reduced by up to 50%, an effect which would be comparable with a doubling of the dose. This could lead to a threefold increase in the risk of the patient suffering a seizure. 

Elderly/Hepatic function impairment- These patients have been observed to have decreased fluvoxamine clearance. It may be appropriate to modify initial dose and subsequent titration. 

Renal function impairment No dose adjustment of citalopram, fluoxetine, or fluvoxamine in renally impaired patients is routinely necessary. 

Elderly Clearance of fluvoxamine is decreased by about 50% in elderly patients. A lower starting dose of paroxetine is recommended. Sertraline plasma clearance may be lower. In 2 pharmacokinetic studies, citalopram AUC was increased by 23% and 30%, respectively, in elderly subjects as compared with younger subjects, and its half-life was increased by 30% and 50%, respectively. In 2 pharmacokinetic studies, escitalopram half-life was increased by approximately 50% in elderly subjects as compared with young subjects and C ax was unchanged. 

Time to reach peak plasma level decreased from 8 hours post-dosing to 5.5 hours. Food does not appear to affect systemic bioavailability of fluoxetine although it may delay absorption. Fluvoxamine and citalopram bioavailability is not affected by food. Thus, fluoxetine, fluvoxamine, and citalopram may be given with or without food. 

Bromocriptine (Parl el) [Antiparkinsonian Agent/Dopamine Receptor Agonist] Uses Parkin on Dz, hyperprolactinemia, acromegaly, pituitary tumors Action Direct-acting on the striatal dopamine receptors X prolactin secretion Dose Initial, 1.25 mg PO bid titrate to effect, w/ food Caution [B, ] Contra Severe ischemic heart Dz or PVD Disp Tabs, caps SE X BP, Raynaud phenomenon (vasospastic disorder resulting in discoloration of the fmgers/toes), dizziness, N, hallucinations Interactions T Effects W/ erythromycin, fluvoxamine, nefazodone, sympathomimetics, antihypertensives X effects W/ phenothiazines, antipsychotics EMS Monitor BP may cause intolerance to EtOH OD May cause NA, severe hypotension give IV fluids symptomatic and supportive... 

Gill, M., LoVecchio, E, and Selden, B. (1999) Serotonin syndrome in a child after a single dose of fluvoxamine. Ann Emerg Med 33 457-459. 

The presence of an active metabolite and the duration of parent compound and metabolite half-life all impact the clinical interpretation of dosing, side effects, and potential for withdrawal. Fluoxetine and its active metabolite, both of which have a relatively long half-life, remain in the system for a long time after discontinuation. Industry prescribing instructions for fluvoxamine recommend a bid dosing regimen, in part because of the absence of an active metabolite. Paroxetine, without an active metabolite and with a relatively short half-life, has been anecdotally associated with late-day withdrawal effects. 

Lethal overdosages are extremely rare (Barbey and Roose, 1998), but have been reported for fluoxetine (260 to 6000 mg), sertraline (1100 mg), paroxetine (530 to 600 mg), and fluvoxamine (unknown dose). Many of these lethal doses occurred in adults reports of lethal overdose in children occur even less frequently. One report of a 4-year-old boy who ingested 400 mg of fluvoxamine described life-threatening complications requiring respiratory and inotropic support (Fraser and South, 1999). The boy presented in a coma with hypotension and bradycardia. After 24 hours, he recovered. 

SSRIs—fluvoxamine, fluoxetine, and paroxetine, more than sertraline and citalopram Inhibition of metabolism at CYP2D6 isoenzyme TCA toxicity due to up to 10-fold increase in TCA levels with coadministration Lower TCA dose Baumann, 1996... 

Some questions have been raised about the relative efficacy of the SSRls, particularly in severe depression. The pooled analyses of the data from blinded, controlled trials have tended to find similar levels of efficacy between the SSRls and the comparator TCA, imipramine. Paroxetine and fluvoxamine were both found in subanalyses of patients with severe depression included in large placebo- and imipramine-controlled studies to be more effective than imipramine in severe depression (S. A. Montgomery 1992a Ottevanger 1991 Tignol et al. 1992 Wakelin 1988]. However, imipramine may not be the TCA that is most effective in severe depression or may not have been used in the trials at an adequate dose. 

The initial reports from open studies (Artigas et al. 1994 Blier and Bergeron 1995) suggest that the combination is associated with improved efficacy with probable faster onset of action. This rapid response was reported with augmentation of fluoxetine and paroxetine, and more recently with nefazodone (Bakish et al. 1997), but interestingly not with sertraline or low doses of fluvoxamine. These results needed to be confirmed in placebo-controlled studies, and the reports from large studies do indeed find an acceleration of response measured as time to response and possible superiority of action with some antidepressants at the end of treatment (Perez et al. 1997 Tome de la Granja et al. 1997). 

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