atb and combined pill

8/7/2019 ATB and combined pill

1/8

REVIEW ARTICLE

Interaction Between Broad-SpectrumAntibiotics and the Combined Oral

Contraceptive PillA Literature ReviewKate Weaver and Anna Glasier

There is considerable variation in opinion about the im-

portance of drug interactions between the combined oral

contraceptive pill (COCP) and broad-spectrum antibiotics.

Clinical practice varies widely, especially between doctors

in Europe and those in the US.

Rifampicin and griseofulvin induce hepatic enzymes and

do appear to have a genuine interaction with the COCP,leading to reduced efficacy. The situation with the broad-

spectrum antibiotics is less clear. There are relatively few

prospective studies of the pharmacokinetics of concurrent

COCP and antibiotic use and few, if any, demonstrate a

convincing basis for any reduced contraceptive efficacy.

There is evidence, however, that variable contraceptive

steroid handling could make some women, at some times,

more susceptible to COCP failure.

Given the serious consequences of unwanted pregnancy,

the cautious approach of using additional or alternative

contraception during short courses of broad-spectrum an-

tibiotics and the initial weeks of long-term antibiotic

administration may be justified to safeguard the few uni-

dentifiable women who may be at risk.

Conflicting opinion and advice is potentially confusing

to both professionals and patients, and instructions for

additional precautions during and after concurrent COCP

and antibiotic use are complicated. Many women are

ignorant of, or confused about, the circumstances that can

cause OC to fail. Health professionals who prescribe the

COCP must continue to strive to educate women about

the mode of action and about the times when there is the

greatest danger of failure. Professionals who feel that

concurrent antibiotic use represents a real threat to con-

traceptive efficacy of the COCP should be prepared topresent the advice for additional contraceptive precautions

in a simple and consistent way, backed up with written

information and reinforced at regular intervals.

CONTRACEPTION 1999;59:7178 1999 Elsevier Science Inc.

All rights reserved.

KEY WORDS: combined oral contraceptives, oral contracep-tive steroids, broad-spectrum antibiotics, drug interactions,

unintended pregnancy

Introduction

The combined oral contraceptive pill (COCP) isamong the most popular methods of contra-ception worldwide. It is easy to use and ex-

tremely effective. Failure rates in clinical trial set-tings are as low as 0.1 per 100 women-years. In typicaluse, however, few populations of women will achievesuch low failure rates and up to 5% of women willhave an unintended pregnancy during the first year ofuse of the COCP.1 One factor with potential impacton both ease of use and reliability of combined oralcontraceptives is their postulated interaction withbroad-spectrum antibiotics. It is widely believed thatconcurrent use of the COCP and broad-spectrumantibiotics may reduce contraceptive efficacy, leadingto bleeding irregularities and even unwanted pregnan-cies. There is little consistent evidence for this, eitherfrom pharmacokinetic studies or in clinical practice.The international literature contains many reports ofalleged antibiotic-induced COCP failures. There are,however, relatively few prospective studies of thepharmacokinetics of concurrent COCP and antibioticuse and few, if any, demonstrate a convincing basis

for any reduced contraceptive efficacy. Rifampicinand griseofulvin do appear to have a genuine interac-tion with the COCP leading to reduced efficacy. Theposition with the broad-spectrum antibiotics is lessclear. Not surprisingly, there are variable and con-flicting opinions on the best way of dealing withperiods of simultaneous COCP and antibiotic use.Not all authorities advocate additional contraceptiveprecautions. Those who do, give a somewhat compli-cated series of instructions that may lead to patient

Edinburgh Healthcare National Health Service Trust, Family Planning & WomanServices, Edinburgh, Scotland

Name and address for correspondence: Dr. Anna Glasier, 18 Dean Terrace,Edinburgh EH4 1NL, Scotland; Fax: 44-131-332-2931

Submitted for publication December 7, 1998Revised January 15, 1999Accepted for publication January 15, 1999

1999 Elsevier Science Inc. All rights reserved. ISSN 0010-7824/99/$20.00655 Avenue of the Americas, New York, NY 10010 PII S0010-7824(99)00009-8


2/8


3/8

mentioned, contributing to the available, activeplasma ethinyl estradiol level.

Antibiotic-induced vomiting (and perhaps severediarrhea) are more overt possible causes of reducedcontraceptive steroid absorption

Symptoms of the illness requiring antibiotic pre-scription, or other side effects of the antibiotics them-selves could make women less consistent about pill-taking

Taking these possible mechanisms of interactiontogether, Back and Orme6 theorized that only a smallgroup of susceptible women might suffer COCP fail-ureperhaps those with a low background bioavail-ability of ethinyl estradiol, a large enterohepatic re-circulation, and gut flora sensitive to the antibioticbeing prescribed.

Shenfield,7 after a literature review, also concluded

that only a subgroup of women will suffer significantinteraction between the COCP and broad-spectrumantibiotics administered concurrently, but that thesewomen cannot currently be identified by any routinediagnostic tests. Breckenridge and colleagues8 foundas much as a 30-fold variation in plasma levels oftherapeutic steroid hormones between different first-pass metabolism and enterohepatic circulation aswell as changes in gut or liver metabolism related todiet, disease, smoking, or coadministration of drugs.Those women with the lowest plasma therapeutichormone levels might be the very subgroup postu-lated by Shenfield.

By the same token, one might logically expect thenewer low-dose estrogen COCP to be more prone topill failure because of any conspiring interactionaleffects further lowering available estradiol levels. In a1998 review of an adverse experience database, Szokaand Edgren9 found an association between low-doseestrogen COCP and recently reported pregnanciesattributed to antibiotic interactions. Disappointingly,this did not seem to have been heralded by any increasein reports of breakthrough bleeding on lower-dose estro-gen COCP in conjunction with antibiotics, althoughthis may simply reflect the inadequacy of any data-

base relying on voluntary reporting of adverse events.

AntibioticCOCP InteractionsThe extensive literature on antibioticCOCP interac-tions falls broadly into three categories. First, thereare retrospective case series, usually without controlgroups, and varying in size, down to individual casereports. Such reports should be considered in the lightof likely recall bias and under-reporting of poor pillcompliance in the inevitably emotive areas of un-wanted pregnancy and requests for termination of

pregnancy. Second, there are prospective, controlled

studies assaying plasma hormone levels in volunteerstaking COCP and antibiotics. Third, there are manyletters and editorials issuing conflicting advice on thelikelihood of COCPantibiotic interaction and rec-ommending various management options.

Observational, Retrospective StudiesThe first reports of worrisome interactions betweenantimicrobials and the COCP appeared in the early1970s when rifampicin was implicated in five un-wanted pregnancies and in frequent breakthroughbleeding among a group of 82 patients on the COCP.10

Studies of urinary excretion of ethinyl estradiol me-tabolities suggested that enhanced metabolism of thesteroid was responsible.11 It has since been convinc-ingly demonstrated that rifampicin induces a hepatic

cytochrome P450 isoenzyme, which accelerates themetabolism of both progestogens and estrogens andpotentially allows failure of both COCP and proges-togen-only-pills.12

Similarly, animal studies implicate griseofulvin inhepatic enzyme induction, and four unintended preg-nancies were identified in a literature search byOrganon.13

In the area of broad-spectrum antibiotics, Helmsand coworkers13 reviewed dermatology case recordscovering a total of 311 women-years of combinedCOCPantibiotic use in 1997. The antibiotics in-cluded tetracyclines, penicillins, and cephalosporins.Five pregnancies occurred, giving a Pearl Index of 1.6pregnancies per 100 women-years. This was com-pared with a large control group taking COCP aloneand not found to be statistically significant. Theauthors concluded that there was no evidence of anincreased failure rate above the normal backgroundfailure rate in clinical practice.

Hughes and Cuncliffe,14 again in a dermatologysetting, surveyed a total of 163 women-years experi-ence of combined COCP-antibiotic use in a group of124 women. Two pregnancies were recorded. Thefirst occurred after a 5-day course of oxytetracycline

in a patient using Microgynon 30 (30 g ethinylestradiol and 150 g levonorgestrel). Interestingly, thesecond pregnancy occurred in a woman taking Brevi-nor (35 g ethinyl estradiol and 500 g norethis-terone) and long-term minocycline. This study lackeda control group, but the authors compared their PearlIndex of 1.2 unfavorably with an index of 0.2 from theliterature (it would, in fact, compare favorably with amore realistic Pearl Index of around 1.0 for typical use).

Yet another dermatology practice yielded 71 wom-en-years of combined COCPantibiotic use (erythro-mycin, tetracycline, or minocycline). London and

Lookingbill

15

found only one conception, on tetracy-

73Contraception Broad-Spectrum Antibiotics and the Combined OC Pill1999;59:7178


4/8

cline and Ortho-Novum 1/35 (35 g ethinyl estradioland 1 mg norethindrone). Interestingly again thisreportedly occurred after long-term coadministration.The Pearl Index of 1.4 for such a small sample was notsignificantly different from the Pearl Index of 0.27

chosen for comparison by the authors.Studying dermatology patients on long-term pre-

scriptions for acne conveniently delivers large num-bers of women-years experience and shows reassur-ingly low rates of COCP failure with broad-spectrumantibiotics, not varying convincingly from back-ground COCP failure rates. However, these data maynot generalize to the more common situation ofwomen on short courses of antibiotics. It is thoughtthat resistant gut flora might emerge after as little as5 days of antibiotic use, restoring the enterohepaticcirculation of estradiol metabolites, in which case,

the women surveyed in the above three studies wouldnot have been at any theoretical increased risk ofCOCP failure for the vast majority of the periodssurveyed. On the other hand, two of the eight preg-nancies recorded actually happened during long-termstable antibiotic use. These could perhaps representnovel fluctuations in factors discussed earlier (envi-ronmental, dietary) or perhaps simple user failure; or,indeed, the theory of an emergent resistant gut floramay not apply to all women.

Kakouris and Kovacs16 identified 113 women pre-senting at family planning or abortion clinics andfound that the majority of the conceptions were notgenuine pill failures but resulted from missed pills,gastrointestinal disturbance, or use of concurrentmedications.17 Twenty percent of the conceptionsoccurred during concurrent use of COCP and antibi-otics. Only 6% of these women recognized the factorspreviously mentioned as threatening reduced contra-ceptive protection and took additional contraceptiveprecautions.

An alternative approach to retrospective studies isto use adverse event reporting systems. In one suchsurvey of reports to the Committee of Safety ofMedicines in the UK between 1968 and1984, there

were 63 reports of COCP failure in which antibioticinteraction was suspected.18 Penicillins accounted for32 of the cases. The under-use of the reporting system isacknowledged in the articles conclusion, in which theauthors state that although no prevalence figures canbe inferred, a warning might be taken that antibioticsmay cause COCP failure in susceptible individuals.

Prospective Studies of AntibioticCOCPInteractionsA number of small prospective studies have looked at

the pharmacology of coadministered COCP and anti-

biotics in healthy volunteers. Murphy and col-leagues18 studied seven healthy, normally menstruat-ing young women during one cycle of coadministeredCOCP and 500 mg tetracycline four times daily. TheCOCP contained 35 g ethinyl estradiol and 1 mg

norethindrone and was commenced de novo in thefollicular phase of a normal menstrual cycle, 1 daybefore starting the tetracycline. Serial blood testswere taken to produce a 24-h profile of steroid hor-mone levels on COCP alone. Sampling was repeatedon the first day of coadministration of COCP andtetracycline, and again between days 5 and 10 ofcoadministration. The subjects thus were used toprovide control data and, on this basis, the resultssuggested no significant depression of plasma hor-mone levels by tetracycline. Furthermore, the authorscomment that the smooth 24-h curves of hormone

levels do not support the notion of secondary peaks ofestradiol absorption due to enterohepatic circulation.Ampicillin is another of the broad-spectrum anti-

biotics sometimes suspected of interacting withCOCP. However, Friedman and colleagues19 found noevidence to support this in their small randomized,controlled study of 11 women on Demulen and am-picillin or placebo, for two consecutive cycles. Hor-mone assays and studies of cervical mucus ferningsuggested that all 11 women remained anovulatory.

Neely and coworkers20 recruited 24 healthy womenvolunteers all of whom were given doxycycline for 1week while on an established regimen of Ortho-Novum (35 g ethinyl estradiol and 1 mg norethin-drone). There was no control group, but measure-ments were made of plasma ethinyl estradiol,norethindrone, and endogenous progesterone on days18, 19 and 20 of both an initial control cycle onOrtho-Novum alone and a subsequent treatment cy-cle in which 100 mg doxycycline was taken twicedaily in addition from days 14 to 21 of the COCPpacket. No patient showed any significant differencesin therapeutic hormone levels while taking doxycy-cline. Further, no subject had endogenous progester-one levels high enough to suggest that escape ovula-

tion had occurred within 7 days of starting theantibiotic. Despite this, the authors noted the hugeinter- and intraindividual variability in plasma levelsof ethinyl estradiol and norethindrone. They specu-late that different timing of pill-taking or of mealsmight be responsible, but also repeat the suspicionthat some individuals have naturally lower bioavail-ability of therapeutic steroid hormone levels and aretheoretically more vulnerable to environmental andpharmacologic interactions with the actions of theCOCP.

In a similar study design, Back and colleagues21

studied 12 women on long-term COCP. All used

74 Weaver and Glasier Contraception1999;59:7178


5/8

30-g ethinyl estradiol pills combined with levonor-gestrel doses ranging from 150 to 250 g. The controlcycle hormone levels were not significantly differentfrom the test cycle in which 600 mg temafloxacin wastaken twice daily from day one of the cycle for 7 days.

Additionally, hormone assays gave no evidence ofescape ovulation. Temafloxacin is a quinolone anti-biotic chosen for its broad-spectrum activity, whichthe investigators expected to include the gastrointes-tinal flora thought to be involved in any enterohe-patic circulation of estradiol.

In a 1996 study, Csemiczky and colleagues22 ran-domized 20 healthy young women to a double-blind,cross-over study of the interaction between Microgy-non and ofloxacin. Microgynon (30 g ethinyl estra-diol and 150 g levonorgestrel) was coadministeredwith a 7-day course of ofloxacin or placebo. Plasma

hormone levels combined with pelvic ultrasoundscanning gave no evidence of escape ovulation ineither group.

In another small double-blind randomized, prospec-tive study, in 1991, Maggioli and coworkers23 studied10 healthy volunteers who were already establishedon a variety of COCP (2040 g ethinyl estradiol and150500 g levonorgestrel or 150 g desogestrel or 75g gestodene). The women were randomly assigned toreceive either placebo or 500 mg ciprofloxacin for 7days in each of two consecutive cycles. Concentra-tions of plasma follicle-stimulating hormone, lutein-izing hormone, and estradiol on days 7, 9, 14, and 16of the cycle failed to show evidence of ovulation orany interaction with ciprofloxacin. None of thewomen reported menstrual disturbance.

Although systemic antifungal drugs do not fall intothe category of broad-spectrum antibiotics, they arevery frequently prescribed for women on the COCP.So, it is perhaps worth noting two small studies, alongsimilar lines to those above, which found no signifi-cant interaction between COCP and either flucon-azole24 or triazole.25

Reassuring as all these studies seem, Neely andcolleagues20 sound a note of caution in their observa-

tion of the vast intra- and interpatient variability inpharmacokinetics of contraceptive steroids. It is pos-sible that the small numbers of women in the abovestudies did not happen to include any of the smallminority of women whose handling of contraceptivesteroids makes them vulnerable to COCP failure. It isalso worth noting that none of the above studiesfound any evidence of reduced effectiveness for theantibiotics during coadministration with COCP. Thisis perhaps a point worth stressing to women whomight otherwise be tempted to abandon their COCPmid-packet in favor of a less safe (or no) contraceptive

method when taking a course of antibiotics.

Advisory Letters, Articles, and EditorialsOn the basis of this rather unsatisfying literature (aswell as personal experience), many have written cau-tionary advice, warning colleagues of the potentialhazards of antibiotics in women taking the combined

oral contraceptive pill. Dental and dermatologic jour-nals seem particularly to abound in advice, by nomeans consistent. The dermatologists have the par-ticular problem of long-term antibiotic administra-tion, often tetracycline for resistant acne. In theory,emergence of resistant gut flora should reconstitutethe enterohepatic circulation within as little as 5days. However, anecdotal reports as discussed earlierlink long-term prescriptions of antibiotics withCOCP failures. Although caution in an uncertainsituation may seem advisable, this too might haveunhappy consequences if it leads dermatologists to

shift away from prescribing tetracyclines, toward reti-noids with their much more worrying teratogenicpotential.26

Advice and opinion does not appear to split downNew World/Old World lines, with no obvious consen-sus emerging on either side of the Atlantic Ocean,although European sources are perhaps more fre-quently cautious in approach. A sample of the litera-ture reveals a range of opinions both about the like-lihood of drug interaction leading to diminishedCOCP efficacy and about the sensible response to thispossible threat.

In the USA, the authoritative textbook Contracep-tive Technology (1998) gives no direct recommenda-tion about antibiotic use.27 The authors note thatthere is no pharmacokinetic evidence to supportanecdotal reports of contraceptive failure due tobroad-spectrum antibiotics and quote the recommen-dations of the International Planned Parenthood Fed-eration.

Alternative Advice From the US LiteratureMiller et al.28 reviewed the literature and recom-mended physicians apprise patients of the small num-

ber of suspected COCP failures attributed to antibi-otic interactions and urged them to report antibioticassociated diarrhea or breakthrough bleeding on theCOCP to a physician. They stopped short, however,of recommending additional contraceptive precau-tions, suggesting instead that physicians emphasizeto their patients that, at the best of times, COCPs arenot perfect.

Nager and Murphy29 felt there was little solidhuman evidence for (COCP) contraceptive failurecaused by broad-spectrum antibiotics. They ques-tioned the importance of enterohepatic recirculation

of ethinyl estradiol, citing evidence that women with



6/8

ileostomy do not suffer lower ethinyl estradiol bio-availability when taking COCP.

Writing in 1982, Hudson and Callen,30 on the otherhand, noted case reports of COCP failure duringtetracycline administration and suggested a change to

an alternative contraception for women on long-termtetracycline.

Angle and colleagues31 similarly advocated whatthey called the conservative approach of additionalback-up contraception when COCP are combinedwith broad-spectrum antibiotics, while acknowledg-ing that the available evidence did not necessarilysupport this approach.

Donley and coworkers32 urged US dentists to keepcareful records and to give advice to patients regard-ing possible interaction and additional contraceptiveprecautions when using the COCP and antibiotics

concurrently. Their position was based partially onthe case of a dentist found legally liable for COCPfailure after prescribing antibiotics and made respon-sible for child support payments.

Winikoff and Wymelenbergs The Whole TruthAbout Contraception is aimed at contraceptiveusers.33 It warns that rifampicin and griseofulvin mayreduce COCP efficacy and suggests you may want touse an alternative contraceptive while on thesedrugs. Broad-spectrum antibiotics are not specificallymentioned, but women are reminded always to men-tion contraceptive use to any doctor prescribing, orany pharmacist dispensing, extra medications.

Evidently, actual practice in the US is quite vari-able. However, some organisations do advocate aconservative approach. For example, the New YorkCity Planned Parenthood Federation recognizes anec-dotal evidence of unplanned pregnancies, mainlywith tetracyclines. To avoid confusion, they rou-tinely advise extra contraceptive protection during aCOCP cycle in which any antibiotic is used (personalcommunication, Dr. B. Winikoff).

On the European side of the Atlantic, the approachis more consistently conservative with a few authorseven suggesting any COCP taken concurrently with

antibiotics should contain 50 g ethinyl estradiol orshould be supplemented to a daily dose of 80 g.34

A review by Geurts and colleagues recommendedadditional contraceptive precautions during, and forseven days after, coadministration of COCP withpenicillins, tetracyclines, and griseofulvin.12 Theyclassified the likelihood of interaction only as prob-able or suspected. Triacetyloleandomycin wasmentioned as possibly causing an interaction leadingto reversible hepatotoxicity and was, therefore, to beavoided during COCP use. For lack of evidence, noadditional contraceptive precautions were suggested

for cotrimoxazole, trimethoprim, dapsone, isoniazid,

metronidazole, cephalosporins, chloramphenicaol,erythromycin, sulphonamides, or fusidic acid.

A recent 1998 survey35 in a general practice settingin the UK focused on the way that advice is given topatients on the combined oral contraceptive pill

rather than what advice should be given. Among 523women using COC in the long term, only 12% knewall the British Family Planning Association pillrules. These are rules governing circumstances (in-cluding concurrent antibiotic use) in which COCPmay fail, as well as subsequent action to avoid risk ofunwanted pregnancy. The same women were sur-veyed again after an intervention consisting of rou-tinely asking the women questions about pill rules atthe time of COCP repeat prescription, or providing asummary leaflet of the pill rules. Among women whowere both questioned and given the leaflet, a signifi-

cantly increased 39% subsequently knew all the pillrules.

ConclusionThe antifungal medication griseofulvin and thebroad-spectrum antibiotic rifampicin have been con-vincingly shown to induce hepatic enzymes and tohave significant interaction with the combined oralcontraceptive pill. When either of these two antimi-crobials is used by women taking the COCP, addi-tional or alternative contraceptive protection is cer-tainly advisable.

Uncertainty persists with respect to the otherbroad-spectrum antibiotics. Medical and dental jour-nals continue to publish rare but worrisome reports ofunwanted pregnancies possibly due to interactionbetween COCP and broad-spectrum antibiotics. Thenumbers are small, making it hard to distinguishthese from the natural background failure rate of theCOCP, and the retrospective nature of the studiesmakes them prone to recall bias and under-reportingof other possible causes of pill failure. Good prospec-tive studies of the pharmacokinetics of these druginteractions are few, and while failing to find specific

evidence for reduced COCP effectiveness on the dosesof broad-spectrum antibiotics used in acute infection,they do suggest that variable contraceptive steroidhandling could make some women, at some times,more susceptible to COCP failure.

The situation with lower dose, long-term antibioticadministration for dermatologic complaints is evenless clear. Given that the pharmacokinetic evidencefor any interaction between the COCP and higherdose antibiotics is tenuous, it seems even less likelythat low maintenance doses of drugs like tetracyclinewould significantly affect steroid hormone levels in

the long-term, especially if resistant gut flora rapidly



7/8

emerges and reestablishes the enterohepatic circula-tion of steroid hormones.

Given the serious consequences of unwanted preg-nancy, the cautious approach of using additional oralternative contraception during short courses of

broad-spectrum antibiotics and the initial weeks oflong-term antibiotic administration may be justified,to safeguard the few unidentifiable women who maybe at risk.

On the other hand, it cannot be denied that thecurrent situation of conflicting opinion and advice ispotentially confusing to both professionals and pa-tients. It will be impossible ever accurately to quan-tify the contribution this confusion could make touser failure of the COCP due to mistakes in tryingto comply with the complicated instructions for ad-ditional precautions during and after concurrent

COCP and antibiotic use. However, the recent surveyby Little and coworkers35 certainly suggests thatmany patients could be at risk for user failure onthe COCP because of ignorance or confusion aboutthe circumstances that can cause the pill to fail.Health professionals who prescribe the COCP mustcontinue to strive to educate women about the modeof action and about the times when there is greatestdanger of failure. Professionals who feel that concur-rent antibiotic use represents a real threat to contra-ceptive efficacy of the COCP should be prepared topresent advice for additional contraceptive precau-tions in a simple and consistent way, backed up bywritten information and reinforced at regular inter-vals.

Doctors and dentists prescribing antibiotics towomen should remember to inquire specificallyabout COCP use and, if necessary, to give adviceabout possible interactions. Ideally, this should ofcourse be identical to the advice given by doctorsissuing the COCP.

References1. Hatcher RA, Trussell J, Stewart F, et al. Contraceptive

Technology, 17th revised edition. New York: IrvingtonPublishers, 1998:448 409.

2. British National Formulary. British Medication Associ-ation and the Pharmaceutical Press, 1998:334.

3. Back DJ, Breckenridge AM, Crawford FE, et al. Reduc-tion of the enterohepatic circulation of norethisteroneby antibiotics in the rat: correlation with changes in thegut flora. J Steroid Biochem 1984;13:95100.

4. Adlercreutz H, Pulkkinen MO, Hamailen EK, KorlelaJT. Studies on the role of intestinal bacteria in metab-olism of synthetic and natural steroid hormones. Ste-roid Biochem 1984;20:21729.

5. Back DJ, Breckenridge AM, Crawford FE, et al. Aninvestigation of the pharmacokinetics of ethinylestra-diol in women using radioimmunoassay. Contraception1979;20:26373.

6. Back DJ, Orme ML. Pharmacokinetic drug interactionswith oral contraceptives. Clin Pharmacokinet 1990;18:47284.

7. Shenfield GM. Oral contraceptives: are drug interac-tions of clinical significance? Drug Safety 1993;9:2137.

8. Breckenbridge AM, Back DJ, Cross K, et al. Influence ofenvironmental chemicals on drug therapy in humans:studies with contraceptive steroids. Ciba Found Symp1980;76:289306.

9. Szoka PR, Edgren RA. Drugs interactions with oralcontraceptives: compilation and analysis of an adverseexperience report database. Fertil Steril 1998;49:318.

10. Nocke-Fink L, Breurer H, Reimers D. Effects of antibi-otics on oestrogen excretion in women taking oralcontraceptives. Acta Endocrinologica 1973;177(suppl):137.

11. Back DJ, Breckenbridge AM, Crawford FE, Hall SM, etal. The effect of rifampicin on the pharmacokinetics ofethinylestradiol in women. Contraception 1980;21:13543.

12. Geurts TBP, Goorissen EM, Sitsen JMA. Summary ofDrug Interactions with Oral Contraceptives. ParthenonPublishing, London, 1993:64 81.

13. Helms SE, Bredle DL, Zajic J, et al. Oral contraceptivefailure rates and oral antibiotics. J Am Acad Dermatol1997; 365:70510.

14. Hughes BR, Cunliffe WJ. Interactions between the oralcontraceptive pill and antibiotics (letter). Br J Dermatol1990;122:7178.

15. London BM, Lookingbill DP. Frequency of pregnancy inacne patients taking oral antibiotics and oral contracep-tives (letter). Arch Dermatol 1994;3:3923.

16. Kakouris H, Kovacs GT. Pill failure and non-use ofsecondary precautions. Br J Fam Plan 1992;18:414.

17. Back BJ, Grimmer SF, Orme ML, et al. Evaluation ofCommittee on Safety of Medicines Yellow Card Re-ports on oral contraceptive-drug interactions with an-ticonvulsants and antibiotics. Br J Clin Pharmacol1988;25:52732.

18. Murphy AA, Zacur HA, Charace P, Burkman RT. Theeffect of tetracycline on level of oral contraceptives.Am J Obstet Gynecol 1991;164:2833.

19. Friedman CI, Huneke AL, Kim MH, Powell J. The effectof ampicillin on oral contraceptive effectiveness. Ob-stet Gynecol 1980;55:337.

20. Neely JL, Abate M, Swinker M, DAngio R. The effectof doxycycline on serum levels of ethinyl estradiol,norethinderone and endogenous progesterone. ObstetGynecol 1991;77:41620.

21. Back DJ, Tija J, Martin C, Millar E, Mant T, Morrison P,Orme M. The lack of interaction between temafloxacinand combined oral contraceptive steroids. Contracep-tion 1991;43:31723.

22. Csemiczky G, Alvendal C, Landgren BM. Risk forovulation in women taking a low-dose oral contracep-tive (Microgynon) when receiving antibacterial treat-ment with a fluoroquinolone (ofloxacin). Adv Contra-cep 1996;12:1019.

23. Maggioli F, Puricelli G, Dottorini M, et al. The effect ofciprofloxacin on oral contraceptive steroid treatments.Drugs under experimental and clinical research. 1991;17:4514.

24. Devenport MH, Crook D, Wynn V, Lees LJ. Metaboliceffects of low-dose fluconazole in healthy female users



8/8

and non-users of oral contraceptives. Br J Clin Pharma-col 1989;27:8519.

25. Lunell NO, Pschera H, Zador G, Carlstrom K. Evalua-tion of the possible interaction of the antifungal tria-zole SCH 39304 with oral contraceptives in normalhealthy women. Gynecol Obstet Invest1991;32:917.

26. De Groot AC, Eshuis H, Stricker BH. Oral contracep-tives and antibiotics in acne (letter). Br J Dermatol1991;124:212.

27. Hatcher RA, Trussell J, Stewart F, et al. ContraceptiveTechnology, 17th revised edition. New York: IrvingtonPublishers, 1998:44950.

28. Miller DM, Helms SE, Brodell RT. A practical approachto antibiotic treatment in women taking oral contra-ceptives. J Am Acad Dermatol 1994;30:100811.

29. Nager C, Murphy AA. Antibiotics and oral contracep-tive pills. Semin Repro Endocrinol 1989;7:2203.

30. Hudson CP, Callen JP. The tetracycline oral contracep-tive controversy. J Am Acad Dermatol 1982;7:269 70.

31. Angle M, Huff PS, Lea JW. Interactions between oralcontraceptives and therapeutic drugs. Outlook 1991;9:16.

32. Donley TG, Smith RF, Roy B. Reduced oral contracep-

tive effectivenss with concurrent antibiotic use: a pro-tocol for prescribing antibiotics to women of childbear-ing age. Compendium 1990;11:3926.

33. Winikoff B, Wymelenberg S. The Whole Truth AboutContraception. Joseph Henry Press, 1998:108.

34. Stockley H. Antibiotics and oral contraceptive failure:an update. Pharmaceut J 1982;229:5258

35. Little P, Griffin S, Kelly J, et al. Effect of educationalleaflets and questions on knowledge of contraception inwomen taking the combined contraceptive pill: random-ised controlled trial. Br Med J 1998;316:194852.


atb and combined pill

Documents