Oral Contraception: Although the primary mechanism of action is inhibition of ovulation, the effectiveness of ALESSE tablets may also result from other mechanisms of action, such as hostility of the cervical mucus to sperm penetration and migration.

Acne: Acne is a disease of the pilosebaceous apparatus characterized by abnormal keratinization, increased sebum production, and bacterial colonization. While the etiology of acne is multifactorial, there is evidence that androgenic action, including stimulation of sebaceous glands, is necessary for the development of acne. The suppression of gonadotropins by ALESSE leads to decreased ovarian production of the androgens, including androstenedione. ALESSE also significantly reduces bioavailable serum testosterone by preserving the estrogen-induced increases in sex hormone binding globulin (SHBG). In addition, ALESSE decreases serum levels of 3 -androstanediol glucuronide (a marker of peripheral 5-reductase activity). These biochemical changes produced by the coadministration of levonorgestrel and ethinyl estradiol are consistent with improvement of acne in otherwise healthy women.

ALESSE Tablets are indicated for conception control.

ALESSE is also indicated for the treatment of moderate acne vulgaris in women ≥14 years of age who have no known contraindications to oral contraceptive therapy, desire contraception, and have achieved menarche.

Combination oral contraceptives (COCs) are contraindicated in the following:

 

Predisposing Factors for Coronary Artery Disease: Cigarette smoking increases the risk of serious cardiovascular side effects and mortality from COC use. This risk increases with age and with the extent of smoking. 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 COCs 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 Combination Oral Contraceptive (COC) users older than 35 years of age. Women should be counselled not to smoke.

Discontinue medication at the earliest manifestation of the following:

A. Venous and arterial thrombosis and thromboembolism: Use of COCs is associated with an increased risk of venous and arterial thrombotic and thromboembolic events. For any particular estrogen/progestin combination, the dosage regimen prescribed should be one which contains the least amount of estrogen and progestin that is compatible with a low failure rate and the needs of the individual patient.

New users of COCs should be started on preparations containing less than 50 µg of estrogen.

Venous thrombosis and thromboembolism: Use of COCs increases the risk of venous thrombotic and thromboembolic events. Reported events include deep venous thrombosis, thrombophlebitis, pulmonary embolism and mesenteric thrombosis. For information on retinal vascular thrombosis see Precautions, Ocular Disease.

The use of any COCs carries an increased risk of venous thrombotic and thromboembolic events compared with no use. The excess risk is highest during the first year a woman ever uses a COC. This increased risk is less than the risk of venous thrombotic and thromboembolic events associated with pregnancy which is estimated as 60 cases per 100 000 woman-years. Venous thromboembolism is fatal in 1-2% of cases.

The risk of venous thrombotic and thromboembolic events is further increased in women with conditions predisposing for venous thrombosis and thromboembolism. Caution must be exercised when prescribing COCs for such women.

Arterial thrombosis and thromboembolism: The use of COCs increases the risk of arterial thrombotic and thromboembolic events. Reported events include myocardial infarction and cerebrovascular events (ischemic and hemorrhagic stroke, transient ischemic attack). For information on retinal vascular thrombosis see Precautions, Ocular Disease.

The risk of arterial thrombotic and thromboembolic event is further increased in women with underlying risk factors. Caution must be exercised when prescribing COCs for women with risk factors for arterial thrombotic and thromboembolic events.

B. Conditions that Predispose to Venous Thrombosis and thromboembolism (e.g. obesity, surgery or trauma with increased risk of thrombosis, immobilization after accidents or confinement to bed during long-term illness, recent delivery or second-trimester abortion [see Dosage, Special Notes on Administration}). Other nonhormonal methods of contraception should be used until regular activities are resumed. For use of oral contraceptives when surgery is contemplated, see Precautions. Examples of risk factors for arterial thrombotic and thromboembolic events are smoking, certain inherited and acquired thrombophilias, hypertension, hyperlipidemias, obesity and increasing age.

C. Visual defects, partial or complete.

D. Papilledema or ophthalmic vascular lesions.

E. Severe headache of unknown etiology, worsening of pre-existing migraine or development of new migraine (particularly migraine with aura). Women with migraine who take COCs may be at increased risk of stroke.

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 COCs compared to never-users. The increased risk gradually disappears during the course of the 10 years after cessation of COC use. These studies do not provide evidence for causation. The observed pattern of increased risk of breast cancer diagnosis maybe due to an earlier detection of breast cancer in COC users, the biological effects of COCs or a combination of both. Because breast cancer is rare in women under 40 years of age, the excess number of breast cancer diagnoses in current and recent COC users is small in relation to the lifetime risk of breast cancer. Breast cancers diagnosed in ever-users tend to be less advanced clinically than the cancers diagnosed in never-users.

Physical Examination and Follow-up: Before COCs 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 follow-up visit should be 3 months after COCs 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.

COCs 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 COC will damage the developing child.

In breast-feeding women, the use of COCs results in the hormonal components being excreted in breast milk and may reduce its quantity and quality. If the use of COCs is initiated after the establishment of lactation, there does not appear to be any effect on the quantity and quality of the milk. Some adverse effects on the child have been reported, including jaundice and breast enlargement.

The use of COCs is generally not recommended until the nursing mother has completely weaned her child.

Hepatic Function: Patients who have had jaundice, including a history of cholestatic jaundice during pregnancy, or a history of COC-related cholestasis, are more likely to have this condition with COC use and, they should be given COCs with great care and under close observation. If these patients receive a COC they should be carefully monitored and, if the condition recurs, the COC should be discontinued.

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 COCs should not be resumed. In patients taking COCs, changes in the composition of the bile may occur and an increased incidence of gallstones has been reported.

Hepatic nodules (adenomas and focal nodular hyperplasia) have been reported, particularly in long-term users of COCs. 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.

Hepatocellular carcinoma may be associated with COC use. The risk appears to increase with duration of COC use. However, the attributable risk (the excess incidence) of liver cancer in OC users is extremely small.

Hypertension: Patients with essential hypertension whose blood pressure is well controlled may be given COCs 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.

Increases in blood pressure have been reported in women taking COCs. Elevated blood pressure associated with COC use will generally return to baseline after stopping COCs, and there appears to be no difference in the occurrence of hypertension among ever- and never-users.

Diabetes: Glucose intolerance has been reported in COC users. Current low-dose COCs 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. Women who are predisposed to diabetes, have impaired glucose tolerance, or who have diabetes mellitus should be carefully monitored if using COCs. 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.

Lipid Effects: A small proportion of women will have adverse lipid changes while taking OCs. Nonhormonal contraception should be considered in women with uncontrolled dyslipidemias. Persistent hypertriglyceridemia may occur in a small proportion of COCs users. Elevations of plasma triglycerides may lead to pancreatitis and other complications.

Women who are being treated for hyperlipidemias should be followed closely if they elect to use COCs.

Ocular Disease: Patients who are pregnant or are taking COCs, 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.

With use of COCs, there have been reports of retinal vascular thrombosis which may lead to partial or complete loss of vision. If there are signs or symptoms such as visual changes, onset of proptosis or diplopia, papilledema, or retinal vascular lesions, the COC should be discontinued and the cause immediately evaluated.

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 COCs (more than 8 years) and starters at early age. In a few women, the use of COCs may accelerate the growth of an existing but undiagnosed breast cancer. Since any potential increased risk related to COC use is small, there is no reason to change prescribing habits at present (see Warnings).

Women receiving COCs 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.

Cervix: Some studies suggest that COC use may be 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 cases of undiagnosed abnormal genital bleeding, adequate diagnostic measures are indicated.

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

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 COCs. Women with a history of depression who use COCs should be carefully observed and the drug discontinued if depression recurs to a serious degree. Patients becoming significantly depressed while taking COCs should stop the medication and use an alternate method of contraception in an attempt to determine whether the symptom is drug-related. 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 COCs. The following laboratory tests are modified:

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.

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.

Thyroid Function Tests: Protein-bound Iodine (PBI): increased. Total Serum Thyroxine (T₃ and T₄): increased. Thyroid Stimulating Hormone (TSH): unchanged. Free T3 Resin Uptake: decreased.

Adrenocortical Function Tests: Plasma Cortisol: increased. Cortisol Binding Globulin: increased. Dehydroepiandrosterone sulfate (DHEAS): decreased.

Renal Function: Plasma Creatinine: increased. Creatinine Clearance: increased.

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 COC therapy when specimens obtained from surgical procedures and Pap smears are submitted for examination.

Return to Fertility: After discontinuing COC therapy, the patient should delay pregnancy until at least 1 normal spontaneous cycle has occurred in order to date the pregnancy. An alternate contraceptive method should be used during this time.

Vaginal Bleeding: In some women withdrawal bleeding may not occur during the tablet-free interval. If the COC has not been taken according to directions prior to the first missed withdrawal bleed, or if two consecutive withdrawal bleeds are missed, tablet-taking should be discontinued and a nonhormonal back-up method of contraception should be used until the possibility of pregnancy is excluded.

Breakthrough bleeding/spotting may occur in women taking COCs, especially during the first three months of use. If this bleeding persists or recurs, nonhormonal causes should be considered and adequate diagnostic measures may be indicated to rule out pregnancy, infection, malignancy, or other conditions. Persistent irregular vaginal bleeding requires assessment to exclude underlying pathology. If pathology has been excluded (see also Precautions, Cervix), continued use of the COC or a change to another formulation may solve the problem.

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.

Other: Patients should be counseled that this product does not protect against HIV infection (AIDS) or other sexually transmitted diseases.

Diarrhea and/or vomiting may reduce hormone absorption resulting in decreased serum concentrations.

Thromboembolic Complications—Post-surgery: There is an increased risk of thromboembolic complications in COC users after major surgery. If feasible, COCs should be discontinued and an alternative method substituted at least 1 month prior to major elective surgery and during periods of prolonged immobilization. COC use should not be resumed for at least two weeks after major elective surgery , and only after the first menstrual period has occurred following hospital discharge.

The concurrent administration of COCs with other substances may result in an altered response to either agent. Decreased ethinyl estradiol (EE) serum concentration may cause an increased incidence of breakthrough bleeding and menstrual irregularities and may possibly reduce efficacy of the COC. During concomitant use of EE-containing products and substances that may lead to decreased EE serum concentration, it is recommended that a nonhormonal back-up method of birth control (such as condoms and spermicide) be used in addition to the regular intake of ALESSE. In the case of prolonged use of such substances, COCs should not be considered the primary contraceptive.

After discontinuation of substances that may lead to decreased EE serum concentrations, use of a nonhormonal back-up method is recommended for at least 7 days. Longer use of a back-up method is advisable after discontinuation of substances that have lead to induction of hepatic microsomal enzymes, resulting in decreased EE serum concentrations. It may sometimes take several weeks until enzyme induction has completely subsided, depending on dosage, duration of use and rate of elimination of the inducing substance.

Reduced effectiveness of the COC, 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 COCs are prescribed.

Examples of substances that may decrease serum EE concentrations:

• Any substance that reduces gastrointestinal transit time.

  
  

• Hypericum perforatum, also known as St. John's wort, and ritonavir (possibly by induction of hepatic microsomal enzymes).

  
  

• Substances that induce hepatic microsomal enzymes, such as rifampicin, rifabutin, dexamethasone, modafinil, some protease inhibitors, topiramate.

  
  

 

Examples of substances that may increase serum EE concentrations:

• Atorvastatin.

  
  

• Competitive inhibitors for sulfation in the gastrointestinal wall, such as ascorbic acid (vitamin C) and acetaminophen.

  
  

• Substances that inhibit cytochrome P 450 3A4 isoenzymes such as indinavir, fluconazole and troleandomycin.

  
  

Troleandomycin may increase the risk of intrahepatic cholestasis during coadministration with COCs.

 

Ethinyl estradiol may interfere with the metabolism of other drugs by inhibiting hepatic microsomal enzymes, or by inducing hepatic drug conjugation, particularly glucuronidation. Accordingly, plasma and tissue concentrations of some drugs may either be increased (e.g., cyclosporine, theophylline, corticosteroids) or decreased (e.g., lamotrigine) by ethinyl estradiol.

For possible drug interactions with COCs, see Table 1 and Table 2.

Table 1: ^aALESSE 21/ALESSE 28

Drugs That May Decrease the Efficacy of Oral Contraceptives

Class of Compound	Drug	Proposed Mechanism	Suggested Management
Anticonvulsants	Carbamazepine Ethosuximide Phenobarbital Phenytoin Primidone	Induction of hepatic microsomal enzymes. Rapid metabolism of estrogen and increased binding of progestin and ethinyl estradiol to SHBG.	Use higher dose of oral contraceptives (50 µg ethinyl estradiol), another drug or another method.
Antibiotics	Ampicillin Cotrimoxazole Penicillin	Enterohepatic circulation disturbance, intestinal hurry.	For short course, use additional method or use another drug.For long course, use another method.
	Rifampin	Increased metabolism of progestins. Suspected acceleration of estrogen metabolism.	Use another method.
	Chloramphenicol Metronidazole Neomycin Nitrofurantoin Sulfonamides Tetracyclines	Induction of hepatic microsomal enzymes. Also disturbance of enterohepatic circulation.	For short course, use additional method or use another drug. For long course, use another method.
	Troleandomycin	May retard metabolism of oral contraceptives, increasing the risk of cholestatic jaundice.
Antifungals	Griseofulvin	Stimulation of hepatic metabolism of contraceptive steroids may occur.	Use another method.
Cholesterol Lowering Agents	Clofibrate	Reduces elevated serum triglycerides and cholesterol; this reduces oral contraceptive efficacy.	Use another method.
Sedatives and Hypnotics	Benzodiazepines Barbiturates Chloral Hydrate Glutethimide Meprobamate	Induction of hepatic microsomal enzymes.	For short course, use additional method or another drug. For long course, use another method or higher dose of oral contraceptives.
Antacids		Decreased intestinal absorption of progestins.	Dose 2 hours apart.
Other Drugs	Phenylbutazoneb Antihistaminesb Analgesicsb Antimigraine preparationsb Vitamin E	Reduced oral contraceptive efficacy has been reported. Remains to be confirmed.

^a. Adapted from Dickey, RP, ed.: Managing Contraceptive Pill Patients, 5th edition, Creative Informatics Inc., Durant, OK, 1987.
^b. Refer to Oral Contraceptives 1994, A Report by the Special Advisory Committee on Reproductive Physiology to the Drugs Directorate, Health Protection Branch, Health Canada.



Table 2: ^aALESSE 21/ALESSE 28

Modification of Other Drug Action by Oral Contraceptives

^a. Adapted from Dickey, RP, ed.: Managing Contraceptive Pill Patients, 5th edition, Creative Informatics Inc., Durant, OK, 1987.

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