Theophylline, fluvoxamine interactions with

Rasmussen BB, Jeppesen U, Gaist D, Brosen K. Griseofulvin and fluvoxamine interactions with the metabolism of theophylline. Ther Drug Monit Q.991) 19, 56-62. 

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

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. 

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. 

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. 

Anagrelide should not be used with other phosphodiesterase III inhibitors (e.g. milrinone) because of the potential for increased inotropic effects. Inhibitors of CYP1A2 (e.g. fluvoxamine) are predicted to increase anagrelide levels. Some caution might be required with concurrent aspirin and other platelet inhibitors. Whether anagrelide inhibits theophylline metabolism to a clinically relevant extent is not known. No pharmacokinetic interaction occurs with digoxin or warfarin. 

The effect of fluvoxamine on theophylline pharmacokinetics has been characterised in two studies in healthy subjects. In the first study the AUC of theophylline (given as a single 442-mg oral dose of aminophylline) was increased almost threefold, the clearance was reduced by 62% and the half-life was prolonged from 7.4 to 32.1 hours by fluvoxamine 50 mg daily for 3 days then 100 mg daily for 13 days. In the seeond study, the elear-ance of theophylline (given as a single 300-mg oral dose of aminophylline) was reduced by about 70% and the half-life was inereased from 6.6 to 22 hours by fluvoxamine 50 to 100 mg daily for 7 days. This interaction was shown to be reduced in patients with mild and severe liver cirrhosis (Child class A and C, respectively), whereas the elearanee of a single 4-mg/kg dose of theophylline elixir was reduced by 62%, 52%, and 10.5% in healthy subjects, patients with mild cirrhosis, and patients with severe cirrhosis, respectively. The half-life of theophylline was increased by 13.6 hours in healthy subjects compared with 10.5 hours in patients with mild cirrhosis and 1 hour in patients with severe cirrhosis, demonstrating the reduced metabolic capabilities of the cirrhotic liver. ... 

In vitro studies with human liver microsomes have shown that fluvoxam-ine inhibits the eytoehrome P450 isoenzyme CYP1A2, the principal enzyme responsible for the metabolism of theophylline. This results in raised theophylline levels and toxieity. This metabolic function, and hence interaction, appears to be severely reduced in patients with severe cirrhosis, probably due to redueed hepatie expression of CYP1A2 and reduced uptake of fluvoxamine. The other SSBIs, citalopram, fluoxetine, paroxetine and sertraline only weakly inhibited CYP1A2 in vitro, and consequently would not be expeeted to interact. ... 

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