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ALESSE (levonorgestrel, ethinyl estradiol)

Health Professional Information Summary

Product Information

Route of
Administration
Dosage Form / StrengthClinically Relevant Nonmedicinal
Ingredients
OralTablet, 100 mcg
levonorgestrel and 20 mcg
ethinyl estradiol
Lactose Monohydrate
For a complete listing see Dosage Forms,
Composition and Packaging section.

Indications And Clinical Use

ALESSE® Tablets are indicated for:

  • Conception control.
  • 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.

Geriatrics (> 65 years of age):
ALESSE is not indicated for use in postmenopausal women.

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.

Contraindications

Combination Oral Contraceptives (COCs) are contraindicated in the following:
 

  • History of or actual thrombophlebitis or thromboembolic disorders.
  • History of or actual cerebrovascular disorders.
  • History of or actual myocardial infarction or coronary arterial disease.
  • Deep vein thrombosis (current or history)
  • Thrombogenic valvulopathies and Thrombogenic rhythm disorders
  • Hereditary or acquired thrombophilias
  • Migraine with focal neurological symptoms such as aura (current or history)
  • Active liver disease or abnormal liver function testing.
  • History of or actual benign or malignant liver tumours.
  • Known or suspected carcinoma of the breast.
  • Known or suspected estrogen-dependent neoplasia.
  • Undiagnosed abnormal vaginal bleeding.
  • Steroid-dependent jaundice, cholestatic jaundice, history of jaundice of pregnancy.
  • 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.
  • Hypersensitivity to any of the components of ALESSE.
  • For a complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section of the product monograph.
  • Diabetes with vascular involvement
  • Uncontrolled hypertension
  • Pancreatitis associated with severe hypertriglyceridemia (current or history)

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.

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.

Adverse Reactions

Adverse Drug Reaction Overview

An increased risk of the following serious adverse reactions has been associated with the use of Combined Oral Contraceptives:

  • Arterial thromboembolism
  • Being diagnosed with breast cancer
  • Benign hepatic tumours (e.g. focal nodular hyperplasia, hepatic adenomas)
  • Cerebral hemorrhage
  • Cerebral thrombosis
  • Cervical cancer
  • Cervical intraepithelial neoplasia
  • Gallbladder disease, including gallstones*
  • Hepatocellular carcinomas
  • Hypertension
  • Inflammatory bowel disease (Crohn’s Disease, ulcerative colitis)
  • Mesenteric thrombosis
  • Myocardial infarction
  • Neuro-ocular lesions (e.g. retinal thrombosis)
  • Pulmonary embolism
  • Stroke
  • Transient ischemic attach
  • Thrombophlebitis
  • Venous thrombosis

* COCs may worsen existing gallbladder disease and may accelerate the development of this disease in previously asymptomatic women.

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

The following adverse reactions have been reported in patients receiving COC and are believed to be drug related:

  • Amenorrhea
  • Breakthrough bleeding
  • Breast changes: pain, tenderness, enlargement, and secretion
  • Change in cervical ectropion and secretion
  • Change in corneal curvature (steepening)
  • Change in menstrual flow
  • Change in weight (increase or decrease)
  • Chloasma (melasma) which may persist
  • Cholestatic jaundice
  • Diminution in lactation when given immediately postpartum
  • Dysmenorrhea
  • Fluid retention/Edema
  • Gastrointestinal symptoms (such as abdominal pain, cramps and bloating)
  • Headache, including migraines
  • Hepatocellular injury (e.g., hepatitis, hepatic function abnormal)
  • Intolerance to contact lenses
  • Mood changes, including depression
  • Rash (allergic)
  • Reduced tolerance to carbohydrates
  • Retinal vascular thrombosis
  • Spotting
  • Temporary infertility after discontinuance of treatment
  • Vaginitis including candidiasis

The following adverse reactions have been reported in users of COCs and the association has been neither confirmed nor refuted:

  • Acne
  • Aggravation of varicose veins
  • Anaphylactic (anaphylactoid reactions, including very rare cases of urticaria, angioedema, and severe reactions with respiratory and circulatory symptoms)
  • Budd-Chiari syndrome
  • Cataracts
  • Cerebrovascular disease with mitral valve prolapse
  • Changes in appetite (increase or decrease)
  • Changes in libido
  • Changes in Serum Lipid levels, including hypertriglyceridemia
  • Colitis
  • Congenital anomalies
  • Cystitis-like syndrome
  • Decrease in serum folate levels**
  • Dizziness
  • Erythema multiforme
  • Erythema nodosum
  • Exacerbation of chorea
  • Exacerbation of porphyria
  • Exacerbation of systemic lupus erythematosus
  • Hemolytic uremic syndrome
  • Hemorrhagic eruption
  • Hepatic adenomas
  • Hepatocellular Carcinomas
  • Hirsutism
  • Impaired renal function
  • Ischemic colitis
  • Loss of scalp hair
  • Lupus-like syndrome
  • Nervousness
  • Optic neuritis***
  • Pancreatitis
  • Premenstrual syndrome
  • Sickle-cell disease
  • Vaginitis

**Serum folate levels may be depressed by COC therapy.
***Optic neuritis may lead to partial or complete loss of vision.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Oral Contraception

Treatment-emergent adverse events were analyzed for 1,477 subjects exposed to the study drug for 7,870 cycles. One or more treatment emergent adverse events were reported for 1,106 (75%) subjects. Table-1 lists the frequency of treatment emergent adverse events that were reported by > 2% of subjects.

Table - 1 FREQUENCY OF TREATMENT EMERGENT ADVERSE EVENTS THAT OCCURRED
IN > 2% OF SUBJECTS
EventNumber (%) of Subjects
(n=1,477)
Headache400 (27%)
Dysmenorrhea210 (14%)
Infection200 (14%)
Pharyngitis146 (10%)
Abdominal pain134 (9%)
Nausea134 (9%)
Metrorrhagia123 (8%)
Sinusitis90 (6%)
Flu syndrome84 (6%)
Vaginal moniliasis71 (5%)
Pain71 (5%)
Back pain66 (4%)
Breast pain65 (4%)
Accidental injury64 (4%)
Acne62 (4%)
Rhinitis54 (4%)
Emotional lability50 (3%)
Vaginitis48 (3%)
Urinary tract infection41 (3%)
Dizziness40 (3%)
Diarrhea40 (3%)
Bronchitis37 (3%)
Depression36 (2%)
Asthenia35 (2%)
Vomiting34 (2%)
Allergic reaction other than to study drug33 (2%)
Amenorrhea30 (2%)

A total of 133 (9%) subjects stopped taking the study medication because of adverse events. Some of the study events that led to subject discontinuation were considered by the medical monitor to be potentially serious: headache (21), hypertension (7), migraine (3), phlebitis (1), palpitations (1), varicose veins (1), vascular disorder (1), hypercholesterolemia/hyperlipidemia(6), depression/emotional lability (16), hypesthesia (1), abnormal vision (2), visual field defect (1), amenorrhea (8), dysmenorrhea (4), menorrhagia (6), irregular bleeding (1), menstrual bloating (1), metrorrhagia (1), fibroid growth (1). No deaths occurred during the multicentre study.

Acne

In the two acne studies (see CLINICAL TRIALS), the safety profile of ALESSE was compared with that of placebo. Treatment-emergent adverse events that were reported by ³ 2% of patients in either treatment group are presented in Table 2.

Table 2. Percentage of Patients (> 2%) Reporting Treatment- Emergent Adverse Events in Either Treatment Group in Studies 0858A1-900, 901
Adverse eventNumber (%) of Subjects
ALESSE
(n=349)
Placebo
(n=355)
Headache110 (31.5)107 (30.1)
Metrorrhagia*77 (21.8)14 (3.9)
Nausea49 (14.0)40 (11.3)
Infection48 (13.8)49 (13.8)
Pharyngitis46 (13.2)58 (16.3)
Pain31 (8.9)36 (10.1)
Abdominal pain27 (7.7)24 (6.8)
Dysmenorrhea27 (7.7)39 (11.0)
Accidental injury21 (6.0)16 (4.5)
Menstrual disorder*21 (6.0)8 (2.3)
Flu syndrome19 (5.4)20 (5.6)
Allergic reaction*16 (4.6)6 (1.7)
Breast pain16 (4.6)11 (3.1)
Rhinitis15 (4.0)13 (3.7)
Sinusitis14 (4.0)2.0 (8)
Asthenia13 (3.7)5 (1.4)
Back pain12 (3.4)12 (3.4)
Dyspepsia12 (3.4)2.3 (8)
Weight gain17 (3.4)12 (2.3)
Emotional lability*12 (3.4)4 (1.1)
Acne13 (3.4)6 (1.4)
Migraine11 (3.2)8 (2.3)
Dizziness11 (3.2)10 (2.8)
Cough increased10 (2.9)8 (2.3)
Vomiting10 (2.6)6 (1.7)
Depression9 (2.6)11 (2.5)
Moniliasis7 (2.0)8 (2.3)
Myalgia7 (2.0)5 (1.4)
Bronchitis7 (2.0)7 (2.0)
Rash7 (2.0)7 (2.0)
Urticaria*7 (2.0)0
Allergic reaction other than drug7 (2.0)7 (2.0)
Diarrhea6 (1.7)10 (2.8)
Unintended pregnancy*2 (0.6)12 (3.1)
* Statistically significantly different between treatment groups (p<0.05).

As expected, menstrual-related events were more frequent in women treated with ALESSE than with placebo. However, other adverse events often associated with oral contraceptive use, including nausea, vomiting, breast pain, headache, migraine, and weight gain, occurred at similar rates in women treated with placebo or ALESSE.

Abnormal Hematologic and Clinical Chemistry Findings

See CLINICAL TRIALS

Drug Interactions

Overview

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 led 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 non-prescription, 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 ritonovir (possibly by induction of hepatic microsomal enzymes)
  • Substances that induce hepatic microsomal enzymes, such as rifampicin, rifabutin, barbiturates, primidone, phenylbutazone, phenytoin, dexamethasone, griseofulvin, topiramate, some protease inhibitors, modafinil
  • Certain antibiotics (eg, ampicillin and other penicillins, tetracyclines), by a decrease of enterohepatic circulation of estrogens.

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 (paracetamol).
  • 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.

EE 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 may either be increased (eg, cyclosporine, theophylline, corticosteroids) or decreased (eg, lamotrigine).

In patients treated with flunarizine, use of oral contraceptives has been reported to increase the risk of galactorrhea.

The prescribing information of concomitant medications should be consulted to identify potential interactions.

For possible drug interactions with COCs, see DRUG INTERACTIONS: Drug-Drug Interactions: Tables 3 and 4.

Drug-Drug Interactions

Table 3*: Drugs That May Decrease the Efficacy of Oral Contraceptives
Class of
Compound
DrugProposed MechanismSuggested Management
AntibioticsAmpicillin
Cotrimoxazole
Penicillin

Enterohepatic circulation disturbance,
intestinal hurry.
For short course, use additional method or use another drug. For long course, use another method.
Rifabutin
Rifampin
Increased metabolism of progestins. Suspected acceleration of estrogen metabolism.Use another method.
Chloramphenicol
Metronidazole
Neomycin
Nitrofurantoin
Sulfonamide
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.
TroleandomycinMay retard metabolism of OCs, increasing the risk of cholestatic jaundice. 
AnticonvulsantsCarbamazepine
Ethosuximide
Felbamate
Lamotrigine
Oxcarbazine
Phenobarbital
Phenytoin
Primidone
Topiramate
Induction of hepatic microsomal enzymes. Rapid metabolism of estrogen and increased binding of progestin and ethinyl estradiol to SHBG.Use higher dose OCs (50 mcg ethinyl estradiol), another drug or another method.
AntifungalsGriseofulvinStimulation of hepatic metabolism of contraceptive sterioids may occur.Use another method.
Cholesterol
Lowering
Agents
ClofibrateReduces elevated serum triglycerides and cholesterol.; this reduces OC efficacyUse another method.
HIV Protease
Inhibitors
RitonavirInduction of hepatic microsomal enzymes.Use another drug or another method.
Non-nucleoside
reverse
transcriptase
inhibitors
NevirapineInduction of hepatic microsomal enzymes
 
Use another drug or 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 OCs.
Antacids Decreased intestinal absorption of progestins.Dose two hours apart
Other DrugsPhenylbutazone**
Antihistamines**
Analgesics**
Antimigraine Preparations**
Vitamin E
Reduced OC efficacy has been reported.
Remains to be confirmed.
 

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

** 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 4*: Modification of Other Drug Action by Oral Contraceptives
Class of
Compound
DrugProposed MechanismSuggested Management

Alcohol
 Possible increased levels of ethanol or acetaldehyde.Use with caution.
Alpha-II
Adrenoreceptor
Agents
 
ClonidineSedation effect increased.Use with caution.
AnticoagulantsAllOCs increase clotting factors, decrease efficacy. However, OCs may potentiate action in some patients.Use another method.
AnticonvulsantsAllEstrogens may increase risk of seizures.Use another method.
LamotrigeneDecrease lamotrigine levels, may lead to breakthrough seizures.Use another method.
Antidiabetic
Drugs
Oral Hypoglycemics and
Insulin
OCs may impair glucose tolerance. and increase blood glucose.Use low-dose estrogen and
progestin OC or another method.
Monitor blood glucose.
Antihypertensive
Agents
Guanethidine and
Methyldopa
Estrogen component causes sodium retention, progestin has no effect.Use low-dose estrogen OC or use another method.
Beta BlockersIncreased drug effect (decreased metabolism)Adjust dose of drug if necessary.
Monitor cardiovascular status.
AntipyreticsAcetaminophenIncreased metabolism and renal clearance.Dose of drug may have to be increased.
 AntipyrineImpaired metabolism.Decrease dose of drug.
 ASAEffects of ASA may be decreased by the short-term use of OCs.Patients on chronic ASA therapy may require an increase in ASA dosage.
Aminocaproic
Acid
 Theoretically, a hypercoagulable state may occur because OCs augment clotting factors.Avoid concomitant use.
Betamimetic
Agents
IsoproterenolEstrogen causes decreased response to these drugs.Adjust dose of drug as necessary. Discontinuing OCs can result in excessive drug activity.
Caffeine The actions of caffeine may be enhanced as OCs may impair the hepatic metabolism of caffeineUse with caution.
Cholesterol-
lowering Agents
ClofibrateTheir action may be antagonized by OCs. OCs may also increase metabolism of clofibrate.May need to increase dose of clofibrate.
CorticosteroidsPrednisoneMarkedly increases serum levels.Possible need for decrease in dose.
Cyclosporine May lead to an increase in cyclosporine levels and hepatoxicity.Monitor hepatic function. The cyclosporine dose may have to be decreased.
Folic Acid OCs have been reported to impair folate metabolism.May need to increase dietary intake, or supplement.
Meperidine Possible increased analgesia and CNS depression due to decreased metabolism of meperidine.Use combination with caution.
Phenothiazine
Tranquilizers
All phenothiazines,
Reserpine, and similar
drugs.
Estrogen potentiates the hyperprolactinemia effect of these drugs.Use other drugs or lower dose OCs. If galactorrhea or hyperprolactinemia occurs, use other method.
Sedatives and
Hypnotics
Chlordiazepoxide
Lorazepam
Oxazepam
Diazepam
Increased effect (increased metabolism)Use with caution.
TheophyllineAllDecreased oxidation, leading to possible toxicity.Use with caution. Monitor theophylline levels.
Tricyclic
Antidepressants
Clomipramine
(possibly others)
Increased side effects: i.e., depression.
Increased serum levels due to decreased clearance.
 
Use with caution.
Vitamin B12 

OCs have been reported to reduce serum levels of Vitamin B12.
 

May need to increase dietary intake, or supplement.

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

Drug-Food Interactions

No data is available.

Drug-Herb Interactions

Hypericum perforatum, also known as St. John’s wort causes decrease in serum EE concentration possibly by induction of hepatic microsomal enzymes.

Drug-Laboratory Interactions

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 (SGOT) and GGTMinor increase
Alkaline PhosphataseVariable increase
Serum BilirubinIncreased, particularly in conditions
predisposing to or associated with
hyperbilirubinemia
  
Coagulation Tests 
Factors II, VII, IX, X, XII and XIIIIncreased
Factor VIIIMild increase
Platelet aggregation and adhesivenessMild increase in response to common
aggregating agents
FibrinogenIncreased
PlasminogenMild increase
Antithrombin IIIMild decrease
Prothrombin TimeDecreased
  
Thyroid Function Tests 
Protein-bound Iodine (PBI)Increased
Total Serum Thyroxine (T3 andT4)Increased
Thyroid Stimulating Hormone (TSH)Unchanged
Free T3 Resin UptakeDecreased
  
Adrenocortical Function Tests 
Plasma CortisolIncreased
Cortisol Binding GlobulinIncreased
Dehydroepiandrosterone sulfate (DHEAS)Decreased
  
Miscellaneous Tests 
Serum FolateOccasionally decreased
Glucose Tolerance TestVariable decrease with return to normal after 6 to 12 months
Insulin ResponseMild to moderate decrease
c- Peptide ResponseMild to moderate decrease

Drug-Lifestyle Interactions

See WARNINGS AND PRECAUTIONS regarding cigarette smoking. The actions of caffeine may be enhanced as OCs may impair the hepatic metabolism of caffeine. Use with caution.
There may be possible increased levels of ethanol or acetaldehyde when combined with alcohol. Use with caution.

Non-Contraceptive 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 and, as a result may decrease the incidence of breast biopsies.
  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. Oral contraceptives decrease the incidence of acute pelvic inflammatory disease and reduce the incidence of ectopic pregnancy.
  7. Oral contraceptives have potential effects on endometriosis.

Dosage And Administration

Recommended Dose and Dosage Adjustment

CONTRACEPTION:

ALESSE® 21 TABLETS REGIMEN:
Each cycle consists of 21 days on medication and a 7-day interval without medication (three weeks on, one week off).

The dosage of ALESSE Tablets is one 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 one ALESSE 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 seven days (one week). Withdrawal bleeding should usually occur within three days following discontinuation of ALESSE.

The patient begins her next and all subsequent 21-day courses of ALESSE 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 seven days after discontinuation, regardless of whether or not withdrawal bleeding is still in progress.

ALESSE® 28 TABLETS REGIMEN:
Each cycle consists of 21 days of pink ALESSE Tablets (active tablets) followed by 7 days of white inert tablets (three weeks on ALESSE, one week on inert tablets).

The dosage of ALESSE Tablets is one tablet daily for 21 consecutive days per menstrual cycle, according to prescribed schedule, followed by one 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 white tablet is taken daily for the following seven consecutive days. Withdrawal bleeding should usually occur within three days following the discontinuation pink ALESSE® Tablets, i.e., during the week the patient is taking the white 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".

ACNE
The timing of initiation of ALESSE treatment for acne should follow the instructions for use of ALESSE for contraception (see the DOSAGE AND ADMINISTRATION information for oral contraception).

Missed Dose

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.

SUNDAY STARTOTHER THAN SUNDAY START
Miss One PillMiss One Pill
Take it as soon as you remember, and take the
next pill at the usual time. This means that you
might take two pills in one day.
Take it as soon as you remember, and take the
next pill at the usual time. This means that you
might take two pills in one day.
Miss Two Pills in a Row

Miss Two Pills in a Row

First two weeks
  1. Take two pills the day you remember and two pills the next day.
  2. Then take one pill a day until you finish the pack.
  3. Use a nonhormonal back-up method of birth control if you have sex in the seven days after you miss the pills.

Third week

  1. Keep taking one pill a day until Sunday.
  2. On Sunday, safely discard the rest of the pack and start a new pack that day.
  3. Use a nonhormonal back-up method of birth control if you have sex in the seven days after you miss the pills.
  4. You may not have a period this month.


If You Miss Two Periods in a Row, Call Your Doctor or Clinic.

First two weeks
  1. Take two pills the day you remember and two pills the next day.
  2. Then take one pill a day until you finish the pack.
  3. Use a nonhormonal back-up method of birth control if you have sex in the seven days after you miss the pills.

Third week

  1. Safely dispose of the rest of the pill pack and start a new pack that same day.
  2. Use a nonhormonal back-up method of birth control if you have sex in the seven days after you miss the pills.
  3. You may not have a period this month.


If You Miss Two Periods in a Row, Call Your Doctor or Clinic.

Miss Three or More Pills in a RowMiss Three or More Pills in a Row
Anytime in the cycle
  1. Keep taking one pill a day until Sunday.
  2. On Sunday, safely discard the rest of the pack and start a new pack that day.
  3. Use a nonhormonal back-up method of birth control if you have sex in the seven days after you miss the pills.
  4. You may not have a period this month.


If You Miss Two periods in a Row, Call Your Doctor or Clinic.

Anytime in the cycle

  1. Safely dispose of the rest of the pill pack and start a new pack that same day.
  2. Use a nonhormonal back-up method of birth control if you have sex in the seven days after you miss the pills.
  3. You may not have a period this month.


If You Miss Two Periods in a Row, Call Your Doctor or Clinic.

Contraceptive reliability may be reduced if active tablets are missed and particularly if the missed tablets extend the tablet-free interval. If active tablets were missed and intercourse took place in the week before the tablets were missed, the possibility of pregnancy should be considered.

Administration

Tablets for oral use.

SPECIAL NOTES ON ADMINISTRATION

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 postpartum (no earlier than day 28 after delivery in the nonlactating mother) or after Day 1 of the first menstrual cycle, contraceptive reliance should not be placed on ALESSE until after the first seven consecutive days of administration. The possibility of ovulation and conception prior to initiation of medication should be considered. Therefore, nonhormonal methods of contraception (such as condoms and spermicide) should be used for the first 7 days of tablet taking.

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.

Advice in case of vomiting and/or diarrhea

If vomiting and/or diarrhea occurs within 4 hours after tablet-taking, tablet absorption may be incomplete. In such event, advice concerning the Management of Missed Tablet is outlined in the above chart. The woman must take the extra active tablet(s) needed from a backup pack.

No hormonal contraceptive use in the past month

Tablet-taking should start on day 1 of the woman’s natural cycle (ie, the first day of her menstrual bleeding). Starting on days 2-7 is allowed, but for the first 7 days of tablet-taking during the first cycle, a nonhormonal back-up method of birth control (such as condoms and spermicide) is recommended.

Changing from another COC pill

The woman should start ALESSE preferably on the day after the last active tablet of her previous COC, but at the latest, on the day following the usual tablet-free or inactive tablet interval of her previous COC.

Changing from a progestin only method (progestin-only pill, implant, intrauterine device [IUD], injection)

The woman may switch any day from the progestin-only pill and should begin ALESSE the next day. She should start ALESSE on the day that a progestin-only implant or a progestin-only IUD is removed. Alesse use should begin on the day that the next progestin-only injection is scheduled. In all of these situations, the woman should be advised to use a nonhormonal back-up method for the first 7 days of tablet-taking.

Following first-trimester abortion

The woman may start ALESSE immediately. Additional contraceptive measures are not needed.

Following delivery or second-trimester abortion

Since the immediate post-partum period is associated with an increased risk of thromboembolism, oral contraceptives should be started no earlier than day 28 after delivery in the nonlactating mother or after second-trimester abortion. The woman should be advised to use a nonhormonal back-up method for the first 7 days of tablet-taking. However, if intercourse has already occurred, the possibility of pregnancy should be ruled out before the actual start of COC use or the woman must wait for her first menstrual period.

Overdosage

Symptoms of COC overdosage in adults and children may include nausea, vomiting, breast tenderness, dizziness, abdominal pain, drowsiness/fatigue; withdrawal bleeding may occur in females. There is no specific antidote and further treatment of overdose, if necessary, is directed to the symptoms.

For management of suspected drug overdose contact your regional Poison Control Centre.

Action And Clinical Pharmacology

Mechanism of Action

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).14, 30 In addition, ALESSE decreases serum levels of 3b-androstanediol glucuronide (a marker of peripheral 5 b-reductase activity).14,30 These biochemical changes produced by the coadministration of levonorgestrel and ethinyl estradiol are consistent with improvement of acne in otherwise healthy women.

Special Populations and Conditions

Geriatrics (> 65 years of age):

ALESSE is not indicated for use in postmenopausal women.

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.

Storage And Stability

Store in original packaging between 15°C and 30°C. Keep out of reach of children and pets. ALESSE® 21 and ALESSE® 28 Tablets should be protected from light once opened using the protective covering provided.

Medications should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medications no longer required. These measures will help to protect the environment.

Special Handling Instructions

None

Dosage Forms, Composition And Packaging

PrALESSE® Tablets are available in 21-day regimen (ALESSE® 21) and 28-day regimen (ALESSE® 28) in blister packs.

Each package consists of 21 pink ALESSE® Tablets, each tablet containing 100 mcg of levonorgestrel and 20mcg ethinyl estradiol. In the 28-day regimen package, there are, in addition, 7 white tablets containing inert ingredients.

Each active tablet contains lactose, microcrystalline cellulose, magnesium stearate, polacrillin, hydroxypropylmethylcellulose, polyethylene glycol, titanium dioxide and red iron oxide. It may also contain montanglycol wax (wax E pharma).

Each inactive tablet (in ALESSE® 28) contains:

  • lactose, microcrystalline cellulose, magnesium stearate, polacrillin, hydroxypropylmethylcellulose, polyethylene glycol, titanium dioxide and montanglycol wax (wax E pharma)

OR

  • lactose, maize starch, magnesium stearate, hydroxypropylmethylcellulose, polyethylene glycol and titanium dioxide

 

Control #: 186115
18 September 2015

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