Elfy Product Monograph

RECENT MAJOR LABEL CHANGES

TABLE OF CONTENTS

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

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

TABLE OF CONTENTS .................................................................................. Error! Bookmark not defined.

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

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

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

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

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

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

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

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

4.2 Recommended Dose and Dosage Adjustment ....................................................................... 6

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

4.5 Missed Dose ........................................................................................................................... 7

5 OVERDOSAGE ............................................................................................................................. 8

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ................................................ 8

7 WARNINGS AND PRECAUTIONS .................................................................................................. 9

7.1 Special Populations .............................................................................................................. 16

7.1.1 Pregnant Women ................................................................................................................. 16

7.1.2 Breast-feeding .......................................................................... Error! Bookmark not defined.

7.1.3 Pediatrics ............................................................................................................................. 17

7.1.4 Geriatrics ............................................................................................................................. 17

7.1.5 Body Mass Index (BMI) ........................................................................................................ 17

8 ADVERSE REACTIONS ................................................................................................................ 17

8.1 Adverse Reaction Overview ................................................................................................. 17

8.2 Clinical Trial Adverse Reactions ............................................................................................ 19

ELFY (ethinyl estradiol tablets / norethindrone acetate and ethinyl estradiol tablets)

8.2.1 Clinical Trial Adverse Reactions – Pediatrics ......................................................................... 20

8.3 Less Common Clinical Trial Adverse Reactions ..................................................................... 20

8.3.1 Less Common Clinical Trial Adverse Reactions – Pediatrics .................................................. 21

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data ..................................................................................................................................... 21

8.5 Post-Market Adverse Reactions ........................................................................................... 21

9 DRUG INTERACTIONS ............................................................................................................... 22

9.2 Drug Interactions Overview ................................................................................................. 22

9.3 Drug-Behavioural Interactions ............................................................................................. 22

9.4 Drug-Drug Interactions ........................................................................................................ 22

9.5 Drug-Food Interactions ........................................................................................................ 27

9.6 Drug-Herb Interactions ........................................................................................................ 27

9.7 Drug-Laboratory Test Interactions ....................................................................................... 28

10 CLINICAL PHARMACOLOGY ....................................................................................................... 28

10.1 Mechanism of Action ........................................................................................................... 28

10.2 Pharmacodynamics .............................................................................................................. 29

10.3 Pharmacokinetics ................................................................................................................. 29

11 STORAGE, STABILITY AND DISPOSAL ........................................................................................ 33

12 SPECIAL HANDLING INSTRUCTIONS .......................................................................................... 33

PART II: SCIENTIFIC INFORMATION ...................................................................................................... 34

13 PHARMACEUTICAL INFORMATION ........................................................................................... 34

14 CLINICAL TRIALS ....................................................................................................................... 35

14.1 Clinical Trials by Indication ................................................................................................... 35

14.2 Comparative Bioavailability Studies .................................................................................... 38

15 MICROBIOLOGY ........................................................................................................................ 40

16 NON-CLINICAL TOXICOLOGY ..................................................................................................... 40

17 SUPPORTING PRODUCT MONOGRAPHS ................................................................................... 44

PATIENT MEDICATION INFORMATION ................................................................................................. 45

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

ELFY (ethinyl estradiol tablets / norethindrone acetate and ethinyl estradiol tablets) is indicated for:

• the prevention of pregnancy.

In a one year (thirteen 28-day cycles) multicenter open-label clinical trial 1,582 women were studied to assess the safety and efficacy of ethinyl estradiol tablets / norethindrone acetate and ethinyl estradiol tablets. In this study 1,270 women 18 to 35 years of age were studied to assess the efficacy of ethinyl estradiol tablets / norethindrone acetate and ethinyl estradiol tablets, completing the equivalent of 12,482 28-day evaluable cycles of exposure. The pregnancy rate (Pearl Index [PI]) in women 18 to 35 years of age was 2.92 pregnancies per 100 women-years of use. See 14 CLINICAL TRIALS.

The efficacy of ethinyl estradiol tablets / norethindrone acetate and ethinyl estradiol tablets in women with a body mass index > 35 kg/m² has not been evaluated.

Exposure to exogenous estrogen with ELFY is less than with other combined oral contraceptives with similar synthetic estrogens. Any benefits from the lower estrogen exposure provided by ELFY have not been evaluated.

1.1 Pediatrics

Pediatrics (< 18 years): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

1.2 Geriatrics

Geriatrics: No data are available to Health Canada; therefore, Health Canada has not authorized an indication for geriatric use.

2 CONTRAINDICATIONS

• Use with the hepatitis C virus (HCV) combination drug regimen ombitasvir, paritaprevir, ritonavir with or without dasabuvir. See 7 WARNINGS AND PRECAUTIONS.
• ELFY is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6 DOSAGE FORMS, COMPOSITION AND PACKAGING.

ELFY should not be used in women with:

• a history of or actual thrombophlebitis or thromboembolic disorders (such as deep vein thrombosis or pulmonary embolism);
• a history of or actual cerebrovascular disorders;
• a history of or actual myocardial infarction or coronary artery disease;
• valvular heart disease with complications;
• history of or actual prodromi of a thrombosis (e.g., transient ischaemic attack, angina pectoris);
• active liver disease, or history of or actual benign or malignant liver tumours;
• known or suspected carcinoma of the breast;
• carcinoma of the endometrium or other 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;
• known or suspected pregnancy;
• current or history of migraine with focal aura;
• history of or actual pancreatitis if associated with severe hypertriglyceridaemia;

• presence of severe or multiple risk factor(s) for arterial or venous or thrombosis such as:

  • severe hypertension (persistent values of ≥ 160/100 mmHg)
  • uncontrolled hypertension
  • hereditary or acquired predisposition for venous or arterial thrombosis such as Factor V Leiden mutation and activated protein C (APC-) resistance, antithrombin-III-deficiency, protein C deficiency, protein S deficiency, hyperhomocysteinemia (e.g., due to MTHFR C677T, A1298 mutations), prothrombin mutation G20210A, and antiphospholipid- antibodies (anticardiolipin antibodies, lupus anticoagulant)
  • severe dyslipoproteinemia
  • over age 35 and smoke
  • diabetes mellitus with vascular involvement
  • major surgery associated with an increased risk of postoperative thromboembolism
  • prolonged immobilization

3 SERIOUS WARNINGS AND PRECAUTIONS BOX

Serious Warnings and Precautions

• Cigarette smoking increases the risk of serious cardiovascular events associated with the use of hormonal contraceptives. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, ELFY should not be used by women who are over 35 years of age and smoke. See 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.

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

To achieve maximum contraceptive effectiveness, ELFY should be taken exactly as directed and at intervals not exceeding 24 hours.

• ELFY tablets may be administered without regard to meals.

• ELFY provides a regimen consisting of 24 blue estrogen-progestin tablets, 2 white

  • estrogen-only tablets, and 2 lilac placebo tablets.

4.2 Recommended Dose and Dosage Adjustment

During the first cycle of use:

• The possibility of ovulation and conception prior to initiation of medication should be considered. The patient is instructed to begin taking ELFY on either Day 1 of menstruation (Day 1 Start) or the first Sunday after the onset of menstruation (Sunday Start). If menstruation begins on a Sunday, the first tablet (blue) is taken that day. One blue tablet should be taken daily for 24 consecutive days followed by one white tablet for 2 consecutive days, followed by one lilac tablet daily for 2 consecutive days. During the first cycle with a Sunday Start, contraceptive reliance should not be placed on ELFY until a blue tablet has been taken daily for 7 consecutive days and a non-hormonal back-up method of birth control (such as latex or polyurethane condoms or spermicide) should be used during those 7 days. ELFY is effective from the first day of therapy if the tablets are begun on the first day of the menstrual cycle.
• The patient begins her next and all subsequent 28-day courses of tablets on the same day of the week on which she began her first course, following the same schedule: 24 days on blue tablets – 2 days on white tablets - 2 days on lilac tablets. If in any cycle the patient starts tablets later than the proper day, she should protect herself against pregnancy by using a non-hormonal back-up method of birth control until she has taken a blue tablet daily for 7 consecutive days.

Health Canada has not authorized an indication for pediatric use. See 1 INDICATIONS.

4.4 Administration

Switching from another hormonal method of contraception:

When the patient is switching to ELFY after completing a 21-day regimen of oral contraceptive tablets, transdermal patches, or a vaginal ring, she should wait 7 days after her last tablet, patch, or ring before she starts ELFY. She will probably experience withdrawal bleeding during that week. She should be sure that no more than 7 days pass after her previous 21-day regimen. When the patient is switching to ELFY after completing a 28-day regimen of oral contraceptive tablets, she should start her first pack of ELFY on the day after her last tablet. She should not wait any days between packs. The patient may switch any day from a progestin-only pill and should begin ELFY the next day. If switching from an implant or injection, the patient should start ELFY on the day of implant removal or, if using an injection, the day the next injection would be due. If switching from an intrauterine device (IUD), depending on the timing of removal, back-up contraception may be needed.

If spotting or breakthrough bleeding occurs:

Breakthrough bleeding or spotting may occur in women taking combination oral contraceptives (COC), especially during the first 3 months of use. The patient is instructed to continue on the same regimen. This type of bleeding is usually transient and without significance; however, if the bleeding is persistent or prolonged, the patient is advised to consult her healthcare provider.

If withdrawal bleeding does not occur:

Although pregnancy is unlikely if ELFY is taken according to directions, if withdrawal bleeding does not occur, the possibility of pregnancy must be considered. If the patient has not adhered to the prescribed schedule (missed one or more tablets or started taking them on a day later than she should have), the probability of pregnancy should be considered at the time of the first missed period and appropriate diagnostic measures taken. If the patient has adhered to the prescribed regimen and misses two consecutive periods, pregnancy should be ruled out. Hormonal contraceptives should be discontinued if pregnancy is confirmed.

Use after pregnancy, abortion or miscarriage:

ELFY should be initiated no earlier than 28 days postpartum in the nonlactating mother due to the increased risk for thromboembolism. When the tablets are administered in the postpartum period, the increased risk of thromboembolic disease associated with the postpartum period must be considered (see 2 CONTRAINDICATIONS, and 7 WARNINGS AND PRECAUTIONS concerning thromboembolic disease). The patient should be advised to use a non-hormonal back-up method for the first 7 days of tablet taking. However, if intercourse has already occurred, the possibility of ovulation and conception prior to initiation of medication should be considered.

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

4.5 Missed Dose

The possibility of follicular growth, ovulation, and risk of pregnancy increases with each successive day that scheduled blue or white tablets are missed. If the patient misses one or more lilac tablets, she is still protected against pregnancy provided she begins taking the active blue tablets again on the proper day. Delayed restarting of active pills may result in reduction of contraceptive reliability.

Missing pills can cause spotting or light bleeding, even if the missed pills are made up. If breakthrough bleeding occurs following missed blue or white tablets, it will usually be transient and of no consequence. Nausea may also occur on the days two pills are taken to make up for missed pills.

The patient should be instructed to use the following chart if she misses 1 or more of her birth control pills. She should be told to match the number of pills missed with the appropriate starting time for her dosing regimen.

Advice in case of vomiting or diarrhea: If vomiting or diarrhea occurs within 3 to 4 hours after a blue or white tablet is taken, absorption may not be complete. In such an event, the advice concerning management of missed pills is applicable.

5 OVERDOSAGE

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

For management of a suspected drug overdose, contact your regional poison control centre.

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table 1 – Dosage Forms, Strengths, Composition and Packaging

ELFY is available in blister cards (dispensers) containing 24 blue active tablets, 2 white active tablets and 2 lilac placebo tablets. Each blue tablet is round, flat, debossed with “10” on one side and with “LO” on the opposite side. Each white tablet is, round, flat, debossed with “11” on one side and with “LO” on the opposite side. Each lilac placebo tablet is round, debossed with “12” on one side and with “XI” on the opposite side.

7 WARNINGS AND PRECAUTIONS

Please see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX.

General

Discontinue medication at the earliest manifestation of:

• Thromboembolic and cardiovascular disorders, such as thrombophlebitis, pulmonary embolism, cerebrovascular disorders, myocardial ischemia, mesenteric thrombosis, proptosis and retinal thrombosis.
• Conditions which 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 Peri-Operative Considerations.
• Visual defects- partial or complete
• Papilledema or ophthalmic vascular lesions
• Severe headache of unknown etiology or worsening of pre-existing migraine headache
• Increase in epileptic seizures

The following information is provided from studies of 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. Other medical conditions which have been associated with adverse circulatory events include systemic lupus erythematosus, hemolytic uremic syndrome, chronic inflammatory bowel disease (Crohn’s disease or ulcerative colitis), sickle cell disease, valvular heart disease and atrial fibrillation.

The following conditions have been reported to occur or deteriorate with both pregnancy and COC use, although a direct association with COCs has not been firmly established: porphyria, systemic lupus erythematosus, hemolytic uremic syndrome, Sydenham’s chorea, herpes gestationis, and otosclerosis- related hearing loss.

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

Carcinogenesis and Mutagenesis

Breast cancer:

Women who currently have or have had breast cancer should not use ELFY because breast cancer is a hormonally-sensitive tumour. See 2 CONTRAINDICATIONS.

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

Women receiving oral contraceptives should be instructed in self-examination of their breasts. Their physicians should be notified whenever any masses are detected. A yearly clinical breast examination is also recommended because, if a breast cancer should develop, estrogen containing drugs may cause a rapid progression.

Cervical cancer:

The most important risk factor for cervical cancer is persistent human papilloma virus (HPV) 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 the confounding effects, e.g., cervical screening and sexual behaviour including use of barrier contraceptives.

Hepatocellular carcinoma:

Hepatocellular carcinoma may be associated with oral contraceptives. The risk appears to increase with duration of hormonal contraceptive use (> 8 years). However, the attributable risk (the excess incidence) of liver cancers in oral contraceptive users is extremely small (< 1 case/million users). A liver tumor should be considered in the differential diagnosis when severe upper abdominal pain, liver enlargement or signs of intra-abdominal hemorrhage occur in women taking COCs. See Hepatic nodules.

Cardiovascular

Predisposing factors for coronary artery disease:

Cigarette smoking increases the risk of serious cardiovascular events and mortality. Birth control pills increase this risk, particularly in women over 35 years of age, and with the number of cigarettes smoked. Convincing data are available to support an upper age limit of 35 years for oral contraceptive use by women who smoke.

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

In low risk, non-smoking women of any age, the benefits of oral contraceptive use outweigh the possible cardiovascular risks associated with low dose formulations. Consequently, oral contraceptives may be prescribed for these women up to the age of menopause.

Hypertension:

COC use is contraindicated in women with uncontrolled hypertension. See 2 CONTRAINDICATIONS.

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

Driving and Operating Machinery

No studies on the effects of ethinyl estradiol tablets / norethindrone acetate and ethinyl estradiol tablets on the ability to drive or use machines have been performed.

Endocrine and Metabolism

Diabetes:

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

Lipid and other metabolic effects:

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

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.

Reduced efficacy:

The efficacy of COCs may be reduced in the event of missed tablets, gastrointestinal disturbances or concomitant medication. See 9 DRUG INTERACTIONS.

Genitourinary

Vaginal bleeding:

Unscheduled (breakthrough or intra-cycle) bleeding and/or spotting (IB/S) sometimes occur in patients on COCs, especially during the first three months of use. In the pivotal trial for ethinyl estradiol tablets/ norethindrone acetate and ethinyl estradiol tablets, a total of 1,257 women (85.9%) experienced IB/S at some time during Cycles 2 to 13 of this study. The incidence of IB/S was highest during Cycle 2 (53%) and lowest at Cycle 13 (36%). The mean number of days per cycle of IB/S decreased from 3.2 days in Cycle 2 to 1.8 days during Cycle 13. See Bleeding Profile.

Persistent irregular vaginal bleeding requires assessment to exclude underlying pathology.

Scheduled (withdrawal) bleeding and/or spotting remained fairly constant over the one year study, with an average of less than 2 days per cycle when including all women and all cycles.

Fibroids:

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

Hematologic

Epidemiological studies have suggested an association between the use of COCs and an increased risk of arterial and venous thrombotic and thromboembolic diseases such as myocardial infarction, deep venous thrombosis, pulmonary embolism, and of cerebrovascular accidents.

Venous thromboembolism (VTE):

The use of any combined oral contraceptive carries an increased risk of VTE compared with no use. The excess risk of VTE is highest during the first year a woman ever uses a combined oral contraceptive or restarts (following a 4-week or greater pill-free interval) the same or a different COC. Data from a large, prospective 3-armed cohort study suggest that this increased risk is mainly present during the first 3 months. VTE is fatal in 1 to 2% of cases.

A large, prospective 3-armed cohort study has shown that the frequency of VTE diagnosis ranges from about 8 to 10 per 10,000 woman-years in users of oral contraceptives with low estrogen content (< 50 mcg ethinyl estradiol). The most recent data suggest that the frequency of VTE diagnosis is approximately 4.4 per 10,000 woman-years in nonpregnant, non-COC users and ranges from 20 to 30 per 10,000 women-years in pregnant women or postpartum.

Overall the risk for VTE in users of COCs with low estrogen content (< 50 mcg ethinyl estradiol) is 2- to 3-fold higher than for nonusers of COCs who are not pregnant and remains lower than the risk associated with pregnancy and delivery.

The risk of VTE with COCs has been shown to be related to the estrogen dose, as risk has decreased as doses have decreased from 100 to 50 to 30 mcg. Whether doses as low as 10 mcg are further protective is unknown. ELFY provides a daily dose of ethinyl estradiol of 10 mcg, for 26 of 28 days each cycle.

Extremely rarely, thrombosis has been reported to occur in other blood vessels (e.g., hepatic, mesenteric, renal, cerebral, or retinal veins and arteries) in COC users. There is no consensus as to whether the occurrence of these events is associated with the use of COCs.

Arterial thromboembolism (ATE):

The risk for ATE in users of oral contraceptives with < 50 mcg ethinyl estradiol ranges from about 1 to 3 cases per 10,000 woman-years. An ATE can include cerebrovascular accident, vascular occlusion, or myocardial infarction.

Arterial thromboembolic events may be fatal.

Other risk factors for venous or arterial thromboembolism or of a cerebrovascular accident:

Other generalized risk factors for venous or arterial thromboembolism include but are not limited to age, severe obesity (body mass index > 30 kg/m²), a personal history, a positive family history (the occurrence of VTE/ATE in a direct relative at a relatively early age may indicate genetic predisposition) and systemic lupus erythematosus. If a hereditary or acquired predisposition for venous or arterial thromboembolism is suspected, the woman should be referred to a specialist for advice before deciding on any COC use. The risk of VTE/ATE may be temporarily increased with prolonged immobilization, major surgery, or trauma. In these situations, it is advisable to discontinue COC use (in the case of elective surgery at least four weeks in advance) and not to resume COC use until two weeks after complete remobilization. Also, patients with varicose veins and leg cast should be closely supervised. Other risk factors may include smoking (with heavier smoking and increasing age, the risk further increases, especially in women over 35 years of age), dyslipoproteinemia, hypertension, migraine, valvular heart disease, and atrial fibrillation.

Biochemical factors that may be indicative of hereditary or acquired predisposition for venous or arterial thrombosis include Factor V Leiden mutation and APC- resistance, antithrombin-III-deficiency, protein C deficiency, protein S deficiency, hyperhomocysteinemia (e.g., due to MTHFR C677T, A1298 mutations), prothrombin mutation G20210A, and antiphospholipid-antibodies (anticardiolipin antibodies, lupus anticoagulant).

When considering risk/benefit, the physician should take into account that adequate treatment of a condition may reduce the associated risk of thrombosis and that the risk associated with pregnancy is higher than that associated with COCs containing < 0.05 mg ethinyl estradiol).

Hepatic/Biliary/Pancreatic

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

Hepatitis C:

ELFY must be discontinued prior to starting therapy with the HCV combination drug regimen ombitasvir, paritaprevir, ritonavir, with or without dasabuvir. See 2 CONTRAINDICATIONS and 9 DRUG INTERACTIONS. During clinical trials with ombitasvir, paritaprevir, ritonavir, with or without dasabuvir, alanine transaminase (ALT) elevations 5 to > 20 times the upper limit of normal were significantly more frequent in healthy female subjects and HCV infected women using ethinyl estradiol-containing medications such as COCs. Physicians are advised to consult the labelling of concurrently-used HCV combination drug regimen ombitasvir, paritaprevir, ritonavir with or without dasabuvir to obtain further information about restarting ELFY.

Jaundice:

Patients who have had jaundice should be given oral contraceptives only with great care and under close observation. Oral contraceptive-related cholestasis has been described in women with a history of pregnancy-related cholestasis. Women with a history of cholestasis may have the condition recur with subsequent hormonal contraceptive use. The development of severe generalized pruritus or icterus requires that the medication be withdrawn until the problem is resolved.

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

Gallbladder disease:

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

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.

Immune

Angioedema:

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

Monitoring and Laboratory Tests

Before oral contraceptives are used, a thorough history and physical examination should be performed, including a blood pressure determination and the family case history carefully noted. 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.

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 Periodic Health Examination.

Neurologic

Migraine and headache:

The onset or exacerbation of migraine or the development of headache of a new pattern that is recurrent, persistent or severe, requires discontinuation of hormonal contraceptives and evaluation of the cause. Women with migraine headaches who take oral contraceptives may be at increased risk of stroke. See 2 CONTRAINDICATIONS.

Ophthalmologic

Ocular disease:

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

Ocular lesions:

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, ELFY should be discontinued and the cause immediately evaluated.

Peri-Operative Considerations

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

Psychiatric

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

Renal

Fluid retention:

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

Reproductive Health

Return to fertility:

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

Amenorrhea:

Women on ELFY may not get a period each month. In the clinical trial with ethinyl estradiol tablets / norethindrone acetate and ethinyl estradiol tablets, the incidence of amenorrhea increased from 32% in Cycle 1 to 49% by Cycle 13. See Bleeding Profile. If ELFY has been taken according to directions, it is unlikely that the woman is pregnant. However, if ELFY has not been taken according to directions prior to the first missed withdrawal bleed, or if two withdrawal bleeds are missed, pregnancy must be ruled out before ELFY 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 6 months or more after withdrawal warrants a careful assessment of hypothalamic-pituitary function.

Skin

Chloasma may occasionally occur with use of COCs, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation while taking COCs. Chloasma is often not fully reversible.

7.1 Special Populations

7.1.1 Pregnant Women

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

7.1.2 Breastfeeding

In breastfeeding women, the use of oral contraceptives results in the hormonal components being excreted in breast milk and may reduce its quantity and quality. If the use of oral contraceptives is initiated after the establishment of lactation, there does not appear to be any effect on the quantity and quality of the milk. There is no evidence that low-dose oral contraceptives are harmful to the nursing infant.

If possible, 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. There have been no formal studies of ethinyl estradiol tablets / norethindrone acetate and ethinyl estradiol tablets in nursing women.

7.1.3 Pediatrics

Pediatrics (< 18 years): The safety and efficacy of ethinyl estradiol tablets / norethindrone acetate and ethinyl estradiol tablets have not been established in women under the age of 18 years. Use of this product before menarche is not indicated.

7.1.4 Geriatrics

ELFY is not indicated for use in postmenopausal women.

7.1.5 Body Mass Index (BMI)

The safety and efficacy of ethinyl estradiol tablets / norethindrone acetate and ethinyl estradiol tablets in women with a body mass index (BMI) > 35 kg/m² has not been evaluated.

8 ADVERSE REACTIONS

8.1 Adverse Reaction Overview

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

• arterial and venous thromboembolism
• being diagnosed with breast cancer
• benign and malignant hepatic tumours
• cerebral hemorrhage
• cerebral thrombosis
• congenital anomalies
• gallbladder disease
• hypertension
• mesenteric thrombosis
• myocardial infarction
• neuro-ocular lesions (e.g., retinal thrombosis)
• pulmonary embolism
• thrombophlebitis

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

Nausea and vomiting, usually the most common adverse reaction, occurs in approximately 10% or fewer of patients during the first cycle. The following other reactions, as a general rule, are seen less frequently or only occasionally:

Blood and lymphatic system disorders: hemolytic uremic syndrome

Ear and labyrinth disorders: auditory disturbances, otosclerosis-related hearing loss¹

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

Gastrointestinal disorders: abdominal pain, Crohn’s disease¹, diarrhea, gastrointestinal symptoms (such as abdominal cramps and bloating), pancreatitis, ulcerative colitis¹

General disorders and administration site conditions: edema

Hepatobiliary disorders: cholestatic jaundice, gallstone formation¹, liver function disturbances¹

Immune system disorders: hypersensitivity

Infections and infestations: rhinitis, vaginal candidiasis, vaginitis

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

Metabolism and nutrition disorders: changes in appetite, hypertriglyceridemia (increased risk of pancreatitis when using COCs)¹, porphyria

Musculoskeletal and connective tissue disorders: systemic lupus erythematosus¹

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

Nervous system disorders: chorea, dizziness, headache, migraine, optic neuritis, Sydenham’s chorea¹

Psychiatric disorders: changes in libido, mental depression, nervousness

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

Reproductive system and breast disorders: amenorrhea during and after treatment, breakthrough bleeding, breast changes including tenderness, enlargement, and secretion, change in menstrual flow, dysmenorrhea, endocervical hyperplasia, possible diminution in lactation when given immediately post- partum, premenstrual-like syndrome, spotting, temporary infertility after discontinuance of treatment, vaginal discharge

Skin and subcutaneous tissue disorders: chloasma or melasma which may persist, loss of scalp hair, hirsutism, erythema multiforme, erythema nodosum, hemorrhagic eruption, herpes gestationis¹, pruritis related to cholestasis¹, rash (allergic), urticaria

Vascular disorders: hypertension¹, Raynaud's phenomenon

1. 1. Occurrence or deterioration of conditions for which association with COC use is not conclusive.

8.2 Clinical Trial Adverse Reactions

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

A multicenter phase 3 clinical trial evaluated the safety and efficacy of ethinyl estradiol tablets / norethindrone acetate and ethinyl estradiol tablets for pregnancy prevention. The study was a one year, open-label, single-arm, uncontrolled study. A total of 1,660 women aged 18 to 45 were enrolled and took at least one dose of ethinyl estradiol tablets / norethindrone acetate and ethinyl estradiol tablets.

A list of adverse reactions experienced by ≥ 1% of the subjects is listed in Table 2.

Table 2 – Treatment-related Adverse Reactions Reported in ≥ 1% of Subjects

The mean weight gain on ethinyl estradiol tablets / norethindrone acetate and ethinyl estradiol tablets was 1.7 lb (SD ± 9.8 lb).

Serious Adverse Events leading to discontinuation included: deep vein thrombosis, ovarian vein thrombosis and cholecystitis.

Adverse Events Leading to Study Discontinuation: 10.7% of the women discontinued from the clinical trial due to an adverse event. Adverse events occurring in ≥ 1% of subjects leading to discontinuation of treatment were, in decreasing order: menstrual irregularities (including metrorrhagia, irregular menstruation, menorrhagia and vaginal hemorrhage) (4%), headache/migraine (1%), mood disorder (including mood swings, depression, anxiety) (1%), and weight fluctuation (1%). Less than 1% of subjects discontinued because of amenorrhea.

8.2.1 Clinical Trial Adverse Reactions – Pediatrics

The safety and efficacy of ethinyl estradiol tablets / norethindrone acetate and ethinyl estradiol tablets have not been established in women under the age of 18 years.

8.3 Less Common Clinical Trial Adverse Reactions

Rare adverse reactions (< 1%) which were observed in clinical trials and deemed to be at least possibly related to ethinyl estradiol tablets / norethindrone acetate and ethinyl estradiol tablets are as follows:

Eye disorders: vision blurred, contact lens intolerance, dry eye

Gastrointestinal disorders: abdominal pain, vomiting, diarrhea, abdominal distension, gastroesophageal reflux disease, constipation, dyspepsia, stomach discomfort, abdominal discomfort

General disorders and administration site conditions: fatigue, irritability, peripheral edema, swelling, edema, drug intolerance

Hepatobiliary disorders: cholecystitis, cholelithiasis

Investigations: abnormal cervical smear, abnormal lab test, blood pressure increased, aspartate serum transaminase (AST) increased, blood cholesterol increased

Infections and Infestations: HPV cervicitis, fungal infection, bronchitis

Metabolism and nutrition disorders: hypercholesterolemia, hypertriglyceridemia, increased appetite, fluid retention, food craving, impaired glucose tolerance, lack of satiety

Musculoskeletal and connective tissue disorders: pain in extremity, muscle spasms

Nervous system disorders: migraine, dizziness, tension headache, lethargy, loss of consciousness, somnolence

Psychiatric disorders: anxiety, depression, insomnia, decreased libido, mood altered, affect liability, tearfulness, suicidal ideation

Renal and urinary disorders: urinary tract infection

Reproductive system and breast disorders: bacterial vaginitis, vulvovaginal mycotic infection, amenorrhea, irregular menstruation, ovarian cyst, vaginal candidiasis, vaginal discharge, breast pain, menorrhagia, pelvic pain, breast mass, vaginal inflammation, fibrocystic breast disease, premenstrual syndrome, dyspareunia, vulvovaginal dryness, breast cyst, breast discharge, breast hypertrophy, vaginal hemorrhage, coital bleeding, vaginal pain, adnexa uteri pain, breast atrophy, breast swelling, cervical discharge, dysfunctional uterine bleeding, nipple pain

Respiratory, thoracic and mediastinal disorders: upper respiratory tract infection, alveolar proteinosis

Skin and subcutaneous tissue disorders: rash, alopecia, urticaria, hyperhidrosis, night sweats, eczema, pruritus, generalized rash, hair texture abnormal, pigmentation disorder, lip pigmentation, generalized pruritis

Vascular disorders: hypertension, hot flush, deep vein thrombosis, hemorrhage, venous thrombosis

8.3.1 Less Common Clinical Trial Adverse Reactions – Pediatrics

The safety and efficacy of ethinyl estradiol tablets / norethindrone acetate and ethinyl estradiol tablets have not been established in women under the age of 18 years.

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

Clinical Trial Findings

In the pivotal trial, a total of 80 abnormal laboratory results (not including positive pregnancy tests) in 31 subjects in the All Treated population were considered clinically significant, consisting mostly of elevated cholesterol and triglycerides; moderately elevated AST, ALT and gamma glutamine transaminase (GGT). In most of these cases values elevated at the end of the study were actually lower than the initial values. Slightly reduced hemoglobin and hematocrit were also common.

8.5 Post-Market Adverse Reactions

The following serious adverse events have been reported in users of ethinyl estradiol tablets / norethindrone acetate and ethinyl estradiol tablets in the post marketing period. These adverse events are compiled from spontaneous reports and are listed regardless of frequency and whether or not a causal relationship with ethinyl estradiol tablets / norethindrone acetate and ethinyl estradiol tablets has been established.

Congenital, familial and genetic disorders: heart disease (congenital)

General disorders and administration site conditions: chest pain

Hepatobiliary disorders: gallbladder disorder, liver disorder

Musculoskeletal and connective tissue disorders: muscular weakness

Neoplasms benign, malignant and unspecified (including cysts and polyps): benign breast neoplasm

Nervous system disorders: cerebrovascular accident, convulsion, epilepsy, grand mal convulsion, hypoaesthesia, intracranial aneurysm, paralysis

Pregnancy, puerperium and perinatal conditions: abortion spontaneous, premature delivery

Psychiatric disorders: suicidal ideation

Renal and urinary disorders: renal infarct

Reproductive system and breast disorders: menorrhagia

Respiratory, thoracic and mediastinal disorders: pulmonary embolism

Vascular disorders: deep vein thrombosis, thrombosis

9 DRUG INTERACTIONS

9.2 Drug Interactions Overview

The concurrent administration of oral contraceptives with other drugs may lead to breakthrough bleeding and/or may result in an altered response to either agent (see Table 3 and Table 4). Reduced effectiveness of the oral contraceptive, should it occur, is more likely with the low-dose formulations. It is important to ascertain all drugs that a patient is taking, both prescription and non-prescription, before oral contraceptives are prescribed.

No formal drug-drug interaction studies were conducted with ethinyl estradiol tablets / norethindrone acetate and ethinyl estradiol tablets.

9.3 Drug-Behavioural Interactions

No studies on the effects of ethinyl estradiol tablets / norethindrone acetate and ethinyl estradiol tablets on the ability to drive or use machines have been performed.

9.4 Drug-Drug Interactions

Table 3 – Drugs which may decrease the efficacy of oral contraceptives

Table 4 – Modification of other drug action by oral contraceptives

Several of the anti-HIV protease inhibitors (e.g., ritonavir) and non-nucleoside reverse transcriptase inhibitors (e.g., nevirapine) have been studied with coadministration of oral combination hormonal contraceptives; significant changes (increase and decrease) in the mean AUC of the estrogen and progestin and the potential to affect hepatic metabolism have been noted in some cases. The efficacy and safety of oral contraceptive products may be affected. Healthcare providers should refer to the label of the individual anti-HIV protease inhibitors for further drug-drug interaction information.

Contraindicated co-administration

Ombitasvir, paritaprevir, ritonavir, with or without dasabuvir (direct-acting antiviral medicinal products) have been shown to be associated with increases in ALT levels 5 to > 20 times the upper limit of normal in healthy female subjects and HCV infected women using ethinyl estradiol-containing medications such as COCs. See 2 CONTRAINDICATIONS and Hepatic/Biliary/Pancreatic.

9.5 Drug-Food Interactions

ELFY tablets may be administered without regard to meals.

Administration of food with a single-dose of a norethindrone acetate and ethinyl estradiol combination tablet did not affect the maximum concentration of norethindrone and increased the extent of absorption by 24%; it decreased the maximum concentration of ethinyl estradiol by 23% and did not affect the extent of absorption.

Administration of food with a single-dose of a ethinyl estradiol alone tablet decreased the maximum concentration of ethinyl estradiol by 31% and did not affect the extent of absorption

9.6 Drug-Herb Interactions

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

9.7 Drug-Laboratory Test Interactions

Results of laboratory tests should be interpreted with the knowledge that the patient is taking an oral contraceptive. The following laboratory tests are modified:

Liver Function Tests

AST - variously reported elevations ALT and GGT - slightly elevated Coagulation Tests

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

Thyroid Function Tests

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

Lipoproteins

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

Gonadotropins

LH and FSH levels are suppressed by the use of oral contraceptives. Wait 2 weeks after discontinuing the use of oral contraceptives before measurements are made.

Glucose Tolerance

Oral glucose tolerance remained unchanged or was slightly decreased.

Tissue Specimens

Pathologists should be advised of oral contraceptive therapy when specimens obtained from surgical procedures and PAP smears are submitted for examination.

10 CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

Like other combination oral contraceptives, ethinyl estradiol tablets / norethindrone acetate and ethinyl estradiol tablets acts by suppression of gonadotropins. These actions include: suppression of follicular development and inhibition of ovulation, other alterations include changes in the cervical mucus (which increase the difficulty of sperm entry into the uterus) and the endometrium (which reduce the likelihood of implantation).

Detailed Pharmacology

See 10.1 Mechanism of Action for additional information.

Both norethindrone (NE) and ethinyl estradiol (EE) have been subject to extensive biological examination over the past four decades. Norethindrone, using the Clauberg assay with rabbits, has been variously estimated to possess an oral progestational activity at least 10 times that of injected progesterone. Only slight estrogenic activity along with some androgenic activity (9% that of methyl testosterone) has been evident. Ethinyl estradiol has been demonstrated to be slightly more active than 17R-estradiol using the vaginal cornification test in rats.

Norethindrone/ethinyl estradiol, in the ratio of 1.0/0.035, fed to female rats for 22 days at a daily dose of 0.15 mg/kg was effective in reducing the littering activity during a period of 15 days cohabitation with fertile males. Subsequent to the dosing period, these females regained their fertility.

Estrogenic, progestational and antigonadotropic characteristics are revealed for the endocrine profile of this combination. In female rats, a uterotropic effect is clearly demonstrated for a range of 0.1 to 0.4 mcg, total oral dose. In rabbits a McPhail index of 2.6 is recorded at a total oral dose of 0.8 mg of this progestin/estrogen combination. At a total dose of 450 mcg (based on EE content) compensatory ovarian hypertrophy is completely inhibited in hemicastrate female rats.

10.2 Pharmacodynamics

No pharmacodynamic studies were conducted with ethinyl estradiol tablets / norethindrone acetate and ethinyl estradiol tablets.

10.3 Pharmacokinetics

Table 5 – Summary of Ethinyl Estradiol Tablets / Norethindrone Acetate and Ethinyl Estradiol Tablets Pharmacokinetic Parameters in Healthy Female Volunteers (n = 15)

Absorption

Norethindrone acetate is completely and rapidly deacetylated to norethindrone after oral administration, and the disposition of norethindrone acetate is indistinguishable from that of orally administered norethindrone. Norethindrone acetate and ethinyl estradiol are rapidly absorbed from ethinyl estradiol tablets / norethindrone acetate and ethinyl estradiol tablets, with maximum plasma concentrations of norethindrone and ethinyl estradiol generally occurring 1 to 2 hours post-dose. Both are subject to first-pass metabolism after oral dosing, resulting in an absolute bioavailability of approximately 64% for norethindrone and 55% for ethinyl estradiol.

The rate of norethindrone and ethinyl estradiol absorption from ethinyl estradiol tablets / norethindrone acetate and ethinyl estradiol tablets containing the combination of 1 mg norethindrone acetate and 10 mcg ethinyl estradiol is slower than that from a norethindrone suspension/ethinyl estradiol solution, but the extent of absorption is equivalent.

Ethinyl estradiol bioavailability from ethinyl estradiol tablets containing 10 mcg ethinyl estradiol alone is equivalent to that from an ethinyl estradiol solution.

The plasma norethindrone and ethinyl estradiol pharmacokinetic profiles and serum sex hormone binding globulin (SHBG) concentrations following multiple-dose administration of ethinyl estradiol tablets / norethindrone acetate and ethinyl estradiol tablets were characterized in 15 healthy female volunteers. The mean plasma concentrations are shown below (Figure 1 and Figure 2), and pharmacokinetic parameters are found in Table 5.

Ethinyl estradiol and norethindrone C_max values increase by a factor of 1.4 and 1.9, respectively, following 24 days administration of norethindrone acetate and ethinyl estradiol combination tablets as compared to single-dose administration. Ethinyl estradiol and norethindrone AUC_0–24h values increase by a factor of 1.6 and 2.5, respectively, following 24 days administration of norethindrone acetate and ethinyl estradiol combination tablets as compared to single-dose administration. Norethindrone concentrations more than double by Day 24 due to both accumulation and increased SHBG concentration. Steady state with respect to ethinyl estradiol and norethindrone is reached by Day 5 and Day 13, respectively.

Figure 1 - Mean plasma ethinyl estradiol concentration versus time profiles following single- and multiple-dose oral administration of ethinyl estradiol tablets / norethindrone acetate and ethinyl estradiol tablets to healthy female volunteers (n = 15)

Figure 2 - Mean plasma norethindrone concentration versus time profiles following single- and multiple-dose oral administration of ethinyl estradiol tablets / norethindrone acetate and ethinyl estradiol tablets to healthy female volunteers (n = 15)

Distribution

Volume of distribution of norethindrone and ethinyl estradiol ranges from 2 to 4 L/kg. Plasma protein binding of both steroids is extensive (> 95%); norethindrone binds to both albumin and SHBG, whereas ethinyl estradiol binds only to albumin. Although ethinyl estradiol does not bind to SHBG, it induces SHBG synthesis.

Metabolism

Norethindrone undergoes extensive biotransformation, primarily via reduction, followed by sulfate and glucuronide conjugation. The majority of metabolites in the circulation are sulfates, with glucuronides accounting for most of the urinary metabolites. A small amount of norethindrone acetate is metabolically converted to ethinyl estradiol.

Ethinyl estradiol is also extensively metabolized, both by oxidation and by conjugation with sulfate and glucuronide. Sulfates are the major circulating conjugates of ethinyl estradiol and glucuronides predominate in urine. The primary oxidative metabolite is 2-hydroxy ethinyl estradiol, formed by the CYP3A4 isoform of cytochrome P450. Part of the first-pass metabolism of ethinyl estradiol is believed to occur in gastrointestinal mucosa. Ethinyl estradiol may undergo enterohepatic circulation.

Elimination

Norethindrone and ethinyl estradiol are excreted in both urine and feces, primarily as metabolites. Plasma clearance values for norethindrone and ethinyl estradiol are similar (approximately 0.4 L/hr/kg). Elimination half-lives of norethindrone and ethinyl estradiol following administration of 1 mg norethindrone acetate/10 mcg ethinyl estradiol tablets are approximately 10 hours and 16 hours, respectively.

Special Populations and Conditions

• Ethnic Origin The effect of race on the disposition of norethindrone and ethinyl estradiol after ethinyl estradiol tablets / norethindrone acetate and ethinyl estradiol tablets administration has not been evaluated.
• Hepatic Insufficiency The effect of hepatic disease on the disposition of norethindrone and ethinyl estradiol after ethinyl estradiol tablets / norethindrone acetate and ethinyl estradiol tablets administration has not been evaluated. However, ethinyl estradiol and norethindrone may be poorly metabolized in patients with impaired liver function.
• Renal Insufficiency The effect of renal disease on the disposition of norethindrone and ethinyl estradiol after ethinyl estradiol tablets / norethindrone acetate and ethinyl estradiol tablets administration has not been evaluated. In premenopausal women with chronic renal failure undergoing peritoneal dialysis who received multiple doses of an oral contraceptive containing ethinyl estradiol and norethindrone, plasma ethinyl estradiol concentrations were higher and norethindrone concentrations were unchanged compared to concentrations in premenopausal women with normal renal function.

11 STORAGE, STABILITY AND DISPOSAL

Store at controlled room temperature (15°C – 30°C). Keep the tablets in their original package.

Keep out of reach and sight of children.

12 SPECIAL HANDLING INSTRUCTIONS

Any unused portion or waste material should be disposed of in accordance with local requirements.

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: ethinyl estradiol

Chemical name: 17-alpha-ethinyl-l,3,5(10)-estratriene-3,17 beta-diol

Molecular formula and molecular mass: C₂₀H₂₄O₂ and 296.41 g/mol Structural formula:

Physicochemical properties: White to practically white crystals or powder. Practically insoluble in water, sparingly soluble in chloroform, very slightly soluble in toluene, soluble in methanol, and freely soluble in ethanol, propranolol, ether and tetrahydrafuran.

Proper name: norethindrone acetate

Chemical name: [19-Norpregn-4-en-20-yn-3-one, 17-(acetyloxy)-, (17α)-] Molecular formula and molecular mass: C₂₂H₂₈O₃ and 340.5 g/mol

Structural formula:

Physicochemical properties: White to practically white crystals or powder with a melting point of 158°C to 164°C. Practically insoluble in water, soluble in ethanol and ether, and freely soluble in acetone, chloroform, dioxane, methanol, methylene chloride and tetrahydrafuran.

14 CLINICAL TRIALS

14.1 Clinical Trials by Indication

Prevention of pregnancy

Table 6 – Summary of patient demographics for clinical trials in the prevention of pregnancy

In a one year (thirteen 28-day cycles) multicenter open-label clinical trial, 1,582 women 18 to 45 years of age, were studied to assess the safety and efficacy of ethinyl estradiol tablets / norethindrone acetate and ethinyl estradiol tablets, completing the equivalent of 15,591 28-day evaluable cycles of exposure. 1,270 women 18 to 35 years of age were studied to assess the efficacy of ethinyl estradiol tablets / norethindrone acetate and ethinyl estradiol tablets and completed the equivalent of 12,482 28-day evaluable cycles of exposure. The racial demographic of all enrolled women was: Caucasian (74.9%), African-American (11.8%), Hispanic (9.8%), Asian (1.3%), and Other (2.2%). Women with body mass index (BMI) greater than 35 kg/m² were excluded from the study. The weight range for those women treated was 89 to 260 lb, with a mean weight of 150 lb. Among the women in the trial, 51% had not used hormonal contraception immediately prior to enrolling in this study. Of treated women, 13.7% were lost to follow-up, 10.7% discontinued due to an adverse event, and 8.9% discontinued by withdrawing their consent.

General Information

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

Reported Pregnancies per 100 Women per Year:

Combination pill less than 1 to 3^a

Intrauterine device (IUD) less than 1 to 6

Condom with spermicidal foam or gel 1 to 6

Mini-pill 3 to 6

Condom 2 to 12

Diaphragm with spermicidal foam or gel 3 to18

Spermicide 3 to21

Sponge with spermicide 3 to 28

Cervical cap with spermicide 5 to 18

Periodic abstinence (rhythm), all types 2 to 20 No birth control 60 to 85

^a Based on the results of one clinical study, about 3 out of 100 women may get pregnant during the first year they use ethinyl estradiol tablets / norethindrone acetate and ethinyl estradiol tablets.

Study Results

Table 7 – Results of study RR-03108 in the prevention of pregnancy

The pregnancy rate (Pearl Index [PI]) in women 18 to 35 years of age was 2.92 (95% confidence interval 1.94 to 4.21) pregnancies per 100 women-years of use, based on 28 pregnancies that occurred after the onset of treatment and extending through the 7 days following the last dose of ethinyl estradiol tablets / norethindrone acetate and ethinyl estradiol tablets (See Table 7). Cycles in which conception did not occur, but which included the use of backup contraception, were not included in the calculation of the PI. The PI includes women who did not take the drug correctly.

Bleeding Profile

The clinical trial that evaluated the efficacy of ethinyl estradiol tablets / norethindrone acetate and ethinyl estradiol tablets also assessed scheduled and unscheduled (intra-cycle) bleeding and/or spotting (IB/S). The participants in this 12-month clinical trial (N = 1,582 who had at least one post-treatment evaluation) completed over 15,000 cycles of exposure.

Total Bleeding/Spotting (scheduled and unscheduled):

The mean number of total bleeding/spotting days (scheduled and unscheduled) was 3.8 days per cycle and tended to decrease throughout the study from Cycle 2 through Cycle 12 (See

Figure 3)

Figure 3: Mean Number of Bleeding Days per Cycle (N = 1582)

5

4

3

Days

2

1

0

1 2 3 4 5 6 7 8 9 10 11 12

Cycle

Scheduled (withdrawal) Bleeding/Spotting:

Scheduled (withdrawal) bleeding and/or spotting remained fairly constant over the one year study, with an average of less than 2 days per cycle when including all women and all cycles. The incidence of withdrawal bleeding decreased over the course of the study, from 43% of subjects during Cycle 1 to 22% during Cycle 13. Incidence and duration of withdrawal bleeds tended to be greater in new users than in switchers.

Intensity of a bleeding/spotting episode was defined by a score of 0 to 3 where 0 = none, 1 = light;

2 = normal; and 3 = heavy. The overall mean median intensity of withdrawal bleeding/spotting was

1.53 for Cycle 2 through Cycle 13.

Unscheduled (intra-cycle) Bleeding and or Spotting (IB/S):

The mean number of days per cycle of IB/S decreased over the course of the study from 3.2 days during Cycle 2 to 1.8 days during Cycle 13. The mean duration throughout the study was 2.6 days/cycle.

A total of 1,257 women (85.9%) experienced IB/S at some time during Cycles 2 to 13 of this study. The incidence of IB/S was highest during Cycle 2 (53%) and lowest at Cycle 13 (36%).

Subjects in the study reported an average of 0.53 episodes per cycle of IB/S during the study. The mean maximum intensity score for IB/S episodes was 1.6 for Cycles 2 through Cycle 13.

In all subgroups (new users, switchers, 18 to 35 and 36 to 45) the numbers of IB/S, spotting only and bleeding-only days per cycle decreased over the course of the study. The incidence of IB/S, the mean number of episodes and the mean intensity for IB/S were higher in younger patients 18 to 35 than those 36 to 45. Measures of IB/S such as incidence and number of episodes, and maximum intensity tended to be higher in new users than in switchers, and decreased over the course of the study.

Amenorrhea:

The incidence of amenorrhea (absence of bleeding throughout the cycle) during Cycles 1 to 3 was approximately 30 to 32%, and increased to 49% for Cycle 13. In general the incidence of absence of bleeding was higher in older subjects (age 36 to 45), and in switchers vs. new users.

14.2 Comparative Bioavailability Studies

A blinded, randomized, two-treatment, two-period, two sequence, single oral dose (0.01 mg/1 mg dose as 1 x 0.01 mg/1 mg), crossover comparative bioavailability study of ELFY (Apotex Inc.) and LOLO (Allergan Inc.) was conducted in healthy, adult, female subjects under fasted conditions. Comparative bioavailability data from 37 subjects that were included in the statistical analysis are presented in the following tables:

SUMMARY TABLES OF THE COMPARATIVE BIOAVAILABILITY DATA

¹ ELFY (ethinyl estradiol / norethindrone acetate) tablets, 0.01 mg/1 mg (Apotex Inc.)

² LOLO (ethinyl estradiol / norethindrone acetate) tablets, 0.01 mg/1 mg (Allergan Inc., Canada)

³ Expressed as the median (range) only

⁴ Expressed as the arithmetic mean (CV%) only

A blinded, randomized, two-treatment, two-period, two sequence, single oral dose (0.01 mg dose as 1 x 0.01 mg), crossover comparative bioavailability study of ELFY (Apotex Inc.) and LOLO (Allergan Inc.) was conducted in healthy, adult, female subjects under fasted conditions. Comparative bioavailability data from 25 subjects that were included in the statistical analysis are presented in the following table:

SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

Ethinyl Estradiol

(1 x 0.01 mg)

Geometric Mean

Arithmetic Mean (CV%)

Parameter

Test¹

Reference²

% Ratio of Geometric Means

90% Confidence Interval

AUC_T

(pg·h/mL)

260.33

272.14 (28.27)

268.93

288.69 (36.23)

96.8

90.8- 103.2

AUC_I

(pg·h/mL)

296.65

308.17 (26.48)

311.00

332.02 (35.17)

95.4

89.9- 101.2

Cmax

(pg/mL)

26.88

27.81 (26.43)

27.55

28.94 (29.90)

97.6

91.8- 103.7

Tmax3

(h)

1.33 (1.00- 3.00)

1.33 (0.75- 1.67)

T1/24

(h)

16.73 (16.41)

18.26 (21.03)

¹ ELFY (ethinyl estradiol) tablets, 0.01 mg (Apotex Inc.))

² LOLO (ethinyl estradiol) tablets, 0.01 mg (Allergan Inc., Canada)

³ Expressed as the median (range) only

1. 4 Expressed as the arithmetic mean (CV%) only

15 MICROBIOLOGY

No microbiological information is required for this drug product.

16 NON-CLINICAL TOXICOLOGY

General Toxicology:

Toxicity Studies of Norethindrone Acetate in Animals

The LD₅₀ value of norethindrone acetate (on intraperitoneal administration to rats was greater than 1000 mg per kg body weight. The drug produced no toxic effects or abnormalities when administered orally to dogs in a single 30 mg dose. Administration of norethindrone acetate by the drug-diet method in rats over a period of 41 weeks produced depression in food intake and weight gain comparable to that following the use of norethindrone. Animals received average daily doses of 6, 14, and 27 mg per kg body weight.

Hematocrit, hemoglobin and leukocyte counts were not noticeably affected. Cholesterol values were low in all drug-fed animals, but all other microchemical determinations (minerals, transaminase, proteins, bilirubin, glucose and urea nitrogen) revealed normal values.

Histologic examination of tissues showed functional depression of testes and seminal vesicles and atrophy of pituitary and adrenal glands at the two higher dosage levels. Liver cell atrophy and several deviations of a minor nature were also noted.

Results indicated that the acetate is as well tolerated as norethindrone in continuous long-term use.

Long-Term Use of Norethindrone in Monkeys

Long-term oral administration of norethindrone to female rhesus monkeys produced only temporary changes in ovarian function. Six monkeys were treated for two years and 12 monkeys for one year at a dosage of 2.5 mg daily for 21 days of each cycle. This is comparable to a dosage of 25 mg daily for eight- and four-year periods in humans. Extensive studies were conducted on the blood, bone marrow, and on the various other tissues and organs, particularly the ovaries. The only noteworthy differences between control and treated animals were found in the genital organs and the pituitary. The treated monkeys could not be differentiated from control on the basis of general health, alertness, and behaviour. Bleeding usually started on the third or fourth day after discontinuation of drug administration each month, lasted three or four days, and was never heavy.

Ovaries from animals treated for one or two years were small, whitish with only small follicles visible, and no sign of recent rupture or of corpora lutea. Germinal epithelium was intact, and the layer of primordial ovocytes and young follicles appeared normal. Inside this cortical layer were small and medium-sized vesicular follicles and many corpora atretica, remnants of old follicles. Follicles had developed normally until the vesicular stage and then degenerated before attaining their full preovulatory growth.

Ovocytes appeared normal in all stages of development until the last pre-ovulatory step when maturation was inhibited. Uteri of treated monkeys had proliferative endometria with no decidual changes in the stroma. The vaginal tracts exhibited moderate to considerable epithelial cornification. Mammary glands were in the resting stage. Pituitaries of treated monkeys showed a decrease of basophilic cells.

Normal ovulatory cycles resumed shortly after medication was stopped. The sexual skin increased in redness, the vaginal epithelium became highly carnified during ovulation, and corpora lutea developed in the ovaries. The number and appearance of ova were normal, as was the rate of atresia. Endometria were proliferative or secretory. The ability to conceive also returned. The conception rate in the treated group compared favourably with that in the control group. Babies of treated animals were all normal at birth, and the females developed normally.

In summary, it was concluded from these studies that continuous administration of norethindrone for periods of one and two years suppressed ovulation without permanent effects on ovarian function and fertility of monkeys.

Chronic Oral Toxicities in Monkeys

Chronic oral toxicity studies were conducted in 8 immature rhesus monkeys - 4 males and 4 females. Norethindrone was administered in the amount of 2.5 mg per kg daily, five days a week for 183 days. No gross or microscopic signs of drug toxicity were found from blood studies, biopsies or at autopsy. As might be anticipated, testicular atrophy occurred in the males. There was also evidence of hormonal stimulation of the sexual skin and mammary glands of both sexes and of the uterine mucosa in females.

Long-Term Oral Studies of the Combination

Dogs

A combination of 50 parts norethindrone acetate to one part ethinyl estradiol was administered orally for 7 years at dosage levels of 0.051, 0.51, and 1.275 mg/kg/day (equivalent to 1, 10 and 25 times the human dose) in 28-day cycles (21 days of drug administration followed by 7 days of drug withdrawal). Sixteen dogs were initiated as controls and at each dosage level.

All dogs were observed daily. Body weights were recorded weekly. Mammary examinations were conducted once each month. Ophthalmoscopic examinations (indirect technique) were done every six months. Clotting studies were conducted for all dogs twice during the control period, six times during the first year, and semi-annually thereafter. Urinary steroid outputs were done once during the control period and annually thereafter.

One control dog and 9 treated dogs died or were sacrificed in extremis during the study. At the end of 7 years of study, the number of dogs surviving in each group was 15, 15, 14 and 10 at the control, 0.051, 0.51, and 1.275 mg/kg/day dosage levels, respectively. One dog at the 0.051 and 0.51 mg/kg/day dosage levels, and 2 dogs at the 1.275 mg/kg/day dose levels were hysterectomized during the study. At the end of 7 years of study, nodules were palpated in the mammary tissue of 5 control dogs, 5 dogs at the 0.051 mg/kg/day dosage level, 6 dogs at the 0.51 mg/kg/day level and 6 dogs at the 1.275 mg/kg/day level. Frequently, nodules disappeared after variable periods of time. Only rarely did nodules reach or exceed 10 mm in diameter, and commonly the behaviour of these indicated that they were cystic in nature.

Alopecia was seen more frequently for treated dogs than for control dogs. Red or brown vaginal discharge was seen most frequently for control dogs and dogs at the 0.051 mg/kg/day dosage level. It was rarely noted for dogs at the 0.51 and 1.275 mg/kg/day dosage levels following 18 months of study. Treated dogs showed greater body weight gains than control dogs. No changes considered to be related to treatment were seen in the mammary development, behaviour or in urinary steroid output.

Fibrinogen concentrations were somewhat greater for treated dogs than for control dogs during the 6th and 7th years of study. No other unusual changes were noted in clotting studies.

Ophthalmologic examinations revealed eye changes for several dogs in each group. No drug relationship was noted with respect to the occurrence of these changes. Drug related gross lesions consisting of alopecia and enlarged and/or cystic uteri were observed in a number of dogs at terminal sacrifice. Organ weight effects were limited to increase in uterine weights of individuals in most experimental groups. Microscopically, drug related changes included absence of ovulation in all dogs in the high-dose group and most dogs in the mid-dose group, and increased incidence and severity of cystic endometrial hyperplasia and uterine adenomyosis in dogs in the high dose group.

The occurrence of benign tumours in vaginas and uteri of several dogs in the high dose group was considered drug related. Hyperplastic nodules and benign tumours occurred in mammary glands of dogs both in control and treated groups, but the incidence at the high-dose level was somewhat greater. No malignant mammary neoplasm occurred in any of the dogs in this study.

Monkeys

A combination of 50 parts of norethindrone acetate to one part ethinyl estradiol was administered orally to mature female rhesus monkeys in a long-term study for a period of 10 years at dosage levels of 0.051, 0.51, and 2.55 mg/kg/day (1, 10, and 50 times the human dose). The dosing regimen consisted of consecutive cycles of 21 days of drug administration followed by 7 days of drug withdrawal. Sixteen monkeys were assigned to each treatment group; while an additional 16 animals received the food vehicle only. Daily observations of general health revealed no evidence of overt effects of drug treatment or significant changes in behaviour. The percent body weight gain of surviving animals was comparable, although the body weights of the treated groups were less than controls at some intervals.

Red vaginal discharge occurred with greater frequency in control and low-dose groups and was usually observed in the withdrawal phase of the mid-and high-dose groups, reflecting the pharmacologic action of the drug combination. No drug related alterations were noted in vaginal cytology or mammary development.

A retinal macular granularity, with and without foci of altered reflectivity, was noted in both control and treated animals beginning at 6 years. Although the incidence and severity of these alterations appeared to be greater in treated animals, no definite relationship to drug administration was considered to have been established.

Reduced total platelet count and increased fibrinogen concentrations were noted more frequently for treated monkeys during the initial 90 months and 48 months of study, respectively. An occasional animal showed an elevated postprandial glucose concentration, but no treatment or dosage relationship was apparent. No drug related alteration in urinary steroid output was observed.

Small nodules were palpable in or near the mammary tissue of five, four, three, and two monkeys in the control, 0.051, 0.51, and 2.55 mg/kg/day dosage groups, respectively, at least at one examination. Detailed physical examinations also revealed an abdominal mass in 2 control monkeys, slight curvature of the spine in 2 low-dose animals, and a pulsating saphenous vein in a high-dose animal. No drug related gross lesions were seen in animals that died, were sacrificed in extremi during the study or were terminally sacrificed. A frequent cause of death in this study, which is a common occurrence in non- human primates, was acute gastric dilatation. The lesions observed at necropsy appeared spontaneous and unrelated to drug administration.

A statistically significant decrease (p < 0.05) in the mean absolute uterine weight at the high-dose level was drug related. Microscopically, drug related lesions included uterine atrophy, slightly increased incidence of occurrence of mucus and inflammatory cells in the cervical canal, and dilatation of acini and ducts in mammary glands of monkeys from the high-dose group, were considered to be related to the pharmacologic effect of the test combination.

No drug related neoplasms were observed in the study. A low overall incidence of neoplasms was seen in all organs and tissues examined. A total of 6 neoplastic microscopic lesions were noted during this entire study; an adenoma (pancreatic duct origin) in a low-dose animal; a granulosa cell carcinoma (ovary) in a control animal with metastasis to liver, lymph node, and lung; and a leiomyoma (uterus) and 2 papillomas (skin) in high-dose animals. With the exception of the granulosa cell carcinoma, no malignant neoplasms were identified.

17 SUPPORTING PRODUCT MONOGRAPHS

1. 1. LOLO® (ethinyl estradiol tablets / norethindrone acetate and ethinyl estradiol tablets, 10 mcg / 1 mg and 10 mcg), submission control no.286305, Product Monograph, AbbVie Corporation, (OCT 17, 2024).