Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/3979
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| rdf:type | |
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ALESSE 28 (Kit)
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| dailymed-instance:dosage |
To achieve maximum contraceptive
effectiveness, ALESSE (levonorgestrel and ethinyl
estradiol tablets) must be taken exactly as directed and at intervals
not exceeding 24 hours. The dosage of ALESSE-28 is one pink tablet
daily for 21 consecutive days, followed by one light-green inert tablet
daily for 7 consecutive days, according to the prescribed schedule.
It is recommended that ALESSE-28 tablets be taken at the same time
each day. 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.<br/>During The First Cycle Of Use: The possibility of ovulation and conception prior
to initiation of medication should be considered. The patient should
be instructed to begin taking ALESSE on either the first Sunday after
the onset of menstruation (Sunday Start) or on Day 1 of menstruation
(Day 1 Start).<br/>Sunday start:: The patient is instructed
to begin taking ALESSE-28 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 one light-green inert tablet daily for 7 consecutive
days. Withdrawal bleeding should usually occur within 3 days following
discontinuation of pink tablets and may not have finished before the
next pack is started. During the first cycle, contraceptive reliance
should not be placed on ALESSE-28 until a pink 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.<br/>Day 1 start:: During the first
cycle of medication, the patient is instructed to begin taking ALESSE-28
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,
followed by one light-green inert tablet daily for 7 consecutive days.
Withdrawal bleeding should usually occur within 3 days following discontinuation
of pink tablets andmay not have finished before the next pack is
started. If medication is begun on day one of the menstrual cycle,
no back-up contraception is necessary. If ALESSE-28 tablets are started
later than day one of the first menstrual cycle or postpartum, contraceptive
reliance should not be placed on ALESSE-28 tablets until after the
first 7 consecutive days of administration, and a nonhormonal back-up
method of birth control should be used during those 7 days.<br/>After the first cycle of use: The patient begins her next and all subsequent courses
of tablets on the day after taking her last light-green tablet. She
should follow the same dosing schedule: 21 days on pink tablets followed
by 7 days on light-green 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 pink tablet daily for 7 consecutive days.<br/>Switching from another hormonal method of contraception: When the patient is switching from a 21-day regimen
of tablets, she should wait 7 days after her last tablet before she
starts ALESSE. 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 ALESSE
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 ALESSE the next day. If switching from an implant or
injection, the patient should start ALESSE on the day of implant removal
or, if using an injection, 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.<br/>If spotting or breakthrough bleeding occurs: 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.<br/>Risk of pregnancy if tablets are missed: 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 ALESSE
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. If thepatient has
adhered to the prescribed regimen and misses two consecutive periods,
pregnancy should be ruled out. 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.<br/>Use after pregnancy, abortion or miscarriage: ALESSE 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 non-hormonal back-up method for the first 7 days
of tablet taking. ALESSE may be initiated immediately
after a first trimester abortion or miscarriage. If the patient starts
ALESSE immediately, back-up contraception is not needed.
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| dailymed-instance:descripti... |
21 pink active tablets each
containing 0.10 mg of levonorgestrel, d(-)-13��-ethyl-17��-ethinyl-17�����hydroxygon-4-en-3-one,
a totally synthetic progestogen, and 0.02 mg of ethinyl estradiol,
17�����ethinyl-1,3,5(10)-estratriene-3, 17��-diol.
The inactive ingredients present are cellulose, hypromellose, iron
oxide, lactose, magnesium stearate, polacrilin potassium, polyethylene
glycol, titanium dioxide, and montanic ester wax. 7 light-green inert tablets, each containing cellulose, FD&C
blue no. 1, hypromellose, iron oxide, lactose, magnesium stearate,
polacrilin potassium, polyethylene glycol, titanium dioxide, and 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 ALESSE 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 ALESSE to 22 women under fasting conditions, maximum serum concentrations
of levonorgestrel are 2.8��0.9 ng/mL (mean��SD) at
1.6��0.9 hours. At steady state, attained from day 19 onwards,
maximum levonorgestrel concentrations of 6.0��2.7 ng/mL
are reached at 1.5��0.5 hours after the daily dose. The minimum
serum levels of levonorgestrel at steady state are 1.9��1.0 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). Unbound levonorgestrel
concentrations increased from day 1 to days 6 and 21 by 25% and 83%,
respectively. 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 62��21 pg/mL are reached at 1.5��0.5 hours. At steady state,
attained from at least day 6 onwards, maximum concentrations of ethinyl
estradiol were 77��30 pg/mL and were reached at 1.3��0.7 hours after the daily dose. The minimum serum levels of ethinyl
estradiol at steady state are 10.5��5.1 pg/mL.
Ethinyl estradiol concentrations did not increase from days 1 to 6,
but did increase by 19% from days 1 to 21 (FIGURE
I). TABLE I provides a summary of levonorgestrel and ethinyl estradiol pharmacokinetic
parameters.<br/>Distribution: Levonorgestrel
in serum is primarily bound to SHBG. Ethinyl estradiol is about 97%
bound to plasma albumin. Ethinyl estradiol does not bind to SHBG,
but induces SHBG synthesis.<br/>Metabolism: Levonorgestrel:
The most important metabolic pathway occurs in the reduction of the��4���3���oxo group and hydroxylation at positions
2��, 1��, and 16��, followed by conjugation. Most of
the metabolites that circulate in the blood 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
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.<br/>Excretion: The elimination
half-life for levonorgestrel is approximately 36��13 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 feces.
The elimination half-life of ethinyl estradiol is 18��4.7 hours
at steady state.<br/>Special Populations:<br/>Race: Based on
the pharmacokinetic study with ALESSE, there are no apparent differences
in pharmacokinetic parameters among women of different races.<br/>Hepatic insufficiency: No formal
studies have evaluated the effect of hepatic disease on the disposition
of ALESSE. 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 dispositionof ALESSE.<br/>Drug-drug interactions: See PRECAUTIONS section
- Drug Interactions
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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 history 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 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 diseaseKnown
or suspected pregnancyHypersensitivity to any of the components
of ALESSE
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| dailymed-instance:supply |
ALESSE-28
tablets (0.10 mg levonorgestrel and 0.02 mg ethinyl estradiol)
are available in packages of 3 MINI-PACK���dispensers of 28
tablets each, NDC 0008-2576-02, as follows: 21 active tablets, NDC 0008-0912, pink, round tablet marked������and���912���. 7 inert tablets, NDC 0008-0650,
light-green, round tablet marked������and���650���. Store at controlled room temperature 20��to 25��C (68��to
77��F). References available upon request.
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| dailymed-instance:boxedWarn... |
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:activeMoi... | |
| dailymed-instance:inactiveI... |
dailymed-ingredient:cellulose,
dailymed-ingredient:hypromellose,
dailymed-ingredient:iron_oxide,
dailymed-ingredient:lactose,
dailymed-ingredient:magnesium_stearate,
dailymed-ingredient:montanic_ester_wax,
dailymed-ingredient:polacrilin_potassium,
dailymed-ingredient:polyethylene_glycol,
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.<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 oralcontraceptives 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 breakthrough bleeding. Examples include rifampin, rifabutin,
barbiturates, primidone, phenylbutazone, phenytoin, dexamethasone,
carbamazepine, felbamate, oxcarbazepine, topiramate, griseofulvin,
and modafinil. In such cases a back-up nonhormonal method of birth
control should be considered. 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.
However, clinical pharmacology studies investigating drug interactions
between combined oral contraceptives and these antibiotics have reported
inconsistent results. Several of the anti-HIV protease inhibitors have been studied with
co-administration 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. Healthcare providers 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.<br/>Increase in Plasma Levels Associated
with Co-Administered Drugs:: Co-administration
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 Co-Administered
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:<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 ALESSE 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 ALESSE
before menarche is not indicated.<br/>15. Geriatric use: ALESSE 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 Patient Labeling Printed Below.
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| dailymed-instance:overdosag... |
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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| dailymed-instance:genericMe... |
levonorgestrel and ethinyl estradiol
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| dailymed-instance:fullName |
ALESSE 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 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 nodosumGastrointestinal 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 |
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 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:<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 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 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 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 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 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 postpartum period is also associated
with an increased risk of thromboembolism, oral contraceptives should
be started no earlier than four weeks after delivery in women who
elect not to breast-feed or 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. 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, 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 andprogestogen 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 40-49 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
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 . 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 beincreased with oral-contraceptive
use after age 40 in healthy nonsmoking women (even with the newer
low-dose formulations), there are greater potential health risks associatedwith 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.<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
oralcontraceptive 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 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 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.<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. 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
developinggallbladder 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 effecton 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: 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 the event of amenorrhea, pregnancy should be ruled out. 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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ALESSE 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. 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 System, depends
upon the reliability with which they are used. Correct and consistent
use of methods can result in lower failure rates. In a clinical trial with ALESSE
(levonorgestrel and ethinyl estradiol tablets), 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.
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ALESSE 28
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