WARNINGS
| Cigarette smoking increases the
risk of serious cardiovascular side effects from oral
contraceptive use. This risk increases with age and
with heavy smoking (15 or more cigarettes per day)
and is quite marked in women over 35 years of age.
Women who use oral contraceptives are strongly
advised not to smoke. |
The use of oral contraceptives is associated with increased
risks of several serious conditions including myocardial
infarction, thromboembolism, stroke, hepatic neoplasia,
and gallbladder disease, although the risk of serious
morbidity or mortality is very small in healthy women
without underlying risk factors. The risk of morbidity
and mortality increases significantly in the presence
of other underlying risk factors such as hypertension,
hyperlipidemias, obesity and diabetes.
Practitioners prescribing oral contraceptives should
be familiar with the following information relating to
these risks.
The information contained in this package insert is principally
based on studies carried out in patients who used oral
contraceptives with higher formulations of estrogens and
progestogens than those in common use today. The effect
of long-term use of the oral contraceptives with lower
formulations of both estrogens and progestogens remains
to be determined.
Throughout this labeling, epidemiological studies reported
are of two types: retrospective or case control studies
and prospective or cohort studies. Case control studies
provide a measure of the relative risk of a disease, namely,
a ratio of the incidence of a disease among oral contraceptive
users to that among nonusers. The relative risk does not
provide information on the actual clinical occurrence
of a disease. Cohort studies provide a measure of attributable
risk, which is the difference in the incidence of disease
between oral contraceptive users and nonusers. The attributable
risk does provide information about the actual occurrence
of a disease in the population (adapted from refs. 2 and
3 with the author's permission). For further information,
the reader is referred to a text on epidemiological methods.
1. THROMBOEMBOLIC DISORDERS AND OTHER VASCULAR
PROBLEMS
a. Myocardial Infarction
An increased risk of myocardial infarction has been attributed
to oral contraceptive use. This risk is primarily in smokers
or women with other underlying risk factors for coronary
artery disease such as hypertension, hypercholesterolemia,
morbid obesity, and diabetes. The relative risk of heart
attack for current oral contraceptive users has been estimated
to be two to six.4-10
The risk is very low under the age of 30. Smoking in
combination with oral contraceptive use has been shown
to contribute substantially to the incidence of myocardial
infarctions in women in their mid-thirties or older with
smoking accounting for the majority of excess cases. 11
Mortality rates associated with circulatory disease have
been shown to increase substantially in smokers, especially
in those 35 years of age and older among women who use
oral contraceptives.
|
CIRCULATORY DISEASE MORTALITY RATES PER
100,000 WOMAN-YEARS BY A.E. SMOKING STATUS AND
ORAL CONTRACEPTIVE USE
|
| Groups |
15-24
|
25-34
|
35-44
|
45-
|
| Ever users
(non-smokers) |
|
9.6
|
26.4
|
48.6
|
| Ever users
(smokers) |
12.9
|
17.9
|
62.9
|
205.7
|
| Controls
(non-smokers) |
|
6.4
|
8.9
|
12.9
|
| Controls
(smokers) |
|
9.3
|
21.4
|
32.1
|
TABLE III. (Adapted from P. M. Layde and V. Beral, ref.
#12.)
Oral contraceptives may compound the effects of well-known
risk factors, such as hypertension, diabetes, hyperlipidemias,
age and obesity.13 In particular, some progestogens are
known to decrease HDL cholesterol and cause glucose intolerance,
while estrogens may create a state of hyperinsulinism.14-18
Oral contraceptives have been shown to increase blood
pressure among users (see Section 9 in
WARNINGS
). Similar effects on risk factors have been associated
with an increased risk of heart disease. Oral contraceptives
must be used with caution in women with cardiovascular
disease risk factors.
b. Thromboembolism
An increased risk of thromboembolic and thrombotic disease
associated with the use of oral contraceptives is well
established. Case control studies have found the relative
risk of users compared to nonusers to be 3 for the first
episode of superficial venous thrombosis, 4 to 11 for
deep vein thrombosis or pulmonary embolism, and 1.5 to
6 for women with predisposing conditions for venous thromboembolic
disease.2,3,19-24 Cohort studies have shown the relative
risk to be somewhat lower, about 3 for new cases and about
4.5 for new cases requiring hospitalization. 25 The risk
of thromboembolic disease associated with oral contraceptives
is not related to length of use and disappears after pill
use is stopped.2
A two-to four-fold increase in relative risk of post-operative
thromboembolic complications has been reported with the
use of oral contraceptives.9 The relative risk of venous
thrombosis in women who have predisposing conditions is
twice that of women without such medical conditions.26
If feasible, oral contraceptives should be discontinued
at least four weeks prior to and for two weeks after elective
surgery of a type associated with an increase in risk
of thromboembolism and during and following prolonged
immobilization. Since the immediate postpartum period
is also associated with an increased risk of thromboembolism,
oral contraceptives should be started no earlier than
four weeks after delivery in women who elect not to breast
feed or four weeks after a second trimester abortion.
c. Cerebrovascular diseases
Oral contraceptives have been shown to increase both
the relative and attributable risks of cerebrovascular
events (thrombotic and hemorrhagic strokes), although,
in general, the risk is greatest among older (> 35
years), hypertensive women who also smoke. Hypertension
was found to be a risk factor for both users and nonusers,
for both types of strokes, and smoking interacted to increase
the risk of stroke.27-29
In a large study, the relative risk of thrombotic strokes
has been shown to range from 3 for normotensive users
to 14 for users with severe hypertension.30 The relative
risk of hemorrhagic stroke is reported to be 1.2 for non-smokers
who used oral contraceptives, 2.6 for smokers who did
not use oral contraceptives, 7.6 for smokers who used
oral contraceptives, 1.8 for normotensive users and 25.7
for users with severe hypertension.30 The attributable
risk is also greater in older women.3
d. Dose-related risk of vascular disease from
oral contraceptives
A positive association has been observed between the
amount of estrogen and progestogen in oral contraceptives
and the risk of vascular disease.31-33 A decline in serum
high density lipoproteins (HDL) has been reported with
many progestational agents.14-16 A decline in serum high
density lipoproteins has been associated with an increased
incidence of ischemic heart disease. Because estrogens
increase HDL cholesterol, the net effect of an oral contraceptive
depends on a balance achieved between doses of estrogen
and progestogen and the activity of the progestogen used
in the contraceptives. The activity and amount of both
hormones should be considered in the choice of an oral
contraceptive.
Minimizing exposure to estrogen and progestogen is in
keeping with good principles of therapeutics. For any
particular estrogen/ progestogen combination, the dosage
regimen prescribed should be one which contains the least
amount of estrogen and progestogen that is compatible
with a low failure rate and the needs of the individual
patient. New acceptors of oral contraceptive agents should
be started on preparations containing 0.035 mg or less
of estrogen.
e. Persistence of risk of vascular disease
There are two studies which have shown persistence of
risk of vascular disease for ever-users of oral contra-ceptives.
In a study in the United States, the risk of developing
myocardial infarction after discontinuing oral contraceptives
persists for at least 9 years for women 40-49 years who
had used oral contraceptives for five or more years, but
this increased risk was not demonstrated in other age
groups.8 In another study in Great Britain, the risk of
developing cerebrovascular disease persisted for at least
6 years after discontinuation of oral contraceptives,
although excess risk was very small.34 However, both studies
were performed with oral contraceptive formulations containing
50 micrograms or higher of estrogens.
2. ESTIMATES OF MORTALITY FROM CONTRACEPTIVE
USE
One study gathered data from a variety of sources which
have estimated the mortality rate associated with different
methods of contraception at different ages (Table IV).
These estimates include the combined risk of death associated
with contraceptive methods plus the risk attributable
to pregnancy in the event of method failure. Each method
of contraception has its specific benefits and risks.
The study concluded that with the exception of oral contraceptive
users 35 and older who smoke, and 40 and older who do
not smoke, mortality associated with all methods of birth
control is low and below that associated with childbirth.
The observation of an increase in risk of mortality with
age for oral contraceptive users is based on data gathered
in the 1970's.35 Current clinical recommendation involves
the use of lower estrogen dose formulations and a careful
consideration of risk factors. In 1989, the Fertility
and Maternal Health Drugs Advisory Committee was asked
to review the use of oral contraceptives in women 40 years
of age and over. The Committee concluded that although
cardiovascular disease risks may be increased with oral
contraceptive use after age 40 in healthy non-smoking
women (even with the newer low-dose formulations), there
are also greater potential health risks associated with
pregnancy in older women and with the alternative surgical
and medical procedures which may be necessary if such
women do not have access to effective and acceptable means
of contraception. The Committee recommended that the benefits
of low-dose oral contraceptive use by healthy non-smoking
women over 40 may outweigh the possible risks.
Of course, older women, as all women, who take oral contraceptives,
should take an oral contraceptive which contains the least
amount of estrogen and progestogen that is compatible
with a low failure rate and individual patient needs.
|
TABLE IV: A.N.A. NUMBER OF BIRTH- RELATED OR
METHOD- RELATED DEATHS
ASSOCIATED WITH CONTROL OF FERTILITY PER 100,000
NON- STERILE WOMEN,
BY FERTILITY CONTROL METHOD ACCORDING TO AGE |
Method of control
and outcome |
15-19
|
20-24
|
25-29
|
30-34
|
35-39
|
40-44
|
No fertility
control methods* |
7.0
|
7.4
|
9.1
|
14.8
|
25.7
|
28.2
|
Oral contraceptives
non- smoker** |
0.3
|
0.5
|
0.9
|
1.9
|
13.8
|
31.6
|
Oral contraceptives
smoker** |
2.2
|
3.4
|
6.6
|
13.5
|
51.1
|
117.2
|
IUD**
|
0.8
|
0.8
|
1.0
|
1.0
|
1.4
|
1.4
|
Condom*
|
1.1
|
1.6
|
0.7
|
0.2
|
0.3
|
0.4
|
Diaphragm/
spermicide* |
1.9
|
1.2
|
1.2
|
1.3
|
2.2
|
2.8
|
Periodic
abstinence* |
2.5
|
1.6
|
1.6
|
1.7
|
2.9
|
3.6
|
| *Deaths are
birth- related |
| ** Deaths are
method- related |
| Adapted from
H. W. Ory, ref. #35. |
3. CARCINOMA OF THE REPRODUCTIVE ORGANS AND BREASTS
Numerous epidemiological studies have been performed
on the incidence of breast, endometrial, ovarian, and
cervical cancer in women using oral contraceptives. While
there are conflicting reports, most studies suggest that
use of oral contraceptives is not associated with an overall
increase in the risk of developing breast cancer. Some
studies have reported an increased relative risk of developing
breast cancer, particularly at a younger age. This increased
relative risk has been reported to be related to duration
of use.36-44,79-89
A meta-analysis of 54 studies reports that women who
are currently using combined oral contraceptives or have
used them in the past 10 years are at a slightly increased
risk of having breast cancer diagnosed although the additional
cancers tend to be localized to the breast. There is no
evidence of an increased risk of having breast cancer
diagnosed 10 or more years after cessation of use.95
Some studies suggest that oral contraceptive use has
been associated with an increase in the risk of cervical
neoplasia in some populations of women.45-48 However,
there continues to be controversy about the extent to
which such findings may be due to differences in sexual
behavior and other factors.
4. HEPATIC NEOPLASIA
Benign hepatic adenomas are associated with oral contraceptive
use, although the incidence of benign tumors is rare in
the United States. Indirect calculations have estimated
the attributable risk to be in the range of 3.3 cases/100,000
for users, a risk that increases after four or more years
of use especially with oral contraceptives of higher dose.49
Rupture of benign, hepatic adenomas may cause death through
intra-abdominal hemorrhage.50,51
Studies have shown an increased risk of developing hepatocellular
carcinoma52-54, 96 in oral contraceptive users. However,
these cancers are rare in the U. S.
5. OCULAR LESIONS
There have been clinical case reports of retinal thrombosis
associated with the use of oral contraceptives. Oral contraceptives
should be discontinued if there is unexplained partial
or complete loss of vision; onset of proptosis or diplopia;
papilledema; or retinal vascular lesions. Appropriate
diagnostic and therapeutic measures should be undertaken
immediately.
6. ORAL CONTRACEPTIVE USE BEFORE OR DURING EARLY
PREGNANCY
Extensive epidemiological studies have revealed no increased
risk of birth defects in women who have used oral contraceptives
prior to pregnancy. 56,57 The majority of recent studies
also do not indicate a teratogenic effect, particularly
in so far as cardiac anomalies and limb reduction defects
are concerned,55,56,58,59 when taken inadvertently during
early pregnancy.
The administration of oral contraceptives to induce withdrawal
bleeding should not be used as a test for pregnancy. Oral
contraceptives should not be used during pregnancy to
treat threatened or habitual abortion.
It is recommended that for any patient who has missed
two consecutive periods, pregnancy should be ruled out
before continuing oral contraceptive use. If the patient
has not adhered to the prescribed schedule, the possibility
of pregnancy should be considered at the time of the first
missed period. Oral contraceptive use should be discontinued
until pregnancy is ruled out.
7. GALLBLADDER DISEASE
Earlier studies have reported an increased lifetime relative
risk of gallbladder surgery in users of oral contraceptives
and estrogens.60,61 More recent studies, however, have
shown that the relative risk of developing gallbladder
disease among oral contraceptive users may be minimal.62-64
The recent findings of minimal risk may be related to
the use of oral contraceptive formulations containing
lower hormonal doses of estrogens and progestogens.
8. CARBOHYDRATE AND LIPID METABOLIC EFFECTS
Oral contraceptives have been shown to cause a decrease
in glucose tolerance in a significant percentage of users.17
This effect has been shown to be directly related to estrogen
dose. 65 Progestogens increase insulin secretion and create
insulin resistance, this effect varying with different
progestational agents.17,66 However, in the non-diabetic
woman, oral contraceptives appear to have no effect on
fasting blood glucose.67 Because of these demonstrated
effects, prediabetic and diabetic women in particular
should be carefully monitored while taking oral contraceptives.
A small proportion of women will have persistent hypertriglyceridemia
while on the pill. As discussed earlier (see
WARNINGS
1a and 1d), changes in serum triglycerides and lipoprotein
levels have been reported in oral contraceptive users.
In clinical studies with ORTHO-CYCLEN there were no clinically
significant changes in fasting blood glucose levels. No
statistically significant changes in mean fasting blood
glucose levels were observed over 24 cycles of use. Glucose
tolerance tests showed minimal, clinically insignificant
changes from baseline to cycles 3, 12, and 24.
In clinical studies with ORTHO TRI-CYCLEN there were
no clinically significant changes in fasting blood glucose
levels. Minimal statistically significant changes were
noted in glucose levels over 24 cycles of use. Glucose
tolerance tests showed no clinically significant changes
from baseline to cycles 3, 12, and 24.
9. ELEVATED BLOOD PRESSURE
An increase in blood pressure has been reported in women
taking oral contraceptives68 and this increase is more
likely in older oral contraceptive users69 and with extended
duration of use.61 Data from the Royal College of General
Practitioners12 and subsequent randomized trials have
shown that the incidence of hypertension increases with
increasing progestational activity.
Women with a history of hypertension or hypertension-related
diseases, or renal disease70 should be encouraged to use
another method of contraception. If women elect to use
oral contraceptives, they should be monitored closely
and if significant elevation of blood pressure occurs,
oral contraceptives should be discontinued. For most women,
elevated blood pressure will return to normal after stopping
oral contraceptives, and there is no difference in the
occurrence of hypertension between former and never users.68-71
It should be noted that in two separate large clinical
trials (N = 633 and N = 911), no statistically significant
changes in mean blood pressure were observed with ORTHO-CYCLEN.
10. HEADACHE
The onset or exacerbation of migraine or development
of headache with a new pattern which is recurrent, persistent
or severe requires discontinuation of oral contraceptives
and evaluation of the cause.
11. BLEEDING IRREGULARITIES
Breakthrough bleeding and spotting are sometimes encountered
in patients on oral contraceptives, especially during
the first three months of use. Non-hormonal causes should
be considered and adequate diagnostic measures taken to
rule out malignancy or pregnancy in the event of breakthrough
bleeding, as in the case of any abnormal vaginal bleeding.
If pathology has been excluded, time or a change to another
formulation may solve the problem. In the event of amenorrhea,
pregnancy should be ruled out.
Some women may encounter post-pill amenorrhea or oligomenorrhea,
especially when such a condition was preexistent.
12. ECTOPIC PREGNANCY
Ectopic as well as intrauterine pregnancy may occur in
contraceptive failures.
PRECAUTIONS
1. PHYSICAL EXAMINATION AND FOLLOW UP
It is good medical practice for all women to have annual
history and physical examinations, including women using
oral contraceptives. The physical examination, however,
may be deferred until after initiation of oral contraceptives
if requested by the woman and judged appropriate by the
clinician. The physical examination should include special
reference to blood pressure, breasts, abdomen and pelvic
organs, including cervical cytology, and relevant laboratory
tests. In case of undiagnosed, persistent or recurrent
abnormal vaginal bleeding, appropriate measures should
be conducted to rule out malignancy. Women with a strong
family history of breast cancer or who have breast nodules
should be monitored with particular care.
2. LIPID DISORDERS
Women who are being treated for hyperlipidemias should
be followed closely if they elect to use oral contraceptives.
Some progestogens may elevate LDL levels and may render
the control of hyperlipidemias more difficult.
3. LIVER FUNCTION
If jaundice develops in any woman receiving such drugs,
the medication should be discontinued. Steroid hormones
may be poorly metabolized in patients with impaired liver
function.
4. FLUID RETENTION
Oral contraceptives may cause some degree of fluid retention.
They should be prescribed with caution, and only with
careful monitoring, in patients with conditions which
might be aggravated by fluid retention.
5. EMOTIONAL DISORDERS
Women with a history of depression should be carefully
observed and the drug discontinued if depression recurs
to a serious degree.
6. CONTACT LENSES
Contact lens wearers who develop visual changes or changes
in lens tolerance should be assessed by an ophthalmologist.
7. DRUG INTERACTIONS
Reduced efficacy and increased incidence of breakthrough
bleeding and menstrual irregularities have been associated
with concomitant use of rifampin. A similar association,
though less marked, has been suggested with barbiturates,
phenylbutazone, phenytoin sodium, carbamazepine, and possibly
with griseofulvin, ampicillin and tetracyclines.72
8. INTERACTIONS WITH LABORATORY TESTS
Certain endocrine and liver function tests and blood
components may be affected by oral contraceptives:
a. Increased prothrombin and factors VII, VIII, IX, and
X; decreased antithrombin 3; increased norepinephrine-induced
platelet aggregability.
b. Increased thyroid binding globulin (TBG) leading to
increased circulating total thyroid hormone, as measured
by protein-bound iodine (PBI), T4 by column or by radioimmunoassay.
Free T3 resin uptake is decreased, reflecting the elevated
TBG, free T4 concentration is unaltered.
c. Other binding proteins may be elevated in serum.
d. Sex hormone binding globulins are increased and result
in elevated levels of total circulating sex steroids;
however, free or biologically active levels either decrease
or remain unchanged.
e. High-density lipoprotein (HDL-C) and total cholesterol
(Total-C) may be increased, low-density lipoprotein (LDL-C)
may be increased or decreased, while LDL-C/HDL-C ratio
may be decreased and triglycerides may be unchanged.
f. Glucose tolerance may be decreased.
g. Serum folate levels may be depressed by oral contraceptive
therapy. This may be of clinical significance if a woman
becomes pregnant shortly after discontinuing oral contraceptives.
9. CARCINOGENESIS See
WARNINGS
Section.
10. PREGNANCY
Pregnancy Category X. See CONTRAINDICATIONS
and
WARNINGS
Sections.
11. NURSING MOTHERS
Small amounts of oral contraceptive steroids have been
identified in the milk of nursing mothers and a few adverse
effects on the child have been reported, including jaundice
and breast enlargement. In addition, oral contraceptives
given in the postpartum period may interfere with lactation
by decreasing the quantity and quality of breast milk.
If possible, the nursing mother should be advised not
to use oral contraceptives but to use other forms of contraception
until she has completely weaned her child.
12. SEXUALLY TRANSMITTED DISEASES
Patients should be counseled that this product does not
protect against HIV infection (AIDS) and other sexually
transmitted diseases.
See also PATIENT INFORMATION section
|
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