Combined oral contraceptives clinical studies

Hannaford PC, Owen-Smith V (1998) Using epidemiological data to guide clinical practice review of studies on cardiovascular disease and use of combined oral contraceptives. Br Med J 316 984-987... 

Quantification of coagulation factors is notoriously difficult, because of the interrelations among the various components of the coagulation cascade, the broad range of normal values, and considerable inter-laboratory variability (52). This variability is illustrated by a WHO study of users of combined oral contraceptives, conducted on several continents, which showed statistically significant differences among clinical centers in prothrombin time, fibrin plate lysis, plasminogen, and activated partial thromboplastin time (SEDA-16, 464). Effects also vary between different populations, users of different doses, users of different products, and tests performed at different periods of the medication cycle (63,69). 

In a small study, the bioavailability of selegiline was markedly higher (mean of about 20-fold) in women taking combined oral contraceptives than in those not taking contraceptives. In a controlled study, the AUC of selegiline was modestly increased by HRT (60%) and the change was not considered clinically relevant. 

A case report describes a woman who had been taking chlorpromazine 100 mg three times daily for one week without problems when a combined oral contraceptive (ethinylestradiol/norgestrel) was started. Four days later she developed severe dyskinesias and tremor, and her chlorpromazine levels were found to have increased by about sixfold. This case was briefly mentioned in an earlier report by the same authors. The reasons are not understood but increased absorption or reduced liver metabolism of the phenothiazines are suggested. The general clinical importance of these findings is not known, and documentation is very limited. There seem to be no other reports of adverse reactions, and the available data are insufficient to justify any general precautions. Further study is needed. 

A study in a group of 10 women found that the sedative effects of a single 1.3-microgram/kg dose of intravenous clonidine were increased by a combined oral contraceptive (ethinylestradiol/levonorgestrel 30 micrograms/150 or 250 micrograms). The clinical importance of this is uncertain. Consider also Antihypertensives + Hormonal contraceptives ,... 

Not established. The pharmaeokinetie and pharmacodynamic evidence in-dieates that eo-trimoxazole is not likely to reduce the effectiveness of combined oral eontraeeptives. Although there are a number of reports of contraceptive failure attributed to co-trimoxazole, these are anecdotal and unconfirmed, whereas the studies suggest increased contraceptive efficacy (but see below). It is possible that the cases are coincidental, and fit within the normal failure rate of combined oral contraceptives. The UK Family Planning Authority considered that it was almost certain that co-trimoxazole and sulphonamides did not interact with combined oral contraceptives. However, the Faculty of Family Planning and Reproductive Health Care (FFPRHC) Clinical Effectiveness Unit has issued guidance on the use of antibacterials with hormonal contraceptives. Although they recognise that there is poor evidence for contraceptive failure, they recommend that additional contraceptives, such as condoms, should be used for short courses of antibacterials, see Hormonal contraceptives + Antibacterials Penicillins , p.981, for more detailed information. This applies to both the oral and the patch form of the combined contraceptive. This advice has usually been applied to only broad-spectrum antibacterials that do not induce liver enzymes but the FFPRHC notes that some confusion has occurred over which antibacterials are considered to be broad-spectrum , and thus they recommend that this advice is applied to all antibacterials that do not induce liver enzymes, which would include co-trimoxazole, sulfonamides and trimethoprim. ... 

Preliminary results of a study show that rufinamide 800 mg twice daily for 14 days decreased the AUC of ethinylestradiol 35 micrograms hy 22% and of norethisterone 1 mg by 14% in healthy women taking a combined oral contraceptive. Inhibition of ovulation was not assessed. These reductions in plasma levels of the contraceptive hormones are similar to those seen with topiramate (see Hormonal contraceptives + Antiepileptics Topiramate , below), and their clinical relevance is unknown. However, given these findings, low-dose contraceptives (ethinylestradiol 20 micrograms) may be considered unsuitable for use with rufinamide. Further study is needed. 

The decrease in the active metabolite of proguanil caused by a combined oral contraceptive has not been fully assessed, although the authors recommended that the dose of proguanil should be increased by 50% in women taking oral contraceptives. However, there is limited evidence that this pharmacokinetic interaction may not be clinically relevant. More study is needed. 

In a placebo-controlled, crossover study in 18 healthy women taking a combined oral contraceptive (ethinylestradiol/norethisterone 35 micrograms/1 mg), rofecoxib 175 mg daily for 2 weeks raised the AUCs of ethinylestradiol and norethisterone by 13% and 18%, respectively. These small changes, although statistically significant, are within the accepted criteria for bioequivalence, and are unlikely to be clinically important. No abnormal menstrual bleeding was reported. No special precautions are required during concurrent use. 

The manufacturer hriefly notes that no clinically significant interaction was seen between indinavir and a combined oral contraceptive eontaining ethinylestradiol and norethisterone. In a retrospective study there were no reports of contraceptive failure in 9 patients taking indinavir (overall... 

A study in 12 healthy women taking a combined oral contraceptive (ethi-nylestradiol/norethisterone 35 micrograms/1 mg) found that atorvastatin 40 mg daily increased the AUC of norethisterone and ethinylestradiol by about 28% and 19%, respectively, and increased their maximum plasma levels by 24% and 30%, respectively. These increases are only moderate and unlikely to be clinically important, but the manufacturers say that they should be considered when selecting an appropriate oral contraceptive dosage for women given atorvastatin. ... 

A study in 21 women found that a single 12.5-mg dose of almotriptan had no clinically significant effect on the pharmacokinetics of a combined oral contraceptive containing ethinylestradiol 30 micrograms and des-... 

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