ETHINYL ESTRADIOL
DESCRIPTION:
PATIENTS SHOULD BE COUNSELED THAT THIS PRODUCT DOES NOT PROTECT AGAINST HIV
INFECTION (AIDS) AND OTHER SEXUALLY TRANSMITTED DISEASES.
Each tablet contains 0.25 mg of levonorgestrel, d(-)-13beta-ethyl,-
17beta- hydroxygon-4en-3-one, a totally synthetic progestogen, and 0.05 mg of
ethinyl estradiol, 17 alpha-ethinyl-1,3,5(10) -estratriene-3, 17beta- diol. The
inactive ingredients present are cellulose, hydroxypropyl methylcellulose, ion
oxide, lactose, magnesium stearate, polacrilin potassium, polyethylene glycol,
titanium dioxide, and wax E.
ACTIONS/CLINICAL PHARMACOLOGY:
Combination oral contraceptives act by suppression of gonadotropins. Although
the primary mechanism of this action is inhibition of ovulation, other
alterations include changes in the cervical mucus (which increase the difficulty
of sperm entry into the uterus) and the endometrium (which reduce the likelihood
of implantation).
PHARMACOKINETICS
ABSORPTION
No specific investigation of the absolute bioavailability of DUOLUTON-L in humans
has been conducted. However, literature indicates that levonorgestrel is rapidly
and completely absorbed after oral administration (bioavailability about 100%)
and is not subject to first-pass metabolism. Ethinyl estradiol is rapidly and
almost completely absorbed from the gastrointestinal tract but, due to first-
pass metabolism in gut mucosa and liver, the bioavailability of ethinyl
estradiol is between 38% and 48%.
After a single dose of DUOLUTON-L to 22 women under fasting conditions, maximum
serum concentrations of levonorgestrel are 2.80.9 ng/mL (meanSD) at 1.6
0.9 hours. At steady state, attained from day 19 onwards, maximum levonorgestrel
concentrations of 6.02.7 ng/mL are reached at 1.50.5 hours after the daily
dose. The minimum serum levels of levonorgestrel at steady state 1.91.0
ng/mL. Observed levonorgestrel concentrations increased from day 1 (single dose)
to days 6 and 21 (multiple doses) by 34% and 96%, respectively (Figure 1). The
kinetics of total levonorgestrel are non-linear due to an increase in binding of
levonorgestrel to sex hormone binding globulin (SHBG), which is attributed to
increased SHBG levels that are induced by the daily administration of ethinyl
estradiol.
Following a single dose, maximum serum concentrations of ethinyl estradiol of
6221 pg/mL are reached at 1.50.5 hours. At steady state, attained from at
least day 6 onwards, maximum concentrations of ethinyl estradiol were 7730
pg/mL and were reached at 1.30.7 hours after the daily dose. The minimum
serum levels of ethinyl estradiol at steady state are 10.55.1 pg/mL. Ethinyl
estradiol concentrations did not increase from days 1 to 6, but did increase by
19% from days 1 to 21 (Figure 1).
Table I provides a summary of levonorgestrel and ethinyl estradiol
pharmacokinetic parameters.
TABLE I: MEAN (SD) PHARMACOKINETIC PARAMETERS OF DUOLUTON-L
OVER A 21-DAY DOSING PERIOD
------------------------------------------------------------------------------
Levonorgestrel
Cmax Tmax AUC CL
Day ng/mL h ng.h/mL mL/h/kg L/kg nmol/L
------------------------------------------------------------------------------
1 2.75(0.88) 1.6(0.9) 35.2(12.8) 53.7(20.8) 2.66(1.09) 57(18)
6 4.52(1.79) 1.5(0.7) 46.0(18.8) 40.8(14.5) 2.05(0.86) 81(25)
21 6.00(2.65) 1.5(0.5) 68.3(32.5) 28.4(10.3) 1.43(0.62) 93(40)
------------------------------------------------------------------------------
Unbound Levonorgestrel
pg/mL h pg.h/mL L/h/kg L/kg fu %
------------------------------------------------------------------------------
1 51.2(12.9) 1.6(0.9) 65.4(201) 2.79(0.97) 135.9(41.8) 1.92(0.30)
6 77.9(22.0) 1.5(0.7) 79.4(240) 2.24(0.59) 112.4(40.5) 1.80(0.24)
21 103.6(36.9) 1.5(0.5) 117.7(452) 1.57(0.49) 78.8(29.7) 1.78(0.19)
------------------------------------------------------------------------------
Ethinyl Estradiol
pg/mL h pg.h/mL mL/h/kg L/kg
------------------------------------------------------------------------------
1 62.0(20.5) 1.5(0.5) 653(227) 567(204) 14.3(3.7)
6 76.7(29.9) 1.3(0.7) 604(231) 610(196) 15.5(4.0)
21 82.3(33.2) 1.4(0.6) 776(308) 486(179) 12.4(4.1)
------------------------------------------------------------------------------
DISTRIBUTION
LEVONORGESTREL: The most important metabolic pathway occurs in the reduction of
the delta4-3oxo group and hydroxylation at positions 2alpha, 1beta, and 16 beta
followed by conjugation. Most of the metabolites that circulate in the blood are
sulfates of the 3alpha,5beta-tetrahydro-levonorgestrel, while excretion occurs
predominantly in the form of glucuronides. Some of the parent levonorgestrel
also circulates as 17beta-sulfate. Metabolic clearance rates may differ among
individuals by several-fold, and this may account in part for the wide variation
observed in the levonorgestrel concentrations among users.
ETHINYL ESTRADIOL: Cytochrom P450 enzymes (CYP3A4) in the liver are responsible
for the 2-hydroxylation that is the major oxidative reaction. The 2-hydroxy
metabolite is further transformed by methylation and glucuronidation prior to
urinary and fecal excretion. Levels of Cytochrome P450 (CYP3A) vary widely among
individuals and can explain the variation in rates of ethinyl estradiol 2-
hydroxylation. Ethinyl estradiol is excreted in the urine and feces as
glucuronide and sulfate conjugates, and undergoes enterohepatic circulation.
EXCRETION
The elimination half-life for levonorgestrel is approximately 3613 hours at
steady state. Levonorgestrel and its metabolites are primarily excreted in the
urine (40% to 68%) and about 16% to 48% are excreted in the feces. The
elimination half-life of ethinyl estradiol is 184.7 hours at steady state.
SPECIAL POPULATIONS
RACE
Based on the pharmacokinetic study with DUOLUTON-L, there are no apparent
differences in pharmacokinetic parameters among women of different races.
HEPATIC INSUFFICIENCY
No formal studies have elevated the effect of hepatic disease on the disposition
of DUOLUTON-L. However, steroid hormones may be poorly metabolized in patients with
impaired liver function.
RENAL INSUFFICIENCY
No formal studies have evaluated the effect of renal disease on the disposition
of DUOLUTON-L.
DRUG-DRUG INTERACTIONS
Interactions between ethinyl estradiol and other drugs have been reported in the
literature.
--INTERACTIONS WITH ABSORPTION: Diarrhea may increase gastrointestinal motility
and reduce hormone absorption. Similarly, any drug which reduces gut transit
time may reduce hormones concentrations in the blood.
--INTERACTIONS WITH METABOLISM: GASTROINTESTINAL WALL: Sulfation of ethinyl
estradiol has been shown to occur in the gastrointestinal (GI) wall. Therefore,
drugs which act as competitive inhibitors for sulfation in the GI wall may
increase ethinyl estradiol bioavailability (e.g., ascorbic acid.) HEPATIC
METABOLISM: Interactions can occur with drugs that induce microsomal enzymes
which can decrease ethinyl estradiol concentrations (e.g., rifampin,
barbiturates, phenylbutazone, phenytoin, griseofulvin).
--INTERFERENCE WITH ENTEROHEPATIC CIRCULATION: Some clinical reports suggest
that enterohepatic circulation of estrogens may decrease when certain
antibiotic agents are given, which may reduce ethinyl estradiol concentrations
(e.g., ampicillin, tetracycline).
--INTERFERENCE IN THE METABOLISM OF OTHER DRUGS: Ethinyl estradiol may
interfere with the metabolism of other drugs by inhibiting hepatic microsomal
enzymes or by inducing hepatic drug conjugation, particularly glucuronidation.
Accordingly, plasma and tissue concentrations may either be increased or
decreased, respectively (e.g., cyclosporine, theophylline).
INDICATIONS AND USAGE:
Oral contraceptives are indicated for the prevention of pregnancy in women who
elect to use this product as a method of contraception.
Oral contraceptives are highly effective. Table II lists the typical accidental
pregnancy rates for users of combination oral contraceptives and other methods
of contraception. The efficacy of these contraceptive methods except
sterilization, the IUD, and Norplant(R) System, depends upon the reliability
with which they are used. Correct and consistent use of methods can result in
lower failure rates.
TABLE II: PERCENTAGE OF WOMEN EXPERIENCING AN UNINTENDED PREGNANCY
DURING THE FIRST YEAR OF USE OF A CONTRACEPTIVE METHOD
------------------------------------------------------------------------------
Method Perfect Typical
Use Use
------------------------------------------------------------------------------
Norplant(R) System (6 capsules) 0.1 0.1
Male sterilization 0.1 0.15
Female sterilization 0.4 0.4
Depo-Provera(R) (injectable progestogen) 0.3 0.3
Oral contraceptives
Combined 0.1 NA
Progestin only 0.5 NA
IUD
Progesterone 1.5 2.0
Copper T 380A 0.6 0.8
Condom (male) without spermicide 3 12
(female) without spermicide 5 21
Cervical cap
Nulliparous women 9 18
Parous women 26 36
Diaphragm with spermicidal cream or jelly 6 18
Spermicides alone (foam, creams, jellies,
and vaginal suppositories 6 21
Periodic abstinence (all methods) 1-9* 20
Withdrawal 4 19
No contraception (planned pregnancy) 85 85
------------------------------------------------------------------------------
NA = not available
*Depending on method (calendar, ovulation, symptothermal, post-ovulation)
Adapted from Hatcher RA et al., Contraceptive Technology, 16th Revised
Edition. New York, NY: Irvington Publishers, 1994.
In a clinical trial with DUOLUTON-L, 1,477 subjects had 7,720 cycles of use and a
total of 5 pregnancies were reported. This represents an overall pregnancy rate
of 0.84 per 100 woman- years. This rate includes patients who did not take the
drug correctly. One or more pills were missed during 1,479 (18.8%) of the 7,870
cycles; thus all tablets were taken during 6,391 (81.2%) of the 7,870 cycles. Of
the total 7,870 cycles, a total of 150 cycles were excluded from the calculation
of the Pearl index due to the use of backup contraception and/or missing 3 or
more consecutive pills.
CONTRAINDICATIONS:
Oral contraceptives should not be used in women with any of the following
conditions:
Thrombophlebitis or thromboembolic disorders
A past history of deep-vein thromboembolic disorders
Cerebrovascular or coronary artery disease
Known or suspected carcinoma of the breast
Carcinoma of the endometrium or other known or suspected estrogen-dependent
neoplasia
Undiagnosed abnormal genital bleeding
Cholestatic jaundice of pregnancy or jaundice with prior pill use
Hepatic adenomas or carcinomas
Known or suspected pregnancy
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 SHOULD BE 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, gallbladder disease and hypertension, 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 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 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 occurrences 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. 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.
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 infarction in women in their mid-
thirties or older with smoking accounting for the majority of excess cases.
Mortality rates associated with circulatory disease have been shown to increase
substantially in smokers over the age of 35 and nonsmokers over the age of 40
(Table III) among women who use oral contraceptives. Click here for
illustration(s).
Oral contraceptives may compound the effects of well-known risk factors, such as
hypertension, diabetes, hyperlipidemias, age and obesity. In particular, some
progestogens are known to decrease HDL cholesterol and cause glucose
intolerance, while estrogens may create a state of hyperinsulinism. 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 been
the relative risk of users compared to non-users 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. 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. The risk of thromboembolic disease due to oral contraceptives
is not related to length of use and disappears after pill use is stopped.
A two- to four-fold increase in relative risk of postoperative thromboembolic
complications has been reported with the use of oral contraceptives. The
relative risk of venous thrombosis in women who have predisposing conditions is
twice that of women without such medical conditions. 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 to
six weeks after delivery in women who elect not to breast-feed, or a
midtrimester pregnancy termination.
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, while smoking interacted
to increase the risk for hemorrhagic strokes.
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.
The relative risk of hemorrhagic stroke is reported to be 1.2 for nonsmokers 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. The attributable risk is also greater
in older women.
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. A decline
in serum high-density lipoproteins (HDL) has been reported with many
progestational agents. 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 oral contraceptive depends
on the balance achieved between doses of estrogen and progestogen and the nature
and absolute amount of progestogen used in the contraceptive. The amount of both
hormones should be considered in the choice of 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 less than 50 mcg of estrogen.
e. Persistence Of Risk Of Vascular Disease
There are two studies which have shown the persistence of risk of vascular
disease for ever- users of oral contraceptives. 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. 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.
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 less than that associated with childbirth.
The observation of a possible increase in risk of mortality with age for oral-
contraceptive users is based on data gathered in the 70's--but not reported
until 1983. However, current clinical practice involves the use of lower
estrogen dose formulations combined with careful restriction of oral-
contraceptive use to women who do not have the various risk factors listed in
this labeling.
Because of these changes in practice and, also, because of some limited new data
which suggest that the risk of cardiovascular disease with the use of oral
contraceptives may now be less than previously observed, the Fertility and
Maternal Health Drugs Advisory Committee was asked to review the topic in 1989.
The Committee concluded that although cardiovascular disease risks may be
increased with oral-contraceptive use after age 40 in healthy nonsmoking women
(even with newer low-dose formulations), there are 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.
Therefore, the Committee recommended that the benefits of oral-contraceptive use
by healthy nonsmoking women over 40 may outweigh the possible risks. Of course,
older women, as all women who take oral contraceptives, should take the lowest
possible dose formulation that is effective.
------------------------------------------------------------------------------
Table IV: ANNUAL NUMBER OF BIRTH-RELATED OR METHOD-RELATED DEATHS ASSOCIATED
WITH CONTROL OF FERTILITY PER 100,000 NONSTERILE WOMEN BY FERTILITY-CONTROL
METHOD AND 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
nonsmoker** 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, Family Planning Perspectives, 15:57-63, 1983.
3. CARCINOMA OF THE REPRODUCTIVE ORGANS
Numerous epidemiological studies have been performed on the incidence of breast,
endometrial, ovarian and cervical cancer in women using oral contraceptives. The
overwhelming evidence in the literature suggests that use of oral contraceptives
is not associated with an increase in the risk of developing breast cancer,
regardless of the age and parity of first use or with most of the marketed
brands and doses. The Cancer and Steroid Hormone (CASH) study also showed no
latent effect on the risk of breast cancer for at least a decade following long-
term use. A few studies have shown a slightly increased relative risk of
developing breast cancer, although the methodology of these studies, which
included differences in examination of users and nonusers and differences at
start of use, has been questioned. Some studies suggest that oral-contraceptive
use has been associated with and increase in the risk of cervical
intraepithelial neoplasia in some populations of women. However, there continues
to be controversy about the extent to which such findings may be due to
differences in sexual behavior and other factors.
In spite of many studies of the relationship between oral-contraceptive use and
breast and cervical cancers, a cause-and-effect relationship has not been
established.
4. HEPATIC NEOPLASIA
Benign hepatic adenomas are associated with oral- contraceptive use, although
these incidences of these 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.
Rupture of rare, benign, hepatic adenomas may cause death through intra-
abdominal hemorrhage.
Studies from Britain have shown an increased risk of developing hepatocellular
carcinoma in long term (>8 years) oral-contraceptive users. However, these
cancers are extremely rare in the U.S. and the attributable risk (the excess
incidence) of liver cancers in oral-contraceptive users approaches less than one
per million users.
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. Studies
also do not suggest a teratogenic effect, particularly in so far as cardiac
anomalies and limb-reduction defects are concerned, when taken inadvertently
during an 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 if pregnancy is confirmed.
7. GALLBLADDER DISEASE
Earlier studies have reported an increased lifetime relative risk of gallbladder
surgery in users of oral-contraceptives and estrogens. More recent studies,
however have shown that the relative risk developing gallbladder disease among
oral-contraceptive users may be minimal. 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 glucose intolerance in a
significant percentage of users. Oral contraceptives containing greater than 75
micrograms of estrogens cause hyperinsulinism, while lower doses of estrogen
cause less glucose intolerance. Progestogens increase insulin secretion and
create insulin resistance, the effect varying with different progestational
agents. However, in the non- diabetic woman, oral contraceptives appear to have
no effect on fasting blood glucose. Because of these demonstrated effects,
prediabetic and diabetic women should be carefully observed 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.
9. ELEVATED BLOOD PRESSURE
An increase in blood pressure has been reported in women taking oral
contraceptives and this increase is more likely in older oral- contraceptive
users and with continued use. Data from the Royal College of General
Practitioners and subsequent randomized trials have shown that the incidence of
hypertension increases with increasing quantities of progestogens.
Women with a history of hypertension or hypertension-related diseases or renal
diseases should be encouraged to use another form of contraception. If women
with hypertension 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 among ever- and never-users.
10. HEADACHE
The onset or exacerbation of migraine or development of headache with a new
pattern that 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. The type and
dose of progestogen may be important. Nonhormonal 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 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.
PRECAUTIONS:
PATIENTS SHOULD BE COUNSELED THAT THIS PRODUCT DOES NOT PROTECT AGAINST HIV
INFECTION (AIDS) AND OTHER SEXUALLY TRANSMITTED DISEASES.
1.PHYSICAL EXAMINATION AND FOLLOW-UP
A periodic history and physical examination is appropriate for all women,
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
diagnostic measures should be conducted to rule out malignancy. Women with
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. (See "WARNINGS,"
1d.)
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
Patients becoming significantly depressed while taking oral contraceptives
should stop the medication and use an alternative method of contraception in an
attempt to determine whether the symptom is drug related. 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 increased incidence of breakthrough bleeding and menstrual
irregularities have been associated with concomitant use of rifampin. A similar
association, though less marked, has been associated with barbiturates,
phenylbutazone, phenytoin, and possibly with griseofulvin, ampicillin, and
tetracyclines.
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
remain unchanged.
e. Triglycerides may be increased.
f. Glucose tolerance may be decreased.
g. Serum folate levels may be depressed by oral- contraceptive therapy. This may
be 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.
INFORMATION FOR THE PATIENT
See Patient Labeling Printed Below.
DRUG INTERACTIONS:
Reduced efficacy increased incidence of breakthrough bleeding and menstrual
irregularities have been associated with concomitant use of rifampin. A similar
association, though less marked, has been associated with barbiturates,
phenylbutazone, phenytoin, and possibly with griseofulvin, ampicillin, and
tetracyclines.
(See Also PRECAUTIONS)
ADVERSE REACTIONS:
An increased risk of the following serious adverse reactions has been associated
with the use of oral contraceptives (see "WARNINGS" section):
Thrombophlebitis
Arterial thromboembolism
Pulmonary embolism
Myocardial infarction
Cerebral hemorrhage
Cerebral thrombosis
Hypertension
Gallbladder disease
Hepatic adenomas or benign liver tumors
There is evidence of an association between the following conditions and the use
of oral contraceptives, although additional confirmatory studies are needed:
Mesenteric thrombosis
Retinal thrombosis
The following adverse reactions have been reported in patients receiving oral
contraceptives and are believed to be drug related:
Nausea
Vomiting
Gastrointestinal symptoms (such as abdominal cramps and bloating)
Breakthrough bleeding
Spotting
Change in menstrual flow
Amenorrhea
Temporary infertility after discontinuation of treatment
Edema
Melasma which may persist
Breast changes: tenderness, enlargement, secretion
Change in weight (increase or decrease)
Change in cervical erosion and secretion
Diminution in lactation when given immediately postpartum
Cholestatic jaundice
Migraine
Rash (allergic)
Mental depression
Reduced tolerance to carbohydrates
Vaginal candidiasis
Change in corneal curvature (steepening)
Intolerance to contact lenses
The following adverse reactions have been reported in users of oral
contraceptives and the association has neither been confirmed nor refuted:
Premenstrual syndrome
Cataracts
Optic neuritis
Changes in appetite
Cystis-like syndrome
Headache
Nervousness
Dizziness
Hirsutism
Loss of scalp hair
Erythema multiforme
Erythema nodosum
Hemorrhagic eruption
Vaginitis
Porphyria
Impaired renal function
Hemolytic uremic syndrome
Budd-Chiari syndrome
Acne
Changes in libido
Colitis
OVERDOSAGE:
Serious ill effects have not been reported following acute ingestion of large
doses of oral contraceptives by young children. Overdosage may cause nausea, and
withdrawal bleeding may occur in females.
NONCONTRACEPTIVE HEALTH BENEFITS
The following noncontraceptive health benefits related to the use of oral
contraceptives are supported by epidemiological studies which largely utilized
oral-contraceptive formulations containing doses exceeding 0.035 mg of ethinyl
estradiol or 0.05 mg of mestranol.
Effects of menses:
Increased menstrual cycle regularity
Decreases blood loss and decreased incidence of iron-deficiency anemia
Decreased incidence of dysmenorrhea
Effects related to inhibition of ovulation:
Decreased incidence of functional ovarian cysts
Decreased incidence of ectopic pregnancies
Effects from long-term use:
Decreased incidence of fibroadenomas and fibrocystic disease of the breast
Decreased incidence of acute pelvic inflammatory disease
Decreased incidence of endometrial cancer
Decreased incidence of ovarian cancer
DOSAGE AND ADMINISTRATION:
To achieve maximum contraceptive effectiveness, DUOLUTON-L(TM) must be taken exactly
as directed at intervals not exceeding 24 hours. The dispenser should be kept in
the wallet supplied to avoid possible fading of the pills. If the pills fade,
patients should continue to take them as directed.
The dosage of DUOLUTON-L-21 is one pink tablet daily for 21 consecutive days,
followed by 7 days when no tablets are taken. It is recommended that DUOLUTON-L-21
tablets be taken at the same time each day.
Sunday Start:
During the first cycle of medication, the patient is instructed to begin taking
DUOLUTON-L-21 on the first Sunday after the onset of menstruation. If menstruation
begins on a Sunday, the first tablet (pink) is taken that day. One pink tablet
should be taken daily for 21 consecutive days, followed by seven days when no
tablet is taken. Withdrawal bleeding should usually occur within three days
following discontinuation of pink tablets. During the first cycle, contraceptive
reliance should not be placed on DUOLUTON-L-21 until a pink tablet has been taken
daily for 7 consecutive days. The possibility of ovulation and contraception
prior to initiation of medication should be considered.
The patient begins her next and all subsequent 21-day courses of tablets on the
same day of the week (Sunday) on which she began her first course, following the
same schedule: 21 days on pink tablets--7 days when no tablets are taken. If in
any cycle the patient starts tablets later than the proper day, she should
protect herself against pregnancy by using another method of birth control until
she has taken a pink tablet daily for 7 consecutive days.
Day 1 Start: During the first cycle of medication, the patient in instructed to
begin taking DUOLUTON-L-21 during the first 24 hours of her period (day one of her
menstrual cycle). One pink tablet should be taken daily for 21 consecutive days.
Withdrawal bleeding should usually occur within three days following
discontinuation of the pink tablets. If medication is begun in day one of the
menstrual cycle, no back-up contraception is necessary. If DUOLUTON-L-21 tablets are
started later than day one of the menstrual cycle, or postpartum, contraceptive
reliance should not be placed on DUOLUTON-L-21 tablets until after the first 7
consecutive days of administration. The possibility of ovulation and conception
prior to initiation medication should be considered.
When the patient is switching from a 21-day regimen of tablets, she should wait
7 days after her last tablet before she starts DUOLUTON-L. She will probably
experience withdrawal bleeding that week. She should be sure that no more than 7
days pass after her 21-day regimen. When the patient is switching from a 28-day
regimen of tablets, she should start her first pack of DUOLUTON-L on the day after
her last tablet. She should not wait any days between packs.
If spotting or breakthrough bleeding occur, the patient is instructed to
continue on the same regimen. This type of bleeding is usually transient and
without significance; however, if the bleeding is persistent or prolonged, the
patient is advised to consult her physician. While there is little likelihood of
ovulation occurring if only one or two pink tablets are missed, the possibility
of ovulation increases with each successive day that scheduled pink tablets are
missed. Although the occurrence of pregnancy is unlikely if DUOLUTON-L is taken
according to directions, if withdrawal bleeding does not occur, the possibility
of pregnancy must be considered. If the patient has not adhered to the
prescribed schedule (missed one or more tablets or started taking them on a day
later than she should have), the probability of pregnancy should be considered
at the time of the first missed period and appropriate diagnostic measures taken
before the medication is resumed. If the patient has adhered to the prescribed
regimen and misses two consecutive periods, pregnancy should be ruled out before
continuing the contraceptive regimen.
The risk of pregnancy increases with each active (pink) tablet missed. For
additional patient instructions regarding missed tablets, see the "WHAT TO DO IF
YOU MISS PILLS" section in the DETAILED PATIENT LABELING below.
In the nonlactating mother, DUOLUTON-L may be initiated postpartum, for
contraception. When the tablets are administered in the postpartum period, the
increased risk of thromboembolic disease associated with the postpartum period
must be considered (See "CONTRAINDICATIONS", "WARNINGS", and "PRECAUTIONS"
concerning thromboembolic disease).