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Antimicrobial Agents and Chemotherapy, December 1998, p. 3266-3268, Vol. 42, No. 12
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
No Interaction between Ciprofloxacin and an Oral
Contraceptive
P. C.
Scholten,1
R. M.
Droppert,1
M.
G. J.
Zwinkels,2
H. L.
Moesker,3
J. J. P.
Nauta,3 and
I. M.
Hoepelman4,*
Department of Gynaecology and
Obstetrics1 and
Division of Infectious
Diseases and AIDS, Department of Medicine,4
University Hospital of Utrecht, 3584 CX Utrecht,
Kendle/U-Gene
Research BV, Utrecht,2 and
Healthcare Division, Medical Department, Bayer B.V., 3640 AB Mijdrecht,3 The Netherlands
Received 20 August 1997/Returned for modification 15 February
1998/Accepted 31 August 1998
 |
ABSTRACT |
Several antibiotics have been reported to lessen the ovarian
suppression produced by oral contraceptive agents, as a result of drug
interactions. The present investigation was designed to study the
likelihood of the occurrence of any such interaction between the
fluoroquinolone antibiotic ciprofloxacin (Ciproxin) at a dosage of 500 mg twice a day and the "low-dose" oral contraceptive Marvelon (30 µg of ethinyl estradiol [EE] plus 150 µg of desogestrel). Twenty-four healthy female volunteers were studied in a double-blind, placebo-controlled, randomized crossover trial. There were no significant differences between measurements of the area under the
concentration-time curve of EE up to 24 h after oral contraceptive intake during placebo and ciprofloxacin administration on days 11 and
16 of the cycles, indicating the absence of pharmacokinetic interaction. Similarly, no clinically significant differences in
the levels of sex hormone binding globulin were found between the
placebo and ciprofloxacin cycles, indicating no major variation in EE
levels during ciprofloxacin and placebo treatment. Ten subjects in each
of the placebo and ciprofloxacin groups had early-follicular-phase levels of 17-
estradiol (<184 ng/liter) at one or more points during their cycles, but none had values above the
early-follicular-phase range, indicating no significant ovarian
activity. In addition, all subjects had progesterone levels of <2
ng/ml, indicating the absence of ovulation. Only two subjects, who
received the placebo, had evidence of sustained follicular growth to a
potentially ovulatory follicle (~18 mm). We conclude that
ciprofloxacin does not interfere with the ovarian suppression produced
by the low-dose oral contraceptive Marvelon.
| |
INTRODUCTION |
Since the introduction of oral
contraceptives in 1961, there has been a trend of reducing the estrogen
content of the preparations in order to minimize side effects. With the
lowering of ethinyl estradiol (EE) levels in the development of the
"low-dose" pill in order to lessen the risk of complications, the
estrogen content of oral contraceptives may have reached its minimal
therapeutic level (2, 14); further lowering of the
concentration of EE in the pill may no longer guarantee effective
contraception. This can occur during the concomitant use of certain
drugs, either as a consequence of interference with the enterohepatic
circulation or by induction of hepatic microsomal drug-metabolizing
enzymes (2, 3, 5, 14). A retrospective analysis concluded
that 41% of unwanted pregnancies among oral-contraceptive users
occurred during the concomitant use of antibiotics (excluding
tuberculostatics) (13). In one study investigating the
possible interaction of ofloxacin (200 mg twice a day for 7 days) with
a low-dose oral contraceptive (Microgynon), no indications of
ovulation were detected (4).
In view of the potential impact of this type of drug interaction on the
reliability of oral contraceptive treatment, we have undertaken a
single-center, double-blind, placebo-controlled, randomized crossover
trial to evaluate the possible interaction of the fluoroquinolone
antibiotic ciprofloxacin (Ciproxin), administered orally, with an oral
low-dose contraceptive (Marvelon).
| |
MATERIALS AND METHODS |
This phase I study was designed to assess whether ciprofloxacin
affects the contraceptive effect of Marvelon (containing 30 µg of EE
plus 150 µg of desogestrel; Organon Laboratories Ltd., Cambridge,
United Kingdom) by lowering the levels of these exogenous hormones
(e.g., EE) in plasma and thus permitting the increase of the
circulating levels of the endogenous hormones estradiol and
progesterone, thereby blocking the effective suppression of the
reproductive cycle. The study also evaluated follicle ripening in
ovaries, which is suppressed by Marvelon, by measuring the increase in
mean follicular diameter in the subovulatory cycles (~18 mm) during
treatment with ciprofloxacin.
Patients.
The study was a double-blind, placebo-controlled,
single-center crossover trial involving 24 healthy female volunteers,
aged 19 to 32 years, with body weights between 51 and 82 kg (within 90 to 120% of the normal range). Based upon the sample size calculation 12 volunteers was sufficient to prove that there was no interaction, up
to a geometric standard deviation of 1.61 for the ratio of the area
under the concentration-time curve (AUC) of EE. In view of the
secondary reliability parameter (induction of follicle ripening) an
increase to at least 24 volunteers was recommended.
Each individual had regular, normal menstrual cycles before starting
contraceptive use or had proven ovulatory cycles (i.e., was
postpartum). All subjects had used Marvelon without gynecological problems or side effects for ~3 months. No other medication was being
taken by the study subjects, and no antibiotic had been taken for ~2
months. Each subject was willing to use an additional contraceptive
(e.g., condoms or an intrauterine device). All subjects gave written
consent after receiving detailed written information. The study was
approved by the ethics committee (Commissie Wetenschappelijk Onderzoek
bij Mensen) of the University Hospital of Utrecht, Utrecht, The Netherlands.
The volunteers were divided into two blocks of 12 individuals, who were
randomly allocated to one of two treatment order groups, with six
individuals per group (Table 1). All
subjects received Marvelon, one tablet daily, on days 8 to 28 (a total
of 21 days) of each cycle (day 1 being the first day of the stop week).
Ciprofloxacin (500 mg) or the placebo was administered twice daily on
days 8 to 17 (a total of 10 days) of cycles I and III. The placebo
matched the active drug in appearance, taste, and weight. The first
morning dose of ciprofloxacin or the placebo was taken with the
Marvelon tablet.
Measurements.
All 24 subjects had a transvaginal ultrasound
(ALOKA ultrasonograph with a 5-MHz transducer) performed at days 8, 10, 12, and 14. If on day 14 the diameters of the follicles seemed to be
10 mm, additional measurements were performed.
The 12 subjects in block I had levels of the following in their blood
measured on cycle days 11 and 16: EE, by radioimmunoassay
(with a kit
from Hazleton, Washington, D.C.); sex hormone binding
globulin (SHBG),
by time-resolved immunoassay (DELFIA kit; Wallac);
and ciprofloxacin,
by high-performance liquid chromatography (
8)
with a
calibration range of 0.010 to 3.00 mg/liter. Samples were
obtained 0, 0.5, 1, 1.5, 2, 4, 6, 8, 12, and 23.59 h after
dosing.
All 24 subjects during both cycles had progesterone levels measured by
time-resolved fluoroimmunoassay (DELFIA kit; Wallac)
on day 20 and
additionally on days 16, 24, and 28 if the follicles
had a diameter of
10
mm.
Single measurements of 17-
estradiol (E
2) in serum, by
time-resolved fluoroimmunoassay (DELFIA kit; Wallac), were done for
all
24 subjects on days 1, 8, 10, 12, and 14. These measurements
were
repeated on days 16, 20, 24, and 28 for subjects with a follicle
diameter of
10 mm on day
14.
Pharmacokinetic parameters were calculated in accordance with the
guidelines found in reference
2a. Hemoglobin and
hematocrit
values were obtained on days 8 and 20 of cycle I and were
repeated
during cycle III if thought to be necessary by the
investigator.
Adverse reactions were
recorded.
Criteria of evaluation.
The primary criteria assessed in the
12 subjects of block I included the AUC from 0 to 24 h
(AUC0-24) of EE on day 11 of cycles I and III. Secondary
criteria included the following: AUC0-24 of EE on day 16 (based on similar measurements for the 12 volunteers of block I);
progesterone levels on day 20 of the cycle (for all 24 subjects); SHBG
levels on cycle days 1, 8, 10, 12, and 14 of both treatment periods
(for all 24 subjects); and single measurements of serum E2
levels on days 1, 8, 10, 12, and 14 for all volunteers. If on day 14 the diameters of the follicles were ~10 mm, measurements of
E2 levels were repeated on days 16, 20, 24, and 28. The
diameters of the follicles on day 10 of the cycle were determined by
vaginal ultrasound (for all 24 subjects). A diameter of ~18 mm was
considered potentially ovulatory, and a diameter of ~10 mm
indicated ovarian activity. In addition, the AUC0-24, the
maximum concentration in serum (Cmax), and
half-life (t1/2) of EE on days 11 and 16 (based
on data from the 12 volunteers of block I) were calculated.
Statistical methods.
The purpose of this trial was to show
that levels of EE in plasma during ciprofloxacin treatment are, on
average, identical to those seen during placebo treatment. To establish
average equivalence between the two treatments in the protocol, the two
one-sided tests procedure was performed; log-transformed parameters
were used for analysis. Typically, confidence intervals of 80 to
125% for bioequivalence are used. When considering potential
therapeutic consequences
(AUCEE+ciprofloxacin/AUCEE) of an interaction (dosage reduction or increases), the acceptance range indicating a lack
of interaction may be wider and was calculated to be 67 to 150%, based
on a log 
(AUCcombination/AUCmonodrug)
of 1.50. This analysis was done for EE at day 11 (confirmatory) and day 16 (exploratory).
| |
RESULTS |
At the conclusion of the study, all 24 subjects met the criteria
for statistical evaluation. Protocol compliance was good.
Ciprofloxacin pharmacokinetics.
All concentrations and derived
pharmacokinetic parameters for the first 12 subjects were
noncontributory and therefore were not reported. In addition, the
ciprofloxacin concentrations were consistent with good compliance with
the treatment.
EE pharmacokinetics.
There was no difference in the
AUC0-24s of EE on day 11 after dosing with ciprofloxacin
or the placebo in the first 12 subjects (Fig.
1; Table
2). The estimated average
intraindividual value (ciprofloxacin/placebo) of EE AUCs was 102%. The
corresponding 90% confidence interval was 80 to 130%, which falls
within the predefined range for equivalence (i.e., 67 to 150%).
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|
FIG. 1.
Mean EE AUC0-24 (nanograms per hour per
liter) on cycle days 11 and 16 in 12 patients taking ciprofloxacin or
the placebo.
|
|
On day 11, the geometric mean values for AUC
0-12 were
638.8 and 629.5 ng · h/liter and for
Cmax
they were 101.0 and
98.9 ng/liter during ciprofloxacin and placebo
treatment, respectively
(Table
3). The
geometric mean
t1/2 of EE was shorter after
ciprofloxacin
treatment (6.5 h) than after placebo treatment (11.2 h);
this
difference was due to the variability of the assay. The median
time to
Cmax was 2.0 h after ciprofloxacin
treatment and 1.8 h
after placebo treatment. The values for
AUC
0-24 of EE on
day 16 show equivalence between the two
treatment groups (Fig.
1; Table
2).
On day 16, the geometric mean values for AUC
0-12 were
656.2 and 677.5 ng · h/liter and
Cmax
values were 109.0 and 101.7
ng/liter after ciprofloxacin and placebo
treatments, respectively.
The
t1/2 values were
also similar (11.2 and 10.5 h, respectively)
(Table
3). The median
values for time to
Cmax were 1.5 h after
ciprofloxacin treatment and 2.0 h after placebo
treatment.
Progesterone pharmacokinetics.
Levels of circulating
progesterone could not be evaluated, because many were below the limit
of determination (10 nmol/liter = 0.31 ng/ml). All subjects had
progesterone levels of <0.31 ng/ml on day 20 of both treatment
periods, except for four subjects, three of whom were receiving the
placebo. The progesterone levels of those subjects were 0.38 ng/ml
(ciprofloxacin) and 0.77, 0.67, and 0.48 ng/ml (placebo). These levels
are all below 2 ng/ml, indicating the absence of ovulation.
Serum estradiol pharmacokinetics.
Ten subjects in each of the
groups receiving placebo and ciprofloxacin had early-follicular-phase
levels of E2 (<184 ng/liter) at one or more points during
their cycles, but none had values above the early-follicular-phase
range, indicating that there was no significant ovarian activity.
Therefore, pharmacokinetic parameters were not assessed. The median of
the highest E2 levels was below the level of detection
(<13.6 ng/liter) in both the placebo and ciprofloxacin
cycles. The highest level detected in the placebo cycles was
232 ng/liter; in the ciprofloxacin cycles it was 32.9 ng/liter.
HBG pharmacokinetics.
The levels of SHBG in the patients
receiving ciprofloxacin and the patients receiving placebo were similar
(Table 4).
Ovarian activity.
Four subjects had an indication of ovarian
activity, with maximal follicle diameters of ~10 mm on day 14 during
ciprofloxacin coadministration, as did two subjects during
coadministration of the placebo. Two of the placebo-treated subjects
were potentially ovulatory (maximal follicle diameter of ~18 mm). The
mean follicle diameters on day 10 are presented in Table
5.
Safety results.
The most common adverse event was mild nausea
in four individuals receiving ciprofloxacin and three subjects during
coadministration of the placebo. Moderate diarrhea was reported by two
individuals receiving ciprofloxacin. There were individual reports of
symptoms such as tiredness, vomiting, pyrosis, meteorism, anomalies of taste, and anorexia in all treatment groups. There were no deaths or dropouts.
| |
DISCUSSION |
Concern was aroused when interaction between rifampin and oral
contraceptives during the treatment of tuberculosis was reported in
1971 (7). Subsequently, rifampin-associated pregnancies were
reported (6, 10). It has been proposed that rifampin, a
potent inducer of hepatic P-450 enzymes, induces the increased degradation of EE by ethinyl estradiol 2-hydroxylase. A later review, summarizing reports to the United Kingdom Committee on Safety of Medicines, implicated penicillin and tetracyclines in 70% of
the pregnancies occurring during
antibiotic-oral-contraceptive coadministration
(1). In other reports, 23 and 18% of
oral-contraceptive failures in reliable pill takers were
attributed to the coadministration of antibiotics (11, 12).
With concentrations of EE in plasma as an index of contraceptive
efficacy, AUC measurements up to 24 h after oral
contraceptive intake were not different during coadministration of
ciprofloxacin or the placebo, reflecting the absence of a
pharmacokinetic interaction during ciprofloxacin coadministration. SHBG
levels in the ciprofloxacin and placebo groups were also similar. Since
SHBG increases with increasing EE levels, these results concur with the
finding of no major variation in EE levels during
coadministration of ciprofloxacin. In addition, none of the subjects
had estradiol levels above the early-follicular-phase range (184 to 227 ng/liter), indicating that there was no
significant ovarian activity. Moreover, all subjects had
progesterone levels of <2 ng/ml, reflecting the absence of
ovulation. Follicular development into potentially ovulatory follicles was observed only in two subjects, both receiving the coadministered placebo.
In conclusion, ciprofloxacin does not appear to alter ovarian activity
when coadministered with the low-dose oral contraceptive Marvelon.
No evidence of pharmacokinetic interaction between the antibiotic
and the contraceptive agent was detected.
| |
ACKNOWLEDGMENT |
We thank H. J. Kloosterboer, Organon Int., Oss, The
Netherlands, for his active contribution.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Department of
Medicine, Division of Infectious Diseases and AIDS, University Hospital of Utrecht, P.O. Box 85500, 3509 GA Utrecht, The Netherlands. Phone:
(31) 30 250 6228. Fax: (31) 30 251 8328. E-mail:
I.M.Hoepelman{at}digd.azu.nl.
| |
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Antimicrobial Agents and Chemotherapy, December 1998, p. 3266-3268, Vol. 42, No. 12
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
