PRODUCT MONOGRAPH. ESME 21 and Pr ESME 28. Levonorgestrel and Ethinyl Estradiol Tablets, USP

Transcription

1 PRODUCT MONOGRAPH Pr ESME 21 and Pr ESME 28 Levonorgestrel and Ethinyl Estradiol Tablets, USP 100 mcg levonorgestrel and 20 mcg ethinyl estradiol tablets Oral Contraceptive Mylan Pharmaceuticals ULC 85 Advance Road Etobicoke, ON M8Z 2S6 Date of Revision: January 29, 2018 Submission Control No.: Page 1 of 55

2 Table of Contents PART I: HEALTH PROFESSIONAL INFORMATION... 3 SUMMARY PRODUCT INFORMATION... 3 INDICATIONS AND CLINICAL USE... 3 CONTRAINDICATIONS... 4 WARNINGS AND PRECAUTIONS... 4 ADVERSE REACTIONS DRUG INTERACTIONS DOSAGE AND ADMINISTRATION OVERDOSAGE ACTION AND CLINICAL PHARMACOLOGY STORAGE AND STABILITY SPECIAL HANDLING INSTRUCTIONS DOSAGE FORMS, COMPOSITION AND PACKAGING PART II: SCIENTIFIC INFORMATION PHARMACEUTICAL INFORMATION CLINICAL TRIALS COMPARATIVE BIOAVAILABILITY STUDY DETAILED PHARMACOLOGY MICROBIOLOGY TOXICOLOGY REFERENCES PART III: CONSUMER INFORMATION Page 2 of 55

3 Pr ESME 21 and Pr ESME 28 Levonorgestrel and Ethinyl Estradiol Tablets, USP PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION Route of Administration Oral Dosage Form / Strength Tablet, 100 mcg levonorgestrel and 20 mcg ethinyl estradiol All Non-Medicinal Ingredients Each pink tablet contains croscarmellose sodium, ferric oxide red, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone and sodium lauryl sulfate. Each inactive green tablet 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. 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. Page 3 of 55

4 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. Page 4 of 55

5 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 Page 5 of 55

6 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. Page 6 of 55

7 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 Page 7 of 55

8 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 Page 8 of 55

9 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/m 2 ) 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 Page 9 of 55

10 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 Page 10 of 55

11 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. Page 11 of 55

12 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 nonhormonal 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. Page 12 of 55

13 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. Page 13 of 55

14 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 Page 14 of 55

15 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 Page 15 of 55

16 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 Event Headache 400 (27%) Dysmenorrhea 210 (14%) Infection 200 (14%) Pharyngitis 146 (10%) Abdominal pain 134 (9%) Nausea 134 (9%) Metrorrhagia 123 (8%) Sinusitis 90 (6%) Flu syndrome 84 (6%) Number (%) of Subjects (n=1,477) Page 16 of 55

17 Vaginal moniliasis 71 (5%) Pain 71 (5%) Back pain 66 (4%) Breast pain 65 (4%) Accidental injury 64 (4%) Acne 62 (4%) Rhinitis 54 (4%) Emotional lability 50 (3%) Vaginitis 48 (3%) Urinary tract infection 41 (3%) Dizziness 40 (3%) Diarrhea 40 (3%) Bronchitis 37 (3%) Depression 36 (2%) Asthenia 35 (2%) Vomiting 34 (2%) Allergic reaction other than to study drug 33 (2%) Amenorrhea 30 (2%) A total of 133 (9%) subjects stopped taking the study medication because of adverse events. Some of the study events that led to subject discontinuation were considered by the medical monitor to be potentially serious: headache (21), hypertension (7), migraine (3), phlebitis (1), palpitations (1), varicose veins (1), vascular disorder (1), hypercholesterolemia/hyperlipidemia (6), depression/emotional lability (16), hypesthesia (1), abnormal vision (2), visual field defect (1), amenorrhea (8), dysmenorrhea (4), menorrhagia (6), irregular bleeding (1), menstrual bloating (1), metrorrhagia (1), fibroid growth (1). No deaths occurred during the multicentre study. Acne In the two acne studies (see CLINICAL TRIALS), the safety profile of 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. Table 2. Percentage of Patients ( 2%) Reporting Treatment-Emergent Adverse Events in Either Treatment Group in Studies 0858A1-900, 901 Adverse event Number (%) of Subjects Levonorgestrel and Placebo Ethinyl Estradiol Tablets (n=355) (n=349) Headache 110 (31.5) 107 (30.1) Metrorrhagia* 77 (21.8) 14 (3.9) Nausea 49 (14.0) 40 (11.3) Infection 48 (13.8) 49 (13.8) Pharyngitis 46 (13.2) 58 (16.3) Pain 31 (8.9) 36 (10.1) Page 17 of 55

18 Table 2. Percentage of Patients ( 2%) Reporting Treatment-Emergent Adverse Events in Either Treatment Group in Studies 0858A1-900, 901 Adverse event Number (%) of Subjects Levonorgestrel and Placebo Ethinyl Estradiol Tablets (n=355) (n=349) Abdominal pain 27 (7.7) 24 (6.8) Dysmenorrhea 27 (7.7) 39 (11.0) Accidental injury 21 (6.0) 16 (4.5) Menstrual disorder* 21 (6.0) 8 (2.3) Flu syndrome 19 (5.4) 20 (5.6) Allergic reaction* 16 (4.6) 6 (1.7) Breast pain 16 (4.6) 11 (3.1) Rhinitis 15 (4.0) 13 (3.7) Sinusitis 14 (4.0) 2.0 (8) Asthenia 13 (3.7) 5 (1.4) Back pain 12 (3.4) 12 (3.4) Dyspepsia 12 (3.4) 2.3 (8) Weight gain 17 (3.4) 12 (2.3) Emotional lability* 12 (3.4) 4 (1.1) Acne 13 (3.4) 6 (1.4) Migraine 11 (3.2) 8 (2.3) Dizziness 11 (3.2) 10 (2.8) Cough increased 10 (2.9) 8 (2.3) Vomiting 10 (2.6) 6 (1.7) Depression 9 (2.6) 11 (2.5) Moniliasis 7 (2.0) 8 (2.3) Myalgia 7 (2.0) 5 (1.4) Bronchitis 7 (2.0) 7 (2.0) Rash 7 (2.0) 7 (2.0) Urticaria* 7 (2.0) 0 Allergic reaction other than drug 7 (2.0) 7 (2.0) Diarrhea 6 (1.7) 10 (2.8) Unintended pregnancy* 2 (0.6) 12 (3.1) * Statistically significantly different between treatment groups (p<0.05). As expected, menstrual-related events were more frequent in women treated with 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 Page 18 of 55

19 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 Certain antibiotics (eg, ampicillin and other penicillins, tetracyclines), by a decrease of enterohepatic circulation of estrogens. Examples of substances that may increase serum EE concentrations: Atorvastatin Competitive inhibitors for sulfation in the gastrointestinal wall, such as ascorbic acid (vitamin C) and acetaminophen (paracetamol). Substances that inhibit cytochrome P 450 3A4 isoenzymes such as indinavir, fluconazole and troleandomycin. Troleandomycin may increase the risk of intrahepatic cholestasis during coadministration with COCs. EE may interfere with the metabolism of other drugs by inhibiting hepatic microsomal enzymes, or by inducing hepatic drug conjugation, particularly glucuronidation. Accordingly, plasma and Page 19 of 55

20 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. 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 Table 3*: Drugs That May Decrease the Efficacy of Oral Contraceptives Class of Compound Drug Proposed Mechanism Suggested Management Antibiotics Ampicillin Cotrimoxazole Penicillin Enterohepatic circulation disturbance, intestinal hurry. For short course, use additional method or use another drug. For long course, use another Anticonvulsants Rifabutin Rifampin Chloramphenicol Metronidazole Neomycin Nitrofurantoin Sulfonamide Tetracyclines Troleandomycin Carbamazepine Ethosuximide Felbamate Lamotrigine Oxcarbazine Phenobarbital Phenytoin Primidone Topiramate Increased metabolism of progestins. Suspected acceleration of estrogen metabolism. Induction of hepatic microsomal enzymes. Also disturbance of enterohepatic circulation. May retard metabolism of OCs, increasing the risk of cholestatic jaundice. Induction of hepatic microsomal enzymes. Rapid metabolism of estrogen and increased binding of progestin and ethinyl estradiol to SHBG. Antifungals Griseofulvin Stimulation of hepatic metabolism of contraceptive sterioids may occur. Cholesterol Lowering Clofibrate Reduces elevated serum triglycerides and Agents cholesterol.; this reduces OC efficacy method. Use another method. For short course, use additional method or use another drug. For long course, use another method. Use higher dose OCs (50 mcg ethinyl estradiol), another drug or another method. Use another method. Use another method. Page 20 of 55

21 Table 3*: Drugs That May Decrease the Efficacy of Oral Contraceptives Class of Compound Drug Proposed Mechanism Suggested Management HIV Protease Inhibitors Ritonavir Induction of hepatic microsomal enzymes. Use another drug or another Non-nucleoside reverse transcriptase inhibitors Sedatives and Hypnotics Antacids Other Drugs method. Nevirapine Induction of hepatic microsomal enzymes Use another drug or another method. Benzodiazepines Induction of hepatic microsomal enzymes. For short course, use Barbiturates additional method or another Chloral Hydrate drug. Glutethimide For long course, use another Meprobamate method or higher dose OCs. Phenylbutazone** Antihistamines** Analgesics** Antimigraine Preparations** Vitamin E Decreased intestinal absorption of progestins. Reduced OC efficacy has been reported. Remains to be confirmed. Dose two hours apart *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 Table 4*: Modification of Other Drug Action by Oral Contraceptives Class of Compound Drug Proposed Mechanism Suggested Management Alcohol Possible increased levels of Use with caution. ethanol or acetaldehyde. Alpha-II Adrenoreceptor Clonidine Sedation effect increased. Use with caution. Agents Anticoagulants All OCs increase clotting factors, Use another method. decrease efficacy. However, OCs may potentiate action in some patients. Anticonvulsants All Estrogens may increase risk Use another method. of seizures. Lamotrigine Decrease lamotrigine levels, Use another method. may lead to breakthrough seizures. Antidiabetic Drugs Oral Hypoglycemics and Insulin Antihypertensive Agents Guanethidine and Methyldopa Beta Blockers OCs may impair glucose tolerance and increase blood glucose. Estrogen component causes sodium retention, progestin has no effect. Increased drug effect (decreased metabolism) Use low-dose estrogen and progestin OC or another method. Monitor blood glucose. Use low-dose estrogen OC or use another method. Adjust dose of drug if necessary. Monitor cardiovascular status. Dose of drug may have to be increased. Antipyretics Acetaminophen Increased metabolism and renal clearance. Antipyrine Impaired metabolism. Decrease dose of drug. ASA Effects of ASA may be Patients on chronic ASA decreased by the short-term therapy may require an use of OCs. increase in ASA dosage. Anti-viral hepatitis C virus Ombitasvir Paritaprevir Ritonavir Dasabuvir May increase the risk of ALT elevations Concomitant use is contraindicated (see CONTRAINDICATIONS) Page 21 of 55

22 Table 4*: Modification of Other Drug Action by Oral Contraceptives Class of Compound Drug Proposed Mechanism Suggested Management Aminocaproic Acid Theoretically, a Avoid concomitant use. hypercoagulable state may occur because OCs augment clotting factors. Betamimetic Agents Isoproterenol Estrogen causes decreased response to these drugs. Adjust dose of drug as necessary. Discontinuing OCs can result in excessive Caffeine The actions of caffeine may be enhanced as OCs may impair the hepatic metabolism of caffeine Cholesterol-lowering Agents Clofibrate Their action may be antagonized by OCs. OCs may also increase metabolism of clofibrate. Corticosteroids Prednisone Markedly increases serum levels. Cyclosporine May lead to an increase in cyclosporine levels and hepatoxicity. Folic Acid OCs have been reported to impair folate metabolism. Meperidine Possible increased analgesia and CNS depression due to decreased metabolism of meperidine. Phenothiazine Tranquilizers Sedatives and Hypnotics All phenothiazines, Reserpine, and similar drugs. Chlordiazepoxide Lorazepam Oxazepam Diazepam Estrogen potentiates the hyperprolactinemia effect of these drugs. Increased effect (increased metabolism) Theophylline All Decreased oxidation, leading to possible toxicity. Tricyclic Antidepressants Clomipramine (possibly others) Vitamin B 12 Increased side effects: i.e., depression. Increased serum levels due to decreased clearance. OCs have been reported to reduce serum levels of Vitamin B 12. drug activity. Use with caution. May need to increase dose of clofibrate. Possible need for decrease in dose. Monitor hepatic function. The cyclosporine dose may have to be decreased. May need to increase dietary intake, or supplement. Use combination with caution. Use other drugs or lower dose OCs. If galactorrhea or hyperprolactinemia occurs, use other method. Use with caution. Use with caution. Monitor theophylline levels. Use with caution. May need to increase dietary intake, or supplement. *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. Page 22 of 55

23 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) AST (SGOT) and GGT Alkaline Phosphatase Serum Bilirubin Coagulation Tests Factors II, VII, IX, X, XII and XIII Factor VIII Platelet aggregation and adhesiveness Fibrinogen Plasminogen Antithrombin III Prothrombin Time Moderate increase Minor increase Variable increase Increased, particularly in conditions predisposing to or associated with hyperbilirubinemia Increased Mild increase Mild increase in response to common aggregating agents Increased Mild increase Mild decrease Decreased Thyroid Function Tests Protein-bound Iodine (PBI) Total Serum Thyroxine (T3 andt4) Thyroid Stimulating Hormone (TSH) Free T3 Resin Uptake Adrenocortical Function Tests Plasma Cortisol Cortisol Binding Globulin Dehydroepiandrosterone sulfate (DHEAS) Miscellaneous Tests Serum Folate Increased Increased Unchanged Decreased Increased Increased Decreased Occasionally decreased Page 23 of 55

24 Glucose Tolerance Test Insulin Response c-peptide Response Variable decrease with return to normal after 6 to 12 months Mild to moderate decrease 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. Combination oral contraceptives reduce the incidence of cancer of the endometrium and ovaries. 2. Oral contraceptives reduce the likelihood of developing benign breast disease and, as a result may decrease the incidence of breast biopsies. 3. Oral contraceptives reduce the likelihood of development of functional ovarian cysts. 4. Pill users have less menstrual blood loss and have more regular cycles thereby, reducing the chance of developing iron-deficiency anemia. 5. The use of oral contraceptives may decrease the severity of dysmenorrhea and premenstrual syndrome, and may improve acne vulgaris, hirsutism, and other androgenmediated disorders. 6. Oral contraceptives decrease the incidence of acute pelvic inflammatory disease and reduce the incidence of ectopic pregnancy. 7. Oral contraceptives have potential effects on endometriosis. DOSAGE AND ADMINISTRATION Recommended Dose and Dosage Adjustment CONTRACEPTION: 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. Page 24 of 55

25 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. SUNDAY START Miss One Pill Take it as soon as you remember, and take the next pill at the usual time. This means that you might take two pills in one day. Miss Two Pills in a Row First two weeks 1. Take two pills the day you remember and two pills the next day. OTHER THAN SUNDAY START Miss One Pill Take it as soon as you remember, and take the next pill at the usual time. This means that you might take two pills in one day. Miss Two Pills in a Row First two weeks 1. Take two pills the day you remember and two pills the next day. Page 25 of 55

26 2. Then take one pill a day until you finish the pack. 3. Use a nonhormonal back-up method of birth control if you have sex in the seven days after you miss the pills. Third week 1. Keep taking one pill a day until Sunday. 2. On Sunday, safely discard the rest of the pack and start a new pack that day. 3. Use a nonhormonal back-up method of birth control if you have sex in the seven days after you miss the pills. 4. You may not have a period this month. If You Miss Two Periods in a Row, Call Your Doctor or Clinic. Miss Three or More Pills in a Row Anytime in the cycle 1. Keep taking one pill a day until Sunday. 2. On Sunday, safely discard the rest of the pack and start a new pack that day. 3. Use a nonhormonal back-up method of birth control if you have sex in the seven days after you miss the pills. 4. You may not have a period this month. If You Miss Two periods in a Row, Call Your Doctor or Clinic. 2. Then take one pill a day until you finish the pack. 3. Use a nonhormonal back-up method of birth control if you have sex in the seven days after you miss the pills. Third week 1. Safely dispose of the rest of the pill pack and start a new pack that same day. 2. Use a nonhormonal back-up method of birth control if you have sex in the seven days after you miss the pills. 3. You may not have a period this month. If You Miss Two Periods in a Row, Call Your Doctor or Clinic. Miss Three or More Pills in a Row Anytime in the cycle 1. Safely dispose of the rest of the pill pack and start a new pack that same day. 2. Use a nonhormonal back-up method of birth control if you have sex in the seven days after you miss the pills. 3. You may not have a period this month. If You Miss Two Periods in a Row, Call Your Doctor or Clinic. Contraceptive reliability may be reduced if active tablets are missed and particularly if the missed tablets extend the tablet-free interval. If active tablets were missed and intercourse took place in the week before the tablets were missed, the possibility of pregnancy should be considered. Administration Tablets for oral use. SPECIAL NOTES ON ADMINISTRATION Page 26 of 55