Drug products: Euphylong, Theo-Dur®, Theophyllin retard-ratiopharm, Uniphyllin, Uniphyllin Continus
ATC code: R03DA04
Substances: theophylline, theophylline monohydrate, theophylline-ethylendiamine hydrate
No published studies with a clinically relevant sex analysis regarding effects and adverse effects of theophylline have been found. Some pharmacokinetic differences have been shown, probably without clinical significance.
The present evidence concerning differences between men and women is limited and do not motivate differentiation in dosing or treatment.
Data from 170 serum samples (100 male, 70 female) following fully bioavailable dosages from theophylline or aminophylline showed that clearance in boys was higher, 31% at 4 years of age and 22% higher at 20 years of age, than that in girls . Furthermore, a study of 314 measured S-theophylline concentrations (56% male) showed that boys had 25% higher theophylline clearance compared to girls at age 1-15 years .
Similarly, in a study of Japanese pediatric patients (63 boys, 33 girls), the mean theophylline clearances of boys were more than 20% higher than that of girls in the age range 2-8 years; although, in boys under 2 years of age the mean clearance was only 10% higher than that of girls . The mechanism of sex difference in theophylline clearance in children is unclear. The authors suggest that the initial dosage of theophylline should be adjusted according to the sex in pediatric patients . However, the clinical relevance of the difference is unclear and there is no general recommendation so far to differentiate dosing according to sex .
Concerning the influence of menstrual cycle on the pharmacokinetics of theophylline, a study of 9 asthmatic women observed that the maximum plasma theophylline concentration and minimum elimination half-life were at mid-cycle. Clearance was highest in the follicular phase, and lowest with longest elimination half-life in the mid-luteal phase . The AUC and volume of distribution did not vary significantly during the cycle. The findings could be explained by an inhibitory effect of oestrogen-progestoren surges in mid-cycle on hepatic oxidative function, the same way that the oral contraceptives influence theophylline pharmacokinetics. However, in contrast to asthmatic women, the pharmacokinetic parameters of theophylline showed no significant differences during the menstrual cycle in 10 healthy young women .
Reduction in theophylline clearance during the third trimester of pregnancy has been reported. In a study assessing the influence of pregnancy on the pharmacokinetics of theophylline in 10 pregnant asthmatic women, clearance during third trimester (34–39 weeks) was reduced by approximately 25% compared to other stages of pregnancy and remained suppressed during the immediate postpartum period (9–13 weeks postpartum). The clearance was not significantly altered during the first and second trimesters relative to pre-pregnancy levels. The increase in the volume of distribution and hypoalbuminemia in concert with pregnancy and subsequent theophylline portioning into enlarged pool of body water and the reduction in theophylline binding to plasma protein respectively may explain these changes .
In adults, 90% of theophylline is metabolized by liver cytochrome CYP1A2. A decreased CYP1A2 activity in women compared to men has been observed [8, 9]. The clinical relevance of the sex related Cyp1A2 activity in theophylline is unclear. However, any possible effect of sex is largely outweighed by individual variability in CYP1A2 activity due to genetic and environmental factors such as smoking and body weight.
No studies regarding sex differences in effect on theophylline have been found. In the study showing fluctuations of the theophylline clearance according to the menstrual cycle, the efficacy of theophylline did not vary during the cycle and no significant correlation between efficacy and individual kinetic parameters was found .
No studies with a clinically relevant sex analysis regarding adverse effects on theophylline have been found.
Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).
Possible sex-associated differences in the clinical and management characteristics of chronic obstructive pulmonary disease (COPD) were evaluated in a total of 10,711 patients (8098 men, 2613 women). The study observed a lower percentage use of theophylline among women than in men, possibly in relation to the lesser severity of airways obstruction among the women. The women with COPD evaluated in this study were younger, smoked less, had lesser disease severity but more co-morbidity and a poorer quality of life compared to men with COPD .
Date of litterature search: 2016-12-02
Reviewed by: Mia von Euler
Approved by: Karin Schenck-Gustafsson