Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/172
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Lybrel (Tablet, Film Coated)
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| dailymed-instance:dosage |
To achieve maximum contraceptive
effectiveness, LYBREL (levonorgestrel and ethinyl estradiol tablets)
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. Women who do not wish to become
pregnant after discontinuation should be advised to immediately use
another method of birth control. The dosage of LYBREL is one yellow
tablet daily without any tablet-free interval. It is recommended that LYBREL tablets be taken at the same time each day.<br/>Initiation of Therapy: Instructions for
beginning LYBREL are provided in Table 4 below. If spotting or
unscheduled 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. The
possibility of ovulation increases with each successive day that scheduled
yellow tablets are missed. 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 beconsidered. Hormonal contraception must be discontinued if pregnancy
is confirmed. The risk of pregnancy increases with each 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. LYBREL 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
. 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 LYBREL immediately, additional contraceptive
measures are not needed.
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| dailymed-instance:descripti... |
Twenty-eight (28) yellow tablets each containing
90 mcg of levonorgestrel (17��)-(���)13-ethyl-17-hydroxy-18,
19-dinorpregn-4-en-20-yn-3-one, a totally synthetic progestogen, and
20 mcg of ethinyl estradiol, (17��)-19-norpregna-1,3,5(10)-trien-20-yne-3,17-diol.
The inactive ingredients present are microcrystalline cellulose, lactose
monohydrate, magnesium stearate, polacrilin potassium, hypromellose,
titanium dioxide, polyethylene glycol 400, iron oxide, polyethylene
glycol 1450, montanic ester wax.
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| dailymed-instance:clinicalP... |
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 likelihood of implantation).<br/>Pharmacokinetics:<br/>Absorption: No specific investigation of the absolute bioavailability
of LYBREL 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%. A summary of the single
dose and multiple dose levonorgestrel and ethinyl estradiol pharmacokinetic
parameters for 18 women under fasting conditions is provided in Table 1. The plasma concentrations of levonorgestrel
and ethinyl estradiol reached steady-state by approximately day 14.
Levonorgestrel and ethinyl estradiol concentrations did not increase
from days 14 to 28, but did increase from days 1 to 28. The mean plasma concentrations of levonorgestrel
and ethinyl estradiol following single (day 1) and multiple (days
14 and 28) oral administrations of levonorgestrel 90 mcg in combination
with ethinyl estradiol 20 mcg to 18 healthy women is provided in Figure 1. The effect of food on the rate and the
extent of levonorgestrel and ethinyl estradiol absorption following
oral administration of LYBREL has not been evaluated.<br/>Distribution: Levonorgestrel in serum is primarily bound to sex
hormone-binding globulin (SHBG). Ethinyl estradiol is about 97% bound
to serum albumin. Ethinyl estradiol does not bind to SHBG, but induces
SHBG synthesis.<br/>Metabolism: Levonorgestrel: The most important metabolic pathways
are reduction of the��4-3-oxo group and hydroxylation at positions
2��, 1��, and 16��, followed by conjugation. Most of
the circulating metabolites are sulfates of 3��, 5��-tetrahydro-levonorgestrel,
while excretion occurs predominantly in the form of glucuronides.
Some of the parent levonorgestrel also circulates as 17��-sulfate.
Metabolic clearance rates may differ among individuals by several-fold,
and this may account in part for the wide variation observed in levonorgestrel
concentrations among users. Ethinyl estradiol:
Cytochrome 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, sulfation,
and glucuronidation prior to urinary and fecal excretion. Levels of
CYP3A4 vary widely among individuals and can explain the variation
in rates of ethinyl estradiol 2-hydroxylation.<br/>Excretion: The terminal elimination half-life for levonorgestrel
in LYBREL is about 36 hours. Levonorgestrel and its metabolites are
excreted in the urine (40% to 68%) and in feces (16% to 48%). The
terminal elimination half-life of ethinyl estradiol in LYBREL is about
21 hours. Ethinyl estradiol is excreted in
the urine and feces as glucuronide and sulfate conjugates and undergoes
enterohepatic recirculation.<br/>Special Populations:<br/>Race: No formal studies on the effect of race on the pharmacokinetic
parameters of LYBREL were conducted.<br/>Hepatic Insufficiency: No formal studies have evaluated the effect of hepatic
disease on the disposition of LYBREL. However, steroid hormones may
be poorly metabolized in patients with impaired liver function.<br/>Renal Insufficiency: No formal studies have evaluated the effect of renal
disease on the disposition of LYBREL.<br/>Drug-Drug Interactions: See PRECAUTIONS section - Drug Interactions.
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Combination oral contraceptives
should not be used in women with any of the following conditions: Thrombophlebitis or thromboembolic
disordersHistory of deep-vein thrombophlebitis or thromboembolic
disordersCerebrovascular or coronary artery disease (current
or past history)Valvular heart disease with thrombogenic complicationsThrombogenic rhythm disordersHereditary or acquired thrombophiliasMajor surgery with prolonged immobilizationDiabetes with vascular
involvementHeadaches with focal neurological symptoms such as
auraUncontrolled 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 diseaseKnown or suspected pregnancyHypersensitivity to any of the components of LYBREL
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| dailymed-instance:supply |
LYBREL (90
mcg levonorgestrel and 20 mcg ethinyl estradiol) Tablets are available
in a ClickCase, NDC 0008-1117-30 containing: 28 round, yellow biconvex, film-coated
tablet debossed with���W���on one side and���1117���on the other side. Store at up
to 25��C (77��F); excursions permitted to 15-30��C (59-86��F) [see USP Controlled Room Temperature]. United States Patent Numbers: 6,500,814; D497,803SReferences available upon request.
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dailymed-ingredient:hypromellose,
dailymed-ingredient:iron_oxide,
dailymed-ingredient:lactose_monohydrate,
dailymed-ingredient:magnesium_stearate,
dailymed-ingredient:microcrystalline_cellulose,
dailymed-ingredient:montanic_ester_wax,
dailymed-ingredient:polacrilin_potassium,
dailymed-ingredient:polyethylene_glycol_1450,
dailymed-ingredient:polyethylene_glycol_400,
dailymed-ingredient:titanium_dioxide
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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. Scheduled withdrawal
bleeding does not occur with the use of LYBREL, therefore, the absence
of withdrawal bleeding cannot be used as a sign of an unexpected pregnancy
and as such, unexpected pregnancy may be difficult to recognize. Although
pregnancy is unlikely if LYBREL is taken as directed, if for any reason,
pregnancy is suspected in a woman using LYBREL, a pregnancy test should
be performed.<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., 1d., and 8.) A small proportion of women will have adverse lipid changes while
taking oral contraceptives. Nonhormonal contraception should be considered
in women with uncontrolled dyslipidemias. Persistent hypertriglyceridemia
may occur in a small population of combination oral contraceptive
users. Elevations of plasma triglycerides may lead to pancreatitis
and other complications.<br/>4. 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.<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 depression recurs to a serious degree.<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 unscheduled bleeding. Examples include rifampin, rifabutin,
barbiturates, primidone, phenylbutazone, phenytoin, dexamethasone,
carbamazepine, felbamate, oxcarbazepine, topiramate, griseofulvin,
and modafinil. In such cases a nonhormonal back-up method of birth
control should be considered. Several cases of contraceptive failure and unscheduled bleeding have
been reported in the literature with concomitant administration of
antibiotics such as ampicillin and other penicillins, and tetracyclines.
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 unscheduled bleeding.<br/>Increase in Plasma Levels Associated with Coadministered Drugs:: Coadministration
of atorvastatin and certain oral contraceptives containing ethinyl
estradiol increases AUC values for ethinyl estradiol by approximately
20%. 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 cyclosporine, prednisolone and other corticosteroids,
and theophylline have been reported with concomitant administration
of oral contraceptives. Decreased plasma concentrations of acetaminophen
and lamotrigine, 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:<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. Pediatric Use: Safety and efficacy
of LYBREL 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/>15. Geriatric Use: This product has
not been studied in women over 65 years of age and is not indicated
in this population.<br/>16. Information for the Patient: See DETAILED PATIENT LABELING printed below.
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| dailymed-instance:overdosag... |
Symptoms of oral contraceptive
overdosage in adults and children may include nausea, vomiting, breast
tenderness, dizziness, abdominal pain, 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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levonorgestrel and ethinyl estradiol
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Lybrel (Tablet, Film Coated)
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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, transient ischemic attack), carcinoma
of the reproductive organs and breasts, hepatic neoplasia/liver disease
(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 symptomsBreast changes: tenderness,
pain, enlargement, secretionBudd-Chiari syndromeCervical
erosion and secretion, change inCholestatic jaundiceChorea,
exacerbation ofColitisContact lenses, intolerance toCorneal curvature (steepening), change inDizzinessEdema/fluid
retentionErythema multiformeErythema nodosumFocal nodular
hyperplasiaGastrointestinal symptoms (such as abdominal pain,
cramps, and bloating)HirsutismInfertility after discontinuation
of treatment, temporaryLactation, diminution in, when given immediately
postpartumLibido, change inMelasma/chloasma which may persistMenstrual flow, change inMood changes, including depressionNauseaNervousnessPancreatitisPorphyria, exacerbation
ofRash (allergic)Scalp hair, loss ofSerum folate levels,
decrease inSpottingSystemic lupus erythematosus, exacerbation
ofUnscheduled bleedingVaginitis, 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 visionPremenstrual
syndromeRenal function, impaired
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| dailymed-instance:warning |
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, stroke, and transient ischemic
attack), 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 principally based 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: LYBREL is a non-cyclic
oral contraceptive that provides a low daily dose of estrogen and
progestin; however, LYBREL provides women with more hormonal exposure
on a yearly basis (13 additional weeks of hormone intake per
year) than conventional cyclic oral contraceptives containing the
same strength of synthetic estrogens and similar strength of progestins.<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 underlyingrisk 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 (Figure 3) 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.
The risk of venous thrombotic and thromboembolic events is further
increased in women with conditions predisposing for venous thrombosis
and thromboembolism. Case control studies have found 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 approximate incidence of
deep-vein thrombosis and pulmonary embolism in users of lowdose (<0.05
mg 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 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 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 post-partum 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 after 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. Transient
ischemic attacks have also been associated with oral contraceptive
use. 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. Women with migraine (particularly migraine/headaches
with focal neurological symptoms such as aura) 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 persisted 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 0.05 mg or higher
of estrogens.<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 3). 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 inolder 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.<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 combination oral contraceptives. However, this
excess risk appears to decrease over time after combination oral contraceptive
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 small increase in risk for women who first use combination oral
contraceptives at a younger age. Most studies show a similar pattern
of risk with combination oral contraceptive use regardless of a woman's
reproductive history or her family breast cancer history. Breast cancers diagnosed
in current or previous oral contraceptive 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. Endometrial biopsies performed in a subset of subjects (Study 1;
n = 93) ages 18 to 49 years, after 6 to 12 months of use of LYBREL,
did not reveal any hyperplasias or malignancies. Endometrial malignancy
is rare in this age group, so change in the risk is unlikely to be
detected with a study of this size.<br/>4. Hepatic Neoplasia: Benign hepatic adenomas
are associated with oral contraceptive use, although the incidence
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 user. 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. The possibility of pregnancy should be considered in any patient
who may be experiencing symptoms of pregnancy, especially if she has
not adhered to the prescribed schedule. Oral-contraceptive use must
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 0.075 mg 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 becarefully
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: 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: When prescribing
LYBREL, the convenience of having no scheduled menstrual bleeding
should be weighed against the inconvenience of unscheduled breakthrough
bleeding and spotting. In Study 313-NA, 385/2,134 (18%) of women discontinued
prematurely due to bleeding that was reported either as an adverse
event or where bleeding was given as one of the reasons for discontinuation
(see INDICATIONS AND
USAGE, Clinical Studies). Figure 4 shows the percentage of
LYBREL subjects in study 313-NA by pill pack who experienced unscheduled
bleeding or spotting only (Defined as���No sanitary protection
required���). Figure 5 shows the percentage
of LYBREL subjects with complete bleeding data in Study 313-NA who
had 4 or more and 7 or more days of bleeding and/or spotting during
each pill pack cycle. During pill pack 2, 67% of subjects experienced
4 or more days of bleeding and/or spotting and 54% of these subjects
experienced 7 or more days of bleeding and/or spotting. During the
final cycle of use of LYBREL (pill pack 13), these percentages were
31% and 20%, respectively. As in any case of
bleeding irregularities, nonhormonal causes should be considered and
adequate diagnostic measures may be indicated to rule out pregnancy,
infection, malignancy, or other conditions. Some women may encounter post-pill amenorrhea or oligomenorrhea (possibly
with anovulation), especially when such a condition was preexistent.<br/>12. Ectopic Pregnancy: Ectopic as well
as intrauterine pregnancy may occur in contraceptive failures.
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LYBREL is indicated for the prevention of pregnancy
in women who elect to use oral contraceptives as a method of contraception. Oral contraceptives are highly effective for pregnancy
prevention. Table 2 lists the typical
unintended 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, depend upon
the reliability with whichthey are used. Correct and consistent use
of methods can result in lower failure rates. Emergency Contraceptive Pills: The FDA has concluded
that certain combined oral contraceptives containing ethinyl estradiol
and norgestrel or levonorgestrel are safe and effective for use as
postcoital emergency contraception. Treatment initiated within 72
hours after unprotected intercourse reduces the risk of pregnancy
by at least 75%. Lactation Amenorrhea
Method: LAM is a highly effective, temporary method of contraception. Source: Trussell
J. Contraceptive efficacy. In: Hatcher RA, Trussell J, Stewart F,
Cates W, Stewart GK, Kowel D, Guest F. Contraceptive Technology: Seventeenth
Revised Edition. New York NY: Irvington Publishers; 1998.<br/>Clinical Studies: The efficacy and
safety of LYBREL were studied in 2 one-year clinical trials of subjects
age 18-49. There were no exclusions for body mass index (BMI), weight,
or bleeding history. The primary efficacy and safety study (313-NA) was a one-year open-label
clinical trial that treated 2,134 subjects in North America. Of these
subjects 1,213 (56.8%) discontinued prematurely, including 102 (4.8%)
discontinued by the Sponsor for early study closure. The mean weight
of subjects in this study was 70.38 kg. The efficacy of LYBREL was
assessed by the number of pregnancies that occurred after the onset
of treatment and within 14 days of the last dose. Among subjects 35
years or less, there were 23 pregnancies (4 of these occurred
during the interval 1 to 14 days after the last day of pill use) during
12,572 28-day pill packs of use. The resulting total Pearl Index was2.38 (95% CI: 1.51, 3.57) and the one-year life table pregnancy rate
was 2.39 (95% CI: 1.57, 3.62). Pill pack cycles during which subjects
used back-up contraception or were not sexually active were not included
in these calculations. Among women 35 years or less who took the pills
completely as directed, there were 15 pregnancies (method failures)
resulting in a Pearl Index of 1.55 (95% CI: 0.87, 2.56) and the one-yearlife table pregnancy rate was 1.59 (95% CI: 0.95-2.67). In a second supportive
study conducted in Europe (315-EU), 641 subjects were randomized to
LYBREL (n=323) or the cyclic comparator of 100 mcg levonorgestrel
and 20 mcg ethinyl estradiol (n=318). The mean weight of subjects
in this study was 63.86 kg. The efficacy analysis among women 35 years
or less included 2,756 LYBREL pill packs and 2,886 cyclic comparator
pill packs. There was one pregnancy in the LYBREL group that occurred
within 14 days following the last dose. There were three pregnancies
in the cyclic comparator group.<br/>Inhibition of Menses (Bleeding Profile): The bleeding profile
for subjects in Study 313-NA also was assessed. Women with a history
of unscheduled bleeding and/or spotting were not excluded from the
study. In
those subjects who provided complete bleeding data, the percentage
of patients who were amenorrheic in a given cycle and remained amenorrheic
through cycle 13 (cumulative amenorrhea rate) was determined (Figure 2). When prescribing LYBREL, the convenience of having no
scheduled menstrual bleeding should be weighed against the inconvenience
of unscheduled bleeding and spotting .
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Lybrel
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