Fluvoxamine Benzodiazepines

Smoking cessation, with or without nicotine substitutes, may alter response to concomitant medication in ex-smokers. Smoking may affect alcohol, benzodiazepines, beta-adrenergic blockers, caffeine, clozapine, fluvoxamine, olanzapine, tacrine, theophylline, clorazepate, lidocaine (oral), estradiol, flecanide, imipramine, heparin, insulin, mexiletine, opioids, propranolol, catecholamines, and cortisol. 

Most benzodiazepines undergo oxidative metabolism in the liver that may be enhanced by enzyme inducers (e.g. carbamazepine, phenytoin) or slowed by inhibitors (sodium valproate, fluoxetine, fluvoxamine). Oxazepam, lorazepam and temazepam are directly conjugated and are not subject to these interactions. 

Treatment of GAD can be undertaken using a number of pharmacological agents. Benzodiazepines have been found to be superior to placebo in several studies and all benzodiazepines appear to be equally effective. However, side effects include sedation, psvchomotor impairment, amnesia and tolerance (Chapter 1). Recent clinical data indicate that SSRIs and SNRIs are effective in the treatment of acute GAD symptoms. Venlafaxine, paroxetine and imipramine have been shown to be effective antianxiety medications in placebo-controlled studies. Case studies also indicate the usefulness of clomipramine, nefazodone, mirtazapine, fluoxetine and fluvoxamine in GAD. Buspirone, a 5-HTla receptor partial agonist, has been shown to be effective in several placebo-controlled, double-blind trials (Roy-Byme and Cowley, 2002). Buspirone has a later onset of action than both benzodiazepines and SSRIs but with the advantage of being non-addictive and non-sedating. 

A larger set of placebo-controlled studies show conclusively that imipramine is also effective for the treatment of panic disorders. Other agents shown to be effective in panic disorders include the SSRIs paroxetine, sertraline, fluvoxamine, fluoxetine and citalopram. Generally, initial treatment of moderate to severe panic disorders may require the initiation of a short course of benzodiazepines e.g. clonazepam (0.5 1 mg twice daily), and an SSRI. The patient will obtain immediate relief from panic attacks with the benzodiazepine whereas the SSRI may take 1 6 weeks to become effective. Once a patient is relieved of initial panic attacks, clonazepam should be tapered and discontinued over several weeks and SSRI therapy continued thereafter. There are no pharmacological treatments available for specific phobias, however controlled trials have shown efficacy for several agents, e.g. phenelzine, moclobemide. clonazepam, alprazolam, fluvoxamine. sertraline and paroxetine in the treatment of social phobia (Roy-Byrne and Cowlev, 2002). 

A third important CYP450 enzyme for antidepressants and mood stabilizers is 3A4. Some benzodiazepines (e.g., alprazolam and triazolam) are substrates for 3A4 (Fig. 6—17). Some antidepressants are 3A4 inhibitors, including the SSRIs fluoxetine and fluvoxamine and the antidepressant nefazodone (Fig. 6—18). Administration of a 3A4 substrate with a 3A4 inhibitor will raise the level of the substrate. For example, fluoxetine, fluvoxamine, or nefazodone will raise the levels of alprazolam or triazolam, requiring dose reduction of the benzodiazepine (Fig. 6—18). 

Cyt 3A3/4 metabolizes clozapine, sertindole, quetiapine common substrates -tricyclic antidepressants, nefazodone, sertraline, carbamazepine, ethosuximide, terfenadine, benzodiazepines, diltiazem, nifedipine, verapamil, erythromycin, cyclosporine, lidocaine, quinidine, cisapride, paracetamol. Common inhibitors -nefazodone, fluvoxamine, fluoxetine, ketoconazole. 

SSRIs and the benzodiazepine alprazolam are often used to treat panic disorder. Pharmacokinetic reactions between them could therefore be important. Alprazolam is metabolized by CYP3A4, which fluvoxamine inhibits (SEDA-22, 13). In 23 out-patients (11 men, 12 women, mean age 39 years) who took alprazolam both as monotherapy (mean dose 1.0 mg/day) and in combination with fluvoxamine (mean dose 34 mg/day), fluvoxamine increased plasma alprazolam concentrations by 58% (97). This was not associated with increased sleepiness, measured by a subjective rating scale, but objective measures of psychomotor function were not carried out and these could have been impaired by raised alprazolam concentrations. 

Via CYP450 3A4 inhibition, fluvoxamine may reduce clearance of carbamazepine and benzodiazepines such as alprazolam and triazolam, and thus require dosage reduction... 

Avoid use of astemizole with fluvoxamine use alternate antihistamine Decrease dose of benzodiazepines Decrease dose of theophylline by approximately 1/3 avoid caffeine intake Monitor INR decrease dose of warfarin if necessary Monitor phenytoin increased dose may be necessary... 

Some SSRIs (notably fluvoxamine and to a lesser extent fluoxetine) and their metabohtes inhibit hepatic oxidative enzymes, particularly CYP2C19 and CYP3A, that metabolize most benzodiazepines, as well as zaleplon, zolpidem, zopiclone, and buspirone (SEDA-22, 39) (SEDA-22, 41) (168,169). Apart from fluvoxamine, SSRIs do not generally have a chnically prominent effect on hypnosedative effects studies vary from those that have found that fluoxetine has a moderate but functionally unimportant impact on diazepam concentrations (170) to results that suggest significant aggravation of the cognitive effects of alprazolam when co-prescribed with the SSRI (171). 

Benzodiazepines Sertraline and fluvoxamine may inhibit the metabolism of alprazolam and diazepam, resulting in elevated serum levels potentially causing sedation and psychomotor impairment. 

The SSRIs (paroxetine, fluoxetine, sertraline, fluvoxamine, citalopram) and SNRI (ven-lafaxine) have an impressive side-effect profile, and this has contributed to their widespread use. Possible adverse effects include nausea, insomnia, and agitation, but these are generally manageable and diminish over time. More significant is the association of the SSRIs with sexual dysfunction, in both men and women. These effects are longer lasting, and can occur in up to 40% of patients (79). A withdrawal syndrome has also been observed with the SSRIs, characterized by dizziness, headache, and irritability upon abrupt discontinuation. This is much less serious than that observed with benzodiazepines. 

With the exception of temazepam, which is eliminated by conjugation, all benzodiazepine hypnotics are metabolized by hepatic microsomal oxidation and then undergo glucuronide conjugation. Oxidation may be inhibited in patients with impaired liver function, advanced age, or concurrent use of drugs that inhibit oxidation. Drugs that inhibit the cytochrome P450 3A4 enzyme (e.g., erythromycin, nefazodone, fluvoxamine, and ketoconazole) reduce the clearance of triazolam and increase its plasma concentrations."... 

Potentially clinically significant interactions include the tendency for fluvoxamine to increase circulating concentrations of oxidatively metabolized benzodiazepines, clozapine, theophylline, and warfarin. Sertraline and fluoxetine can increase levels of benzodiazepines, clozapine, and warfarin. Paroxetine increases levels of clozapine, theophylline, and warfarin. Fluoxetine also potentiates tricyclic antidepressants and some class 1C antiarrhythmics with a narrow therapeutic index (including encainide, flecainide, and propafenone). Nefazodone potentiates benzodiazepines other than lorazepam and oxazepam. 

Vandenberghe, H. MacDonald, J.C. Analysis of fluvoxamine, clobazam and other benzodiazepines on the same HPLC system (Abstract 40). Ther.Drug Monit, 1995, 17, 393... 

Fluvoxamine inhibits liver drug-metabolizing enzymes. Dosages of alprazolam, theophylline, and warfarin must be reduced if any of these drugs are given concomitantly with fluvoxamine. Nefazodone may also decrease the metabolism of benzodiazepines, and venlafaxine may inhibit haloperidol metabolism. The answer is (B). 

There is some evidence to suggest that the metabolism of some benzodiazepines (such as alprazolam, bromazepam, diazepam, and also possibly midazolam, nitrazepam and triazolam) may be reduced by some SSRIs (such as fluoxetine and fluvoxamine). On the whole, no clinically significant interaction appears to occur between other SSRIs and the benzodiazepines or related dri s such as cloral hydrate or zaleplon. There is some evidence to support the su estion that sedation is likely to be increased by the concurrent use of SSRIs and benzodiazepines. Rare cases of hallucinations have been seen with zolpidem and some SSRb. Symptoms of the serotonin syndrome have been reported in two patients taking paroxetine and a benzodiazepine. 

The evidence suggests that fluvoxamine inhibits the metabolism of those benzodiazepines that undergo oxidation (e.g. alprazolam, bromazepam, diazepam) thereby increasing and prolonging their effects, but not those that are metabolised by glucuronidation (e.g. lorazepam). Zaleplon is metabolised by aldehyde oxidase and therefore does not interact. 

Van Harten J, Holland RL, Wesnes K, Influence of multiple-dose administration of fluvoxamine on the pharmacokinetics of the benzodiazepines bromazepam and lorazepam a randomised, cross-over study, EurNeuropsychopharmacol (1992) 2,381. 

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