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ALESSE (levonorgestrel, ethinyl estradiol) Warnings And Precautions

Warnings And Precautions

Serious Warnings and Precautions

Cigarette smoking increases the risk of serious adverse effects on the heart and blood vessels. This risk increases with age and becomes significant in hormonal contraceptive users older than 35 years of age who smoke. Women should be counselled not to smoke. (see WARNINGS AND PRECAUTIONS: Cardiovascular).

Patients should be counselled that birth control pills DO NOT PROTECT against sexually transmitted infections (STIs) including HIV/AIDS. For protection against STIs, it is advisable to use latex or polyurethane condoms IN COMBINATION WITH birth control pills.

General

For any 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 mcg of estrogen.

Discontinue Medication at the Earliest Manifestation of the following:

  1. Thromboembolic and cardiovascular disorders, such as thrombophlebitis, pulmonary embolism, cerebrovascular disorders, myocardial ischemia, mesenteric ischemia, mesenteric thrombosis and retinal thrombosis.
  2. Conditions that predispose to venous stasis and to vascular thrombosis (e.g. immobilization after accidents or confinement to bed during long-term illness). Other non-hormonal methods of contraception should be used until regular activities are resumed. For use of oral contraceptives when surgery is contemplated, see WARNINGS AND PRECAUTIONS: Peri-Operative Considerations.
  3. Visual defects - partial or complete
  4. Papilledema or ophthalmic vascular lesions
  5. Severe headache of unknown etiology, or worsening of pre-existing migraine headache
  6. Increase in epileptic seizures.

The following information is provided from studies of combination oral contraceptives (COCs).

The use of combination hormonal contraceptives is associated with increased risks of several serious conditions including myocardial infarction, thromboembolism, stroke, hepatic neoplasia and gallbladder disease, although the risk of serious morbidity and mortality is small in healthy women without underlying risk factors. The risk of morbidity and mortality increases significantly if associated with the presence of other risk factors such as hypertension, hyperlipidemias, obesity and diabetes.

Carcinogenesis and Mutagenesis

Breast Cancer

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 may be 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.

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 eight 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.

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.

Cervical Cancer

The most important risk factor for cervical cancer is persistent human papillomavirus infection. Some epidemiological studies have indicated that long-term use of COCs may further contribute to this increased risk but there continues to be controversy about the extent to which this finding is attributable to confounding effects, e.g., cervical screening and sexual behaviour including use of barrier contraceptives

Hepatocellular Carcinoma

Alesse is contraindicated in patients with a history of or actual benign or malignant liver tumours.

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.

Cardiovascular

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, non-smoking 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.

Hypertension

COC use is contraindicated in women with uncontrolled hypertension (see CONTRAINDICATIONS)
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.

Endocrine and Metabolism

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, with 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 and Other Metabolic Effects

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.

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

Gastrointestinal

Published epidemiological studies indicate a possible association of COC use and the development of Crohn’s disease and ulcerative colitis, although this has not been firmly established.

Absorption

Vomiting and/or diarrhea may reduce absorption of oral contraceptives resulting in decreased serum concentration and therefore may reduce contraceptive efficacy. Physicians should advise the patients of the need for a back-up contraceptive method in the case of such gastrointestinal symptoms.

Genitourinary

Vaginal Bleeding

Persistent irregular vaginal bleeding requires assessment to exclude underlying pathology. See also WARNINGS AND PRECAUTIONS: Sexual Function/Reproduction.

Fibroids

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

Hematologic

Venous and arterial thrombosis and thromboembolism

Use of COCs is associated with an increased risk of venous and arterial thrombotic and thromboembolic events.

Venous thrombosis and thromboembolism

Epidemiological studies have shown that the incidence of venous thromboembolism (VTE) in users of oral contraceptives with low estrogen content (<50 mcg ethinyl estradiol) ranges from about 20 to 40 cases per 100,000 women-years; this risk estimate varies according to the progestogen. This compares with 5 to 10 cases per 100,000 women-years for non-users.

The use of any combined oral contraceptive carries an increased risk of VTE compared with no use. Reported events include deep venous thrombosis, thrombophlebitis, pulmonary embolism and mesenteric thrombosis. The excess risk of VTE is highest during the first year a woman ever uses a combined oral contraceptive. The increased risk is less than the risk of VTE associated with pregnancy, which is estimated as 60 cases per 100,000 women-years. VTE is fatal in 1-2% of cases.

Other Risk Factors for Venous Thromboembolism

Other generalized risk factors for venous thromboembolism include but are not limited to a personal history, a family history (the occurrence of VTE in a direct relative at a relatively early age may indicate genetic predisposition), severe obesity (body mass index ≥30 kg/m2) and systemic lupus erythematosus. The risk of VTE also increases with age. The risk of VTE may be temporarily increased with prolonged immobilization, major surgery, trauma, recent delivery, or second-trimester abortion. Also, patients with a leg cast should be closely supervised.

If a hereditary or acquired predisposition for venous thromboembolism is suspected, the woman should be referred to a specialist for advice before deciding on any COC use.

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 WARNINGS AND PRECAUTIONS: Ophthalmologic.

The risk of arterial thrombotic and thromboembolic event is further increased in women with underlying risk factors. Examples of risk factors for arterial thrombotic and thromboembolic events are smoking hypertension, hyperlipidemias, obesity and increasing age. Caution must be exercised when prescribing COCs for women with risk factors for arterial thrombotic and thromboembolic events.

Hepatic/Biliary/Pancreatic

Hepatic Function

ALESSE is contraindicated in patients with active liver disease or abnormal liver function testing (see CONTRAINDICATIONS and DRUG INTERACTIONS: Drug-Laboratory Test Interactions).

Acute or chronic disturbances of liver function necessitate the discontinuation of COC use until markers of liver function return to normal.

Hepatitis C

During clinical trials with patients treated for HCV infections with the combination of ombitasvir, paritaprevir, ritonavir and dasabuvir with or without ribavirin, it was found that transaminase (ALT) elevations higher than 5 times the upper limit of normal (ULN) were significantly more frequent in women using ethinyl estradiol-containing medications such as COCs. Therefore Alesse 21 and Alesse 28 are contraindicated in hepatitis C patients during treatment with these drugs (see CONTRAINDICATIONS and DRUG INTERACTIONS).

Gallbladder Disease

For women with symptomatic gall bladder disease, consideration should be given to whether the benefits of COCs outweigh the risks. COC use these patients may worsen existing disease.

Jaundice

Patients who have had jaundice, should be given oral contraceptives only with great care and under close observation. Oral contraceptive-related cholestasis has been described in women with a history of pregnancy-related cholestasis. Women with a history of cholestasis may have the condition recur with subsequent hormonal contraceptive use, and in this instance, ALESSE 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 oral contraceptives should not be resumed. In patients taking hormonal contraceptives, changes in the composition of the bile may occur and an increased incidence of gallstones has been reported.

Hepatic Nodules

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 presenting with an abdominal mass, acute abdominal pain, or evidence of intra-abdominal bleeding.

Hepatocellular injury has been reported with COC use. Early identification of drug-related hepatocellular injury can decrease the severity of hepatotoxicity when the drug is discontinued. If hepatocellular injury is diagnosed, patients should stop their COC, use a non-hormonal form of contraception and consult their doctor.

Pancreatic Function

Please see WARNINGS AND PRECAUTIONS: Endocrine and Metabolism: Lipid and Other Metabolic Effects.

Immune

Angioedema

Exogenous estrogens may induce or exacerbate symptoms of angioedema, particularly in women with hereditary angioedema.

Neurologic

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 COCs and evaluation of the cause. (see CONTRAINDICATIONS)

Women with migraine headaches who take oral contraceptives may be at increased risk of stroke. (see CONTRAINDICATIONS)

Ophthalmologic

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.

Peri-Operative Considerations

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 one 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.

Psychiatric

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.

Renal

Fluid Retention

Hormonal contraceptives may cause some degree of fluid retention.

Sexual Function/Reproduction

Return to Fertility

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

Vaginal Bleeding

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 WARNINGS AND PRECAUTIONS: Cervical Cancer), continued use of the COC or a change to another formulation may solve the problem.

Amenorrhea

In some women, withdrawal bleeding may not occur during the tablet-free interval. If the COC has been taken according to directions, it is unlikely that the woman is pregnant. However, 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 non- hormonal back-up method of contraception should be used until the possibility of pregnancy is excluded. Pregnancy must be ruled out before COC use is continued.

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 six months or more after withdrawal, warrants a careful assessment of hypothalamic-pituitary function.

Reduced Efficacy

The efficacy of COCs may be reduced in the event of missed tablets, gastro-intestinal disturbances or concomitant medication (see DRUG INTERACTIONS).

Skin

Chloasma may occasionally occur with use of hormonal contraceptives, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should protect the affected area from exposure to the sun or ultraviolet radiation while taking hormonal contraceptives.

Special Populations

Pregnant Women

Oral contraceptives should not be taken by pregnant women. If pregnancy occurs during treatment with ALESSE, further intake should be stopped. 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.

Nursing Women 10, 13 18, 22, 23, 31

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. Published studies have indicated that during lactation, 0.1% of the daily maternal dose of levonorgestrel and 0.02% of the daily maternal dose of ethinyl estradiol could be transferred to the newborn via milk.

Adverse effects on the child have been reported, including jaundice and breast enlargement.

The nursing mother should be advised not to use oral contraceptives but to use other forms of contraception until she has completely weaned her child.

Pediatrics (< 16 years of age)

Safety and efficacy of ALESSE tablets have been established in women of reproductive age.
Use of this product before menarche is not indicated.

Geriatrics (> 65 years of age)

ALESSE is not indicated for use in postmenopausal women.

Monitoring and Laboratory Tests

Physical Examination and Followup

Before oral contraceptives are used, a thorough individual and family history and physical examination should be performed, including a blood pressure determination. In addition, disturbances of the clotting system must be ruled out if any members of the family have suffered from thromboembolic diseases (e.g., deep vein thrombosis, stroke, myocardial infarction) at a young age. Breasts, liver, extremities and pelvic organs should be examined and a Papanicolaou (PAP) smear should be taken if the patient has been sexually active or if it is otherwise indicated.

The first follow-up visit should be done three 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 Task Force on the Preventive Health Care.

Tissue Specimens

Pathologists should be advised of COC therapy when specimens obtained from surgical procedures and Pap smears are submitted for examination.

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