Esme 21 Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

ESME 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):

ESME is not indicated for use in postmenopausal women.

Pediatrics (< 16 years of age):

Safety and efficacy of ESME 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 ESME. 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)
• Use with the anti-viral Hepatitis C Virus (HCV) combination drug regimen ombitasvir, paritaprevir, ritonavir and dasabuvir, with or without ribavirin (see WARNINGS AND PRECAUTIONS: Hepatic/Biliary/Pancreatic and DRUG INTERACTIONS).

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:

A. Thromboembolic and cardiovascular disorders, such as

thrombophlebitis, pulmonary embolism, cerebrovascular disorders, myocardial ischemia, mesenteric ischemia, mesenteric thrombosis and retinal thrombosis.

B. Conditions that predispose to venous stasis and to vascular thrombosis (e.g. immobilization after accidents or confinement to bed during long-term illness). Other 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.

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.

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

ESME 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

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

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

Hepatitis C

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

Gallbladder Disease

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

Jaundice

Patients who have had jaundice, should be given oral contraceptives only with great care and under close observation. Oral contraceptive-related cholestasis has been described in women with a history of pregnancy-related cholestasis. Women with a history of cholestasis may have the condition recur with subsequent hormonal contraceptive use, and in this instance, ESME 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 ESME, 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 ESME tablets have been established in women of reproductive age. Use of this product before menarche is not indicated.

Geriatrics (> 65 years of age)

ESME is not indicated for use in postmenopausal women.

Monitoring and Laboratory Tests

Physical Examination and Follow-up

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

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 Levonorgestrel and Ethinyl Estradiol Tablets was compared with that of placebo. Treatment-emergent adverse events that were reported by ≥ 2% of patients in either treatment group are presented in Table 2.

As expected, menstrual-related events were more frequent in women treated with Levonorgestrel and Ethinyl Estradiol Tablets 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 Levonorgestrel and Ethinyl Estradiol Tablets.

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 ESME. 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

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.

There have been reports of pregnancy when COCs were co-administered with certain antibiotics (e.g., ampicillin and other penicillins, tetracyclines).

Concomitant use with the combination drug regimen ombitasvir, paritaprevir, ritonavir and dasabuvir, with or without ribavirin may increase the risk of ALT elevations (see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS:

Hepatic/Biliary/Pancreatic). Therefore, COC users must switch to an alternative method of contraception (e.g., progestagen-only contraception or non-hormonal methods) prior to starting therapy with anti-viral HCV drug combinations such as ombitasvir, paritaprevir, ritonavir, and dasabuvir with or without ribavirin. COCs can be restarted 2 weeks following completion of treatment with an anti-viral HCV medicinal product.

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

*Adapted from Dickey, RP, ed.: Managing Contraceptive Pill Patients, 5^th 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

*Adapted from Dickey, RP, ed.: Managing Contraceptive Pill Patients, 5^th 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 GGT Minor increase

Alkaline Phosphatase Variable increase

Serum Bilirubin Increased, particularly in conditions predisposing to or associated with hyperbilirubinemia

Coagulation Tests

Factors II, VII, IX, X, XII and XIII Increased

Factor VIII Mild increase

Platelet aggregation and adhesiveness Mild increase in response to common aggregating agents

Fibrinogen Increased

Plasminogen Mild increase

Antithrombin III Mild decrease

Prothrombin Time Decreased

Thyroid Function Tests

Protein-bound Iodine (PBI) Increased

Total Serum Thyroxine (T3 andT4) Increased

Thyroid Stimulating Hormone (TSH) Unchanged

Free T3 Resin Uptake Decreased

Adrenocortical Function Tests

Plasma Cortisol Increased

Cortisol Binding Globulin Increased

Dehydroepiandrosterone sulfate (DHEAS) Decreased

Miscellaneous Tests

Serum Folate Occasionally decreased

Glucose Tolerance Test Variable decrease with return to normal after

6 to 12 months

Insulin Response Mild to moderate decrease

c-Peptide Response Mild 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. 1. Combination oral contraceptives reduce the incidence of cancer of the endometrium and ovaries.
2. 2. Oral contraceptives reduce the likelihood of developing benign breast disease and, as a result may decrease the incidence of breast biopsies.
3. 3. Oral contraceptives reduce the likelihood of development of functional ovarian cysts.
4. 4. Pill users have less menstrual blood loss and have more regular cycles thereby, reducing the chance of developing iron-deficiency anemia.
5. 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. 6. Oral contraceptives decrease the incidence of acute pelvic inflammatory disease and reduce the incidence of ectopic pregnancy.
7. 7. Oral contraceptives have potential effects on endometriosis.

DOSAGE AND ADMINISTRATION

Recommended Dose and Dosage Adjustment

CONTRACEPTION:

ESME 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 ESME 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 ESME 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 ESME.

The patient begins her next and all subsequent 21-day courses of ESME 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.

ESME 28 TABLETS REGIMEN:

Each cycle consists of 21 days of pink ESME Tablets (active tablets) followed by 7 days of green inert tablets (three weeks on ESME, one week on inert tablets).

The dosage of ESME 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 green tablet is taken daily for the following seven consecutive days. Withdrawal bleeding should usually occur within three days following the discontinuation pink ESME Tablets, i.e., during the week the patient is taking the green inert tablets.

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

ACNE

The timing of initiation of ESME treatment for acne should follow the instructions for use of ESME 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.

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 ESME Tablets be taken at the same time each day, preferably after the evening meal or at bedtime.

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

If ESME 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 ESME 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 ESME 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 ESME the next day. She should start ESME on the day that a progestin-only implant or a progestin-only IUD is removed. ESME 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 ESME 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

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

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.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

Oral Contraception:

Although the primary mechanism of action is inhibition of ovulation, the effectiveness of ESME 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 levonorgestrel and ethinyl estradiol leads to decreased ovarian production of the androgens, including androstenedione. Levonorgestrel and ethinyl estradiol also significantly reduces bioavailable serum testosterone by preserving the estrogen-induced increases in sex hormone binding globulin (SHBG).^14,30 In addition, levonorgestrel and ethinyl estradiol decreases serum levels of 3β-androstanediol glucuronide (a marker of peripheral 5 β-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):

ESME is not indicated for use in postmenopausal women.

Pediatrics (< 16 years of age):

Safety and efficacy of ESME 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.

ESME 21 and ESME 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

^Pr ESME Tablets are available in 21-day regimen (ESME 21) and 28-day regimen (ESME 28) in blister packs.

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

Each pink, round flat tablet with beveled edges, debossed with “405” on one side and plain on the other side contains croscarmellose sodium, ferric oxide red, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone and sodium lauryl sulfate.

Each inactive green, round, flat tablet with beveled edges, debossed with “471” on one side and plain on the other side (in ESME 28) contains croscarmellose sodium, FD&C Blue No. 1 aluminum lake (aluminium chloride, aluminium hydroxide, brilliant blue), ferric oxide (yellow), lactose monohydrate, magnesium stearate, microcrystalline cellulose and povidone.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Levonorgestrel Ethinyl Estradiol Chemical name (Index): Levonorgestrel: 18,19-Dinorpregn-4-en-20-yn-3-one,13-ethyl-

17-hydroxy-,(17α)-(-)- Ethinyl Estradiol: 19-Norpregna-1,3,5(10)-trien-20-yne-3,17- diol,(17 α)-

Molecular formula and

molecular mass:

Levonorgestrel: C₂₁H₂₈O₂

Ethinyl Estradiol: C₂₀H₂₄O₂ Levonorgestrel: 312.45 g/mol Ethinyl Estradiol: 296.40 g/mol

Structural formulae:

Levonorgestrel

Ethinyl Estradiol

Physicochemical properties:

Description Levonorgestrel: A white or almost white, crystalline powder Ethinyl

Estradiol:

White or slightly yellowish-white crystalline powder

Solubility: Levonorgestrel: Practically insoluble in water and n-hexane, slightly soluble in acetone and ethanol, sparingly soluble in dichloromethane and soluble in chloroform.

Ethinyl

Estradiol:

Freely soluble in ether, ethanol, acetone, dioxane, soluble in alkali hydroxide solutions, sparingly soluble in chloroform and practically insoluble in water.

Melting Point: Levonorgestrel: Between 232° C and 239°C (range should not exceed 4°C)

Ethinyl

Estradiol:

Ethinylestradiol is found to exist in an anhydrated form and a hemihydrate. The anhydrated form melts between 180°C and 185°C (according to USP: 180°C to 186°C). The hemihydrate melts between 145°C and 152°C. (In the USP monograph the melting range 142 to 146°C is assigned to a second polymorphic form, which corresponds to the melting range of the hemihydrate).

Biological Properties: Levonorgestrel: A unique, totally synthetic progestogen.

Levonorgestrel is the International Nonproprietary Name for this biologically active enantiomer of norgestrel.

Ethinyl

Estradiol:

A semisynthetic estrogen. The presence of the ethinyl group at C 17 on ring D of the steroid nucleus prevents enzymatic degradation of the estradiol molecule and results in an orally active compound.

CLINICAL TRIALS

COMPARATIVE BIOAVAILABILITY STUDY

A two-way blinded, single-dose, randomized, two-period, two-treatment, crossover, fasting bioequivalence study of ESME^TM (100 mcg levonorgestrel and 20 mcg ethinyl estradiol) tablets versus Alesse^® tablets (100 mcg levonorgestrel and 20 mcg ethinyl estradiol) was conducted in 34 healthy, adult female subjects. Thirty one subjects completed the study. One subject withdrew from the study for personal reasons and two subjects were discontinued due to an adverse event (vomiting).

Results from a randomized, two-way, cross-over comparative bioavailability study in which the rate and extent of absorption of levonorgestrel and ethinyl estradiol were determined and compared following the oral administration of either Mylan Pharmaceuticals ULC’s levonorgestrel and ethinyl estradiol tablets, 0.1 mg/0.02 mg or Wyeth’s Alesse^® Tablets, 0.1 mg/0.02 mg to healthy female volunteers under fasting conditions.

Geometric Mean and Arithmetic Mean (%CV) Levonorgestrel Pharmacokinetic Parameters in Thirty-one Healthy Adult Female Subjects Following a Single Oral 0.2 mg/0.04 mg (2 x 0.1 mg/0.02 mg) Dose of Levonorgestrel and Ethinyl Estradiol Tablets under Fasting Conditions.

^* Levonorgestrel and Ethinyl Estradiol 0.1 mg/0.02 mg tablets, Mylan Pharmaceuticals ULC ^† Alesse^® 0.1 mg/0.02 mg tablets, Wyeth Canada, were purchased in Canada.

Source: Module 5, Table 14.2, and Appendix 16.2.6.1

Geometric Mean and Arithmetic Mean (%CV) Ethinyl Estradiol Pharmacokinetic Parameters in Thirty-one Healthy Adult Female Subjects Following a Single Oral 0.2 mg/0.04 mg (2 x 0.1 mg/0.02 mg) Dose of Levonorgestrel and Ethinyl Estradiol Tablets under Fasting Conditions.

^* Levonorgestrel and Ethinyl Estradiol 0.1 mg/0.02 mg tablets, Mylan Pharmaceuticals ULC ^† Alesse^® 0.1 mg/0.02 mg tablets, Wyeth Canada, were purchased in Canada. Source: Module 5, Table 14.3, and Appendix 16.2.6

This study demonstrates that ESME^TM (100 mcg levonorgestrel and 20 mcg ethinyl estradiol) tablets are bioequivalent to Wyeth’s Alesse^® tablets (100 mcg levonorgestrel and 20 mcg ethinyl estradiol) following a single, oral 0.2 mg/0.04 mg (2 x 0.1 mg/0.02 mg) dose administered under fasting conditions.

ORAL CONTRACEPTION

A total of 1477 patients completed 7,720 cycles with the drug over 15 months of use. In this study 5 pregnancies were reported which could be attributed to medication failure. Based on 13 cycles per year, the Pearl Index was 0.84. Four additional subjects were pregnant before receiving the study medication. Five other pregnancies occurred which were associated with omission of tablets for more than three consecutive days of study medication or stopped taking the study medication (return to fertility).

The mean cycle length, excluding cycle 1, was 29.1 days, and 90% of the cycles ranged in duration from 26 to 30 days. The withdrawal bleeding period during this monophasic regimen was between 3 and 7 days in 86% of cycles, and the mean bleeding intensity was light for the most common episode lengths (between 4 and 6 days).

Breakthrough bleeding alone and spotting alone occurred during 4.3% and 12.1% of cycles, respectively. Breakthrough bleeding and spotting occurred during 11.0% of the cycles, while breakthrough bleeding and/or spotting occurred during 27.3% of the cycles. The medication should not be halted during intermenstrual bleeding. If the bleeding persists, the usual diagnostic procedures should be undertaken to determine the cause of the vaginal bleeding.

The incidence of amenorrhea was low with the use of Levonorgestrel and Ethinyl Estradiol Tablets (see ADVERSE REACTIONS: Clinical Trials Adverse Drug Reactions: Table 1). If one period is missed, however, appropriate diagnostic procedures should be undertaken to rule out pregnancy and medication should be discontinued during this time, and an alternate method of contraception employed.

Clinical Laboratory Results:

Out-of-range clinical laboratory test values were flagged in the database and examined by the medical monitors to assess the clinical importance of these findings. Most of the abnormal values during therapy represented either transient or minimal changes from baseline and had no clinical importance.

Endometrial Biopsy: Endometrial biopsies were scheduled during the late luteal phase (last 7 days) of the pretreatment cycle and during days 15 to 21 of specified treatment cycles. Of the twenty-seven subjects who underwent a biopsy, twenty-four subjects had a secretory or proliferative endometrium before treatment. During treatment, most specimens were characterized as secretory, proliferative, or hypoplastic. None of the subjects had endometrial hyperplasia. The results of this study show that the effects of the monophasic regimen of levonorgestrel/ethinyl estradiol 100 mcg/20 mcg on the endometrium were consistent with those seen with other low-dose oral contraceptives.

Results of Cervical Cytologic Studies: Of the 1,477 subjects, 1,240 (84%) subjects had normal Pap smears at baseline. During the study and at any later period (including poststudy), the percentage of subjects with normal smears was always greater than 75%. Epithelial abnormalities noted during the study were mostly atypical squamous cells of undetermined significance (ASCUS) smears, with a few indicating low-grade squamous intraepithelial lesion (SIL). Two subjects developed high-grade SIL during the study and were referred for further evaluation and treatment. These two subjects were withdrawn from the study because of protocol violation. One additional subject was listed as having a cervical neoplasm. Further examination 5 months later showed that her Pap smear was normal.

No microinvasive or invasive cancers were noted at any time throughout the study.

Vital Signs and Weight Gain: More than 97% of the subjects had normal BP (systolic BP ≤ 140 mm Hg; diastolic BP ≤ 90 mm Hg) at baseline and during treatment. Seven subjects (< 1%) withdrew because of elevated blood pressure.

Of the six subjects who discontinued because of weight gain, only one subject had an increase of more than 10% from her prestudy weight. Forty-one subjects gained more than 10% of their baseline weight and 17 subjects lost more than 10% of their baseline weight. These fluctuations in body weight were not considered clinically significant.

ACNE

In two randomized, placebo-controlled, 6-cycle, multicenter clinical trials in 721 women with moderate acne, treatment with Levonorgestrel and Ethinyl Estradiol Tablets in 359 women produced significant mean percent reductions in the number of inflammatory lesions, and in the overall total number of lesions compared with women treated with placebo (Figure 1).

In addition, improvement in the clinical global assessment of acne at the end of the study was also greater in patients treated with Levonorgestrel and Ethinyl Estradiol Tablets than with placebo (see CLINICAL TRIALS: Acne: Table 5).

Table 5: Clinician Global Assessment at Cycle-6 and End of Study Analyses for Combined

Intent-To-Treat Population

a: Last observation carried forward (LOCF).

In these acne studies, ^{14, 15} the measured weight change and the incidence of some adverse events commonly attributed to OC use (such as nausea, breast tenderness, headache) were similar in women treated with Levonorgestrel and Ethinyl Estradiol Tablets and with placebo (see ADVERSE REACTIONS: Clinical Trials Adverse Drug Reactions: Table 2).

DETAILED PHARMACOLOGY

Animal Pharmacology

Norgestrel is a racemate, composed of 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.

Intensive biological investigations have been carried out with norgestrel alone and in combination with ethinyl estradiol in rats, mice, rabbits, dogs and monkeys.

In tests for progestational alteration of the endometrium of rabbits, norgestrel by the subcutaneous route proved to be about nine times more active than progesterone and about one hundred times more active than norethisterone by oral and subcutaneous routes. In contrast to norethisterone, which is inactive, norgestrel will maintain pregnancy in spayed laboratory rats and produce endometrial gland development in rabbits when administered directly into the uterine lumen. In a broad series of biological tests, its activities are similar to those of progesterone. Although certain androgenic effects typical of many relatives of 19nortestosterone are evident at high doses, norgestrel is devoid of such effects at usual clinical doses, and the separation of progestational from androgenic effects for norgestrel is greater than for related compounds. Norgestrel is not estrogenic, nor is it apparently converted in vivo to estrogen; it is an exceedingly potent estrogen antagonist. When combined with ethinyl estradiol, norgestrel tends to ameliorate the effects of the estrogen, while the estrogen will modify the effects of the progestogen. In rats, suppression of fertility with norgestrel/ethinyl estradiol combinations is followed by recovery of normal fertility and fecundity. Additional experiments in laboratory animals were directed toward evaluating the endocrine effects and safety of the norgestrel and ethinyl estradiol formulation at dose levels approximating those employed clinically (on a milligram per kilogram basis). Metrotropic effects (uterine glandular development and growth) were most clearly demonstrated. Blockade of pituitary gonadotrophins can be produced by the estrogenic component alone at the clinical dose range; this pituitary effect does not appear to be modified by addition of the progestogen.

The following properties, observed with high doses of norgestrel or norgestrel/ethinyl estradiol combinations, were absent at doses approximating the clinical range: pregnancy maintenance in spayed female rats; parturition delay in pregnant rats; estrogenic changes in mouse vaginal cytology; anti-estrogenic effect in mouse uterine growth or vaginal smear tests; androgenic, myotrophic or fetal masculinizing effects in rats; claudogenic (antinidatory) effects in rats; thymolymphatic involution in mice; mineralocorticoid effects in rats and dogs and antimineralocorticoid effects in rats. No glucocorticoid (rat liver glycogen) or anti-inflammatory (Selye pouch, TBR-arthritis or granuloma pellet mtests) effects have been seen at any dose.

Human Pharmacology

Progestogens can have, in addition to progestational activity, estrogenic, anti-estrogenic and androgenic activity. When combined with estrogen, the progestogen will markedly affect the overall biological activity by producing a synergistic, summative or diminutional effect on activity. Comparisons of progestogen potency are not considered scientifically valid because the effects of one progestogen cannot be directly compared with those of another.²¹

A study of serum luteinizing hormone (LH), follicle stimulating hormone (FSH), progesterone and 17β-estradiol in patients taking low dose oral contraceptives indicated reduction or abolition of the mid-cycle ovulatory peak and post-ovulatory levels commonly associated with these hormones and gonadotrophins respectively.

Endometrial biopsies taken during the course of therapy with 250 mcg d-norgestrel (as 500 mcg of the dl-racemate) plus 50 mcg ethinyl estradiol revealed a histological sequence in the menstrual cycle of early glandular epithelial stimulation followed by later inhibition after the first half of the menstrual cycle.

Cervical mucus studies with 250 mcg d-norgestrel (as 500 mcg of the dl-racemate) plus 50 mcg ethinyl estradiol, and 37.5 mcg d-norgestrel (as 75 mcg of the dl-racemate) would suggest a similar action for Levonorgestrel and Ethinyl Estradiol Tablets on the cervical mucus, viz., absence of ferning and decreased spinnbarkeit, indicative of poor conditions for sperm penetration and migration.

The results of assays for prolactin in a group of 11 normally ovulating women given 150 mcg dnorgestrel (as 300 mcg of the dl-racemate) plus 30 mcg ethinyl estradiol over a continuous period of three months indicated no clinically or statistically significant elevation or depression of hormone levels during the course of active drug ingestion, nor in the first post-treatment cycle.

A human study of the metabolism of ¹⁴C-labelled norgestrel, revealed that most of the urinary excretion of norgestrel occurred on the first day. There was no difference in the rate of excretion of norgestrel whether administered orally or intravenously. The amount of radioactivity in plasma fell rapidly within the first few hours and at the end of two days only small amounts were present. The foregoing and other studies with ¹⁴C-labelled and unlabelled norgestrel have shown that saturation of the 4,5-double bond with and without concomitant reduction of the 3-carbonyl to a 3-hydroxyl group are important reactions during metabolism.

MICROBIOLOGY

Not applicable.

TOXICOLOGY

Acute Toxicity

Acute oral toxicity studies have been carried out with oral, intraperitoneal and subcutaneous doses of levonorgestrel alone, ethinyl estradiol alone and in a combination of 5:1 ratio respectively. The following table represents the findings of these studies:

Table 6: - ACUTE TOXICITY

SPECIES ROUTE

OF

ADMIN

LD50 LEVONORGESTREL

ETHINYL

ESTRADIOL

LEVONORGESTREL

+

ETHINYL ESTRADIOL

(5+1)

Mice oral > 4.0 g/kg >2.5 g/kg >2.5 g/kg Mice i.p. > 3.9 g/kg 0.69 g/kg 1.32-1.65 g/kg Mice s.c. > 4.0 g/kg > 2.6 g/kg > 2.5 g/kg Rats oral > 4.0 g/kg susp. > 5.0 g/kg

solu. 1.5g/kg

> 2 g/kg

Rats i.p. > 5.0 g/kg 0.97 g/kg approx. 2 g/kg Rats s.c. > 4.0 g/kg

hair loss

> 2 g/kg

Dogs oral > 1.0 g/kg Both compounds were found to be almost non-toxic in the acute toxicity studies.

Reproduction and Teratology

At doses in the clinical range, norgestrel, ethinyl estradiol and their combinations have no demonstrable effects on pregnant rats, their pregnancies, their offspring or the reproductive potential of the young.

Also at doses approximating the clinical range, norgestrel and/or ethinyl estradiol have no observable effects on lactating rats, the lactation process or the nursing young.

At doses in the clinical range and above, a small dose-related increase in the number of abnormal fetuses is observed in mice treated during pregnancy with norgestrel/ethinyl estradiol combinations in a ratio of 5:1. Abnormalities include open eye, cleft palate, exencephaly and umbilical hernia. Rabbits treated during pregnancy with doses of norgestrel and ethinyl estradiol in the clinical range and above, failed to demonstrate any teratogenic potential for the drug.

REFERENCES

1. 1.

   Archer DF, Maheux R, DelConte A, O’Brien F.B. and the North American

   Levonorgestrel Study Group (NALSG). A New Low-Dose Monophasic combination Oral contraceptive (Alesse^TM) with Levonorgestrel 100 µg and Ethinyl Estradiol 20 µg.

2. 2.

   Bagshaw S. The Combined Oral Contraceptive. Risks and Adverse Effects in

   Perspective. Drug Saf 1995; 12:91-6.

3. 3.

   Baur DA, Butler RCD. Current concepts in the pathogenesis and treatment of acne. J

   Oral Maxillofac Surg 1998;56:651-5.

4. 4.

   Bradley DD, Wongerd J, Pettitti DB, Drauss RM, Ramcharan S. Serum High-density

   Lipoprotein Cholesterol in Women using Oral Contraceptives, Estrogens and Progestins. N Engl J Med 1978; 299:17-20.

5. 5. Carlborg L. Cyproterone acetate versus levonorgestrel combined with ethinyl estradion on the treatment of acne. Acta Obstel Gynecol Scand 1986 Suppl 134:29-32.
6. 6. DeGroot HE, Friedlander SF. Update on acne. Curr Opin Pediatrics 1998;10: 381-6.
7. 7. Drugs taken with Oral Contraceptives. Br Med J 1967; 1:287.
8. 8.

   Federman DG, Kirsner RS. Acne vulgaris: pathogenesis and therapeutic approach. Am

   J Managed Care 2000; 61:78-87.

9. 9.

   Francis WG, Dalziel D. Accidental Ingestion of Oral Contraceptives by Children. Can

   Med Assoc J. 1965; 92:191.

10. 10. Hull VJ. The effects of hormonal contraceptives on lactation: Current findings, methodological considerations, and future priorities. Stud Fam Plann 1981; 12(4): 134-155.
11. 11. Inman WHW, Vessey MP, Westerholm B, Engelund A. Thromboembolic Disease and the Steroidal Content of Oral Contraceptives. A Report to the Committee on Safety of Drugs Br Med J 1970; 2:203-9.
12. 12.

    Kay CR. Progestogens and Arterial Disease - Evidence from the Royal College of

    General Practitioners' Study. Am J Obstet Gynecol 1982; 142:762-765.

13. 13. Koetsawang S. The effects of contraceptive methods on the quality and quantity of breast milk. Int J Gynecol Obstet 1987; 25(Suppl): 115-127.
14. 14. Kolmansberger CL, Li D, Harrison DD. Efficacy of levonorgestrel 100 µg/20 µg for the treatment of moderate acne: final report (protocol 0858A1-901). Wyeth-Ayerst CSR039056, 2000.
15. 15. Kolmansberger CL, Li D, Harrison DD. Efficacy of levonorgestrel 100 µg/20 µg for the treatment of moderate acne: final report (protocol 0858A1-900). Wyeth-Ayerst CSR039055, 2000.
16. 16. Lemay A, Dewailly SD, Grenier R, Huard J. Attenuation of mild hyperandrogenic activity in postpubertal acne by a triphasic oral contraceptive containing low doses of ethinyl estradiol and d,l.-norgestrel. J Clin Endocrinol Metab 1990;71:8-14.
17. 17. Leyden JJ. Therapy for acne vulgaris. New Engl J Med 1997;336:1156-62.
18. 18. Lonnerdal B, Forsum E, Hambraeus L. Effect of oral contraceptives on composition and volume of breast milk. Am J Clin Nutrit 1980; 33: 816-824.
19. 19.

    Lucky AW. Endocrine aspects of acne. Pediatric Clinics of North America 1983;

    30:495-9.

20. 20.

    Mishell DR. Jr. Correcting Misconceptions About Oral Contraceptives. Am J Obstet

    Gynecoland Ethinyl Estradiol. J Reprod Med. 1983; 28(1), Suppl.:53-56.

21. 21.

    Mishell DR. Oral Contraception - Past, Present, and Future Perspectives. Int J Fertil

    1991;6:7-18.

22. 22. Nilsson S, Nygren KG, Johansson EDB: Ethinyl estradiol in human milk and plasma after oral administration. Contraception 1978; 17(2): 131-139.
23. 23. Nilsson S, Nygren KG, Johansson EDB. d-Norgestrel concentrations in maternal plasma, milk and child plasma during administration of oral contraceptives to nursing women. Am J Obstet Gynecol 1977; 129(2): 178-184.
24. 24.

    Oral Contraceptives, 1994. A Report by the Special Advisory Committee on

    Reproductive Physiology to the Drugs Directorate, Health Protection Branch, Health Canada.

25. 25. Palatsi R, Hirvensalo E, Liukko P, Malmiharju T, Mattila I, Rithloma P, et al. Serum total and unbound testosterone and sex hormone binding globulin (SHBG) in female acne patients treated with two different oral contraceptives. Acta Derm Venereol (Stockh) 1984:64:517-23.
26. 26.

    Rothe MJ, Grant-Kels JM. Acne: update on therapeutic choices. Consultant 1999;

    9:1061-80.

27. 27.

    Sarteretto JM, Recio JCO. Clinical Evaluation of a Low Dosage Estrogen-Progesterone

    Association (100 µg of d-norgestrel and 20 µg ethinyl [sic] estradiol). Clinicae Terapeutica 1974;3:399-404. (TRANSLATION).

28. 28. Spona J, Feichtinger W, Kindermann Ch, Wunsch C, Brill K. Inhibition of Ovulation by an Oral Contraceptive containing 100 µg Levonorgestrel in combination with 20 µg Ethinylestradiol. Contraception 1996; 54:299-304.
29. 29.

    Stolley PD, Tonascia JA, Tockman MS, et al. Thrombosis with Low-estrogen Oral

    Contraceptives. An J Epidemiol 1975;102:197-208.

30. 30.

    Thorneycroft IH, Stanczyk FZ, Bradshaw KD, Ballagh SA, Nichols M, Weber ME.

    Effect of low-dose oral contraceptives on androgenic markers and acne. Contraception 1999;60:255-62.

31. 31. Toddywalla VS, Mehta S, Virkar KD, Saxena BN. Release of 19-nor-testosterone type of contraceptive steroids through different drug delivery systems into serum and breast milk of lactating women. Contraception 1980; 21(3): 217-223.
32. 32. Toxicity of Oral Contraceptives. Br Med J. 1967; 1:38.
33. 33.

    Wynn V, Adams PW, Godsland I, et al. Comparison of Effects of Different Combined

    Oral-Contraceptive Formulations on Carbohydrate and Lipid Metabolism. Lancet 1979;i:1045-1049.

34. 34.

    ^Pr Alesse^® 21 and ^Pr Alesse^® 28, ® T.M. Wyeth, Product Monograph dated: June 26,

    2018, Control No.: 215227.