Theophylline dosing

Tobacco smoke contains chemicals that induce the cytochrome P-450 isoenzymes 1A1,1A2, and 2E1. Theophylline is metabolized by 1A2 and 2E1, and therefore smoking leads to increased clearance and subsequently decreased plasma levels of the drug.15 Because most patients with COPD are current or past smokers, it is important to assess current tobacco use and adjust the theophylline dose as required based on altered plasma theophylline levels if tobacco use changes. 

Theophylline is also a CYP1A2 substrate may need to increase the usual theophylline dose when a patient begins to smoke, or decrease the theophylline dose if smoking is stopped or nicotine replacement is used instead of smoking. 

Disulfiram inhibits CYP1A2, resulting in an increase in theophylline blood levels monitor theophylline blood concentration may need to decrease theophylline dose. 

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. 

MEXILETINE BRONCHODILATORS -THEOPHYLLINE Theophylline levels may be t by mexiletine cases of theophylline toxicity have been reported Mexiletine inhibits CYP1A2-mediated metabolism of theophylline 1 the theophylline dose (by up to 50%). Monitor theophylline levels and watch for toxicity... 

Yeung MY, Smyth IP. Concurrent frusemide-theophylline dosing reduces serum vancomycin concentrations in preterm infants. Aust J Hosp Pharm 1999 29 269-72. 

Recommendations have been presented for correction of theophylline doses dnring concomitant medication with some of the above dmgs (SEDA-8, 130) (45). Concomitant therapy with aUopnrinol, cimetidine, erythromycin, furosemide, isoprenahne, or propranolol requires a reduction in dose of abont 20-30% for oleandomycin the reduction shonld be abont 50%. 

Co-medication with phenobarbital may require an increase in the theophylline dose by about 30% concurrent use with phenytoin may require an increase of as much as 75% (45). 

Bronchodilators Theophylline Therapeutic drug monitoring recommended may require theophylline dose increase. 

Theophylline is not only characterized by a narrow therapeutic index and distinct relationships between serum concentration and therapeutic and toxic effects, but also by a high interindividual pharmacokinetic variabihty. This variability is predominantly based on a high patient-to-patient variability in the metabolic clearance of theophylline that is confounded by numerous additional physiological, pathophysiological, and enviromnental factors. Intravenous theophylhne (given as aminophyl-line), for example, has been shown to result in considerable variations in serum concentrations among patients despite the same dose, and theophylline dose requirements to maintain serum concentration in the range of 10 to 20 lig/ml varied from 400 to 3200 mg/day. ... 

The average clearance Cl and resulting half-life values t,/2 for theophylline in various subpopulations and disease states are summarized in Table 10.3. Although the metabolism of theophylline appears to proceed as a first-order process, single metabolism pathways may already reach saturation within therapeutic concentrations, resulting in nonlinear elimination. Thus, increases in theophylline dose may result in disproportionally larger increases in serum concentrations. " " ... 

Increase theophylline dose by 25% and measure theophylline serum concentration after 1 week of concurrent therapy. 

Decrease theophylline dose by half and monitor serum concentrations. 

Theophylline dose should be reduced by 30% and serum concentrations measured after 5 days of concurrent dierapy. Low-estrogen-containing preparations should be preferred if clinically justifiable. 

Decrease theophylline dose and monitor serum concentrations. p2-Blocking effect may also decrease pharmacological efficacy of theophylline. 

A man taking theophylline was diagnosed with a bipolar disorder and started on lithium while in hospital for an exacerbation of COPD. When the dose of theophylline was raised, because of a worsening in his condition, his lithium dose also had to be increased to control the emergence of manic symptoms. He received a maximum theophylline dose of 1.5 g daily, during which time he needed 2.7 g of lithium daily. When the theophylline was stopped, he only needed around 1.5 g of lithium daily to eontrol his manic symptoms. Two studies support the evidence from these eases with the finding that lithium excretion is increased by about 50% by ami-nophylline or theophylline. ... 

An open-label, erossover study in 12 healthy subjects found that donepezil 5 mg daily for 10 days had no signifieant effeets on the pharmacokineties of theophylline. Dose modification or additional monitoring is not required during coneurrent use. ... 

NicholsCTi JP, Basile SA, Cury JD. Massive theophylline dosing in a heavy smoker receivii both phenytoin and phenobarbital. Am Pharmacother (1992) 26,334-6. 

A patient with chronic obstructive pulmonary disease had a 53% reduction in his serum theophylline levels accompanied by bronchospasm when he was fed continuously through a nasogastric tube with OsmoUte. The interaction occurred with both theophylline tablets (Theo-Dur) and liquid theophylline, but not when the theophylline was given intravenously as aminophylline. It was also found that the interaction could be avoided by interrupting feeding 1 hour either side of the oral liquid theophylline dose. Conversely, hourly administration of 100 mL of OsmoUte did not affect the extent of theophylline absorption from a slow-release preparation Slo-bid Gyrocaps) in healthy subjects, although the rate of absorption was slowed. Similarly, in healthy subjects, hourly administration of 100 mL of Ensure for 10 hours did not affect the rate or extent of absorption of theophylline from Theo-24 tablets. ... 

Information seems to be limited to this study. The clinical importance of this interaction has not been assessed, but monitor the effects of concurrent use and be alert for the need to adjust the theophylline dose. More... 

---