Seasonale Product Monograph

RECENT MAJOR LABEL CHANGES

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TABLE OF CONTENTS

Sections or subsections that are not applicable at the time of authorization are not listed.

RECENT MAJOR LABEL CHANGES .............................................................................................. 2

TABLE OF CONTENTS ................................................................................................................ 2

PART I: HEALTH PROFESSIONAL INFORMATION ....................................................................... 4

1 INDICATIONS................................................................................................................. 4

1.1 Pediatrics ................................................................................................................. 4

1.2 Geriatrics ................................................................................................................. 4

2 CONTRAINDICATIONS ................................................................................................... 4

3 SERIOUS WARNINGS AND PRECAUTIONS BOX .............................................................. 5

4 DOSAGE AND ADMINISTRATION ................................................................................... 5

4.1 Dosing Considerations ............................................................................................. 5

4.2 Recommended Dose and Dosage Adjustment ........................................................ 5

4.4 Administration ......................................................................................................... 6

4.5 Missed Dose ............................................................................................................ 6

5 OVERDOSAGE ............................................................................................................... 7

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ................................... 7

7 WARNINGS AND PRECAUTIONS .................................................................................... 7

7.1 Special Populations ............................................................................................... 13

7.1.1 Pregnant Women ........................................................................................................ 13

7.1.2 Breast-feeding ............................................................................................................. 13

7.1.3 Pediatrics ..................................................................................................................... 13

7.1.4 Geriatrics ..................................................................................................................... 14

8 ADVERSE REACTIONS .................................................................................................. 14

8.1 Adverse Reaction Overview ................................................................................... 14

8.2 Clinical Trial Adverse Reactions ............................................................................. 15

8.3 Less Common Clinical Trial Adverse Reactions ...................................................... 16

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data ............................................................................................................ 19

8.5 Post-Market Adverse Reactions ............................................................................ 19

9 DRUG INTERACTIONS .................................................................................................. 20

9.2 Drug Interactions Overview ................................................................................... 20

9.3 Drug-Behavioural Interactions............................................................................... 20

9.4 Drug-Drug Interactions .......................................................................................... 20

9.5 Drug-Food Interactions ......................................................................................... 24

9.6 Drug-Herb Interactions .......................................................................................... 24

9.7 Drug-Laboratory Test Interactions ........................................................................ 24

10 CLINICAL PHARMACOLOGY ......................................................................................... 25

10.1 Mechanism of Action ......................................................................................... 25

10.2 Pharmacodynamics ............................................................................................ 25

10.3 Pharmacokinetics ............................................................................................... 25

11 STORAGE, STABILITY AND DISPOSAL ........................................................................... 27

12 SPECIAL HANDLING INSTRUCTIONS ............................................................................. 27

PART II: SCIENTIFIC INFORMATION ........................................................................................ 28

13 PHARMACEUTICAL INFORMATION .............................................................................. 28

14 CLINICAL TRIALS .......................................................................................................... 29

14.1 Clinical Trials by Indication ................................................................................. 29

Prevention of pregnancy ........................................................................................................... 29

15 MICROBIOLOGY .......................................................................................................... 30

16 NON-CLINICAL TOXICOLOGY ....................................................................................... 30

PATIENT MEDICATION INFORMATION.................................................................................... 32

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

Seasonale^® (levonorgestrel and ethinyl estradiol, USP) tablets are indicated for the prevention of pregnancy.

1.1 Pediatrics

Pediatrics (< 18 years of age): No data are available in women under the age of 18 years; therefore, Health Canada has not authorized an indication for pediatric use.

Use of this product before menarche is not indicated.

1.2 Geriatrics

Geriatrics: Seasonale is not indicated for use in post-menopausal women.

2 CONTRAINDICATIONS

Oral contraceptives should not be used in women who have the following conditions:

• Patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.
• History of or actual thrombophlebitis or thromboembolic disorders.
• History of or actual cerebrovascular disorders.
• History of or actual myocardial infarction or coronary artery disease.
• Valvular heart disease with complications.
• Active liver disease or history of or actual benign or malignant liver tumours.
• Steroid-dependent jaundice, cholestatic jaundice, history of jaundice in pregnancy
• Known or suspected carcinoma of the breast.
• Carcinoma of the endometrium or other known or suspected estrogen-dependent neoplasia.
• Undiagnosed abnormal vaginal bleeding.
• Any ocular lesion arising from ophthalmic vascular disease, such as partial or complete loss of vision or defect in visual fields.
• Known or suspected pregnancy.

• Presence of severe or multiple risk factor(s) for arterial or venous thrombosis:

  -diabetes mellitus with vascular symptoms

  -severe hypertension (persistent values of ≥160/100mm Hg)

  -severe dyslipoproteinemia

  -hereditary or acquired predisposition for venous or arterial thrombosis, such as Factor V Leiden mutation and activated protein C (APC-) resistance, antithrombin-III-deficiency, protein C deficiency, protein S deficiency, hyperhomocysteinaemia (e.g., due to MTHFR C677 T, A1298 mutations), prothrombin mutation G20210A and antiphospholipid-antibodies (anticardiolipin-antibodies, lupus anticoagulant).

  -major surgery associated with an increased risk of post-operative thromboembolism

  -prolonged immobilization

  -heavy smoking (>15 cigarettes per day) and over age 35

• Current or history of migraine with focal neurological symptoms.
• History of/or actual pancreatitis if associated with severe hypertriglyceridemia.
• Use of Hepatitis C drug combinations containing, glecaprevir/pibrentasvir and sofosbuvir/velpatasvir/voxilaprevir due to the potential for ALT elevations.

3 SERIOUS WARNINGS AND PRECAUTIONS BOX

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 oral contraceptive users older than 35 years of age. For this reason, Combination Oral Contraceptives, including Seasonale are contraindicated in women over 35 years of age and who smoke (see 2 CONTRAINDICATIONS and 7 WARNINGS AND PRECAUTIONS, Cardiovascular sections).

Birth control pills DO NOT PROTECT against sexually transmitted infections including HIV/AIDS. For protection against STIs, it is advisable to use latex condoms IN COMBINATION WITH birth control pills.

Use of Seasonale provides women with more hormonal exposure on a yearly basis than conventional monthly oral contraceptives containing similar strength synthetic estrogens and progestins (9 additional weeks of hormonal exposure per year). While this added exposure may pose an additional risk of thrombotic and thromboembolic diseases, studies to date with Seasonale have not suggested, nor can exclude, this additional risk.

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

This product (like all oral contraceptives) is intended to prevent pregnancy. Oral contraceptives do not protect against transmission of HIV (AIDS) and other sexually transmitted diseases such as chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B and syphilis.

The patient should be advised to use a non-hormonal back-up method for the first 7 days of tablet-taking. However, if intercourse has already occurred, the possibility of ovulation and conception prior to initiation of medication should be considered.

The tablets should not be removed from the protective blister packaging to avoid damage to the product. The plastic dispenser should be kept in the foil pouch until dispensed to the patient.

4.2 Recommended Dose and Dosage Adjustment

The dosage of Seasonale is one pink (active) tablet taken daily for 84 consecutive days followed by 7 days of white (inert) tablets. To achieve maximum contraceptive effectiveness, Seasonale must be taken exactly as directed and at intervals not exceeding 24 hours. Ideally, the tablets should be taken at the same time of the day on each day of active treatment.

During the first cycle of medication, the patient is instructed to begin taking Seasonale on the first Sunday after the onset of menstruation. If menstruation begins on a Sunday, the first tablet (pink) is taken that day. One pink tablet should be taken daily for 84 consecutive days, followed by 7 days on which a white (inert) tablet is taken. Withdrawal bleeding should occur during the 7 days following discontinuation of pink active tablets.

During the first cycle, contraceptive reliance should not be placed on Seasonale until a pink (active) tablet has been taken daily for 7 consecutive days and a non-hormonal back-up method of birth control (such as condoms or spermicide) should be used during those 7 days. The possibility of ovulation and conception prior to initiation of medication should be considered.

The patient begins her next and all subsequent 91-day course of tablets without interruption on the same day of the week (Sunday) on which she began her first course, following the same schedule: 84 days on which pink tablets are taken followed by 7 days on which white tablets are taken.

If in any cycle the patient starts the tablets later than the proper day, she should protect herself against pregnancy by using a non-hormonal back-up method of birth control until she has taken a pink tablet daily for 7 consecutive days.

Health Canada has not authorized an indication for pediatric use.

4.4 Administration

If spotting or breakthrough bleeding occurs:

Breakthrough bleeding or spotting may occur in women taking combination oral contraceptives (COC). The patient is instructed to continue on the same regimen. This type of bleeding is usually transient and without significance; however, if the bleeding is persistent or prolonged, the patient is advised to consult her healthcare provider.

If withdrawal bleeding does not occur:

Correct use of contraceptives can result in lower failure rates. If withdrawal bleeding does not occur while taking white (inactive) tablets, the possibility of pregnancy must be considered. Appropriate diagnostic measures to rule out pregnancy should be taken at the time of any missed menstrual period. Seasonale should be discontinued if pregnancy is confirmed.

Use after pregnancy or abortion:

In the non-lactating mother, Seasonale may be initiated no earlier than Day 28 of postpartum for contraception due to the increased risk for thromboembolism. When the tablets are administered in the postpartum period, the increased risk of thromboembolic disease associated with the postpartum period must be considered (see also 2 CONTRAINDICATIONS and 7 WARNINGS AND PRECAUTIONS).

Seasonale may be initiated immediately after a first-trimester abortion; if the patient starts Seasonale immediately, additional contraceptive measures are not needed.

4.5 Missed Dose

Detailed patient instructions regarding missed pills are presented in the Missed Dose section of Part III in the product monograph. If a patient misses one pink tablet, she should take it as soon as possible, meaning she can take two tablets in one day. If a patient misses two pink tablets, she should take 2 tablets on the day she remembers and 2 tablets on the following day. Should three or more tablets be missed, the regular dosing schedule should be resumed, that is one pink tablet per day. Any time the patient misses two or more pink tablets, she should also use another method of non-hormonal back-up contraception until she has taken a pink tablet daily for seven consecutive days. If the patient misses one or more white tablets, she is still protected against pregnancy provided she begins taking pink tablets again on the appropriate day. The possibility of ovulation increases with each successive day that scheduled pink tablets are missed. The risk of pregnancy increases with each active (pink) tablet missed.

5 OVERDOSAGE

Serious ill effects have not been reported following acute ingestion of large doses of oral contraceptives by young children. Overdosage may cause nausea, vomiting, breast tenderness, dizziness, abdominal pain, drowsiness/fatigue; and withdrawal bleeding may occur in females. There is no antidote and further treatment should be symptomatic.

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table 1 – Dosage Forms, Strengths, Composition and Packaging

Seasonale (levonorgestrel and ethinyl estradiol, USP) tablets are available in Extended-Cycle Tablet Dispensers. The Tablet Dispenser consists of three plastic leaves in a booklet configuration where individual blister cards are inserted and held in place. Each of these leaves contains either 28 or 35 holes for tablets to be pushed out of the blister cards through the aluminum foil. The first two blister cards contain 28 active pink tablets and the third blister card contains 28 active pink tablets and 7 inert white tablets for a total of 35 tablets. Altogether, the 3 blister cards hold 91 tablets consisting of 84 active pink tablets (each containing 0.15 mg of levonorgestrel and 0.03 mg ethinyl estradiol) and 7 inert white tablets. The compact is then packaged in a foil pouch with a desiccant. One foil pouch is packaged in each carton. The active pink tablets are round, film-coated, biconvex, unscored tablets with a debossed S on one side and 62 on the other side. The inert tablets are white, round, biconvex, unscored tablets debossed with S on one side and 197 on the other side.

7 WARNINGS AND PRECAUTIONS

Please see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX.

General

Discontinue Medication at the Earliest Manifestation of:

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

B. Conditions that predispose to venous stasis and 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 7 WARNINGS AND PRECAUTIONS, Peri-Operative Considerations, below.

C. Visual defects - partial or complete

D. Papilledema or ophthalmic vascular lesions

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

F. Increase in epileptic seizures

Seasonale Oral Contraceptive

Seasonale is a 91-day cyclic dosing regimen (84 days with active oral tablets of 0.15 mg levonorgestrel and 0.03 mg ethinyl estradiol, followed by 7 days with placebo tablets). Pregnancy should be ruled out in cases of unanticipated bleeding/spotting, missed withdrawal bleeding/amenorrhea or signs and symptoms of pregnancy.

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

The information contained in this section is principally from studies carried out in women who used combination oral contraceptives with higher formulations of estrogens and progestogens than those in common use today. The effect of long-term use of combination hormonal contraceptives with lower doses of both estrogen and progestogen administered orally remains to be determined.

Carcinogenesis and Mutagenesis

Breast cancer

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

Women receiving oral contraceptives should be instructed in self-examination of their breasts. Their healthcare professionals 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 papilloma virus (HPV) infection. Some studies suggest that oral contraceptive use has been associated with an increase in 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 the findings may be due to differences in sexual behaviours and other factors.

Hepatocellular carcinoma

Hepatocellular carcinoma may be associated with oral contraceptives. The risk appears to increase with duration of hormonal contraceptive use. However, the attributable risk (the excess incidence) of liver cancers in oral contraceptive users is extremely small.

Also see 16 NON-CLINICAL TOXICOLOGY.

Cardiovascular

See also 2 CONTRAINDICATIONS, 3 SERIOUS WARNINGS AND PRECAUTIONS BOX, 7 WARNINGS AND PRECAUTIONS – General, Haematologic, Ophthalmologic

Use of Seasonale provides women with more hormonal exposure on a yearly basis than conventional monthly oral contraceptives containing similar strength synthetic estrogens and progestins (9 additional weeks of hormonal exposure per year). While this added exposure may pose an additional risk of thrombotic and thromboembolic diseases, studies to date with Seasonale have not suggested, nor can exclude, this additional risk. Two subjects had pulmonary embolism and one subject had myocardial infarction while on Seasonale in clinical studies. Coagulation profile has not been studied with Seasonale.

In the post-market period, there have been cases of myocardial infarction, stroke, deep vein thrombosis and pulmonary embolism reported with the use of Seasonale.

Prescribers are advised to carefully assess a patient’s baseline and cumulative risk of thromboembolism and discuss the risk of thromboembolism with all patients before prescribing Seasonale.

Predisposing Factors for Coronary Artery Disease

Cigarette smoking increases the risk of serious cardiovascular side effects and mortality. Birth control pills increase this risk, especially with increasing age. Convincing data are available to support an upper age limit of 35 years for oral contraceptive use by women who smoke.

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

Thromboembolism

See 7 WARNINGS AND PRECAUTIONS, Haematologic section.

Hypertension

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

Endocrine and Metabolism

Diabetes

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

Lipid and other metabolic effects

A small proportion of women will have adverse lipid changes while on oral contraceptives. Alternative contraception should be used in women with uncontrolled dyslipidemias (see also 2 CONTRAINDICATIONS). Elevations of plasma triglycerides may lead to pancreatitis and other complications.

Genitourinary

Vaginal Bleeding and Bleeding Irregularities

In the pivotal, controlled clinical study 7.7% of subjects on Seasonale discontinued medication prematurely due to unacceptable bleeding vs. 1.8% of subjects on the 28-day cycle regimen.

The following table shows the percentage of subjects with inter-menstrual bleeding and /or spotting.

Table 2. Percentage of Subjects with Inter-menstrual Bleeding and/or Spotting

* Based on spotting and/or bleeding on days 1-84 of a 91-day cycle in the Seasonale subjects and days 1-21 of a 28-day cycle over 4 cycles in the 28-day dosing regimen.

Persistent irregular vaginal bleeding requires assessment to exclude underlying pathology.

Fibroids

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

Hematologic

Epidemiological studies have shown that the incidence of VTE in users of oral contraceptives with low estrogen content (<50 µg ethinyl estradiol) ranges from about 20 to 40 cases per 100,000 women-years, but 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 venous thromboembolism (VTE) compared with no use. 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 pregnancies. 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, obesity, 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), systemic lupus erythematosus, hemolytic uremic syndrome, inflammatory bowel disease such as Crohn’s disease or ulcerative colitis, and sickle cell disease. The risk of VTE also increases with age and smoking. The risk of VTE may be temporarily increased with prolonged immobilization, major surgery or trauma. Also patients with varicose veins and leg cast should be closely supervised.

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

Hepatic/Biliary/Pancreatic

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.

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

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

Hepatic nodules

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.

Risk of ALT Elevations with Concomitant Hepatitis C Treatment

Discontinue Seasonale prior to starting therapy with the hepatitis C combination drug regimen glecaprevir/pibrentasvir and sofosbuvir/velpatasvir/voxilaprevir due to the potential for ALT elevations (see 2 CONTRAINDICATIONS).

Seasonale can be restarted approximately 2 weeks following completion of treatment with the Hepatitis C combination drug regimen.

Immune

Angioedema

Exogenous estrogens may induce or exacerbate symptoms of angioedema, in particular in women with hereditary and acquired angioedema.

Chloasma

Chloasma may occur with combination oral contraceptives use including Seasonale, especially in women with a history of chloasma gravidarum. Women who tend to develop chloasma should avoid exposure to the sun or ultraviolet radiation while taking Seasonale.

Gallbladder disease

Users of oral contraceptives have a greater risk of developing gallbladder disease requiring surgery within the first year of use. The risk may double after four or five years of use.

Monitoring and Laboratory Tests

Physical Examination and Follow-up

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

The first follow-up visit should be three months after the initiation of hormonal contraceptive therapy. Thereafter, examinations should be performed at least once a year, or more frequently if indicated. Women with a strong family history of breast cancer or who have breast nodules should be monitored with particular care. At each annual visit, examination should include those procedures that were done at the initial visit, as outlined above or as per the recommendations of the Canadian Task Force on the Periodic Health Examination.

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 oral contraceptives and evaluation of the cause. Women with migraine (particularly migraine with aura) who take combination oral contraceptives may be at an increased risk of stroke (see 2 CONTRAINDICATIONS).

Ophthalmologic

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

Peri-Operative Considerations

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

Psychiatric

Emotional Disorders/Depression

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

Renal

Fluid retention

Hormonal contraceptives may cause some degree of fluid retention. They should be prescribed with caution, and only with careful monitoring, in patients with conditions which might be aggravated by fluid retention.

Reproductive Health: Female Potential

Return to Fertility

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

Amenorrhea

Seasonale is a 91-day cyclic dosing regimen (84 days with active oral tablets of 0.15 mg levonorgestrel and 0.03 mg ethinyl estradiol, followed by 7 days with placebo tablets). In the case of unanticipated bleeding/spotting, missed withdrawal bleeding or amenorrhea, the possibility of pregnancy must be considered.

Women with 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, which continues for six months or more after withdrawal, warrants a careful assessment of hypothalamic-pituitary function.

7.1 Special Populations

7.1.1 Pregnant Women

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

7.1.2 Breast-feeding

In breast-feeding women, the use of hormonal contraceptives results in the hormonal components being excreted in breast milk and may reduce its quantity and quality. If the use of oral contraceptives is initiated after the establishment of lactation, there does not appear to be any effect on the quantity and quality of the milk.

A few adverse effects on the child have been reported, including jaundice and breast enlargement. The nursing mother should be advised not to use combination oral contraceptives, but to use other forms of contraception until she has completely weaned her child.

7.1.3 Pediatrics

Pediatrics (< 18 years of age): No data are available in women under the age of 18 years; therefore, Health Canada has not authorized an indication for pediatric use.

Use of this product before menarche is not indicated.

7.1.4 Geriatrics

Seasonale is not indicated for use in post-menopausal women.

8 ADVERSE REACTIONS

8.1 Adverse Reaction Overview

An increased risk of the following serious adverse reactions has been associated with the use of oral contraceptives:

• thrombophlebitis
• pulmonary embolism
• mesenteric thrombosis
• neuro-ocular lesions (e.g., retinal thrombosis)
• myocardial infarction
• cerebral thrombosis
• cerebral hemorrhage
• hypertension
• benign hepatic tumours
• gallbladder disease
• congenital anomalies

The following adverse reactions also have been reported in patients receiving oral contraceptives:

Nausea and vomiting, usually the most common adverse reaction, occurs in approximately 10 % or fewer of patients during the first cycle.

The following other reactions, as a general rule, are seen less frequently or only occasionally:

Blood and lymphatic system disorders: hemolytic uremic syndrome.

Ear and labyrinth disorders: auditory disturbances.

Eye disorders: cataracts, change in corneal curvature (steepening), retinal thrombosis, intolerance to contact lenses.

Gastrointestinal disorders: gastrointestinal symptoms (such as abdominal cramps and bloating), pancreatitis.

General disorders and administrative site conditions: edema.

Hepatobiliary disorders: cholestatic jaundice.

Infections and infestations: rhinitis, vaginal candidiasis, vaginitis.

Investigations: change in weight (increase or decrease), reduced tolerance to carbohydrates.

Metabolism and nutritional disorders: changes in appetite, porphyria.

Neoplasm benign, malignant and unspecified (including cysts and polyps): increase in size of uterine leiomyomata.

Nervous system disorders: chorea, dizziness, headache, migraine, optic neuritis.

Psychiatric disorders: changes in libido, mental depression, nervousness.

Renal and urinary disorders: cystitis-like syndrome, impaired renal function.

Reproductive system and breast disorders: breakthrough bleeding, spotting, change in menstrual flow, dysmenorrhea, amenorrhea during and after treatment, temporary infertility after discontinuation of treatment, breast changes (tenderness, enlargement, secretion), endocervical hyperplasia, possible diminution in lactation when given immediately postpartum, premenstrual like syndrome.

Skin and subcutaneous tissue disorders: chloasma or melasma which may persist, loss of scalp hair, hirsutism, erythema multiforme, erythema nodosum, hemorrhagic eruption, rash (allergic).

Vascular disorder: Raynaud’s phenomenon.

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.

Seasonale included 15,027 28-day equivalent cycles for the safety ITT data; 609 subjects completed 1 year treatment, 123 subjects completed 18 months treatment and 108 subjects completed 2 years treatment.

Two subjects had pulmonary embolism and one subject had myocardial infarction while on Seasonale in clinical studies.

The comparative safety data with a conventional monthly oral contraceptive containing similar strength synthetic estrogens and progestins on lipids profile were used as controls; liver functions and endometrial biopsies (50 subjects only) is available for one year only.

Study SEA-301 (A Phase III, Parallel, Randomized, Multicenter, Open-Label Clinical Study to Evaluate the Efficacy and Safety of Seasonale Extended Oral Contraceptive Therapy - 84-Day Active Cycle)

Table 3 shows the incidence rates for the most frequently reported adverse events for all treated patients with 1 year of treatment. The table displays results where the 5% or greater criterion was observed within any treatment group.

Table 3: Study SEA 301: Incidence of Most Frequently Reported Adverse Events Occurring in 5% or More Patients - All Treated Patients (ITT)

*Control: a conventional monthly oral contraceptive containing similar strength synthetic estrogens and progestins

Study SEA-301A (A Phase IIIb, Parallel, Multicenter, Open-Label Clinical Study To Evaluate The Safety Of Seasonale Extended Oral Contraceptive Therapy – 84-Day Active Cycle), is an extension study to Study SEA-301 providing an additional 2 years of safety data (n=189) for Seasonale [levonorgestrel levonorgestrel (150 μg); ethinyl estradiol (30 μg), oral]. The adverse reactions most commonly reported in Study SEA-301A were similar to those observed in Study SEA-301.

8.3 Less Common Clinical Trial Adverse Reactions

Less Common Clinical Trial Adverse Drug Reactions (≥1% to <5%)

Study SEA-301

Infections and Infestations: Urinary Tract Infection, Bronchitis, Pharyngitis Streptococcal, Ear Infection, Vaginitis Bacterial, Vaginosis Fungal, Bladder Infection, Pharyngitis, Vaginal Candidiasis.

Gastrointestinal Disorders: Abdominal Pain Upper, Vomiting, Dyspepsia, Toothache, Abdominal Pain, Diarrhoea, Abdominal Distension, Constipation.

Nervous System: Migraine, Dizziness (Excl. Vertigo), Sinus Headache.

Musculoskeletal and Connective Tissue Disorders: Muscle Cramps, Arthralgia, Pain In Limb, Myalgia, Neck Pain, Muscle Spasms, Tendonitis.

Reproductive System and Breast Disorders: Breast Tenderness.

Skin and Subcutaneous Tissue Disorders: Acne, Acne Aggravated, Rash.

General Disorders and Administration Site Conditions: Influenza Like Illness, Fatigue, Pain, Pyrexia, Chest Pain.

Respiratory, Thoracic and Mediastinal Disorder: Sinus Congestion, Cough, Nasal Congestion, Asthma.

Psychiatric Disorders: Depression, Insomnia, Mood Swings, Libido Decreased.

Injury, Poisoning and Procedural Complications: Muscle Strain, Post Procedural Pain, Accident, Road Traffic Accident.

Investigations: Weight Increased.

Immune System Disorders: Hypersensitivity, Seasonal Allergy.

Ear and Labyrinth Disorders: Ear Pain.

Less Common Clinical Trial Adverse Drug Reactions (< 1 %)

Study SEA-301

Infections and Infestations: Tonsillitis, Tooth Abscess, Cervicitis, Gastroenteritis Viral, Cystitis, Gastroenteritis, Herpes Simplex, Herpes Viral Infection, Herpes Zoster, Lice Infestation, Lower Respiratory Tract Infection, Meningitis Viral, Pneumonia, Staphylococcal Infection, Tooth Infection, Upper Respiratory Tract Infection Viral, Bacterial Infection, Eye Infection, Furuncle (Excl Genital), Genital Warts, Gingival Abscess, Kidney Infection, Laryngitis, Localised Infection, Lyme Disease, Malaria, Nail Fungal Infection, Oral Candidiasis, Otitis Media, Pertussis, Respiratory Tract Infection, Sinusitis Acute, Skin Bacterial Infection, Stye, Upper Respiratory Tract Infection, Vaginal Infection, Vaginitis, Viral Infection, Vulvitis, Wound Infection.

Gastrointestinal Disorders: Flatulence, Gastro-Oesophageal Reflux Disease, Abdominal Pain Lower, Gastric Ulcer, Tooth Disorder, Abdominal Discomfort, Colitis, Colon Spastic, Constipation Aggravated, Dry Mouth, Gastrointestinal Upset, Hemorrhoidal Bleeding, Hiatus Hernia, Inguinal Hernia, Irritable Bowel Syndrome, Oral Pain, Rectal Haemorrhage, Salivary Gland Calculus.

Nervous System: Tension Headaches, Hypoaesthesia, Headache Aggravated, Migraine Aggravated, Cluster Headaches, Disturbance In Attention, Facial Palsy, Paraesthesia, Sciatica, Syncope, Vasovagal Attack.

Musculoskeletal and Connective Tissue Disorders: Bursitis, Joint Swelling, Arthritis, Bone Disorder, Plantar Fasciitis, Bone Spur, Intervertebral Disc Herniation, Musculoskeletal Chest Pain, Neck Stiffness, Rotator Cuff Syndrome, Swelling, Temporomandibular Joint Disorder.

Reproductive System and Breast Disorders: Breast Enlargement, Dyspareunia, Premenstrual Syndrome, Oligomenorrhoea, Pelvic Pain, Uterine Cervix Ulcer, Vaginal Discharge, Vulvovaginal Dryness, Breast Discharge, Breast Fibrosis, Cervical Cyst, Genital Rash, Ovarian Cyst, Ovarian Pain, Post-Coital Bleeding, Uterine Cervical Disorder, Uterine Cyst, Vaginal Irritation, Vaginal Odour, Vulval Disorder.

Skin and Subcutaneous Tissue Disorders: Genital Pruritus Female, Night Sweats, Pruritus, Contusion, Dermatitis Atopic, Skin Cysts, Urticaria, Alopecia, Dermatitis Contact, Eczema, Erythema, Onychoclasis, Rash Papular, Skin Disorder, Skin Lesion, Skin Ulcer, Solar Urticaria, Sweating Increased.

General Disorders and Administration Site Conditions: Facial Pain, Analgesic Effect, Fatigue Aggravated, Feeling Hot, Groin Pain, Injection Site Pain, Limb Discomfort, Oedema Lower Limb, Thirst.

Respiratory, Thoracic and Mediastinal Disorder: Rhinitis, Upper Respiratory Tract Congestion, Asthma Aggravated, Nasal Sinus Drainage, Pulmonary Congestion, Rhinitis Allergic, Sinus Pain, Chest Wall Pain, Dyspnoea, Postnasal Drip, Rhinitis Atrophic, Rhinitis Seasonal, Sinus Disorder.

Psychiatric Disorders: Anxiety, Irritability, Mood Alteration, Attention Deficit/Hyperactivity Disorder, Bipolar I Disorder, Emotional Disturbance, Loss Of Libido, Nervousness, Obsessive-Compulsive Disorder, Panic Attack, Sleep Disorder, Stammering.

Injury, Poisoning and Procedural Complications: Arthropod Bite, Joint Sprain, Back Injury, Limb Injury, Animal Bite, Bite, Burns, Burns Second Degree, Caustic Injury, Concussion, Ear Canal Abrasion, Facial Bones Fracture, Foot Fracture, Gun Shot Wound, Hand Fracture, Laceration, Ligament Injury, Ligament Sprain, Nerve Injury, Post-Traumatic Wound, Infection, Sunburn, Whiplash Injury.

Investigations: Smear Cervix Abnormal, Weight Decreased, Blood Cholesterol Increased, Blood Pressure Increased, Blood Urine Present, Colonoscopy, Heart Rate Increased, Helicobacter Pylori, Antibody Positive, Lipids Increased, Liver Function Tests Abnormal, White Blood Cell Count Increase.

Immune System Disorders: Allergy Aggravated, Drug Hypersensitivity, Allergy to Insect Sting, Food Allergy.

Ear and Labyrinth Disorders: Motion Sickness, Ear Congestion, Eustachian Tube Disorder, Labyrinthitis, Sensation of Block in Ear, Vertigo.

Surgical and Medical Procedures: Tooth Extraction, Eye Operation, Breast Operation, Cervical Cautery, Cholecystectomy, Dental Operation, Knee Operation, Ligament Repair.

Blood and Lymphatic System Disorders: ABO Haemolytic Disease of Newborn, Anaemia, Lymphadenopathy, Iron Deficiency Anaemia, Mononucleosis Syndrome.

Vascular Disorders: Carotid Artery Occlusion, Hot Flushes, Hypertension.

Eye Disorders: Conjunctivitis, Vision Blurred, Conjunctival Hyperaemia, Corneal Ulcer, Eye Irritation, Lacrimal Disorder, Pterygium, Retinal Detachment.

Metabolism and Nutrition Disorders: Appetite Increased, Fluid Retention, Hunger.

Neoplasms Benign, Malignant and Unspecified (Incl. Cysts and Polyps): Breast Lump, Basal Cell Carcinoma, Fibrocystic Breast Disease.

Renal and Urinary Disorders: Loin Pain, Urinary Frequency, Urine Odour Foul.

Cardiac Disorders: Palpitations, Palpitations Aggravated.

Endocrine Disorders: Goitre.

Hepatobiliary Disorders: Cholecystitis.

Less common adverse reactions reported in Study SEA-301A (2-year duration) were similar to those observed in Study SEA-301 (1-year duration).

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data

In study SEA-301 (1-year trial), for triglycerides, the percentage of patients on Seasonale going from normal to high was 6.2% compared to that of 1.9% for patients on control (median increase of 136 (43.6%) for Seasonale patients compared to 206 (63.1%) for control patients). For LDL, 17.9% of patients on Seasonale shifted from normal to high values, compared to that of 14.6% for patients on control (median increase in LDL of 40 (27.2%) for Seasonale patients compared to an increase of 37 (22.8%) for control patients). The percentage of Seasonale patients who went from normal to high for total cholesterol was 22.1% compared to that of 23.4% for patients on control (median increase of 37 (17.2%) for Seasonale patients compared to 29 (13.3%) for control patients).

In study SEA-301A (2-year extension trial of SEA-301 with no control), 5 subjects had increase in cholesterol/LDL or triglycerides above the normal ranges among 173 tested Seasonale subjects. Seven subjects had increase in liver enzymes above the normal range excluding the subject with large common bile duct stone.

The coagulation profile was not studied with this Seasonale regimen.

8.5 Post-Market Adverse Reactions

The following other serious and unexpected adverse events have been reported in users of Seasonale in the post marketing period. These adverse events are compiled from spontaneous reports and are listed regardless of frequency and whether or not a causal relationship with Seasonale has been established.

Blood and Lymphatic System Disorders: Anaemia.

Cardiac Disorders: Cardiac Arrest, Myocardial Infarction, Supraventricular Tachycardia.

Congenital, Familial and Genetic Disorders: Arnold-Chiari Malformation, Bicuspid Aortic Valve, Brain Malformation, Patent Ductus Arteriosus, Spina Bifida, Talipes.

Endocrine Disorders: Hyperprolactinaemia.

Gastrointestinal Disorders: Colitis Ischemic.

Musculoskeletal and Connective Tissue Disorders: Acquired Macrocephaly, Muscle Mass.

Neoplasms Benign, Malignant and Unspecified (Incl. Cysts and Polyps): Renal Neoplasm.

Nervous System Disorders: Brain Damage, Convulsion, Epilepsy, Hydrocephalus, Hypotonia, Stroke.

Pregnancy, Puerperium and Perinatal Conditions: Abortion Spontaneous, Intra-Uterine Death.

Psychiatric Disorders: Suicidal Ideation.

Renal and Urinary Disorders: Neurogenic Bladder.

Reproductive System and Breast Disorders: Cervical Polyp, Dysfunctional Uterine Bleeding, Pelvic Pain, Vaginal Haemorrhage.

Skin and Subcutaneous Tissue Disorders: Acute Febrile Neutrophilic Dermatosis, Leukocytoclastic Vasculitis, Skin Lesion.

Vascular Disorders: Deep vein thrombosis, Pulmonary Embolism.

9 DRUG INTERACTIONS

9.2 Drug Interactions Overview

The concurrent administration of oral contraceptives with other drugs may result in an altered response to either agent (see Tables 7 and 8). Reduced effectiveness of the oral contraceptive, should it occur, is more likely with the low-dose formulations. It is important to ascertain all drugs that a patient is taking, both prescription and non-prescription, before oral contraceptives are prescribed.

9.3 Drug-Behavioural Interactions

Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives should be strongly advised not to smoke.

9.4 Drug-Drug Interactions

The drugs listed in Tables 7 and 8 are based on either drug interaction case reports or studies, or potential interactions due to the expected magnitude and seriousness of the interaction (i.e., those identified as contraindicated).

Refer to Oral Contraceptives 1994 (Chapter 8), Health Canada, for possible drug interactions with hormonal contraceptives.

Several of the anti-HIV protease inhibitors have been studied with co-administration of combination oral contraceptives; significant changes (increase and decrease) in the mean AUC of the estrogen and progestogen have been noted in some cases. The efficacy and safety of oral contraceptive products may be affected. Healthcare providers should refer to the label of the individual anti-HIV protease inhibitor for further drug-drug interaction information.

9.5 Drug-Food Interactions

Interactions with food have not been established.

9.6 Drug-Herb Interactions

Herbal products containing St. John’s Wort (hypericum perforatum) may induce hepatic enzymes (cytochrome P450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids. This may also result in breakthrough bleeding.

9.7 Drug-Laboratory Test Interactions

Laboratory Tests

Results of laboratory tests should be interpreted with the knowledge that the patient is taking an oral contraceptive.

The following laboratory tests are modified:

A. Liver Function Tests

Aspartate serum transaminase (AST) - variously reported elevations

Alkaline phosphatase and gamma-glutamyl transferase (GGT) - slightly elevated.

B. Coagulation Tests

Minimal elevation of test values reported for such parameters as prothrombin and Factors VII, VIII, IX and X.

C. Thyroid Function Tests

Protein binding of thyroxine is increased as indicated by increased total serum thyroxine concentrations and decreased T3 resin uptake.

D. Lipoproteins

Small changes of unproven clinical significance may occur in lipoprotein cholesterol fractions.

E. Gonadotropins

LH and FSH levels are suppressed by the use of oral contraceptives. Wait two weeks after discontinuing the use of oral contraceptives before measurements are made.

F. Glucose tolerance

Oral glucose tolerance remained unchanged or was slightly decreased.

Tissue Specimens

Pathologists should be advised of hormonal contraceptive use when specimens from surgical procedures and/or Pap smears are submitted for examination.

10 CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

Combination oral contraceptives act by suppression of gonadotropins. Although the primary mechanism of this action is inhibition of ovulation, other alterations include changes in the cervical mucus (which increase the difficulty of sperm entry into the uterus) and changes in the endometrium (which reduce the likelihood of implantation).

10.2 Pharmacodynamics

Norgestrel is a racemate containing equal parts of D- and L- enantiomers. The L-enantiomer has been tested in a broad range of biological assays and its inactivity has been confirmed. The D-enantiomer (named levonorgestrel) accounts for all the biological activity found in norgestrel, as levonorgestrel was twice as potent as the racemate in experiments in which norgestrel was effective.

10.3 Pharmacokinetics

Absorption: No specific investigation of the absolute bioavailability of Seasonale in humans has been conducted. However, published literature indicates that levonorgestrel is rapidly and completely absorbed after oral administration (bioavailability nearly 100%) and is not subject to first-pass metabolism. Ethinyl estradiol is rapidly and almost completely absorbed from the gastrointestinal tract but, due to first-pass metabolism in gut mucosa and liver, the bioavailability of ethinyl estradiol is approximately 43%.

The effect of food on the rate and extent of absorption of levonorgestrel and ethinyl estradiol following oral administration of Seasonale has not been evaluated.

The mean plasma pharmacokinetic parameters of Seasonale following a single dose of two tablets in normal healthy women under fasting conditions are reported in Table 9.

Table 9: Summary of Mean ± SD Pharmacokinetic Parameters Following a Single Dose Administration of Seasonale in Healthy Female Subjects Under Fasting Conditions

Distribution: The apparent volume of distribution of levonorgestrel and ethinyl estradiol are reported to be approximately 1.8 L/kg and 4.3 L/kg, respectively. Levonorgestrel is about 97.5-99% protein-bound, principally to the sex hormone binding globulin (SHBG) and, to a lesser extent, serum albumin. Ethinyl estradiol is about 95-97% bound to serum albumin. Ethinyl estradiol does not bind to SHBG, but induces SHBG synthesis, which leads to decreased levonorgestrel clearance. Following repeated daily dosing of combination levonorgestrel and ethinyl estradiol oral contraceptives, levonorgestrel plasma concentrations accumulate more than when predicted based on single-dose kinetics, due in part, to increased SHBG levels that are induced by ethinyl estradiol and a possible reduction in hepatic metabolic capacity.

Metabolism: Following absorption, levonorgestrel is conjugated at the 17β-OH position to form sulfate and to a lesser extent, glucuronide conjugates in plasma. Significant amounts of conjugated and unconjugated 3α,5β-tetrahydrolevonorgestrel are also present in plasma, along with much smaller amounts of 3α,5α-tetrahydrolevonorgestrel and 16β-hydroxylevonorgestrel. Levonorgestrel and its Phase I metabolites are excreted primarily as glucuronide conjugates. Metabolic clearance rates may differ among individuals by several-fold, and this may account in part for the wide variation observed in levonorgestrel concentrations among users.

First-pass metabolism of ethinyl estradiol involves formation of ethinyl estradiol-3-sulfate in the gut wall followed by 2-hydroxylation of a portion of the remaining untransformed ethinyl estradiol by hepatic CYP3A4. Levels of CYP3A4 vary widely among individuals and can explain the variation in rates of ethinyl estradiol hydroxylation. Hydroxylation at the 4-, 6- and 16- positions may also occur, although to a much lesser extent than 2-hydroxylation. The various hydroxylated metabolites are subject to further methylation and/or conjugation.

Elimination: About 45% of levonorgestrel and its metabolites are excreted in the urine and about 32% are excreted in feces, mostly as glucuronide conjugates. The terminal elimination half-life for levonorgestrel after a single dose of Seasonale was found to be about 30 hours.

Ethinyl estradiol is excreted in the urine and feces as glucuronide and sulfate conjugates and it undergoes enterohepatic recirculation. The terminal elimination half-life of ethinyl estradiol after a single dose of Seasonale was found to be about 15 hours.

Special Populations and Conditions

Pediatrics: The safety and efficacy of Seasonale has not been established in women under the age of 18 years. Use of this product before menarche is not indicated.

Geriatrics: Seasonale is not indicated for use in post-menopausal women.

Genetic Polymorphism: No data are available.

Ethnic Origin: No formal studies on the effect of race on the pharmacokinetics of Seasonale have been conducted.

Hepatic Insufficiency: No formal studies have been conducted to evaluate the effect of hepatic disease on the pharmacokinetics of Seasonale. However, steroid hormones may be poorly metabolized in patients with impaired liver function.

Renal Insufficiency: No formal studies have been conducted to evaluate the effect of renal disease on the pharmacokinetics of Seasonale.

11 STORAGE, STABILITY AND DISPOSAL

Store at room temperature (15 to 30 °C).

Keep out of the reach of children and pets.

12 SPECIAL HANDLING INSTRUCTIONS

Not applicable.

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Levonorgestrel

Ethinyl Estradiol

Chemical name: Levonorgestrel: 13β-ethyl-17β-hydroxy-18,19-dinor-17α-pregn-4-en-20-yn-3-one

Ethinyl Estradiol: 17α-Ethynyl-1,3,5(10)-estratriene-3,17-β-diol

Molecular formula and molecular mass: Levonorgestrel: C₂₁H₂₈O₂, 312.45

Ethinyl Estradiol: C₂₀H₂₄O₂, 296.40

Structural formula:

Levonorgestrel:

Ethinyl Estradiol:

Physicochemical properties:

Solubility:

Levonorgestrel: Slightly soluble in alcohol, insoluble in water

Ethinyl Estradiol: Insoluble in water, soluble in alcohol, chloroform, ether, vegetable oil and in alkaline solutions

Melting points:

Levonorgestrel: 234-240 °C

Ethinyl Estradiol: 180-186 °C

Biological properties:

Levonorgestrel: This is a synthetic progestogen in the (-)-isomer of norgestrel. It is the biologically active form of the racemic norgestrel.

Ethinyl Estradiol: This is a synthetic estrogen.

14 CLINICAL TRIALS

General Information

The following table gives reported pregnancy rates for various forms of birth control, including no birth control. The reported rates represent the number of women out of 100 who would become pregnant in one year.

Reported Pregnancies per 100 Women per Year:

Combination pill less than 1 to 2

Intrauterine device (IUD) less than 1 to 6

Condom with spermicidal foam or gel 1 to 6

Mini-pill 3 to 6

Condom 2 to 12

Diaphragm with spermicidal foam or gel 3 to 18

Spermicide 3 to 21

Sponge with spermicide 3 to 28

Cervical cap with spermicide 5 to 18

Periodic abstinence (rhythm), all types 2 to 20

No birth control 60 to 85

14.1 Clinical Trials by Indication

Prevention of pregnancy

Table 10 - Summary of patient demographics for clinical trials in the prevention of pregnancy

*Control: a conventional monthly oral contraceptive containing similar strength synthetic estrogens and progestins

In a one year (4 x 91-day cycles) multicenter open-label clinical trial, 456 women 18 to 40 years of age, were studied to assess the safety and efficacy of SEASONALE. The racial demographic of all enrolled women was: Caucasian (76.97%), African-American (10.96%), Hispanic (7.02%), Asian (2.19%), and Other (2.85%). The weight range for these women treated was 84 to 304 lb (BMI: 14.47 to 45.29), with a mean weight of 156.39 lb (BMI: 26.16). Among the women in the trial, 18.86% were current smokers; 63.16% were continuous users of oral contraceptives, 28.95% were prior users of oral contraceptives, and 7.68% were fresh starts.

The demographics of women receiving Nordette (N=226) were similar to those receiving Seasonale.

Study results

In a 1-year controlled clinical trial, 4 pregnancies occurred in women 18-35 years of age during 809 completed 91-day cycles of Seasonale during which no backup contraception was utilized. This represents an overall use-efficacy Pregnancy rate of 1.98 per 100 women-years of use.

15 MICROBIOLOGY

Not applicable.

16 NON-CLINICAL TOXICOLOGY

General Toxicology:

Levonorgestrel and ethinyl estradiol have been extensively studied and are well-characterized pharmaceuticals. These approved pharmaceuticals in combination are both safe and effective when indicated for the prevention of pregnancy.

Carcinogenicity:

The association of mammary tumours in beagle dogs and steroid contraceptive use has been extensively reported in the published literature. Much of the published literature looked at the suitability of the beagle dog as a test model to assess the tumourigenic potential of certain progestogens in inducing mammary tumours and comparing it to the human model. Early toxicology studies in beagle dogs showed the overall incidence of mammary tumours were more common and frequent by a factor of three to four than in women. However, the beagle dog differs significantly from other animal species and humans mainly due to its differences in reproductive physiology and endocrinology. The beagle dog species are more susceptible to show mammary tumours as they have a fairly high natural incidence of mammary cancer. Some of the published literature has reported that many of the more potent progestogens have been shown to induce mammary tumours compared to the less potent progestational compounds. Evidence has shown that long-term administration of norgestrel has less progestational activity and incidence of mammary tumours over more potent progestogens.

Steroid-related canine mammary tumours were unlikely to be indicative of a potential hazard to women.