Fluvoxamine adverse effects

The manufacturers of olanzapine suggest that lower olanzapine doses may be needed if fluvoxamine is given. Monitor for fluvoxamine adverse effects. Other SSRIs appear not to interact significantly, although the case report with paroxetine suggests that additive adverse effects are a possibility. 

SSRIs are widely used for treatment of depression, as well as, for example, panic disorders and obsessive—compulsive disorder. These dmgs are well recognized as clinically effective antidepressants having an improved side-effect profile as compared to the TCAs and irreversible MAO inhibitors. Indeed, these dmgs lack the anticholinergic, cardiovascular, and sedative effects characteristic of TCAs. Their main adverse effects include nervousness /anxiety, nausea, diarrhea or constipation, insomnia, tremor, dizziness, headache, and sexual dysfunction. The most commonly prescribed SSRIs for depression are fluoxetine (31), fluvoxamine (32), sertraline (52), citalopram (53), and paroxetine (54). SSRIs together represent about one-fifth of total worldwide antidepressant unit sales. 

The results from an open-label, pilot study evaluating the efficacy of fluvoxamine for hypochondriasis were recently published (Fallon et al, 2003). The study sample included six Hispanics (subgroup unknown). Significant improvement (57.1%) was noted for the intent-to-treat group (eight out of fourteen) based on physicianrated and self-rated scales. The sample size was too small to identify differences in response or adverse effects by ethnicity. 

Fluoxetine, along with sertraline, fluvoxamine, and paroxetine, belongs to the more recently developed group of SSRI. The clinical efficacy of SSRI is considered comparable to that of established antidepressants. Added advantages include absence of cardiotoxicity, fewer autonomic nervous side effects, and relative safety with overdosage. Fluoxetine causes loss of appetite and weight reduction. Its main adverse effects include overarousal, insomnia, tremor, akathisia, anxiety, and disturbances of sexual function. 

In general, the SSRIs have a more tolerable side effect profile than the tricyclic antidepressants with their anticholinergic effects. Review of the rate that subjects in the controlled studies discontinued a SSRI because of adverse effects provides some perspective on how well tolerated the medications are, although the specifics may vary according to dosage and design (e.g., forced titration) and are not directly comparable. The rate of discontinuation was reported to be 12% (4/48) for fluoxetine (Emslie et ah, 1997), 9.7% for paroxetine (Keller et ah, 2001), 13% (12/92) for sertraline (March et ah, 1998), and 33% (19/57) (Riddle et ah, 2001) and 7.9% (5/63) for fluvoxamine (Walkup et ah, 2001). 

Adverse effects. Postmarketing surveillance, in which more than 34,000 patients were studied, revealed that fluvoxamine is generally well tolerated if initial dose titration is employed (Wilde et al. 1993). By far the most common side effect reported was nausea (15.7%) other adverse effects included somnolence (6.4%), asthenia (5.1%), headache (4.8%), and dry mouth (4.8%) these events had an incidence of >1%. On reviewing the manufacturer s database, Henry (1991) found that 310 cases of overdose with fluvoxamine had been reported worldwide. The overwhelming majority recovered with no sequelae the 13 fatalities were associated with multiple substance ingestion, making the contribution of any single substance difficult to assess. 

Clozapine is principally metabolized to N -desmethylclozapine (norclozapine). It is also metabolized to and n-oxide, other hydroxyl metabolites, and a protein-reactive metabolite. The n-oxide can be converted back to clozapine. The enzyme responsible for the metabolism of clozapine to norclozapine is the cytochrome P450 1A2 enzyme (325). This is consistent with a study showing that caffeine, a marker for 1A2, is cleared in relationship to the conversion of clozapine to norclozapine ( 326). Discontinuation of coffee intake can decrease the clozapine plasma levels by more than 50%, and increasing caffeine intake can produce a reemergence of the side effects (e.g., drowsiness, excess salivation). Additionally, smoking, which induces 1A2, lowers clozapine plasma levels. Fluvoxamine, an inhibitor of 1A2, dramatically increases plasma levels, and on occasion, adverse effects are seen ( 327). This phenomenon can lead to clozapine intoxication in patients on high doses of fluvoxamine. 

Fluvoxamine, fluoxetine, and paroxetine have nonlinear pharmacokinetics, which means that dose increases lead to disproportionately greater increases in plasma drug levels (25). In contrast, citalopram and sertraline have linear pharmacokinetics. For these reasons, dose increases with fluvoxamine, fluoxetine, and paroxetine can lead to greater than proportional increases in concentration-dependent effects such as serotonin-mediated adverse effects (e.g., nausea) and inhibition of specific CYP enzymes. 

In 1988, fluoxetine became the first SSRI marketed in the United States. Since then, sertraline (1992), paroxetine (1993), fluvoxamine (1994) and citalopram (1998) have been marketed. Their widespread acceptance has added substantially to the patient-years of experience with these medications. Thus, the confidence in our knowledge of the adverse effect profile of these drugs in the general population and in special populations (e.g., the elderly, the medically ill) has grown substantially over the past decade. 

All SSRIs have an antipanic effect. Their advantages are limited adverse effects and lack of toxicity. Because of more acceptable adverse effect profiles, the SSRIs are usually the drugs of choice. Several studies consistently indicate that SSRIs such as fluoxetine, sertraline, paroxetine, fluvoxamine, as well as agents such as clomipramine and trazodone, all possess antipanic efficacy, although the last may be less effective than imipramine ( 24, 105, 106, 107, 108 and 109). 

Gastrointestinal adverse effects are one of the major disadvantages of SSRIs. The most common is nausea, and the incidence is said to be 20% or more for paroxetine (45,46), sertraline (47), fluvoxamine (5), fluoxetine (48), and citalopram (10,49). Although nausea can lead to drug withdrawal, it usually disappears after a few weeks. Other gastrointestinal symptoms that occur commonly with fluoxetine and sertraline are loose stools and diarrhea (47,48,50), while constipation has been more often reported with fluvoxamine (5) and paroxetine (45,46). 

The ability of SSRIs to cause delayed ejaculation has been used in controlled trials of men with premature ejaculation (61,62). Of the SSRIs, paroxetine and sertraline produced the most benefit in terms of increase in time to ejaculation, but fluvoxamine did not differ from placebo. Clomipramine was more effective than the SSRIs but caused most adverse effects. From a practical point of view many patients might prefer to take medication for sexual dysfunction when needed rather than on a regular daily basis, and it would be of interest to study the beneficial effects of SSRIs on premature ejaculation when used in this way. 

Fluvoxamine increases clozapine plasma concentrations (34,35). In 16 patients taking clozapine monotherapy, fluvoxamine 50 mg was added in the hope of ameliorating the negative symptoms of schizophrenia (36). At steady state the serum concentrations of clozapine and its metabolites increased up to five-fold (average two- to three-fold). However, adverse effects were almost unchanged in frequency and severity, in spite of the pharmacokinetic interaction. 

In two studies of short duration (18 patients each) there were benefits of using low doses of clozapine plus fluvoxamine, and the authors suggested taking advantage of this interaction (40). Patients taking fluvoxamine required relatively low doses of clozapine and had clinically significant reductions in the symptoms of their illness while avoiding the sedative adverse effects associated with the usual doses of clozapine. 

Sexual dysfunction is a common adverse effect of SSRIs and various treatments have been proposed, of which sildenafil is the only strategy with consistent support from controlled trials. Sildenafil is metabolized by CYP3A4, which is inhibited by fluvoxamine. The effects of fluvoxamine (100 mg/day for 10 days) on the pharmacokinetics of sildenafil (50 mg orally) has been evaluated in 12 healthy men (mean age 25 years) using a doubleblind, placebo-controlled, crossover design (46). Fluvoxamine increased the AUC of sildenafil by about... 

There are many other ways in which SSRIs can interfere with sexual function, for example by causing loss of sexual interest and erectile difficulties. In an open, prospective study of 1000 Spanish patients taking a variety of antidepressants, there was an overall incidence of sexual dysfunction of 59% (15). The highest rates, 60-70%, were found with SSRIs (including fluvoxamine) and venlafax-ine. The lowest rates were found with mirtazepine (24%), nefazodone (8%), and moclobemide (4%). Spontaneous resolution of this adverse effect was uncommon - 80% of subjects had no improvement in sexual function over 6 months of treatment. 

A 34-year-old man, who had taken clozapine for 3 years in a dose that had been gradually increased up to 900 mg/day, was also given fluvoxamine 100 mg/day and 6 days later developed dystonia, dysarthria, hypersalivation, and dizziness fluvoxamine was withdrawn and the adverse effects abated completely within 1 week (257). 

The addition of low-dose fluvoxamine (50-100 mg/day) to neuroleptic drug treatment may improve the negative symptoms in patients with schizophrenia, but involves a risk of a drug interaction. In 12 in-patients with schizophrenia receiving 6 mg/day of haloperidol, incremental doses of fluvoxamine (25, 75, and 150 mg/day for 2 weeks each) respectively increased haloperidol plasma concentrations by 120%, 139%, and 160% of those before fluvoxamine co-administration in spite of the increase, there were no particular adverse effects (50). 

In 23 patients with obsessive-compulsive disorder who had not responded to a 6-month course of fluvoxamine (300 mg/day), olanzapine (5 mg/day) was added in an open comparison (28). There was a significant reduction in the mean score on the Yale-Brown Obsessive-Compulsive Scale concomitant schizotypal personality disorder was the only factor significantly associated with a response. The most common adverse effects were mild to moderate weight gain and sedation. 

SSRIs ATOMOXETINE t plasma concentrations and risk of adverse effects (abdominal pain, vomiting, nausea, fatigue, irritability) Atomoxetine is a selective norepinephrine reuptake inhibitor, t plasma concentrations due to inhibition of CYP2D6 by fluoxetine and paroxetine (potent), fluvoxamine and sertraline (less potent) and escitalopram and citalopram (weak) Avoid concurrent use. The interaction is usually severe with fluoxetine and paroxetine... 

FLUOXETINE, FLUVOXAMINE, PAROXETINE, SERTRALINE BUPROPION t plasma concentrations of bupropion and risk of adverse effects Inhibition of CYP2B6 Warn patients about adverse effects, and use alternatives when possible... 

FLUVOXAMINE, SERTRALINE GRAPEFRUIT JUICE Possibly t efficacy and t adverse effects Possibly 1 metabolism Clinical significance unclear... 

BUPROPION 1. ANTICANCER DRUGS - thiotepa 2. ANTIDEPRESSANTS-fluoxetine, fluvoxamine, paroxetine, sertraline 3. ANTIVIRALS - efavirenz, protease inhibitors t plasma concentrations of bupropion and risk of adverse effects Inhibition of CYP2B6 Warn patients about adverse effects and use alternatives when possible. Avoid co-administration of bupropion with protease inhibitors. Co-adminis-ter efavirenz and bupropion with caution. A retrospective study showed that two patients received a combination without reported adverse effects. Potential T risk of seizures... 

---