Fluvoxamine clozapine

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. 

Peritogiannis V, Tsouli S, Pappas D, Mavreas V. Acute effects of clozapine-fluvoxamine combination. Schizophr Res 2005 79 345-6. 

Clozapine 1A2 3A3/4, 2D6, 2C19 Fluvoxamine, ciprofloxacin, paroxetine Cigarette smoking... 

Fluvoxamine Pharmacokinetic—CYP1A2 inhibition TCAs Clozapine Theophylline... 

Lu, M. L. et al. (2000). Fluvoxamine reduces the clozapine dosage needed in refractory schizophrenic patients. /. Clin. Psychiatry, 61, 594—9. 

CYP1A2 TCAs, clozapine, haloperidol, fluvoxamine, mirtazepine, olanzapine... 

Jerling M, Lindstrom L, Bondesson U, Bertilsson L. Fluvoxamine inhibition and carbamazepine induction of the metabolism of clozapine evidence from a therapeutic drug monitoring service. 

CypP450 3A3 /4 Antidepressants tricyclics, nefazodone, fluoxetine, fluvoxamine, citalopram, mirtazepine, venlafaxine Antipsychotics chlorpromazine, clozapine, pimozide, quetiapine, risperidone... 

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. 

Substrates Inhibitors Inducers CYP1A2 Acetaminophen, caffeine, clozapine, imipramine, theophylline, propranolol Most fluoroquinolone antibiotics, fluvoxamine, cimetidine Tobacco smoking, charcoal-broiled foods, cruciferous vegetables, omeprazole... 

In most cases, SSRIs are the first choice for drugs to combat OCD. Clomipramine, fluvoxamine, fluoxetine, paroxetine, sertraline, and citalopram are all SSRIs that have been proven effective in reducing OCD symptoms. However, in about 40 to 60% of patients, these drugs do not completely alleviate all the symptoms. When this is the case, a second type of drug called a neuroleptic is often added. Neuroleptic drugs, such as haloperidol, clozapine, risperidone, and chlorpromazine... 

P450 IID6 -fin women Inhibited by OCs Hydroxylation of nortriptyline and desipramine, haloperidol, clozapine, risperidone, venlafaxine Fluoxetine, fluvoxamine, paroxetine, sertraline... 

Clozapine is metabolized by hepatic CYP 1A2 and, to a lesser degree, CYP 3A3/4 therefore, the drug is subject to changes in serum concentration when combined with medications that inhibit or induce these enzymes. Serum clozapine levels increase with coadministration of fluvoxamine or erythromycin and decrease with coadministration of phenobarbital or phenytoin and with cigarette smoking (Byerly and DeVane 1996). These pharmacokinetic interactions are particularly important because of the dose-dependent risk of seizures. 

Wetzel H, Anghelescu 1, Szegedi A, et al Pharmacokinetic interactions of clozapine with selective serotonin reuptake inhibitors differential effects of fluvoxamine and paroxetine in a prospective study. J Clin Psy-chopharmacol 18 2-9, 1998... 

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. 

Koponen HJ, Leinonen E, Lepola U. Fluvoxamine increases the clozapine serum level significantly. Eur Neuropsychopharmacol 1996 6 69-71. 

GFJ has been shown to increase the exposure of carbamazepine (175), cisapride (176-179), fluvoxamine (184), losartan (188), methadone (189), scopolamine (191), and sertraline (192). However, only the interaction of GFJ with carbamazepine and cisapride seems to be clinically relevant. No alteration in exposure was observed for clozapine (180,181), heophylline (195), halo-peridol (196), and omeprazole (190). Reports of increased pharmacokinetic parameters of clozapine, theophylline, and haloperidol suggest that an interaction is unlikely to be clinically relevant. Contradicting results were reported for itraconazole (185-187), digoxin (75,183), and sildenafil (193,194). An increased effect on concomitant use of diclofenac and GFJ was observed in rats (182). Overall, the clinical relevance for this drug class appears to be low. 

A2 Tertiary amine TCAs, duloxetine, theophylline, phenacetin, TCAs (demethylation), clozapine, diazepam, caffeine Fluvoxamine, fluoxetine, moclobemide, ramelteon Tobacco, omeprazole... 

FIGURE 11-44. Clozapine and olanzapine are substrates for cytochrome P450 1A2 (CYP450 1A2). When these drugs are given with an inhibitor of this enzyme, such as the antidepressant fluvoxamine, plasma levels of olanzapine and clozapine can rise. 

Cyt 1A2 metabolizes clozapine common substrates - amitriptyline, clomipramine, propranolol, theophylline, warfarin, caffeine. Common inhibitors - fluvoxamine, paroxetine. 

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. 

Ozdemir V, Kalow W, Okey AB, Lam MS, Albers LJ, Reist C, Fourie J, Posner P, Collins EJ, Roy R. Treatment-resistance to clozapine in association with ultrarapid CYP1A2 activity and the C A polymorphism in intron 1 of the CYP1A2 gene effect of grapefruit juice and low-dose fluvoxamine. J Clin Psychopharmacol 2001 21 603-607. 

In a prospective study fluvoxamine, in a low dosage of 50 mg/day, produced a threefold increase in plasma clozapine concentrations (n = 16) (24). 

Other reports have confirmed that fluvoxamine increases plasma concentrations of clozapine and its metabolites 25,26 (SEDA-21, 12). The mechanism is probably inhibition of CYP1A2. 

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 another study there were similar increases in plasma clozapine concentrations and adverse reactions in 18 patients taking fluvoxamine 50 mg (week 5, mean dose 97 mg) (37). 

In nine men who were given a single dose of clozapine 50 mg on two separate occasions with a 2-week interval, fluvoxamine increased clozapine plasma concentrations, and the total mean clozapine AUC was increased by a factor of 2.6 all the patients were sedated during combined therapy (38). 

Combined therapy with clozapine and fluvoxamine (n = 11) and clozapine monotherapy (n = 12) have been monitored before and during the first 6 weeks of medication (39). The co-administration of fluvoxamine attenuated and delayed the clozapine-induced increase in plasma concentrations of tumor necrosis factor-alpha, enhanced and accelerated the clozapine-induced increase in leptin plasma concentrations without a significant effect on clozapine-induced weight gain, and reduced granulocyte counts. 

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. 

Esposito G, Pinto A, Maj M. Fluvoxamine increases plasma and urinary levels of clozapine and its major metabolites in a time- and dose-dependent manner. J Clin Psychopharmacol 2000 20(6) 708-10. 

Markowitz JS, Gill HS, Lavia M, Brewerton TD, DeVane CL. Fluvoxamine-clozapine dose-dependent interaction. Can J Psychiatry 1996 41(10) 670-1. 

Szegedi A, Anghelescu I, Wiesner J, Schlegel S, Weigmann H, Harder S, Hiemke C, Wetzel H. Addition of low-dose fluvoxamine to low-dose clozapine monotherapy in schizophrenia drug monitoring and tolerability data from a prospective clinical trial. Pharmacopsychiatry 1999 32(4) 148-53. 

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