Theophylline + SSRIs - Drug Interactions

Theophylline serum levels can be markedly and rapidly increasedby fluvoxamine. Toxicity will develop if theophylline dosage isnot suitably reduced. Some preliminary clinical evidence suggeststhat fluoxetine and citalopram may not interact,and in vitro evidence suggests that paroxetine and sertraline are also unlikely tointeract.

In a study in 13 healthy subjects citalopram 40mg daily for 21 days (to achieve steady-state) did not affect pharmacokinetics of a single 300mg oral dose of theophylline (See reference number 1)

The pharmacokinetics of theophylline were unchanged in 8 healthy subjects when they were given a 6-mg/kg infusion of aminophylline over 30 minutes,8 hrs after a single 40mg dose of fluoxetine (See reference number 2).

The effect of fluvoxamine on theophylline pharmacokinetics has been characterised in two studies in healthy subjects. In first study AUC of theophylline (given as a single 442mg oral dose of aminophylline) was increased almost threefold, clearance was reduced by 62 % and half-life was prolonged from 7.4 to 32.1 hrs by fluvoxamine 50mg daily for 3 days then 100mg daily for 13 days (See reference number 3). In second study, clearance of theophylline (given as a single 300mg oral dose of aminophylline) was reduced by about 70 % and half-life was increased from 6.6 to 22 hrs by fluvoxamine 50 to 100mg daily for 7 days (See reference number 4). This interaction was shown to be reduced in patients with mild and severe liver cirrhosis (Child class A and C, respectively), whereas clearance 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 hrs in healthy subjects compared with 10.5 hrs in patients with mild cirrhosis and 1 hour in patients with severe cirrhosis, demonstrating reduced metabolic capabilities of cirrhotic liver (See reference number 5).

A number of case reports have described fluvoxamine-induced theophylline toxicity. Agitation and tachycardia (120 bpm) developed in an 83-year-old man taking theophylline 600mg daily (Theostat) about a week after he started to take fluvoxamine 100mg daily. His serum theophylline levels were found to have risen from under 15 mg/L to 40 mg/L (See reference number 6). A 70-year-old man similarly developed theophylline toxicity,with theophylline levels of about 32 mg/L (reference range 10 to 20 mg/L), when fluvoxamine was added. Subsequently theophylline concentrations were found to parallel a number of changes in fluvoxamine dosage (See reference number 7). The clearance of theophylline in an 84-year-old man was approximately halved while he was taking fluvoxamine (See reference number 8). An 11-year-old boy complained of headaches,tiredness and vomiting within a week of starting to take fluvoxamine. His serum theophylline levels were found to have doubled,from 14.2 to 27.4 mg/L (See reference number 9). A 78-year-old woman became nauseous within 2 days of starting to take fluvoxamine 50mg daily, and by day 6, when fluvoxamine was stopped, her serum theophylline levels were found to have increased about threefold. She experienced a seizure,became comatose, and had supraventricular tachycardia (200 bpm) requiring intravenous digoxin and verapamil. She recovered uneventfully (See reference number 10). A patient taking fluvoxamine 100mg daily developed nausea,vomiting, confusion, reduced sleep and a poor appetite 5 days after she began to take theophylline 300mg twice daily for COPD. Her theophylline level was found to be

In vitro studies with human liver microsomes have shown that fluvoxamine inhibits cytochrome P450 isoenzyme CYP1A2, principal enzyme responsible for metabolism of theophylline (See reference number 12,13). This results in raised theophylline levels and toxicity. This metabolic function,and hence interaction, appears to be severely reduced in patients with severe cirrhosis, probably due to reduced hepatic expression of CYP1A2 and reduced uptake of fluvoxamine (See reference number 5). The other SSRIs,citalopram, fluoxetine, paroxetine and sertraline only weakly inhibited CYP1A2 in vitro, and consequently would not be expected to interact (See reference number 12,13).

The interaction between fluvoxamine and theophylline is established and clinically important. The CSM in UK advise that concurrent use should usually be avoided, but that if this is not possible, reduce theophylline dosage by half when fluvoxamine is added and monitor theophylline levels (See reference number 14). . There is evidence to suggest that extent of this interaction is markedly reduced in patients with liver cirrhosis, particularly severe Child class C, despite higher levels of fluvoxamine,(See reference number 5) although caution should still be applied with concurrent use in this patient group as they are more likely to have high levels of theophylline due to reduced metabolism. There is good in vitro evidence to suggest that fluvoxamine is only SSRI likely to interact (because it is only one that significantly affects CYP1A2). This would seem to be borne out by lack of studies and case reports in literature describing problems with any of other SSRIs.

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