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A FREE CONTINUING EDUCATION LESSON
OBJECTIVES
Upon successful completion of this
lesson, the pharmacist will:
1. understand the differences between
continuous combined oral contraceptives and cyclic or extended cycle combined oral contraceptives.
2. be familiar with the unique benefits of
combined oral contraceptives taken
continuously.
3. understand which patients might benefit from continuous use of a combined
oral contraceptive.
4. understand how continuous combined
oral contraceptives can improve management of conditions affected by
hormonal fluctuations such as endometriosis and menstrual migraines.
5. be familiar with side effects that can
occur with continuous combined oral
contraceptives.
6. be able to effectively counsel patients
on continuous combined oral contraceptives.
INSTRUCTIONS
1. After carefully reading this lesson, study
each question and select the one
answer you believe to be correct. Circle
the appropriate letter on the attached
reply card.
2. To pass this lesson, a grade of 70%
(14 out of 20) is required. If you pass,
your CEU(s) will be recorded with the
relevant provincial authority(ies).
(Note: some provinces require individual pharmacists to notify them.)
ANSWERING OPTIONS
A. For immediate results, answer online
at www.pharmacygateway.ca.
B. Mail or fax the printed answer card to
(416) 764-3937. Your reply card will
be marked and you will be advised of
your results within six to eight weeks
in a letter from Rogers Publishing.
THIS FREE LESSON
Continuous Use of
Combined Oral
Contraceptives
By Jodi Wilkie, BScPharm
Jodi Wilkie works in retail pharmacy at Canada Safeway in Edmonton. She also works for the Caritas
Health Group in the Women's Wellness Program Menopause Clinic where she sees patients one-on-one
and works closely with physicians to maximize patient-care outcomes.
The author, expert reviewers and Pharmacy Practice magazine have each declared that there is no real
or potential conflict of interest with the sponsor of this lesson.
INTRODUCTION
Hormonal contraceptive pills containing
synthetic estrogen and progestin have
been available since the 1960’s and continue to be a very popular reversible
method of birth control. In Statistics
Canada’s 1996/97 National Population
Health Survey, 18% of women aged 15
to 49 reported using combined oral contraceptives (COCs).1 In general, COCs
are safe, effective and well-tolerated by
women across the reproductive age span.
Over the years, doses and types of
hormones found in COCs have
changed. Initially, estrogen doses were
relatively high. Most COCs now contain
35 µg of ethinyl estradiol or less. A number of different progestins are found in
currently available COCs. Recently, two
combined hormonal contraceptives with
novel delivery methods became available
to Canadian women—a transdermal
patch and a vaginal ring. Although
doses, components and delivery methods have changed, the typical COC regimen has remained relatively constant.
IS APPROVED FOR
1.5 CE UNITS
Women usually take estrogen and progestin for 21 consecutive days, followed
by a 7-day hormone-free interval. It is
during this 7-day interval that withdrawal uterine bleeding may occur.
When COCs were first developed,
the typical 21/7 regimen was designed
arbitrarily to mimic a regular 28-day
menstrual cycle. It was thought that
COCs would be considered more natural and appealing to women and their
physicians if regular monthly bleeding
occured.2 At the time, no consideration
was given to alternative regimens. The
withdrawal bleeding that occurs with a
standard COC regimen is not biological,
but is induced by the drop in hormone
levels when active tablets are stopped.3 It
is iatrogenic. It does not serve a medical
purpose, but it may help to reassure a
woman that she is not pregnant.
Occasionally women and their physicians manipulate this standard regimen
for the purpose of convenience. A
woman on COCs whose menstrual period is due during a scheduled vacation or
SUPPORTED BY AN EDUCATIONAL GRANT FROM
Approved for 1.5 CE units
by the Canadian Council
on Continuing Education in
Pharmacy. File #388-0306.
May 2006 | Answer online at www.pharmacygateway.ca
Continuous Use of Combined Oral Contraceptives |
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event may take two packages of
monophasic COC in a row without a
pill-free interval in order to postpone
menstruation. Seventy percent of the
providers in one survey had prescribed
COCs to delay or stop a patient’s periods
for a certain amount of time.4
Different hormonal contraception
regimens have been studied. The duration of active tablets has been extended
for two or more cycles followed by a 7day or shorter pill-free interval.5 In the
United States, two hormonal contraceptive products with unique regimens are
available. With Mircette®, ethinyl estradiol 20 µg and desogestrel 150 µg are
taken for 21 days, followed by a 2-day
pill-free interval and then 5 days of
ethinyl estradiol 10 µg. Another product, Seasonale®, provides 84 days of
ethinyl estradiol 30 µg and levonorgestrel 150 µg followed by a 7-day
pill-free interval. With Seasonale’s
extended cycle regimen, withdrawal
bleeding occurs 4 times per year. This
product may be available in Canada in
the future.
Pending approval by Health Canada,
a novel COC will be available to
Canadian women. The new product,
called Anya®, will contain 20 µg of
ethinyl estradiol and 90 µg of levonorgestrel per tablet and will be taken
on a continuous daily basis without a
pill-free interval. Pills will be available in
packages containing a 28-day supply of
medication. A study conducted in over
2,000 women for 12 months has shown
this regimen to be safe, effective and
well-tolerated.6
The purpose of a continuous regimen, besides preventing pregnancy, is to
suppress menstruation. Women taking a
COC continuously may go without a
period for a prolonged length of time.
During this time, hormone levels will
stay constant. Fluctuation of hormone
levels, which is a regular occurrence
within a natural menstrual cycle and
with standard 21/7 combined hormonal
contraceptive methods, will not occur.
Menstrual suppression and stabilization
of hormone levels has the potential to be
beneficial for many women. Continuous
use of a COC without a hormone-free
break may be a good option for women
who experience severe symptoms during
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TABLE 1:
Percentage of current COC users (N=193) experiencing hormone
withdrawal symptoms during active pills days vs. during the hormone-free
interval of one cycle of use8
Active pill days (%)
Hormone-free interval (%)
Pelvic pain
21
70
Headaches
53
70
Use of pain medication
43
69
Bloating or swelling
19
58
Breast tenderness
16
38
their menstrual period each month or
who have conditions that are aggravated
by hormone fluctuations, such as
endometriosis or menstrual migraines.
Alternatively, some women may choose a
continuous regimen mainly for convenience.
HORMONE WITHDRAWAL
SYMPTOMS
With a standard 21/7 COC regimen,
many women experience symptoms
associated with withdrawal bleeding.
Menstrual symptoms such as sore
breasts, menstrual cramps and headaches
may be a mild nuisance for some
women. For others, symptoms may be
more severe resulting in reduced productivity because of school or work time
missed. Symptoms may contribute to
problems with COC compliance leading
to discontinuation and unintended pregnancy.7
A group of researchers documented
the timing, frequency and severity of
hormone-related symptoms in COC
users during active pills and the pill-free
interval of a standard regimen.8 Women
monitored and recorded pelvic pain,
bleeding, headaches, analgesic use, nausea or vomiting, bloating or swelling and
breast tenderness throughout the course
of the study. New COC users recorded
symptoms for three full cycles and current COC users recorded symptoms over
two full cycles. The researchers determined that in almost all current COC
users symptoms were more frequent
(P<0.001) during the 7-day hormonefree interval than during active pills. (See
Table 1 for results.)
In new COC users, similar results
were seen in the second and third cycles
of COC. In their first COC cycle, incidence of headaches and breast tender-
| Continuous Use of Combined Oral Contraceptives
ness in new COC users was similar during active pills and during the first hormone-free interval.
Interestingly in this study, breast tenderness and bloating or swelling began
to increase in the week prior, and worsened during the hormone-free interval.
The researchers theorized that estradiol
levels began increasing during the hormone-free interval, peaked during the
second week of active pills and decreased
in the third week of active pills, thereby
bringing on these symptoms prior to the
next hormone-free interval.
Because hormone levels are maintained for a prolonged length of time
with an extended or continuous COC
regimen, hormone withdrawal symptoms may be reduced or eliminated. In a
prospective, open clinical trial, 50
women with complaints experienced
during the hormone-free interval of their
current COCs were permitted to extend
their active tablets to see whether frequency of these symptoms would be
reduced.9 These women experienced dysmenorrhea (painful menstruation),
menorrhagia (heavy menstruation), premenstrual-type symptoms and menstrual migraines with the standard 21/7 regimen. Of 37 patients who continued to
extend their active tablets to 6, 9 or 12
weeks, all reported that doing so delayed
the onset and decreased the severity of
their reported menstrual complaints.
Thirteen patients chose not to continue
with an extended regimen, mainly
because of breakthrough bleeding, spotting or headaches.
A one year open-label phase 3 study
evaluated how continuous ethinyl estradiol 20 µg/levonorgestrel 90 µg would
affect cycle-related symptoms and dysmenorrhea.10 Thirty-six women recorded
occurrence and severity of cycle-related
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symptoms using the Penn Daily
Symptom Rating diary, a validated
symptom diary, during a baseline cycle
without the COC and during three 28day pill packages of COC. Cycle-related
symptom scores decreased significantly
compared to baseline during the three
pill packages of study. In women with
dysmenorrhea (N=259), pain scores
decreased from baseline by 71% and
85% in pill packs 2 and 3 respectively.
Continuous COC in this study appears
to have been very effective in reducing
menstrual cramps.
EFFICACY OF CONTINUOUS
COMBINED ORAL CONTRACEPTIVES
The primary mechanism of action of
hormonal contraceptives is the inhibition of ovulation. COCs suppress release
of follicle stimulating hormone (FSH)
and luteinizing hormone (LH) from the
pituitary and prevent ovarian follicular
development and ovulation. As well, cervical mucus thickens and becomes
impenetrable to sperm, and the endometrial environment becomes less receptive
to an ovum if fertilization occurs.11
When standard COCs are taken as
prescribed, pregnancy rates are very low
with less than 1 pregnancy per 100
women per year of use.12 Pregnancy rates
approach 6 to 8 per 100 women per year
with typical use.12 Inconsistent pill-taking time and omission of one or more
pills per cycle contribute to reduced efficacy. As a large number of women occasionally miss a pill or take their pills at
slightly different times of day, a hormonal contraceptive method with increased
efficacy is desirable.
During the 7-day pill-free interval of
a standard 21/7 COC, some ovarian follicular development occurs in response
to rising FSH levels, with corresponding
increases in endogenous estrogen levels.13-15 If this pill-free interval is extended, more follicular growth ensues with
the potential for ovulation.13 Missing
pills at the end of one cycle or near the
beginning of another or forgetting to restart the COC has the effect of lengthening the pill-free interval and increases
the likelihood that ovulation and pregnancy could occur. If the pill-free interval is shortened or eliminated, there is
less potential for follicular growth and
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ovulation.14,15 It is not known if this
reduced follicular growth translates into
fewer unintended pregnancies when a
COC is used on a continuous basis.
One unpublished phase 3 study of
continuous ethinyl estradiol 20 µg/levonorgestrel 90 µg reported a Pearl Index
of 1.6 after one year of use.6 The Pearl
Index, a measurement of contraceptive
effectiveness, is a statistical estimation of
the number of unintended pregnancies
per 100 women per year of use. A 2005
Cochrane review of six studies comparing continuous or extended cycle COCs
to standard cyclic COCs concluded that
risk of pregnancy did not differ between
regimens except in one trial that showed
fewer pregnancies in the continuous
COC group.16
POTENTIAL BENEFITS OF
CONTINUOUS COMBINED
ORAL CONTRACEPTIVES
Women take COCs for various reasons.
Most often the primary reason is to reduce
the risk of pregnancy. Although not specifically approved for these indications,
women may use COCs for therapeutic
purposes as well. By maintaining constant
hormone levels, continuous administration of a COC may benefit conditions
such as premenstrual syndrome, menstrual migraines, endometriosis and polycystic
ovary syndrome that may be worsened by
hormonal fluctuations.
Premenstrual syndrome
Premenstrual syndrome (PMS) is a constellation of symptoms that occurs in the
luteal phase of the menstrual cycle on a
recurring basis. Symptoms can be physical and psychological and may include
irritability, mood swings, depression,
anxiety, fatigue, breast tenderness, bloating, changes in appetite and sleep problems. These symptoms can have a negative impact on quality of life. When
symptoms are so severe that they disrupt
functioning in the home or workplace,
the condition is termed premenstrual
dysphoric disorder (PMDD). Although
the exact cause is unknown, it is believed
that women who suffer from PMS or
PMDD have an altered sensitivity to
estradiol and progesterone that interferes
with serotonergic function.17
There is some evidence available
May 2006 | Answer online at www.pharmacygateway.ca
regarding the use of combined oral contraceptives for the relief of PMS or
PMDD. In a randomized, single-blind
study comparing three different kinds of
COCs for PMS, all COCs had a beneficial effect on PMS symptoms compared
to the pre-treatment period.18 Another
COC was studied in a randomized, placebo controlled trial for its effect on
PMDD.19 Improvement from baseline
was noted for 22 different premenstrual
symptoms. Although these studies used
standard 21/7 COC regimens, there is
limited data supporting the use of continuous COCs as well.10 An unpublished
study presented at the 2005 Conjoint
Meeting of the American Society for
Reproductive Medicine and the
Canadian Fertility and Andrology Society
found significant improvement in premenstrual symptom scores from baseline
in women with PMS during three 28-day
pill packages of continuous ethinyl estradiol 20 µg/levonorgestrel 90 µg.10
Menstrual migraines
Menstrual migraines are migraine
headaches that occur in close proximity
to a woman’s menstrual period. Within a
natural menstrual cycle, they occur from
two days prior to menses until three days
into menses. They can also occur during
the 7-day hormone-free interval of
COCs. Women may also experience
migraines at different times of the
month in response to other triggers. It
may be helpful for a woman to keep a
migraine diary, charting frequency and
severity of headaches, to determine if
migraines are specifically menstrual. It is
thought that menstrual migraines are
triggered by the drop in estrogen levels
that occurs prior to menstruation.20,21
Acute treatment of menstrual
migraines involves triptans and/or
NSAIDs, although for some women,
these measures are relatively ineffective.21
Menstrual migraines are often quite
severe with prolonged duration possibly
because of the continued drop in estrogen levels at that time in the cycle. Pain
medication or triptan may be effective
temporarily, but the headache returns
because the trigger is still present.
Because a drop in estrogen levels contributes to menstrual migraines, maintaining constant estrogen levels for an
Continuous Use of Combined Oral Contraceptives |
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extended period of time with a continuous COC has potential to be a helpful
preventive and therapeutic measure.21
Use of COCs in women with
migraine, particularly migraine with
aura, is controversial.21 Clinical practice
guidelines from the Society of
Obstetricians and Gynecologists of
Canada list migraine with aura as an
absolute contraindication to COC use.11
COCs can have unpredictable effects on
migraine course. When starting on
COCs, patients may experience an
improvement or a worsening in migraine
symptoms and occurrence. It is important for patients to monitor migraine
frequency and severity and the presence
and nature of an aura preceding the
migraine attack. Migraine appears to be
an independent risk factor for ischemic
stroke, with increased risk occurring
with migraine with aura.22 COCs also
increase stroke risk although risk is lower
for COCs containing less than 50 µg
ethinyl estradiol.11 The main concern is
that these individual risk factors may
have a synergistic effect. It is important
to consider a woman’s other stroke risk
factors including age, smoking, hypertension, hypercholesterolemia and diabetes when weighing benefits and risks
of hormonal contraceptive use. COCs
should be discontinued in a woman who
experiences an aura for the first time, a
worsening of migraine aura or a worsening of migraine headaches.
Endometriosis
Endometriosis is a condition where
endometrial tissue grows outside of the
uterus. This tissue responds to hormonal stimulation the same way that the
uterine endometrial tissue does, with
menstrual bleeding occurring cyclically.
Symptoms of endometriosis may include
pelvic, back or flank pain before and
during menstruation, very painful menstrual cramps, abnormal or heavy menstrual flow and bowel and urinary symptoms. The purpose of endometriosis
treatment is to control the hormonal
stimulation of the endometrial tissue to
reduce or stop bleeding each month.23
COCs may serve this purpose, but further research is needed. A Cochrane
review found that there was little evidence available regarding use of cyclic
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COCs for the treatment of endometriosis pain despite their frequent use.24
If pain is linked to hormone withdrawal, maintaining hormone levels
with continuous use of a COC has the
potential to prevent endometriosis pain
and promote endometrial atrophy and
amenorrhea.23 A continuous low-dose
COC was compared to daily cyproterone acetate 12.5 mg in one
endometriosis study.25 Patients had
undergone surgery for endometriosis
and were experiencing recurrent pain.
After 3 months of therapy, 46% of 41
women taking the COC were amenorrheic compared to 65% of 43 women
taking cyproterone acetate. The
researchers concluded that both treatments were similarly effective in reducing pelvic pain after surgery and were
generally well tolerated. Both improved
health-related quality of life as well.
Polycystic ovary syndrome
The main endocrine abnormalities seen
in women with polycystic ovary syndrome (PCOS) are elevated LH levels
and insulin resistance.26 High LH and
hyperinsulinemia contribute to ovarian
growth and cyst formation and increased
production of androgens.26 Women are
at higher risk of cardiovascular disease.
Ovulation does not occur regularly and
this contributes to irregular menstrual
cycles. Excessive estrogen production
without postovulatory progesterone can
contribute to endometrial proliferation
and increased risk of endometrial cancer.
For women who desire contraception,
combined hormonal contraceptives are a
treatment of choice for PCOS.27 The
progestin component in the COC provides endometrial protection from
unopposed estrogen and reduces risk of
endometrial cancer. COCs also reduce
androgen levels by suppressing FSH and
LH, which decrease ovarian androgen
production, and by increasing levels of
sex hormone binding globulin, which
binds to testosterone.
Large randomized, controlled trials
comparing continuous and cyclic COCs
have not been done. In a small study, 14
women with PCOS took a cyclic COC,
continuous COC or a gonadotropin
releasing hormone agonist (leuprolide
acetate) for 3 months.28 In the women
| Continuous Use of Combined Oral Contraceptives
on cyclic COC, LH and testosterone levels increased during the 7-day pill-free
interval. LH and testosterone levels
remained suppressed in the women on
continuous COC. A cohort study of
continuous ethinyl estradiol and cyproterone acetate for 36 cycles in 66 women
with PCOS concluded that for symptoms due to androgen excess including
acne, hirsutism and seborrhea, continuous administration of a hormonal contraceptive may be necessary to maintain
symptom control.29
ADVERSE EFFECTS OF
CONTINUOUS COMBINED
ORAL CONTRACEPTIVES
Breakthrough uterine bleeding and spotting are possible side effects with any
hormonal contraceptive product and are
one of the most frequent reasons for discontinuation.30 Generally, breakthrough
bleeding is heavier and may require sanitary protection while spotting is very
light bleeding that may not require protection. Factors that may contribute to
breakthrough bleeding include irregular
pill taking, smoking, pill malabsorption,
pregnancy, uterine or cervical pathology
and drug interactions (see Table 2).11
Irregular or unpredictable breakthrough bleeding or spotting may occur
with a continuous COC. One review
concluded that breakthrough bleeding
or spotting may be more common in
new COC users compared to women
who switch from a cyclic COC regimen
to a continuous regimen.31 Two studies
compared bleeding patterns of continuous and cyclic COCs containing 20 µg
ethinyl estradiol and 100 µg levonorgestrel.32,33 Both found that women
on continuous COC reported significantly fewer bleeding days requiring sanitary protection and were more likely to
be amenorrheic (no bleeding or spotting) than women on cyclic COC. In
one study,32 women kept a daily bleeding
calendar for 6 cycles or 168 days.32 By
cycle 5, 9 out of 16 women in the continuous group reported amenorrhea
compared to 1 out of 16 in the cyclic
group. In the other study, 60 out of 79
women randomized completed 12 cycles
or 336 days of COC.33 During cycles 1
to 3, 16% of women in the continuous
group reported amenorrhea compared to
Answer online at www.pharmacygateway.ca | May 2006
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0% in the cyclic group. During cycles
10-12, 72% of women in the continuous group reported amenorrhea compared to 4% in the cyclic group.
In the phase 3 study of continuous
ethinyl estradiol 20 µg/levonorgestrel
90 µg, 44.8% of women had no spotting
or bleeding after seven 28-day cycles of
pill use;6 70.8% of participants experienced either spotting only or no bleeding after this length of time.
Other side effects of COCs are generally mild and occur most often during
the first three months of use. Nausea,
weight changes, mood changes, bloating,
breast tenderness and headaches may
occur.11 In one prospective study, 27% of
women discontinued taking COCs
because of side effects.30 In studies comparing continuous with standard COC,
women reported similar incidences of
headache, breast tenderness, nausea,
depression and PMS. Continuous participants reported less bloating and menstrual pain however.32,33
LONG-TERM SAFETY OF
CONTINUOUS COMBINED
ORAL CONTRACEPTIVES
Reproductive cancers
Current evidence regarding how COCs
affect risk of hormone sensitive cancers
such as endometrial, ovarian and breast
cancer does not distinguish between
cyclic or continuous use. The information available reflects current history of
COC use, which has primarily been
cyclic. Further study is warranted to confirm the effects of long-term continuous
COC use on cancer risk.
Some researchers feel that the incessant ovulation that occurs from menarche to menopause in women is to blame
for the increasing incidence of reproductive cancers in women who live in developed countries.34 There is good evidence
that by suppressing ovulation, COCs
reduce the risk of ovarian cancer. A
recent review estimates that rates of ovarian cancer are 40-50% lower in women
who have ever used combined hormonal
contraceptives and this protective effect
appears to increase with longer duration
of COC use.35
Endometrial cancer risk is estimated
to be reduced by 90% with COC use.35
Ultrasound and endometrial biopsy
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results from patients in continuous
COC studies provide reassurance that
the endometrial lining does not build up
with continuous COC use.33,36 Although
these studies were only one year long, no
hyperplasia was observed within this
time. The concern is that endometrial
hyperplasia may progress to cancer.
A small increase in breast cancer risk
(RR 1.24) occurs among women under
the age of 35 when they are taking
COCs and for a period of 10 years after
discontinuing COCs.37 Because this is a
time when breast cancer incidence is
lowest, absolute risk is small. However,
even a small increased risk is significant
because of the large numbers of young
women who take COCs. In women aged
35 to 64 years, current or past use of
COCs is not associated with a significant
increased risk of breast cancer.37 Ethinyl
estradiol doses above 35 µg may confer
greater risk of breast cancer.38 It is possible that cumulative dose of estrogen and
progestin has greater impact on breast
cancer risk than the manner by which it
is taken.
Risk of blood clots
A small, elevated risk of venous thromboembolism occurs with low-dose COC
use. Risk is increased by 3- to 6-fold compared to nonusers.39 This risk is highest in
the first year of use and increases with
other genetic (family history) or acquired
(obesity) risk factors for thrombosis.39
Absolute risk is estimated to be 1 to 1.5
events per 10,000 users per year of use.11
Currently there is no information regarding whether a continuous COC regimen
will affect risk of blood clots differently
than a standard COC regimen.
Return of fertility
It appears that fertility may return relatively quickly following continuous use
of a COC. A recent study evaluated
ovarian suppression and return to ovulation following 84 days of continuous
ethinyl estradiol 20 µg/levonorgestrel 90
µg.40 Of 37 women who participated in
the study, all had documented ovulation
prior to the study. During an 84-day
treatment period, none of the women
ovulated and all resumed ovulation within 31 days of stopping the COC. In
another continuous COC study, one
May 2006 | Answer online at www.pharmacygateway.ca
woman became pregnant immediately
after discontinuing continuous COC
administration.33 It was previously confirmed by transvaginal ultrasound at
study completion that her endometrium
was inactive.
ACCEPTANCE OF CONTINUOUS
COMBINED ORAL CONTRACEPTIVES
Old habits are hard to break. It may
seem strange or unnatural for women to
be able to manipulate their menstrual
cycles. However, once educated about
the potential benefits of a long-cycle or
continuous COC regimen, most women
are willing to give it a try. Many find it
acceptable and refuse to go back to a
standard regimen. Surveys of women
have indicated that up to 70% of women
would prefer not to have a period every
month.4,41 Fifty percent of women over
the age of 45 would choose not to menstruate at all.41 One survey also sampled
providers and found that 44% agreed
that menstrual suppression is a good
idea.4
In a retrospective review, patients
who were taking a standard 21/7 COC
regimen were given the option of
extending their active tablets for 6, 9 or
12 weeks or indefinitely because of
hormone withdrawal symptoms such as
headaches, dysmenorrhea, hypermenorrhea and PMS, convenience, endometriosis and menstrual-associated acne.42 0f
292 patients followed, 91% of patients
tried an extended regimen. Of these,
57 chose to stop using COCs due to a
worsening of side effects or a reduced
need for contraception. Thirty-eight
patients chose to return to the standard
21/7 regimen because of side effects
including increased breakthrough bleeding or spotting or other concerns. The
majority of women, 59% of 292
women, continued with an extended
regimen. These patients reported an
improvement in their original problem
and their quality of life.
Another potential benefit of continuous COCs is cost savings. Once women
on a continuous regimen are amenorrheic, sanitary products are no longer
required. It is also likely that women
with severe cycle-related complaints will
miss fewer workdays when symptoms are
better controlled.
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THE PHARMACIST’S ROLE
Pharmacists, as the most accessible
health professionals, are in a position to
educate women about birth control
options available to them. A continuous
COC may not be best for all women,
but many will find it an attractive
option. Pharmacists can screen for
women who might benefit from a continuous regimen. They can ask their
patients on standard COC regimens
whether or not they experience bothersome hormone withdrawal symptoms
such as headaches, menstrual cramps,
breast tenderness or bloating. Patients
taking medication for dysmenorrhea,
endometriosis or menstrual migraines
may also be candidates.
Pharmacists have an essential role to
play in counselling patients about the
proper use of COCs prescribed continuously. Patients may use any of the currently available monophasic combined
hormonal contraceptives continuously,
without the usual hormone-free interval
between packages. When a continuoususe COC becomes available in Canada,
this may be a convenient option for
women. Taking the COC without interruption between packages is important
and pharmacists should reinforce this.
This helps to ensure contraceptive efficacy and minimizes hormone fluctuations
that can contribute to side effects.
Pharmacists may recommend that their
patients keep an extra package of COC
on hand instead of waiting until a package is finished to obtain their next refill.
Pharmacists must be knowledgeable
about common side effects of continuous COCs and how they can be managed. Most women who discontinue
COCs do so within the first two months
of use.30 Taking the pill at bedtime or
with a small meal or snack may help to
relieve nausea. Sometimes, dietary
changes such as reducing caffeine and
salt may help with bloating and breast
tenderness. The most important thing
for women starting or switching to continuous COCs to know is that breakthrough bleeding or spotting is possible
and may be irregular and unpredictable.
Patients should be reassured that breakthrough bleeding or spotting is not
harmful, does not indicate a lack of contraceptive efficacy and will usually
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resolve on its own. The majority of
women do not have any bleeding after
12 months on a continuous regimen.
Women should be counselled to take
their pill at the same time each day to
minimize fluctuations in hormone levels
that may contribute to adverse effects.
Pharmacists should also be familiar
with absolute and relative contraindications to COCs and about potential drug
interactions that may occur between
COCs and current or new medications.
(See Tables 2, 3 and 4.)
TABLE 2:
SUMMARY
• <6 weeks postpartum if breastfeeding
• smoker over the age of 35
(≥15 cigarettes/day)
• hypertension (≥160/100 mmHg)
• current or past history of venous
thromboembolism (VTE)
• ischemic heart disease
• history of cerebrovascular accident
• complicated valvular heart disease
• migraine headache with aura
• current breast cancer
• diabetes with complications
• severe cirrhosis
• liver tumour
Taking combined oral contraceptives on
a continuous basis may seem unnatural
to many who feel that monthly menstruation is normal and necessary for
women. However, there may be advantages to a continuous regimen. Many
women who take COCs cyclically may
experience bothersome symptoms associated with withdrawal bleeding each
month. Extending active COC tablets
may eliminate some or all of these symptoms. For women with hormone sensitive conditions such as PMS, menstrual
migraines, endometriosis or PCOS,
maintaining constant hormone levels
with a continuous COC may contribute
to symptom improvement. However,
more well-designed trials are needed to
provide additional supportive evidence
for these uses. For pregnancy prevention,
evidence indicates that continuous
COCs are as effective as cyclic COCs.
Although women on continuous COC
regimens may experience more irregular
or unpredictable bleeding, for most this
will lessen as time goes on.
REFERENCES
1. Wilkins K, Johansen H, Beaudet M, et al. Oral
Contraceptive Use. Statistics Canada. Health Reports
2000;11(4):25-37.
2. Gladwell M. John Rock’s Error. The New Yorker
2000;(March 13):52-63.
3. Kaunitz, Andrew M. Menstruation: Choosing
whether… and when. Contraception 2000;62:277-84.
4. Andrist L, Arias R, Nucotola D, et al. Women’s
and providers’ attitudes toward menstrual suppression with extended use of oral contraceptives.
Contraception 2004;70:359-63.
5. Wiegratz I, Kuhl H. Long-cycle treatment with
oral contraceptives. Drugs 2004;64(21):2447-62.
6. Archer D, Jensen J, Johnson H, et al. Efficacy
and safety of a continuous-use regimen of levonorgestrel/ethinyl estradiol: North American phase 3
study results. Abstract. 2005 Conjoint Meeting of the
American Society for Reproductive Medicine and the
| Continuous Use of Combined Oral Contraceptives
Drug interactions11
Medications that may contribute to
combined oral contraceptive failure
anti-epileptics: carbamazepine, phenobarbital, phenytoin, primidone, topiramate
antimicrobials: griseofulvin, rifampin
ritonavir
OTC: St. John’s Wort
TABLE 3:
TABLE 4:
Absolute contraindications
to combined oral
contraceptives11
Relative contraindications
to combined oral
contraceptives11
• smoker over the age of 35
(<15 cigarettes/day)
• adequately controlled hypertension
• hypertension (140-59/90-99 mmHg)
• migraine headache over the age of 35
• symptomatic gallbladder disease
• mild cirrhosis
• history of combined OC-related
cholestasis
• taking medications that may interfere
with combined OC metabolism
Canadian Fertility and Andrology Society.
7. Sulak P, Carl J, Gopalakrishnan I, et al. Outcomes
of extended oral contraceptive regimens with a shortened hormone-free interval to manage breakthrough
bleeding. Contraception 2004;70(4):281-7.
8. Sulak P, Scow R, Preece C, et al. Hormone withdrawal symptoms in oral contraceptive users. Obstet
Gynecol 2000;95:261-6.
9. Sulak P, Cressman B, Waldrop E, et al.
Extending the duration of active oral contraceptive
pills to manage hormone withdrawal symptoms.
Obstetrics & Gynecology Feb 1997;89(2):179-83.
10. Freeman E, Borisute H, Deal L, et al. A continuous-use regimen of levonorgestrel/ethinyl estradiol
significantly alleviates cycle-related symptoms: results
of a phase 3 study. Abstract. 2005 Conjoint Meeting of
the American Society for Reproductive Medicine and
the Canadian Fertility and Andrology Society.
11. Black A, Francoeur D, Rowe T. SOGC Clinical
Answer online at www.pharmacygateway.ca | May 2006
WYETH_CE_Contraceptive_0506_E
4/27/06
9:35 AM
Practice Guidelines Canadian Contraception Consensus
Part 2. J Obstet Gynecol Can 2004 Mar;143:219-54.
12. Black A, Francoeur D, Rowe T. SOGC Clinical
Practice Guidelines Canadian Contraception Consensus
Part 1. J Obstet Gynecol Can 2004 Feb;143:143-56.
13. Killick SR. Ovarian follicles during oral contraceptive cycles: Their potential for ovulation. Fertility &
Sterility 1989 Oct;52(40):580-2.
14. Spona J, Elstein M, Feichtinger W, et al.
Shorter pill-free interval in combined oral contraceptives decreases follicular development. Contraception
1996 Aug;54(2):71-7.
15. Schlaff W, Lynch A, Hughes H, et al.
Manipulation of the pill-free interval in oral contraceptive pill users: The effect on follicular suppression.
Am J Obstet Gynecol 2004;190:943-51.
16. Edelman A, Gallo M, Jensen J, et al.
Continuous or extended cycle vs. cyclic use of combined oral contraceptives for contraception. The
Cochrane Database of Systematic Reviews. The
Cochrane Collaboration. 2006, Volume 1.
17. Kessel B. Premenstrual syndrome. Advances
in diagnosis and treatment. Obstetrics & Gynecology
Clinics of North America Sep 2000;27(3):625-39.
18. Backstrom T. Oral contraceptives in premenstrual syndrome: A randomized comparison of triphasic and monophasic preparations. Contraception Sep
1992;46(3):253-68.
19. Freeman E. Evaluation of a unique oral contraceptive (Yasmin) in the management of premenstrual dysphoric disorder. European Journal of
Contraception & Reproductive Health Care Dec
2002;7 Suppl 3:27-34, 42-3.
20. Hutchinson, S. Hormonal influence on
migraine. Clinics in Family Practice Sep 2005;7(3):
529-43.
21. Chavanu K, O’Donnell D. Hormonal interventions for menstrual migraines. Pharmacotherapy Nov
2002;22(11):1442-57.
22. Becker W. Use of oral contraceptives in
patients with migraine. Neurology Sep 1999;53(4)
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Suppl.1:S19-25.
23. Winkel C. Evaluation and management of
women with endometriosis. Obstetrics & Gynecology
Aug 2003;102(2):397-408.
24. Moore J, Kennedy S, Prentice A. Modern combined oral contraceptives for pain associated with
endometriosis. The Cochrane Database of Systematic
Reviews. The Cochrane Collaboration. 2005, Volume 4.
25. Vercellini P, De Giorgi O, Mosconi P, et al.
Cyproterone acetate versus a continuous monophasic
oral contraceptive in the treatment of recurrent pelvic pain
after conservative surgery for symptomatic endometriosis.
Fertility & Sterility Jan 2002;77(1):52-61.
26. Pannill M. Polycystic ovary syndrome: An
overview. Topics in Advanced Practice Nursing eJournal 2002;2(3).
27. Richardson M. Current perspectives in polycystic ovary syndrome. American Family Physician
Aug 2003;68(4):697-704.
28. Ruchhoft E, Elkind-Hirsch K, Malinak R.
Pituitary function is altered during the same cycle in
women with polycystic ovary syndrome treated with
continuous or cyclic oral contraceptives or a
gonadotropin-releasing hormone agonist. Fertility &
Sterility Jul 1996;66(1):54-60.
29. Falsetti L, Galbignani E. Long-term treatment
with the combination ethinylestradiol and cyproterone
acetate in polycystic ovary syndrome. Contraception
Dec 1990;42(6):611-9.
30. Rosenberg M, Waugh M. Oral contraceptive
discontinuation: A prospective evaluation of frequency and reasons. American Journal of Obstetrics &
Gynecology Sep 1998;179(3):577-82.
31. Henzl M, Polan M. Avoiding menstruation—A
review of health and lifestyle issues. J Reprod Med
Mar 2004;49(3):162-74.
32. Kwiecien M, Edelman A, Nichols M, et al.
Bleeding patterns and patient acceptability of standard or continuous dosing regimens of a low-dose
oral contraceptive: A randomized trial. Contraception
2003;67:9-13.
33. Miller L, Hughes J. Continuous combination
oral contraceptive pills to eliminate withdrawal bleeding: A randomized trial. Obstetrics & Gynecology Apr
2003;101(4):653-61.
34. Eaton SB, Pike M, Short R, et al. Women’s
reproductive cancers in evolutionary context. The
Quarterly Review of Biology Sep 1994;69(3):353-67.
35. Rager K, Omar H. Hormonal contraception:
Noncontraceptive benefits and medical contraindications. Adolesc Med 2005;16:539-51.
36. Johnson J, Grubb G. Endometrial histology in
subjects on a continuous-use regimen of levonorgestrel/ethinyl estradiol: Results of a phase 3
study. Abstract.
37. Collins J, Crosignani P for the ESHRE Capri
Workshop Group. Hormones and breast cancer.
Human Reproduction Update 2004;10(4):281-93.
38. Althuis M, Brogan D, Coates R, et al.
Hormonal content and potency of oral contraceptives
and breast cancer risk among young women. British
Journal of Cancer Jan 2003;88(1):50-7.
39. Tanis B, Rosendaal F. Venous and arterial
thrombosis during oral contraceptive use: Risks and
risk factors. Seminars in Vascular Medicine Feb
2003;3(1):69-84.
40. Archer D, Kovalevsky G, Ballagh S, et al. Effect
on ovarian activity of a continuous-use regimen of
oral levonorgestrel/ethinyl estradiol. Abstract. 2005
Conjoint Meeting of the American Society for
Reproductive Medicine and the Canadian Fertility and
Andrology Society.
41. den Tonkelaar I, Oddens B. Preferred frequency
and characteristics of menstrual bleeding in relation to
reproductive status, oral contraceptive use, and hormone replacement therapy use. Contraception Jun
1999;59(6):357-62.
42. Sulak P, Kuehl T, Ortiz M, Shull B. Acceptance
of altering the standard 21-day/7-day oral contraceptive regimen to delay menses and reduce hormone withdrawal symptoms. Am J Obstet Gynecol Jun
2002;186(6):1142-9.
QUESTIONS
1. Common COC withdrawal symptoms
include all of the following EXCEPT:
a) headaches
b) abdominal bloating
c) breast tenderness
d) leg cramps
2. Continuous COCs might be a good
option for all of the following patients
EXCEPT:
a) an active-duty female military recruit
b) a new mom who is breastfeeding
c) an athlete training for a triathlon
d) a 16-year-old girl with heavy periods
every 2 to 3 months
3. What percentage of women will have
no bleeding after 6 months of continuous combined hormonal contraception?
a) 70%
b) 100%
c) 40%
d) 50%
4. Which statement best describes
uterine bleeding that can occur with a
continuous COC regimen?
a) regular withdrawal bleeding every 28
days
b) regular withdrawal bleeding every 91
days
c) irregular bleeding or spotting that
gradually lessens over several months
d) regular monthly bleeding with irregular spotting in between
5. Regarding contraceptive efficacy,
which statement(s) is/are TRUE?
a) The Pearl Index is the value used to
describe the number of pregnancies
expected to occur in 100 women using
a contraceptive method for one year.
b) Current evidence indicates that continuous COCs are clearly more effective than standard 21/7 COCs.
c) Current evidence indicates that continuous COCs are clearly less effec-
May 2006 | Answer online at www.pharmacygateway.ca
tive than standard 21/7 COCs.
d) a and b
e) a and c
6. All of the following factors can
increase the likelihood of ovulation
occurring with a continuous COC
EXCEPT:
a) fluctuation of FSH and LH levels
b) missing several pills in a row because
of having the stomach flu
c) taking topiramate for migraine prophylaxis
d) inconsistent pill-taking times
7. JR is a 25-year-old woman with a
very busy job and active lifestyle. She
has a history of horrible monthly periods with severe bloating, cramping
and heavy flow. She is getting married
in two months and would like some
information about “the pill”. What is
the BEST information to give her?
Continuous Use of Combined Oral Contraceptives |
7
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QUESTIONS continued
a) There are many combined hormonal
contraceptives available including a pill,
transdermal patch and vaginal ring.
b) She could try naproxen sodium for
her menstrual cramps and use condoms. A COC will most likely worsen
her period-related symptoms.
c) A continuous COC might help relieve
her hormone withdrawal symptoms
and will provide effective birth control.
d) All of the above.
8. JR’s physician prescribes a COC to
be taken on a continuous basis. Which
side effect is most likely?
a) nausea with or without vomiting
b) migraine headaches
c) weight gain of 5 pounds
d) chloasma—a darkening of facial skin
pigmentation
9. You may want to discuss some of
the non-contraceptive benefits of
COCs with JR. They include the following EXCEPT:
a) decreased risk of cervical cancer
b) decreased risk of endometrial cancer
c) decreased risk of ovarian cancer
d) improved acne and hirsutism
10. Appropriate information to tell JR
about the breakthrough bleeding or
spotting that can occur with a continuous COC includes which of the following?
a) If this occurs she should notify her
physician immediately.
b) This is common and will taper off
over time.
c) Missing pills may contribute to bleeding or spotting.
d) b and c
e) all of the above
11. A continuous COC may help symptoms associated with severe PMS by
the following mechanism:
a) prevention of estrogen and progesterone fluctuations which can exacerbate symptoms
b) binding to testosterone which can
contribute to acne
c) prevention of FSH surges which contribute to mood swings
d) all of the above
12. All of the following conditions can
be aggravated by hormonal fluctuations EXCEPT:
8
| Continuous Use of Combined Oral Contraceptives
a)
b)
c)
d)
menstrual migraines
cluster headaches
endometriosis
polycystic ovary syndrome
13. CS is a 34-year-old woman who
has suffered from migraine headaches
since puberty. She takes rizatriptan
and flurbiprofen to help manage her
migraine symptoms. She is currently
not taking any other medications. Over
the last few months her migraines
have increased in frequency. What
would be your first suggestion for CS?
a) She should change her migraine
medications.
b) She should keep a detailed migraine
diary to determine possible migraine
triggers and the timing of attacks relative to her menstrual cycle.
c) She should start continuous hormonal contraception.
d) She should take daily low-dose ASA
to reduce her risk of stroke.
14. After keeping a migraine diary for
3 months, CS realizes that most of her
migraines occur within a few days of her
period starting. She is diagnosed with
menstrual migraine and her physician
starts her on a continuous course of a
low-dose OC. What should she monitor?
a) frequency and severity of migraines
b) presence and amount of breakthrough bleeding or spotting
c) presence and nature of an aura that
occurs with her migraines
d) a and c
e) all of the above
15. TG is a 30-year-old woman with
endometriosis. Which statement(s)
about endometriosis is/are TRUE?
a) endometrial tissue grows outside of
the uterus and bleeds each month in
response to normal hormone fluctuations
b) symptoms include severe dysmenorrhea, heavy flow and constipation
c) treatment is aimed at reducing hormonal stimulation of endometrial tissue
d) a and c
e) all of the above
16. TG’s physician prescribes a
continuous low-dose COC for her.
The desired primary outcome of this
therapy is:
a) TG will become amenorrheic and will
no longer have dysmenorrhea and
menorrhagia
b) TG will not get pregnant
c) TG’s androgen levels will be suppressed.
d) TG will not develop menstrual
migraines.
17. Continuous COCs may help control symptoms related to androgen
excess with polycystic ovary syndrome
by the following mechanism:
a) lowering endogenous estrogen and
progesterone levels
b) causing weight loss which reduces
insulin resistance
c) increasing sex hormone binding globulin which binds to testosterone
d) increasing production of testosterone
in the ovaries
18. Which statement is TRUE?
a) It takes 6 months for fertility to return
following a course of continuous
combined oral contraception.
b) Most physicians would not be willing
to prescribe an extended or continuous COC regimen.
c) Having a menstrual period every
month is medically necessary except
during pregnancy.
d) The majority of women would prefer
not to have a period every month.
19. All of the following have the
potential to interact with COCs and
may reduce their effectiveness except:
a) gingko biloba
b) carbamazepine
c) St. John’s Wort
d) rifampin
20. ML is a 28-year-old married
woman who has been taking a COC on
a continuous basis for the past three
years. She prefers not to menstruate
and tolerates this regimen well.
However, she and her husband would
like to have a baby. Although return of
ovulation does not guarantee pregnancy, how soon might ovulation return
following discontinuation of the COC?
a) two months
b) one year
c) three months
d) one month
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