Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/1183
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LO/OVRAL 28 (Kit)
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To achieve maximum contraceptive effectiveness, Lo/Ovral-28
must be taken exactly as directed and at intervals not exceeding 24 hours.
The possibility of ovulation and conception prior to initiation of medication
should be considered. The dosage of Lo/Ovral-28
is one white tablet daily for 21 consecutive days, followed by one pink inert
tablet daily for 7 consecutive days, according to prescribed schedule. It
is recommended that tablets be taken at the same time each day. During the first cycle of medication, the patient is instructed
to begin taking Lo/Ovral-28 on the first Sunday after the onset of menstruation.
If menstruation begins on a Sunday, the first tablet (white) is taken that
day. One white tablet should be taken daily for 21 consecutive days followed
by one pink inert tablet daily for 7 consecutive days. Withdrawal bleeding
should usually occur within three days following discontinuation of white
tablets and may not have finished before the next pack is started. During
the first cycle, contraceptive reliance should not be placed on Lo/Ovral-28until a white tablet has been taken daily for 7 consecutive days and a nonhormonal
back-up method of birth control should be used during those 7 days. The possibility
of ovulation and conception prior to initiation of medication should be considered. The patient begins her next and all subsequent 28-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 white tablets���7 days
on pink inert tablets. If in any cycle the patient starts tablets later than
the proper day, she should protect herself against pregnancy by using a nonhormonal
back-up method of birth control until she has taken a white tablet daily for
7 consecutive days. When the patient is switching
from a 21-day regimen of tablets, she should wait 7 days after her last tablet
before she starts Lo/Ovral-28. She will probably experience withdrawal bleeding
during that week. She should be sure that no more than 7 days pass after her
previous 21-day regimen. When the patient is switching from a 28-day regimen
of tablets, she should start her first pack of Lo/Ovral-28 on the day after
her last tablet. She should not wait any days between packs. The patient may
switch any day from a progestin-only pill and should begin Lo/Ovral-28 the
next day. If switching from an implant or injection, the patient should start
Lo/Ovral-28 on the day of implant removal or the day the next injection would
be due. In switching from a progestin-only pill, injection, or implant, the
patient should be advised to use a nonhormonal back-up method of birth control
for the first 7 days of tablet-taking. If spotting
or breakthrough bleeding occurs, 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 health-care professional. Although pregnancy is unlikely if
Lo/Ovral-28is 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. If the patient has adhered to the prescribed
regimen and misses two consecutive periods, pregnancy should be ruled out.
Hormone contraception should be discontinued if pregnancy is confirmed. For additional patient instructions regarding missed tablets,
see the WHAT TO DO IF YOU MISS
PILLS section in theDETAILED PATIENT LABELING below. Any time the patient misses two or more white tablets, she
should also use another method of contraception until she has taken a white
tablet daily for seven consecutive days. If the patient misses one or more
pink tablets, she is still protected against pregnancy provided she begins taking white tablets again on the proper day. If breakthrough bleeding occurs following missed white tablets,
it will usually be transient and of no consequence. The possibility of ovulation
increases with each successive day that scheduled white tablets are missed. Lo/Ovral-28 may be initiated no earlier than day 28 postpartum
in the nonlactating mother or after a second-trimester abortion due to the
increased risk for thromboembolism (see CONTRAINDICATIONS, WARNINGS,
and PRECAUTIONS concerning thromboembolic
disease). The patient should be advised to use a nonhormonal back-up method
for the first 7 days of tablet-taking. However, if intercourse has already
occurred, pregnancy should be excluded before the start of combined oral contraceptive
use or the patient must wait for her first menstrual period. In the case of
first-trimester abortion, if the patient starts Lo/Ovral-28 immediately, additional
contraceptive measures are not needed.
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| dailymed-instance:descripti... |
21 white LO/OVRAL tablets, each containing 0.3 mg
of norgestrel (dl-13-beta-ethyl-17-alpha-ethinyl-17-beta-hydroxygon-4-en-3-one),
a totally synthetic progestogen, and 0.03 mg of ethinyl estradiol (19-nor-17��-pregna-1,3,5
(10)-trien-20-yne-3,17-diol), and 7 pink inert tablets. The inactive ingredients
present are cellulose, D&C Red 30, lactose, magnesium stearate, and polacrilin
potassium.
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Mode of Action: 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 likelihoodof implantation).
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| dailymed-instance:contraind... |
Combination oral contraceptives should not be used
in women with any of the following conditions: Thrombophlebitis
or thromboembolic disordersA past history of deep-vein thrombophlebitis
or thromboembolic disordersCerebral-vascular or coronary-artery disease
(current or history)Thrombogenic valvulopathiesThrombogenic rhythm
disordersMajor surgery with prolonged immobilizationDiabetes with
vascular involvementHeadaches with focal neurological symptomsUncontrolled
hypertensionKnown or suspected carcinoma of the breast or personal history
of breast cancerCarcinoma of the endometrium or other known or suspected
estrogen-dependent neoplasiaUndiagnosed abnormal genital bleedingCholestatic
jaundice of pregnancy or jaundice with prior pill useHepatic adenomas
or carcinomas, or active liver disease, as long as liver function has not
returned to normalKnown or suspected pregnancyHypersensitivity to
any of the components of Lo/Ovral-28
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Lo/Ovral-28 Tablets (0.3 mg
norgestrel and 0.03 mg ethinyl estradiol) are available in packages of
6 PILPAK dispensers, each containing 28 tablets as follows: 21 active tablets, NDC 0008-0078, white, round tablet
marked���WYETH���and���78���. 7
inert tablets, NDC 0008-0486, pink, round tablet marked���WYETH���and���486���. Store
at controlled room temperature 20��C
to 25��C (68��F to 77��F). References
available upon request.
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Cigarette smoking
increases the risk of serious cardiovascular side effects from oral-contraceptive
use. This risk increases with age and with the extent of smoking (in epidemiologic
studies, 15 or more cigarettes per day was associated with a significantly
increased risk) and is quite marked in women over 35 years of age. Women who
use oral contraceptives should be strongly advised not to smoke.
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| dailymed-instance:precautio... |
1. General: Patients should
be counseled that oral contraceptives do not protect against transmission
of HIV (AIDS) and other sexually transmitted diseases (STDs) such as chlamydia,
genital herpes, genital warts, gonorrhea, hepatitis B, and syphilis.<br/>2. Physical Examination and Follow-Up: A periodic personal and family medical history and
complete physical examination are 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 a strong family
history of breast cancer or who have breast nodules should be monitored with
particular care.<br/>3. 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,
1a. and 1d., and 8.) In patients with defects of lipoprotein
metabolism, estrogen-containing preparations may be associated with rare but
significant elevations of plasma triglycerides which may lead to pancreatitis.<br/>4. Liver Function: If jaundice develops in any woman receiving hormonal
contraceptives, the medication should be discontinued. Steroid hormones may
be poorly metabolized in patients with impaired liver function.<br/>5. 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.<br/>6. Emotional Disorders: Patients becoming significantly depressed while
taking oral contraceptives should stop the medication and use an alternate
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 significant depression occurs.<br/>7. Contact Lenses: Contact-lens wearers who develop visual changes
or changes in lens tolerance should be assessed by an ophthalmologist.<br/>8. Gastrointestinal: Diarrhea and/or vomiting may reduce hormone absorption
resulting in decreased serum concentrations.<br/>9. Drug Interactions:<br/>Changes in contraceptive effectiveness
associated with coadministration of other products:: Contraceptive effectiveness may be reduced when
hormonal contraceptives are coadministered with antibiotics, anticonvulsants,
and other drugs that increase the metabolism of contraceptive steroids. This
could result in unintended pregnancy or breakthrough bleeding. Examples include
rifampin, rifabutin, barbiturates, primidone, phenylbutazone, phenytoin, dexamethasone,carbamazepine, felbamate, oxcarbazepine, topiramate, griseofulvin, and modafinil. Several cases of contraceptive failure and breakthrough
bleeding have been reported in the literature with concomitant administration
of antibiotics such as ampicillin and other penicillins, and tetracyclines,
possibly due to a decrease of enterohepatic recirculation of estrogens. However,
clinical pharmacology studies investigating drug interactions between combined
oral contraceptives and these antibiotics have reported inconsistent results.
Enterohepatic recirculation of estrogens may also be decreased by substances
that reduce gut transit time. Several of
the anti-HIV protease inhibitors have been studied with coadministration of
oral combination hormonal contraceptives; significant changes (increase and
decrease) in the plasma levels of the estrogen and progestin have been noted
in some cases. The safety and efficacy of oral contraceptive products may
be affected with coadministration of anti-HIV protease inhibitors. Health-care
professionals should refer to the label of the individual anti-HIV protease
inhibitors for further drug-drug interaction information. Herbal products containing St. John's Wort (Hypericum
perforatum) may induce hepatic enzymes (cytochrome P 450) and p-glycoprotein
transporter and may reduce the effectiveness of contraceptive steroids. This
may also result in breakthrough bleeding. During
concomitant use of ethinyl estradiol containing products and substances that
may lead to decreased plasma steroid hormone concentrations, it is recommended
that a nonhormonal back-up method of birth control be used in addition to
the regular intake of Lo/Ovral-28. If the use of a substance which leads to
decreased ethinyl estradiol plasma concentrations is required for a prolonged
period of time, combination oral contraceptives should not be considered the
primary contraceptive. After discontinuation
of substances that may lead to decreased ethinyl estradiol plasma concentrations,
use of a nonhormonal back-up method of birth control is recommended for 7 days.
Longer use of a back-up method is advisable after discontinuation of substances
that have led to induction of hepatic microsomal enzymes, resulting in decreased
ethinyl estradiol concentrations. It may take several weeks until enzyme induction
has completely subsided, depending on dosage, duration of use, and rate of
elimination of the inducing substance.<br/>Increase in plasma levels associated with coadministered drugs:: Coadministration of atorvastatin and certain oral
contraceptives containing ethinyl estradiol increase AUC values for ethinyl
estradiol by approximately 20%. The mechanism of this interaction is unknown.
Ascorbic acid and acetaminophen increase the bioavailability of ethinyl estradiol
since these drugs act as competitive inhibitors for sulfation of ethinyl estradiol
in the gastrointestinal wall, a known pathway of elimination for ethinyl estradiol.
CYP 3A4 inhibitors such as indinavir, itraconazole, ketoconazole, fluconazole,
and troleandomycin may increase plasma hormone levels. Troleandomycin may
also increase the risk of intrahepatic cholestasis during coadministration
with combination oral contraceptives.<br/>Changes in plasma levels of coadministered drugs:: Combination hormonal contraceptives containing
some synthetic estrogens (eg, ethinyl estradiol) may inhibit the metabolism
of other compounds. Increased plasma concentrations of cyclosporin, prednisolone
and other corticosteroids, and theophylline have been reported with concomitant
administration of oral contraceptives. Decreased plasma concentrations of
acetaminophen and increased clearance of temazepam, salicylic acid, morphine,
and clofibric acid, due to induction of conjugation (particularly glucuronidation),
have been noted when these drugs were administered with oral contraceptives. The prescribing information of concomitant medications
should be consulted to identify potential interactions.<br/>10. Interactions With Laboratory Tests: Certain endocrine- and liver-function tests and
blood components may be affected by oral contraceptives: This may be of clinical significance if a woman
becomes pregnant shortly after discontinuing oral contraceptives.<br/>11. Carcinogenesis: See WARNINGS section.<br/>12. Pregnancy: Pregnancy Category X. See CONTRAINDICATIONS and WARNINGS sections.<br/>13. Nursing Mothers: Small amounts of oral-contraceptive steroids and/or
metabolites 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, combination 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
combination oral contraceptives but to use other forms of contraception until
she has completely weaned her child.<br/>14. Fertility Following Discontinuation: Users of combination oral contraceptives may experience
some delay in becoming pregnant after discontinuation of COCs, especially
those women who had irregular menstrual cycles prior to use. Conception may
be delayed an average of 1-2 months among women stopping COCs compared to
women stopping nonhormonal contraceptive methods. Women
who do not wish to become pregnant after discontinuation of COCs should be
advised to use another method of birth control.<br/>15. Pediatric Use: Safety and efficacy of Lo/Ovral-28 tablets have
been established in women of reproductive age. Safety and efficacy are expected
to be the same for postpubertal adolescents under the age of 16 and for
users 16 years and older. Use of this product before menarche is not indicated.<br/>16. Geriatric Use: This product has not been studied in women over
65 years of age and is not indicated in this population.<br/>Information for the Patient: See Patient Labeling Printed
Below.
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Symptoms of oral contraceptive overdosage in adults
and children may include nausea, vomiting, and drowsiness/fatigue; withdrawal
bleeding may occur in females. There is no specific antidote and further treatment
of overdose, if necessary, is directed to the symptoms.
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Norgestrel and Ethinyl Estradiol
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LO/OVRAL 28 (Kit)
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| dailymed-instance:adverseRe... |
An increased risk of the following serious adverse
reactions (see WARNINGS section for additional information) has been associated with the
use of oral contraceptives: Thromboembolic and
thrombotic disorders and other vascular problems (including thrombophlebitis
and venous thrombosis with or without pulmonary embolism, mesenteric thrombosis,
arterial thromboembolism, myocardial infarction, cerebral hemorrhage, cerebral
thrombosis), carcinoma of the reproductive organs and breasts, hepatic neoplasia
(including hepatic adenomas or benign liver tumors), ocular lesions (including
retinal vascular thrombosis), gallbladder disease, carbohydrate and lipid
effects, elevated blood pressure, and headache including migraine. The following adverse reactions have been reported in patients
receiving oral contraceptives and are believed to be drug-related (alphabetically
listed): AcneAmenorrheaAnaphylactic/anaphylactoid
reactions, including urticaria, angioedema, and severe reactions with respiratory
and circulatory symptomsBreakthrough bleedingBreast changes: tenderness,
pain, enlargement, secretionBudd-Chiari syndromeCervical erosion
and secretion, change inCholestatic jaundiceChorea, exacerbation
ofColitisCorneal curvature (steepening), change inDiminution
in lactation when given immediately postpartumDizzinessEdema/fluid
retentionErythema multiformeErythema nodosumGastrointestinal
symptoms (such as abdominal pain, cramps, and bloating)HirsutismIntolerance
to contact lensesLibido, changes inLoss of scalp hairMelasma/chloasma
which may persistMenstrual flow, change inMood changes, including
depressionNauseaNervousnessPancreatitisPorphyria, exacerbation
ofRash (allergic)Serum folate levels, decrease inSpottingSystemic
lupus erythematosus, exacerbation ofTemporary infertility after discontinuation
of treatmentVaginitis, including candidiasisVaricose veins, aggravation
ofVomitingWeight or appetite (increase or decrease), change in The following adverse reactions have been reported in users
of oral contraceptives: CataractsCystitis-like
syndromeDysmenorrheaHemolytic uremic syndromeHemorrhagic eruptionOptic
neuritis, which may lead to partial or complete loss of visionPorphyriaPremenstrual
syndromeRenal function, impaired
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| dailymed-instance:warning |
Cigarette smoking
increases the risk of serious cardiovascular side effects from oral-contraceptive
use. This risk increases with age and with the extent of smoking (in epidemiologic
studies, 15 or more cigarettes per day was associated with a significantly
increased risk) 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 venous and arterial
thrombotic and thromboembolic events (such as myocardial infarction, thromboembolism,
and 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 certain
inherited or acquired thrombophilias, hypertension, hyperlipidemias, obesity,diabetes, and surgery or trauma with increased risk of thrombosis. Practitioners prescribing oral contraceptives should be
familiar with the following information relating to these risks. The information contained in this package insert is based
principally on studies carried out in patients who used oral contraceptives
with higher doses of estrogens and progestogens than those in common use today.
The effect of long-term use of the oral contraceptives with lower doses 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 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.
For further information, the reader is referred to a text on epidemiological
methods.<br/>1. Thromboembolic Disorders And Other Vascular Problems:<br/>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 infarctions
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 II) among women
who use oral contraceptives. 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.<br/>b. Venous thrombosis and thromboembolism: An increased risk of venous 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. Cohort studies
have shown the relative risk to be somewhat lower, about 3 fornew cases and
about 4.5 for new cases requiring hospitalization. The approximate incidence
of deep-vein thrombosis and pulmonary embolism in users of low dose (<50
mcg ethinyl estradiol) combination oral contraceptives is up to 4 per 10,000
woman-years compared to 0.5-3 per 10,000 woman-years for non-users. However,
the incidence is substantially less than that associated with pregnancy (6
per 10,000 woman-years). The excess risk is highest during the first year
a woman ever uses a combined oral contraceptive. Venous thromboembolism may
be fatal. The risk of venous thrombotic and thromboembolic events is further
increased in women with conditions predisposing for venous thrombosis and
thromboembolism. The risk of thromboembolic disease due to oral contraceptives
is not related to length of use and gradually 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
shouldbe started no earlier than four weeks after delivery in women who elect
not to breast-feed, or a midtrimester pregnancy termination.<br/>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. Oral contraceptives also
increase the risk for stroke in women with other underlying risk factors such
as certain inherited or acquired thrombophilias, hyperlipidemias, and obesity. Women with migraine (particularly migraine/headaches with
focal neurological symptoms, see CONTRAINDICATIONS) who take combination oral contraceptives may be at an increased
risk of stroke.<br/>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 an
oral contraceptive depends on a 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 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 the lowest estrogen content which is
judged appropriate for the individual patient.<br/>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 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 to 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 mcg or higher of estrogen.<br/>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 III).
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 1970'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 the 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 suchwomen 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.<br/>3. Carcinoma of the Reproductive Organs and Breasts: Numerous epidemiological studies have examined the
association between the use of oral contraceptives and the incidence of breast
and cervical cancer. The risk of having breast
cancer diagnosed may be slightly increased among current and recent users
of COCs. However, this excess risk appears to decrease over time after COC
discontinuation and by 10 years after cessation the increased risk disappears.
Some studies report an increased risk with duration of use while other studies
do not and no consistent relationships have been found with dose or type of
steroid. Some studies have reported a smallincrease in risk for women who
first use COCs at a younger age. Most studies show a similar pattern of risk
with COC use regardless of a woman's reproductive history or her family
breast cancer history. Breast cancers diagnosed
in current or previous OC users tend to be less clinically advanced than in
nonusers. Women with known or suspected carcinoma
of the breast or personal history of breast cancer should not use oral contraceptives
because breast cancer is usually a hormonally-sensitive tumor. Some studies suggest that oral-contraceptive use has been
associated with an increase in the risk of cervical intraepithelial neoplasia
or invasive cervical cancer 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 combination oral-contraceptive
use and breast and cervical cancers, a cause-and-effect relationship has not
been established.<br/>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. 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.<br/>5. Ocular Lesions: There have been clinical case reports of retinal
thrombosis associated with the use of oral contraceptives that may lead to
partial or complete loss of vision. 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.<br/>6. Oral-Contraceptive Use Before or During Early Pregnancy: Extensive epidemiological studies have revealed
no increased risk of birth defects in infants born to women who have used
oral contraceptives prior to pregnancy. Studies also do not suggest a teratogenic
effect, particularly insofar as cardiac anomalies and limb-reduction defects
are concerned, 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 if pregnancy is confirmed.<br/>7. Gallbladder Disease: Combination oral contraceptives may worsen existing
gallbladder disease and may accelerate the development of this disease in
previously asymptomatic women. 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 of 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.<br/>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 mcg of estrogens cause hyperinsulinism, while lower doses
of estrogen cause less glucose intolerance. Progestogens increase insulin
secretion and create insulin resistance, this effect varying with different
progestational agents. However, in the nondiabetic 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 , changes in serum triglycerides and lipoprotein levels have been
reported in oral-contraceptive users.<br/>9. Elevated Blood Pressure: Women with uncontrolled hypertension should not
be started on hormonal contraception. 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 disease, should be encouraged to
use another method 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.<br/>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.<br/>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. If
bleeding persists or recurs, 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 a change to another formulation may
solve the problem. In some women withdrawal bleeding may not occur during
the���tablet-free���or���inactive-tablet���interval.
If the COC has not been taken according to directions prior to the first missed
withdrawal bleed, or if two consecutive withdrawal bleeds are missed, tablet-taking
should be discontinued and a nonhormonal method of contraception should be
used until the possibility of pregnancy is excluded. Some
women may encounter post-pill amenorrhea or oligomenorrhea (possibly with
anovulation), especially when such a condition was pre-existent.<br/>12. Ectopic Pregnancy: Ectopic as well as intrauterine pregnancy may occur
in contraceptive failures.
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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
I 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 implants depends
upon the reliability with which they are used. Correct and consistent use
of methods can result in lower failure rates.
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LO/OVRAL 28
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