Fluvoxamine theophylline

FIGURE 6-13. Theophyllin is a substrate for CYP450 1A2. Thus, in the presence of the 1A2 inhibitor fluvoxamine, theophyllin levels rise. The theophyllin dose must be lowered when it is given with fluvoxamine in order to avoid side effects. 

Yao C, Kunze KL, Kharasch ED, et al. Fluvoxamine-theophylline interaction gap between in vitro and in vivo inhibition constants toward cytochrome P4501A2. Clin Pharmacol Ther 2001 70 415 424. 

Theophylline Ciprofloxacin, fluvoxamine, etc. CYP1A2 Theophylline toxicity... 

Fluvoxamine Pharmacokinetic—CYP1A2 inhibition TCAs Clozapine Theophylline... 

Beta agonists (terbutaline, albuterol) Theophylline Antidepressants Bupropion Citalopram Escitalopram Duloxetine Fluoxetine Fluvoxamine... 

Theophylline is a narrow therapeutic index drug with significant difference in bioavailability following oral administration. The half-life of the drug is increased by heart failure, cirrhosis and viral infections, in elderly patients, and by certain drugs, such as cimetidine, ciprofloxacin, oral contraceptives and fluvoxamine. The half-life is decreased in smokers, chronic alcoholism, and by certain drugs, such as phenytoin, rifampicin and carbamazepine. 

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. 

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

Values were back calculated from actual in vivo DDI data for fluconazole and S-warfarin (fee, CYP2C9 = 0.91), fluvoxamine and theophylline (fcL,CYPiA2 = 0.8), fluvoxamine and S-mephenytoin (fcL,CYP2C9 = 1). ketoconazole and midazolam fcL,CYP3A,hepatic = 0.93), and quinidine and desipramine (fcL,CYP2D6 = 0.9). 

CYP1A2 Theophylline, unipramine Omeprazole, tobacco smoke Fluvoxamine, furafyUine... 

P450 IA2 -fin women Inhibited by P-estradiol, progesterone, and OCs Caffeine, theophylline, demethylation of TCAs Fluvoxamine... 

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 Acetaminophen, antipyrine, caffeine, clomipramine, phenacetin, tacrine, tamoxifen, theophylline, warfarin Smoking, charcoal-broiled foods, cruciferous vegetables, omeprazole Galangin, furafylline, fluvoxamine... 

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

An example of a potentially important drug interaction is that which occurs when fluvoxamine is given along with theophyllin (Figure 6—13). In that case, the theo-phyllin dose must be lowered or else the blood levels of theophyllin will rise and possibly cause side effects, even toxic side effects such as seizures. The same may occur with caffeine. Fluvoxamine also affects the metabolism of atypical anti-psychotics. 

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

In contrast, decreases in theophylline metabolism by selective inhibitors of CYP1A2, such as fluvoxamine and some quinolone antibiotics, or by selective and potent inhibitors of CYP3A4, such as the macrolide antibiotics, have resulted in serious theophylline toxicity (22). It is postulated that taken over time, the macrolide antibiotics act as mechanism-based inhibitors of CYP isoforms other than just CYP3A4. Some nonselective inhibitors of P450s, such as cimetidine, some p-blockers and calcium channel blockers, and others (19,22), also appear to inhibit the metabolism of theophylline enough to cause toxicity. 

Theophylline, caffeine, aminophylline, theobromine, p-hydrocyethyltheophylline, phenylbutazone, hydro-chloro-thiazide, acetominophen Fluvoxamine and possible isomers Hydroquinone and ethers Serotonin and metabolites... 

Fluvoxamine is a potent inhibitor of cytochrome CYP1A2, which may lead to interactions with several tricyclic antidepressants and theophylline (174). 

Orlando R, Padrini R, Perazzi M, et al. (2006) Liver dysfunction markedly decreases the inhibition of cytochrome P450 lA2-mediated theophylline metabolism by fluvoxamine. Clin Pharmacol Ther 79 489-499. 

FLUVOXAMINE BRONCHODILATORS- THEOPHYLLINE Possible t plasma concentrations of theophylline Fluvoxamine is potent inhibitor of CYP1A2, and fluoxetine is less potent as an inhibitor. Paroxetine, sertraline, escitalopram and citalopram are not currently known to cause any inhibition Consider an alternative antidepressant... 

THEOPHYLLINE SSRIs - FLUVOXAMINE T theophylline levels Fluvoxamine is potent inhibitor of CYP1A2 Consider an alternative antidepressant... 

Via CYP4501A2 inhibition, fluvoxamine may reduce clearance of theophylline and clozapine, thus raising their levels and requiring their dosing to be lowered... 

Fluvoxamine administered with either caffeine or theophylline can thus cause jitteriness, excessive stimulation, or rarely seizures, so concomitant use should proceed cautiously... 

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... 

Theophylline Fluvoxamine inhibits the metabolism of theophylline. Faroxetine may also inhibit the metabolism of theophylline. 

CYP1A2 Antidepressants amitriptyline, clomipramine, imipramine, fluvoxamine Neuroleptics haloperidol, phenothiazines, thiothixene, clozapine, olanzapine Others tacrine, caffeine, theophylline, acetaminophen, phenacetin No report of polymorphism until 1999 significance of following findings remains unclear 1C reduced activity 23% in Japanese 1F higher inducibility 32% in Caucasians... 

Given concurrently with TCAs they may cause serious adverse effects. Fluvoxamine may raise levels of caffeine and theophylline, and fluoxetine can interfere with the metabolism of clozapine, cyclosporin, and tefenadine (18, 46). SSWs should never be given with MAO inhibitors because a fatal "serotonin syndrome" has been reported with fluoxetine in this combination (18). 

CYP1A2 Caffeine Theophylline Tobacco Charcoal-broiled meat Fluvoxamine (Yes)" Caffeine... 

I With fluvoxamine (due to cytochrome P450-1A2 inhibition) caffeine, clozapine, theophylline. 

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