Combined hormonal contraceptives

Hatcher RA, Nelson A. Combined hormonal contraceptive methods. In Hatcher RA, Trussel J, Stewart F, et al, eds. Contraceptive Technology. 18th revised ed. New York Ardent Media 2004 391-460. 

Adverse Effects of Combined Hormonal Contraception (CHC) and Management"... 

Adverse effects associated with combined hormonal contraceptives (CHCs) and their management are shown in Table 30-3. 

World Health Organization Precautions in the Provision of Combined Hormonal Contraceptives (CHCs)... 

Serious Symptoms That May Be Associated with Combined Hormonal Contraception... 

Cilest is a combined hormonal contraceptive that contains ethinylestradiol and norgestimate. These products may cause nausea, especially on commencement of therapy. Other side-effects that may occur in decreasing order of probability include fluid retention, reduced menstrual loss and photosensitivity. Acne is not commonly associated with combined hormonal contraceptive. Hormone therapy consisting of ethinylestradiol and cyproterone may be used for the management acne in women. 

Prescribers are advised to consult the package insert of any medication administered concomitantly with hormonal contraceptives, because some medications may decrease the effectiveness of these birth control products. Patients should be prospectively cautioned not to self-medicate with the herbal supplement St. John s wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding while on oral contraceptives shortly after starting St. John s wort. Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St. John s wort. 

Q7 What risk factors and potential adverse effects should be considered when using combined hormonal contraceptives ... 

Hormonal contraceptives, which use oral oestrogen and/or progesterone, such as combined hormonal contraceptives and progestogen-only contraceptives. 

One of the risks associated with use of combined hormonal contraceptives is venous thromboembolism, but in women without other contributing risk factors the risk of thrombosis is less than that observed during pregnancy. The risk of thromboembolism increases with both age and the presence of other risk factors, such as obesity or an immobilizing illness. There is also a small risk of arterial disease, particularly if the woman has a previous history of arterial disease, hypertension, diabetes mellitus or if she is obese. 

This is only a very brief review of this subject, but the risks of hypertension with combined hormonal contraceptives appear to be modest. Nevertheless, they need to be considered in the context of other possible cardiovascular risk factors. Where possible, blood pressure should be monitored before and during contraceptive use. 

Eplerenone 100 mg daily was given to 24 healthy subjects on days 1 to 11 of a 28-day cycle of a combined hormonal contraceptive (ethinylestradi-oEnorethisterone 35 micrograms/1 mg). There was no change in the ethinylestradiol AUC, but there was a small 17% increase in the nore-thisterone AUC, which is unlikely to be clinically relevant. ... 

The oral contraceptives are of two main types the combined hormonal contraceptives containing both an oestrogen and a progestogen (monophasic, biphasie, triphasie, or sequential), available as tablets or a patch, and the progestogen-only contraceptives, which are available as tablets (sometimes ealled mini pills), parenteral preparations (implants, depot injections) and intrauterine devices. 

Almost all of the interactions of the hormonal contraceptives described in this publication involve the combined hormonal contraceptives. Most of the elinically important interactions with the eombined hormonal contraceptives involve increased metabolism. The major route for hepatic metabolism of ethinylestradiol is hydroxylation by the cytochrome P450 isoenzyme CYP3A4, and progestagens are also substrates for this enzyme. Thus, inducers of this enzyme can increase the clearance ofthe contraceptive steroids and possibly increase breakthrough bleeding and decrease contraceptive efficacy (see Hormonal contraceptives + Antiepileptics Barbiturates or Phenytoin , p.985). The drugs that have been shown to induce the metabolism of hormonal contraceptives are listed in Table 28.1 , (see below). Conversely, inhibitors of CYP3A4 may... 

Co-cyprindiol is a mixture of the anti-androgenic progestogen, cyproter-one acetate 2 mg, with ethinylestradiol 35 micrograms. It is used for the treatment of acne and moderately severe hirsutism in women who may also wish to use it as an oral contraceptive, and its contraceptive efficacy is expected to be reduced by the same hepatic enzyme inducers (see Table 28. r, (p.975)) that interact with conventional combined oral contraceptives. The precautions described in this section for the combined hormonal contraceptives with the various drugs listed in Table 28.1 , (p.975), should therefore be followed, see Hormonal contraceptives + Antiepileptics Barbiturates or Phenytoin , p.985. 

The manufacturer also points out that combined oral contraceptives (and presumably the combined hormonal contraceptive patch) must not be taken with co-cyprindiol. To do this would be analogous to doubling the ethinylestradiol dose with consequent increased risk of adverse effects. In addition, some of the progestagens in combined oral contraceptives have weak androgenic effects, which could oppose the benefits of cyproterone. 

The macrolides clarithromycin, dirithromycin, roxithromycin and telithromycin appear unlikely to cause combined hormonal contraceptive failure. Erythromycin is also not considered to cause failure of combined hormonal contraceptives, but isolated anecdotal cases have been reported. An isolated case has also been reported with spiramycin. 

The interaction between metronidazole and combined oral contraceptives is not established, and the whole issue of any interaction with broad-spectrum antibacterials remains very controversial. Bearing in mind the extremely wide use of both metronidazole and combined oral contraceptives, any increased incidence of contraceptive failure above that seen in general usage is clearly very low indeed. The Faculty of Family Planning and Reproductive Health Care (FFPRHC) Clinical Effectiveness Unit has issued guidance on the use of antibacterials with combined hormonal contraceptives. Although they recognise that there is poor evidence for contraceptive failure, they recommend that additional form of contraception, 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 metronidazole. ... 

The interaetion between combined hormonal eontraceptives and penicillins is inadequately established and controversial. Almost all of the evidence is anecdotal with no controls. The total number of failures is extremely small when viewed against the number of women worldwide using combined hormonal contraceptives (estimated at 70 million in 1996 by WHO ), so most women are apparently not at risk. 

On the other hand, the personal and ethical consequences of an unwanted pregnancy can be very serious. For this reason, the Faculty of Family Planning and Reproductive Health Care (FFPRHC) Clinical Effectiveness Unit recommends that women taking combined hormonal contraceptives should routinely use a second form of contraception, such as condoms, while taking a short course of less than 3 weeks of an antibacterial, and for 7 days after the antibacterial has been stopped. In addition, the FFPRHC recommends that if fewer than 7 active pills are left in the pack after the antibacterial has been stopped, the new packet should be started without a pill-free break, omitting any of the inactive tablets. For patients using the combined contraceptive patch, if the 7 days after the antibacterial has been stopped runs into the usual 7 day patch-free period, a new patch should be applied when it is due to be changed and the patch-free week delayed by 7 days. ... 

The FFPRHC also says that after 3 weeks of treatment the gut flora becomes resistant to the antibacterial. Therefore women taking a long-term antibacterial that does not induce liver enzymes (for example, for acne) no longer need additional contraceptive protection after the initial 3 weeks of concurrent use. However, if the antibacterial is changed or another antibacterial is started, additional contraceptive cover is required. Women who have already been taking long-term antibacterials that do not induce liver enzymes, who start a combined hormonal contraceptive, do not require additional contraception, unless the antibacterial is changed. ... 

The FFPRHC advise that additional contraceptive protection is not required in established users of the combined hormonal contraceptive patch taking tetracycline. This is in line with the findings of the study cited above. 

Note that doxycycline is increasingly used in the treatment of malaria. See Hormonal contraceptives + Antibacterials Tetracyclines , p.983, for further information on possible combined hormonal contraceptive failure with tetracyclines. 

Although information is limited, the pharmacokinetic interaction between the ethinylestradiol component of combined hormonal contraceptives and nelfinavir or ritonavir appears to be established and is likely to be clinically important. Similar decreases in plasma levels of ethinylestradiol caused by other drugs have resulted in reduced efficacy and reliability of combined oral contraceptives, and one retrospective report suggests that this has occurred with nelfinavir. It seem likely that the reduced contraceptive levels seen with fosamprenavir, lopinavir and tipranavir were due to the concurrent use of ritonavir (as would be common in practice). Similarly, although no interaction was reported with saquinavir, and raised contraceptive steroid levels were reported with amprenavir and atazanavir, in practice these drugs would be given with ritonavir (as a pharmacokinetic enhancer), and so the levels of combined hormonal contraceptives can reasonably be expected to be reduced. The Faculty ofFamily Planning... 

Amprenavir levels are decreased by combined hormonal contraceptives, but the effects are modest. There appears to be no evidence to suggest that combined hormonal contraceptives decrease the antiretroviral efficacy of HAART. but evidence is preliminary and more study is needed. 

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