Alesse (Levonorgestrel – Ethinyl Estradiol)




Levonorgestrel – Ethinyl Estradiol

Oral Contraceptive

Action And Clinical Pharmacology: Although the primary mechanism of action is inhibition of ovulation, the effectiveness of Alesse may also result from other mechanisms of action, such as hostility of the cervical mucus to sperm penetration and migration.

Indications And Clinical Uses: For conception control.

Contra-Indications: History of or actual thrombophlebitis or thromboembolic disorders. History of or actual cerebrovascular disorders. History of or actual myocardial infarction or coronary arterial disease. Active liver disease or history of or actual benign or malignant liver tumors. Known or suspected carcinoma of the breast. Known or suspected estrogen-dependent neoplasia. Undiagnosed abnormal vaginal bleeding. Any ocular lesion arising from ophthalmic vascular disease, such as partial or complete loss of vision or defect in visual fields. When pregnancy is suspected or diagnosed.

Manufacturers’ Warnings In Clinical States: Predisposing Factors for Coronary Artery Disease: Cigarette smoking increases the risk of serious cardiovascular side effects and mortality. Birth control pills increase this risk, especially with increasing age. Convincing data are available to support an upper age limit of 35 years for oral contraceptive use in women who smoke.

Other women who are independently at high risk for cardiovascular disease include those with diabetes, hypertension, abnormal lipid profile, obesity or a family history of these. Whether oral contraceptives accentuate this risk is unclear.

In low risk, nonsmoking women of any age, the benefits of oral contraceptive use outweigh the possible cardiovascular risks associated with low dose formulations. Consequently, oral contraceptives may be prescribed for these women up to the age of menopause.

Cigarette smoking increases the risk of serious adverse effects on the heart and blood vessels. This risk increases with age and becomes significant in oral contraceptive users older than 35 years of age. Women should be counselled not to smoke.

Discontinue Medication at the Earliest Manifestation of the following:

A. Thromboembolic and cardiovascular disorders such as thrombophlebitis, pulmonary embolism, cerebrovascular disorders, myocardial ischemia, mesenteric thrombosis, and retinal thrombosis.

B. Conditions that predispose to venous stasis and to vascular thrombosis (e.g., immobilization after accidents or confinement to bed during long-term illness). Other nonhormonal methods of contraception should be used until regular activities are resumed. For use of oral contraceptives when surgery is contemplated, see Precautions.

C. Visual defects, partial or complete.

D. Papilledema or ophthalmic vascular lesions.

E. Severe headache of unknown etiology or worsening of pre-existing migraine headache.

A meta-analysis from 54 epidemiological studies reported that there is a slightly increased relative risk (RR=1.24) of having breast cancer diagnosed in women who are currently using combined oral contraceptives. The increased risk gradually disappears during the course of the 10 years after cessation of combined oral contraceptive use. Because breast cancer is rare in women under 40 years of age, the excess number of breast cancer diagnoses in current and recent combined oral contraceptive use is small in relation to the lifetime risk of breast cancer. These studies do not provide evidence for causation. The observed pattern of increased risk maybe due to an earlier diagnosis of breast cancer in combined oral contraceptive users, the biological effects of combined oral contraceptives or a combination of both. The breast cancers diagnosed in ever-users tend to be less advanced clinically than the cancers diagnosed in never-users.

Precautions: Physical Examination and Followup: Before oral contraceptives are used, a thorough history and physical examination should be performed, including a blood pressure determination. Breasts, liver, extremities and pelvic organs should be examined and a Papanicolaou smear should be taken if the patient has been sexually active.

The first followup visit should be 3 months after oral contraceptives are prescribed. Thereafter, examinations should be performed at least once a year or more frequently if indicated. At each annual visit, examination should include those procedures that were done at the initial visit as outlined above or per recommendations of the Canadian Workshop on Screening for Cancer of the Cervix. Their suggestion was that, for women who had two consecutive negative Pap smears, screening could be continued every 3 years to the age of 69.

Pregnancy: Oral contraceptives should not be taken by pregnant women. However, if conception accidentally occurs while taking the pill, there is no conclusive evidence that the estrogen and progestin contained in the oral contraceptive will damage the developing child.

Lactation: In breast-feeding women, the use of oral contraceptives results in the hormonal components being excreted in breast milk and may reduce its quantity and quality. If the use of oral contraceptives is initiated after the establishment of lactation, there does not appear to be any effect on the quantity and quality of the milk. There is no evidence that low-dose oral contraceptives are harmful to the nursing infant.

Hepatic Function: Patients who have had jaundice, including a history of cholestatic jaundice during pregnancy, should be given oral contraceptives with great care and under close observation.

The development of severe generalized pruritus or icterus requires that the medication be withdrawn until the problem is resolved.

If a patient develops jaundice that proves to be cholestatic in type, the use of oral contraceptives should not be resumed. In patients taking oral contraceptives, changes in the composition of the bile may occur and an increased incidence of gallstones has been reported.

Hepatic nodules (adenoma and focal nodular hyperplasia) have been reported, particularly in long-term users of oral contraceptives. Although these lesions are extremely rare, they have caused fatal intra-abdominal hemorrhage and should be considered in women with an abdominal mass, acute abdominal pain, or evidence of intra-abdominal bleeding.

Hypertension: Patients with essential hypertension whose blood pressure is well controlled may be given oral contraceptives but only under close supervision. If a significant elevation of blood pressure in previously normotensive or hypertensive subjects occurs at any time during the administration of the drug, cessation of medication is necessary.

Migraine and Headache: The onset or exacerbation of migraine or the development of headache of a new pattern that is recurrent, persistent or severe, requires discontinuation of oral contraceptives and evaluation of the cause.

Diabetes: Current low-dose oral contraceptives exert minimal impact on glucose metabolism. Diabetic patients, or those with a family history of diabetes, should be observed closely to detect any worsening of carbohydrate metabolism. Patients predisposed to diabetes who can be kept under close supervision may be given oral contraceptives. Young diabetic patients whose disease is of recent origin, well controlled, and not associated with hypertension or other signs of vascular disease such as ocular fundal changes, should be monitored more frequently while using oral contraceptives.

Ocular Disease: Patients who are pregnant or are taking oral contraceptives, may experience corneal edema that may cause visual disturbances and changes in tolerance to contact lenses, especially of the rigid type. Soft contact lenses usually do not cause disturbances. If visual changes or alterations in tolerance to contact lenses occur, temporary or permanent cessation of wear may be advised.

Breasts: Increasing age and a strong family history are the most significant risk factors for the development of breast cancer. Other established risk factors include obesity, nulliparity and late age for first full-term pregnancy. The identified groups of women that may be at increased risk of developing breast cancer before menopause are long-term users of oral contraceptives (more than 8 years) and starters at early age. In a few women, the use of oral contraceptives may accelerate the growth of an existing but undiagnosed breast cancer. Since any potential increased risk related to oral contraceptive use is small, there is no reason to change prescribing habits at present (see Warnings).

Women receiving oral contraceptives should be instructed in self-examination of their breasts. Their physicians should be notified whenever any masses are detected. A yearly clinical breast examination is also recommended because, if a breast cancer should develop, drugs that contain estrogen may cause a rapid progression.

Vaginal Bleeding: Persistent irregular vaginal bleeding requires assessment to exclude underlying pathology.

Fibroids: Patients with fibroids (leiomyomata) should be carefully observed. Sudden enlargement, pain, or tenderness requires discontinuation of the use of oral contraceptives.

Emotional Disorders: Patients with a history of emotional disturbances, especially the depressive type, may be more prone to have a recurrence of depression while taking oral contraceptives. In cases of a serious recurrence, a trial of an alternate method of contraception should be made, which may help to clarify the possible relationship. Women with premenstrual syndrome (PMS) may have a varied response to oral contraceptives, ranging from symptomatic improvement to worsening of the condition.

Laboratory Tests: Results of laboratory tests should be interpreted in the light that the patient is on oral contraceptives. The following laboratory tests are modified:

A. Liver Function Tests: Bromsulphthalein Retention Test (BSP): moderate increase. AST and GGT: minor increase. Alkaline Phosphatase: variable increase. Serum Bilirubin: increased, particularly in conditions predisposing to or associated with hyperbilirubinemia.

B. Coagulation Tests: Factors II, VII, IX, X, XII and XIII: increased. Factor VIII: mild increase. Platelet Aggregation and Adhesiveness: mild increase in response to common aggregating agents. Fibrinogen: increased. Plasminogen: mild increase. Antithrombin III: mild decrease. Prothrombin Time: increased.

C. Thyroid Function Tests: Protein-bound Iodine (PBI): increased. Total Serum Thyroxine (T4): increased. Thyroid Stimulating Hormone (TSH): unchanged.

D. Adrenocortical Function Tests: Plasma Cortisol: increased.

E. Miscellaneous Tests: Serum Folate: occasionally decreased. Glucose Tolerance Test: variable increase with return to normal after 6 to 12 months. Insulin Response: mild to moderate increase. c-Peptide Response: mild to moderate increase.

Tissue Specimens: Pathologists should be advised of oral contraceptive therapy when specimens obtained from surgical procedures and Pap smears are submitted for examination.

Return to Fertility: After discontinuing oral contraceptive therapy, the patient should delay pregnancy until at least one normal spontaneous cycle has occurred in order to date the pregnancy. An alternate contraceptive method should be used during this time.

Amenorrhea: Women having a history of oligomenorrhea, secondary amenorrhea, or irregular cycles may remain anovulatory or become amenorrheic following discontinuation of estrogen-progestin combination therapy.

Amenorrhea, especially if associated with breast secretion, that continues for 6 months or more after withdrawal, warrants a careful assessment of hypothalamic-pituitary function.

Thromboembolic Complications – Post-surgery: There is an increased risk of thromboembolic complications in oral contraceptive users after major surgery. If feasible, oral contraceptives should be discontinued and an alternative method substituted at least 1 month prior to major elective surgery. Oral contraceptive use should not be resumed until the first menstrual period after hospital discharge following surgery.

Drug Interactions: The concurrent administration of oral contraceptives with other drugs may result in an altered response to either agent. Reduced effectiveness of the oral contraceptive, should it occur, is more likely with the low-dose formulations. It is important to ascertain all drugs that a patient is taking, both prescription and nonprescription, before oral contraceptives are prescribed.

Noncontraceptive Benefits of Oral Contraceptives: Several health advantages other than contraception have been reported.

1. Combination oral contraceptives reduce the incidence of cancer of the endometrium and ovaries.

2. Oral contraceptives reduce the likelihood of developing benign breast disease.

3. Oral contraceptives reduce the likelihood of development of functional ovarian cysts.

4. Pill users have less menstrual blood loss and have more regular cycles, thereby reducing the chance of developing iron-deficiency anemia.

5. The use of oral contraceptives may decrease the severity of dysmenorrhea and premenstrual syndrome, and may improve acne vulgaris, hirsutism, and other androgen-mediated disorders.

6. Other noncontraceptive benefits are outlined in Oral Contraceptives 1994, Health Canada.

Oral contraceptives do not protect against sexually transmitted diseases (STDs) including HIV/AIDS. For protection against STDs, it is advisable to use latex condoms in combination with oral contraceptives.

Adverse Reactions: An increased risk of the following serious adverse reactions has been associated with the use of oral contraceptives: thrombophlebitis; arterial thromboembolism; pulmonary embolism; mesenteric thrombosis; neuro-ocular lesions (e.g., retinal thrombosis); myocardial infarction; cerebral thrombosis; cerebral hemorrhage; hypertension; benign hepatic tumors; Hepatic adenomas or benign liver tumors; gallbladder disease.

The following adverse reactions also have been reported in patients receiving oral contraceptives: nausea and vomiting, usually the most common adverse reaction, occurs in approximately 10% or fewer of patients during the first cycle. Other reactions, as a general rule, are seen less frequently or only occasionally.

Other Adverse Reactions: The following adverse reactions have been reported in patients receiving oral contraceptives and are believed to be drug related: gastrointestinal symptoms (such as abdominal cramps and bloating); breakthrough bleeding; spotting; change in menstrual flow; amenorrhea; temporary infertility after discontinuance of treatment; edema; melasma which may persist; breast changes: tenderness, enlargement, and secretion; change in weight (increase or decrease); change in cervical erosion and secretion; diminution in lactation when given immediately postpartum; cholestatic jaundice; migraine; rash (allergic); depression; reduced tolerance to carbohydrates; vaginal candidiasis; change in corneal curvature (steepening); intolerance to contact lenses; retinal thrombosis.

The following adverse reactions have been reported in users of oral contraceptives and the association has been neither confirmed nor refuted: congenital anomalies; premenstrual syndrome; cataracts; optic neuritis; changes in appetite; cystitis-like syndrome; headache; nervousness; dizziness; hirsutism; loss of scalp hair; erythema multiforme; erythema nodosum; hemorrhagic eruption; vaginitis; porphyria; impaired renal function; hemolytic uremic syndrome; Budd-Chiari syndrome; acne; changes in libido; colitis; sickle-cell disease; cerebrovascular disease with mitral valve prolapse; lupus-like syndrome.

Symptoms And Treatment Of Overdose: Symptoms: With levonorgestrel/ethinyl estradiol, acute doses in excess of clinical levels when administered to experimental animals, have been shown to have a minimal deleterious effect. The LD50 values for the combination of levonorgestrel and ethinyl estradiol in acute oral administration approximates 500 000 times the equivalent human oral dose (for an explanation of the relationship between norgestrel and levonorgestrel, see Pharmacology). In humans, however, the extent of ill effects to be expected following accidental ingestion of a large dose of any oral contraceptive has not been firmly established.

Depending upon the amount ingested, liver toxicity, temporary interference with the function of the seminiferous tubules, or in the case of females, possible withdrawal bleeding within a few days of consumption, are theoretically possible. However, case histories of both male and female children, some of whom ingested more than half a month’s supply of oral contraceptive tablets, indicate that the effects are asymptomatic and without immediate consequence. Despite the frequency of nausea and vomiting in adult females during the first few cycles of use, none of these children presented such symptoms.

Treatment: Although the physiologic effects of oral contraceptives may be theoretically offset by concomitant administration of gonadotrophin preparations, there are no known chemotherapeutic agents which will neutralize their effects subsequent to accidental ingestion. In the practical management of an acute overdosage, gastric lavage may be of value if the offending agent has recently been swallowed. The general rules for observation and symptomatic resolution should be followed. Liver function tests should be conducted, particularly transaminase levels, 2 to 3 weeks after consumption.

Dosage And Administration: Alesse 21: 21-Day Regimen: Each cycle consists of 21 days on medication and a 7-day interval without medication (3 weeks on, 1 week off).

The dosage is 1 tablet daily for 21 consecutive days per menstrual cycle, according to prescribed schedule. For the first cycle of medication, the patient is instructed to take 1 tablet daily for 21 consecutive days beginning on Day 1 of her menstrual cycle, on Day 5, or on the first Sunday after her period begins. (For the first cycle only, the first day of menstrual flow is considered Day 1.) The tablets are then discontinued for 7 days (1 week). Withdrawal bleeding should usually occur within 3 days following discontinuation of Alesse.

The patient begins her next and all subsequent 21-day courses of tablets (following the same 21 days on, 7 days off) on the same day of the week that she began her first course. She begins taking her tablets 7 days after discontinuation, regardless of whether or not withdrawal bleeding is still in progress.

Alesse 28: 28-Day Regimen: Each cycle consists of 21 days of pink tablets followed by 7 days of light green inert tablets (3 weeks on, 1 week on inert tablets).

The dosage is 1 tablet daily for 21 consecutive days per menstrual cycle, according to prescribed schedule, followed by 1 inert tablet daily for 7 consecutive days according to prescribed schedule. For the first cycle of medication, the patient is instructed to take one pink tablet daily for 21 consecutive days beginning on Day 1 of her menstrual cycle, on Day 5, or on the first Sunday after her period begins. (For the first cycle only, the first day of menstrual flow is considered Day 1.) One light green tablet is taken daily for the following 7 consecutive days. Withdrawal bleeding should usually occur within 3 days following the discontinuation of pink Alesse tablets, i.e., during the week the patient is taking the light green inert tablets.

The patient begins her next and all subsequent 28-day courses of tablets on the same day of the week that she began her first course. She continues her next course of 28 tablets immediately after the last course, regardless of whether or not a period of withdrawal bleeding is still in progress. There is no need for the patient to count days between cycles because there are no “off-tablet days”.

Special Notes on Administration: It is recommended that Alesse tablets be taken at the same time each day, preferably after the evening meal or at bedtime.

Alesse is effective from the first day of therapy if the tablets are begun on the first day of the menstrual cycle.

If Alesse tablets administration is initiated after Day 1 of the first menstrual cycle of medication or postpartum, contraceptive reliance should not be placed on Alesse until after the first 7 consecutive days of administration. The possibility of ovulation and conception prior to initiation of medication should be considered. Therefore, nonhormonal methods of contraception (with the exception of the rhythm or temperature methods) should be used for the next 7 days. In the nonlactating mother, Alesse may be prescribed in the postpartum period either immediately or at the first postpartum examination, whether or not menstruation has resumed.

If spotting or breakthrough bleeding occurs, the patient is instructed to continue on the same regimen. This type of bleeding usually is transient and without significance; however, if the bleeding is persistent or prolonged, the patient is advised to consult her physician. The patient should be instructed to use the following chart if she misses one or more of her birth control pills. She should be told to match the number of pills with the appropriate starting time for her type of pill.

Availability And Storage: Alesse 21: Each pink tablet contains: levonorgestrel 100 µg and ethinyl estradiol 20 µg. Nonmedicinal ingredients: hydroxypropyl methylcellulose, lactose, magnesium stearate, microcrystalline cellulose, polacrillin potassium, polyethylene glycol, synthetic red iron oxide, titanium dioxide and wax E. Blister packs for the 21-day regimen.

Alesse 28: Each pink tablet contains: levonorgestrel 100 µg and ethinyl estradiol 20 µg. The green tablets are inactive. Nonmedicinal ingredients: hydroxypropyl methylcellulose, lactose, magnesium stearate, microcrystalline cellulose, polacrillin potassium, polyethylene glycol, synthetic red iron oxide, titanium dioxide and wax E; green tablets: FD&C Blue No. 1 aluminum lake, hydroxypropyl methylcellulose, lactose, magnesium stearate, microcrystalline cellulose, polacrillin potassium, polyethylene glycol, synthetic yellow iron oxide, titanium dioxide and wax E. Blister packs for the 28-day regimen (21 active pink tablets and 7 inactive green tablets).

Store at 15 to 30°C. Protect from light source once opened using the protective covering provided.

ALESSE™ 21 ALESSE™ 28 Wyeth-Ayerst Levonorgestrel – Ethinyl Estradiol Oral Contraceptive

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