Mirvala 21 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 .............................................................................................................. 2

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

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

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

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

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

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

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

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

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

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

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

5 OVERDOSAGE .............................................................................................................. 9

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ............................... 10

7 WARNINGS AND PRECAUTIONS ................................................................................ 11

7.1 Special Populations ............................................................................................... 19

7.1.1 Pregnant Women ........................................................................................ 19

7.1.2 Breastfeeding .............................................................................................. 19

7.1.3 Pediatrics ..................................................................................................... 19

7.1.4 Geriatrics ..................................................................................................... 19

8 ADVERSE REACTIONS ................................................................................................ 20

8.1 Adverse Reaction Overview .................................................................................. 20

8.2 Clinical Trial Adverse Reactions ............................................................................. 22

8.5 Post-Market Adverse Reactions ............................................................................ 24

9 DRUG INTERACTIONS ................................................................................................ 24

9.2 Drug Interactions Overview .................................................................................. 25

9.4 Drug-Drug Interactions .......................................................................................... 25

9.5 Drug-Food Interactions ......................................................................................... 31

9.6 Drug-Herb Interactions ......................................................................................... 31

9.7 Drug-Laboratory Test Interactions ....................................................................... 31

10 CLINICAL PHARMACOLOGY ....................................................................................... 32

10.1 Mechanism of Action ........................................................................................... 32

10.2 Pharmacodynamics ............................................................................................... 32

10.3 Pharmacokinetics .................................................................................................. 33

11 STORAGE, STABILITY AND DISPOSAL ......................................................................... 35

12 SPECIAL HANDLING INSTRUCTIONS ........................................................................... 36

PART II: SCIENTIFIC INFORMATION ....................................................................................... 37

13 PHARMACEUTICAL INFORMATION ............................................................................ 37

14 CLINICAL TRIALS ........................................................................................................ 38

14.1 Clinical Trial by Indication...................................................................................... 38

14.2 Comparative Bioavailability Studies ...................................................................... 42

16 NON-CLINICAL TOXICOLOGY ..................................................................................... 44

17 SUPPORTING PRODUCT MONOGRAPHS .................................................................... 50

PATIENT MEDICATION INFORMATION .................................................................................. 51

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

MIRVALA (desogestrel and ethinyl estradiol tablets) is indicated for:

• Conception control

1.1 Pediatrics

Pediatrics: The safety and efficacy of desogestrel and ethinyl estradiol tablets has not been established in women under the age of 18 years.

Use of this product before menarche is not indicated.

1.2 Geriatrics

Geriatrics: MIRVALA is not indicated in postmenopausal women.

2 CONTRAINDICATIONS

Combined hormonal contraceptives (CHCs) should not be used in the presence of any of the conditions listed below. Should any of the conditions appear for the first time during CHC use, the product should be stopped immediately.

• MIRVALA 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, STRENGTHS, COMPOSITION AND PACKAGING.
• presence or history of venous thrombosis (deep vein thrombosis, pulmonary embolism);
• a history of or actual cerebrovascular disorders;
• presence or history of arterial thrombosis (myocardial infarction, cerebrovascular accident) or prodromal conditions (eg, transient ischaemic attack, angina pectoris);
• valvular heart disease with complications;
• presence or history of severe hepatic disease as long as liver function values have not returned to normal;
• use with the Hepatitis C virus combination drug regimen ombitasvir/paritaprevir/ritonavir with or without dasabuvir or medicinal products containing glecaprevir/pibrentasvir (see 7 WARNINGS AND PRECAUTIONS and 9 DRUG INTERACTIONS);
• presence or history of liver tumours (benign or malignant);
• known or suspected sex steroid-influenced malignancies (e.g. of the genital organs or of the breast);
• undiagnosed abnormal vaginal bleeding;
• steroid-dependant 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 hypertriglyceridemia;

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

  • severe hypertension (persistent values of ≥160/100 mmHg)
  • 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
  • smoking and over age 35
  • diabetes mellitus with vascular involvement
  • major surgery associated with an increased risk of postoperative thromboembolism (see 7 WARNINGS AND PRECAUTIONS)
  • prolonged immobilization (see 7 WARNINGS AND PRECAUTIONS);

3 SERIOUS WARNINGS AND PRECAUTIONS BOX

Serious Warnings and Precautions

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

Patients should be instructed to read the package insert prior to starting MIRVALA and any time they are unsure of administration. Patients should be instructed to read the package insert and the Day of the Week Label Strip. If they have additional questions, they should call their doctor or clinic.

MIRVALA tablets may be prescribed as a 21-day or a 28-day regimen. MIRVALA tablets must be taken at approximately the same time every day until the pack is empty. The patient may begin taking MIRVALA on Day 1 of her menstrual cycle (i.e., the first day of menstrual flow) or on the first Sunday after her period begins. If the patient’s period starts on Sunday, she should start that same day.

4.2 Recommended Dose and Dosage Adjustment

MIRVALA 21 (21-Day Regimen): One white tablet is to be taken for 21 consecutive days (three weeks). Tablets are then discontinued for one week. The patient must not be off the pill for more than seven consecutive days. A new pack will be started on the eighth day. The patient will have a period during the seven days off the pill (bleeding may be lighter and shorter than their usual period.)

MIRVALA 28 (28-Day Regimen): One white tablet is to be taken for 21 consecutive days (three weeks), followed by a green tablet for seven consecutive days (one week). A new pack (white tablet) will be started on the eighth day, following the completion of the green tablets. The patient will have a period while they are on the green tablet. On this regimen the patient must not go a day without taking a pill.

4.4 Administration

It is recommended that MIRVALA be taken at the same time each day. The patient should be counselled to associate taking the pill with some regular activity like eating a meal or going to bed.

The first-time user may wish to use a second method of birth control (e.g., latex condoms and spermicidal foam or gel) for the first seven days of the first cycle of pill use. This will provide a back-up in case pills are forgotten while they are getting used to taking them.

If spotting, light bleeding, or feeling sick to their stomach occurs during the first three months the women should be counselled to not stop taking the pill. The problem will usually go away. If it does not subside, the patient should consult her doctor or clinic.

The dosage regimen should not be altered (i.e., the pill should not be stopped) even if the women does not have sex very often.

When receiving any medical treatment, patients should tell their doctor that they are using birth control pills.

Advice in case of vomiting

In case of severe gastro-intestinal disturbance, absorption may not be complete and additional contraceptive measures should be taken. If vomiting occurs within 3 to 4 hours after tablet-taking, the advice concerning the Management of missed tablets is outlined below. If the woman does not want to change her normal tablet-taking schedule, she has to take the extra tablet(s) needed from another pack.

When to start MIRVALA

No hormonal contraceptive use in the preceding cycle: Tablet taking should start on Day 1 of the woman’s menstrual cycle or on the first Sunday after her period begins.

Switching from another combination hormonal contraceptive (combined oral contraceptive (COC), vaginal ring, or transdermal patch): The woman should start MIRVALA preferably on the day after the last active tablet of her previous COC, but at the latest, on the day following the usual tablet-free or inactive tablet of her previous COC. In case a vaginal ring or transdermal patch has been used, the woman should start using MIRVALA preferably on the day of removal, but at the latest when the next application would have been due.

Switching from a progestogen-only-method (mini-pill, injection, implant) or from a progestogen-releasing intrauterine system (IUS): The woman may switch from the mini-pill to MIRVALA on any day of her cycle. Patients using a progestogen injection should start MIRVALA on the day the next injection is due. Patients using an implant or an IUS should start MIRVALA on the day it is removed. In all cases, the woman should be advised to use an additional barrier method for the first 7 days of MIRVALA use.

Following complete first-trimester abortion: The woman may start using MIRVALA immediately. When doing so, she need not take additional contraceptive measures.

Following delivery or second-trimester abortion: Women should be advised to start MIRVALA on Day 21 to 28 after delivery or second trimester abortion, after consulting with their physician. When starting later, the woman should be advised to use an additional barrier method for the first seven days of tablet-taking. However, if intercourse has already occurred, pregnancy should be excluded before the actual start of use or the woman should be advised to wait for her first menstrual period prior to starting MIRVALA.

The increased risk of venous thromboembolism (VTE) during the postpartum period should be considered when restarting MIRVALA (see 7 WARNINGS AND PRECAUTIONS).

For breastfeeding women, see 7 WARNINGS AND PRECAUTIONS - Breastfeeding.

4.5 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 missed with the appropriate starting time for her dosing regimen.

Missing pills can cause spotting or light bleeding, even if the missed pills are made up. The woman may also feel a little sick to her stomach on the days she takes two pills to make up for missed pills.

If a woman misses pills at any time, she could get pregnant. The greatest risks for pregnancy are starting a pack late or missing a pill(s) at the beginning or at the very end of the pack.

The patient should be counselled to always have another kind of birth control (such as latex condoms and spermicidal foam or gel) to use as a back-up in case they miss pills, and an extra, full pack of pills available.

If the patient forgets more than one pill, two months in a row, they should be instructed to talk to their doctor or clinic. The patient may require further counselling about ways to make pill-taking easier or about using another method of birth control.

NOTE to Patients on the 28-day regimen (MIRVALA 28): If the patient forgets any of the seven green pills (without hormones) in Week 4, she should be advised to safely dispose of the pills she missed and then keep taking one pill each day until the pack is empty. A back-up method of birth control is not needed.

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 withdrawal bleeding may occur in females. There are no antidotes 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

Packaging

MIRVALA 21

Push-through strips of 21 white tablets each. The push-through strip consists of PVC- PVDC/aluminium blisters.

MIRVALA 28

Push-through strips of 21 white and 7 green tablets each. The push-through strip consists of PVC-PVDC/aluminium blisters.

Dosage Forms

• MIRVALA 21: Each carton contains a sleeve and blister pack with 21 round white tablets with MI and 7 debossed on opposite sides. Each tablet for oral administration contains 0.15 mg desogestrel and 0.03 mg ethinyl estradiol.

• MIRVALA 28: Each carton contains a sleeve and blister pack with 21 round white tablets with MI and 7 debossed on opposite sides, and 7 round green tablets without

  • 0.03 mg ethinyl estradiol. Each green tablet for oral administration contains inert ingredients.

Dissolution test is as per Test 2 of the USP monograph.

7 WARNINGS AND PRECAUTIONS

General

Discontinue Medication at the Earliest Manifestation of:

1. A. Thromboembolic and cardiovascular disorders, such as thrombophlebitis, pulmonary embolism, cerebrovascular disorders, myocardial ischemia, mesenteric thrombosis, and retinal thrombosis.
2. B. Conditions which predispose to venous stasis and to vascular thrombosis (eg, 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.
3. C. Visual defects - partial or complete.
4. D. Papilledema or ophthalmic vascular lesions.
5. E. Severe headache of unknown etiology or worsening of pre-existing migraine headache.
6. F. Increase in epileptic seizures

Throughout this section the general term combined hormonal contraceptives (CHC) is used when data exist for oral and non-oral contraceptives. The term combined oral contraceptives (COC) is used when data exist only for oral contraceptives.

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

The use of COCs 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: jaundice and/or pruritus related to cholestasis; gallstone formation; porphyria, systemic lupus erythematosus, hemolytic uremic syndrome, Sydenham’s chorea, herpes gestationis and otosclerosis-related hearing loss; (hereditary) angioedema.

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

Carcinogenesis and Mutagenesis

Breast Cancer

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

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

Cervical Cancer

The most important risk factor for cervical cancer is persistent human papilloma virus (HPV) infection. Some 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 behavior 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. However, the attributable risk (the excess incidence) of liver cancers in oral contraceptive users is extremely small.

Cardiovascular

Predisposing Factors for Coronary Artery Disease

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

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

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

Hypertension

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.

Endocrine and Metabolism

Diabetes

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

Lipid and Other Metabolic Effects

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

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.

Genitourinary

Vaginal Bleeding

Persistent irregular vaginal bleeding requires assessment to exclude underlying pathology.

Fibroids

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

Hematologic

Epidemiological studies have shown an association between the use of CHCs and an increased risk of arterial and venous thrombotic and thromboembolic diseases such as myocardial infarction, stroke, deep venous thrombosis, and pulmonary embolism.

Epidemiological studies have shown that the incidence of venous thromboembolism (VTE) in users of CHC with low estrogen content (<50 mcg ethinyl estradiol) ranges from about 3 to 12 cases per 10,000 women-years, but the risk estimate varies according to the progestogen. This compares with 1 to 5 cases per 10,000 women-years for non-CHC users.

The use of CHCs 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 CHC. The increased risk is less than the risk of VTE associated with pregnancy, which is estimated as 5 to 20 cases per 10,000 women-years or the risk in the postpartum period which is estimated as 40 to 65 cases per 10,000 women-years. The risk is also increased after initially starting a CHC or restarting the same or different CHC after a break in use of 4 weeks or more. VTE is fatal in 1 to 2% of cases.

Several epidemiological studies indicate that third generation oral contraceptives, including those containing desogestrel, are associated with a higher risk of venous thromboembolism than certain second generation oral contraceptives. These studies indicate an approximate 2-fold difference in risk, which corresponds to 1 to 2 cases of venous thromboembolism per 10,000 women-years of use. However, data from additional studies have not shown this difference in risk.

Extremely rarely, thrombosis has been reported to occur in other blood vessels, e.g., hepatic, mesenteric, renal, cerebral or retinal veins and arteries, in CHC users.

Symptoms of venous or arterial thrombotic/thromboembolic events or of a cerebrovascular accident can include: unilateral leg pain and/ or swelling; sudden severe pain in the chest, whether or not it radiates to the left arm; sudden breathlessness; sudden onset of coughing; any unusual, severe, prolonged headache; sudden partial or complete loss of vision; diplopia; slurred speech or aphasia; vertigo; collapse with or without focal seizure; weakness or very marked numbness suddenly affecting one side or one part of the body; motor disturbances; ‘acute’ abdomen.

Other Risk Factors for Venous Thromboembolism

Other generalized risk factors for venous thromboembolism include but are not limited to:

• a personal history,
• a positive family history (the occurrence of VTE in a direct relative at a relatively early age). 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 CHC use.
• severe obesity (body mass index >30kg/m²),
• systemic lupus erythematosus.

The risk of VTE also increases with increasing age and smoking.

The risk of VTE may be temporarily increased with prolonged immobilization, major surgery, any surgery to the legs or major trauma. In these situations it is advisable to discontinue CHC use (in the case of elective surgery at least four weeks in advance) and not to resume until two weeks after complete remobilization (see 2 CONTRAINDICATIONS).

Also, patients with superficial thrombophlebitis and varicose veins and leg cast should be closely supervised. There is no consensus about the possible role of these conditions in the etiology of venous thromboembolism.

Other Risk Factors for Arterial Thromboembolism

The risk of arterial thromboembolic complications increases with:

• increasing age;
• smoking (with heavier smoking and increasing age the risk further increases, especially in women over 35 years of age);
• dyslipoproteinemia;
• obesity (body mass index over 30 kg/m²);
• hypertension;
• migraine;
• valvular heart disease;
• atrial fibrillation;
• a positive family history (i.e. arterial thrombosis ever in a sibling or parent at a relatively early age). If a hereditary predisposition is suspected, the woman should be referred to a specialist for advice before deciding about any hormonal contraceptive use.

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.

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.

Hepatitis C

During clinical trials with some HCV combination drug regimens, ALT elevations were observed in women using ethinylestradiol containing medications. For example, the HCV combination drug regimen ombitasvir /paritaprevir/ritonavir with and without dasabuvir, ALT elevations greater than 5 times the upper limit of normal (ULN) were significantly more frequent in women using ethinylestradiol-containing medications such as CHCs. Additionally, in patients treated with glecaprevir/pibrentasvir, ALT elevations were observed in women using ethinylestradiol-containing medications such as CHCs. MIRVALA must be discontinued prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir with or without dasabuvir or medicinal products containing glecaprevir/pibrentasvir. (see 2 CONTRAINDICATIONS and 9 DRUG INTERACTIONS). MIRVALA can be restarted approximately 2 weeks following completion of treatment with the HCV combination drug regimen.

Immune

Angioedema

Exogenous estrogens may induce or exacerbate symptoms of hereditary and acquired angioedema.

Monitoring and Laboratory Tests

Physical Examination and Follow-up

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 headaches with 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

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

Peri-Operative Considerations

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

Psychiatric

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 (PMS) may have a varied response to oral contraceptives, ranging from symptomatic improvement to worsening of the condition.

Renal

Fluid Retention

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

Reproductive Health: Female potential

Fertility

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

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

Reduced Efficacy

The efficacy of MIRVALA may be reduced in the event of missed tablets, gastro-intestinal disturbances or concomitant medications that decrease the plasma concentration of ethinyl estradiol and/or etonogestrel, the active metabolite of desogestrel (see 9 DRUG INTERACTIONS).

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.

7.1 Special Populations

7.1.1 Pregnant Women

Oral contraceptives should not be taken by pregnant women. If pregnancy occurs during treatment with MIRVALA, 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.

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. 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 new-born 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.

7.1.3 Pediatrics

The safety and efficacy of desogestrel 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

MIRVALA is not indicated in postmenopausal women.

8 ADVERSE REACTIONS

8.1 Adverse Reaction Overview

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

• arterial and venous thromboembolism
• benign and malignant hepatic tumors
• 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 other adverse reactions also have been reported in patients receiving combination hormonal 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:

• abdominal pain
• amenorrhea during and after treatment
• angioedema (exogenous estrogens may induce or exacerbate symptoms of hereditary and acquired angioedema)^a
• auditory disturbances
• breakthrough bleeding
• breast changes (tenderness, enlargement, and secretion)
• cataracts
• changes in appetite
• change in corneal curvature (steepening)
• changes in glucose tolerance or effect on peripheral insulin resistance
• changes in libido
• change in menstrual flow
• change in weight (increase or decrease)
• chloasma or melasma which may persist
• cholestatic jaundice
• chorea
• Crohn’s disease
• cystitis-like syndrome
• diarrhea
• dizziness
• dysmenorrhea
• edema
• endocervical hyperplasia
• erythema multiforme
• erythema nodosum
• gallstone formation^a
• gastrointestinal symptoms (such as abdominal cramps and bloating)
• headache
• hemolytic uremic syndrome
• hemorrhagic eruption
• herpes gestationis^a
• hirsutism
• hypersensitivity
• hypertension^a
• hypertriglyceridemia (increased risk of pancreatitis when using COCs)
• impaired renal function
• increase in size of uterine leiomyomata
• intolerance to contact lenses
• jaundice related to cholestasis^a
• liver function disturbances
• loss of scalp hair
• mental depression
• migraine
• nervousness
• optic neuritis
• otosclerosis-related hearing loss^a
• pancreatitis
• porphyria
• possible diminution in lactation when given immediately postpartum
• premenstrual-like syndrome
• pruritus related to cholestasis^a
• rash (allergic)
• Raynaud's phenomenon
• reduced tolerance to carbohydrates
• retinal thrombosis
• rhinitis
• spotting
• Sydenham’s chorea^a
• Systemic lupus erythematosus^a
• temporary infertility after discontinuation of treatment
• ulcerative colitis
• urticaria
• vaginal candidiasis
• vaginal discharge
• vaginitis

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

8.2 Clinical Trial Adverse 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 reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Eighty-six per cent of the 1,195 subjects reported 1 or more adverse experiences. The majority of these (64%) were considered (by the investigators) to be unrelated to desogestrel and ethinyl estradiol tablets usage. Of the total population, approximately 12% of the subjects discontinued due to an adverse experience.

Table 2 - OVERALL ASSESSMENT OF CLINICAL ADVERSE EXPERIENCES (AES) ALL-PATIENTS- TREATED-GROUP

^aPercentages are of total patients entered.

^bStarter/Switcher status could not be determined in one subject.

^cA total of 145 patients actually had a clinical AE as the primary reason for discontinuation.

With the exception of menses-related adverse experiences, no significant changes in the incidence of adverse experiences over time were seen. No drug-related adverse effects were observed during general physical or pelvic examination. The breast examination showed a reduction in nodularity. No changes in body mass index or blood pressure were observed. Baseline distribution of abnormalities in cervical cytology was comparable to those at last visit. No patient developed a clinically significant abnormal value for routine laboratory analytes that led to either early discontinuation or hospitalization.

Detailed ophthalmologic examinations, including slit-lamp, were performed in a subset of 28 healthy women at baseline and after 12 cycles. No patients were found to have a decrease in visual acuity. Complete ophthalmological examination failed to identify possible desogestrel and ethinyl estradiol tablets related changes.

Table 3 - PREVALENCE OF MOST FREQUENT^a SIDE EFFECTS OVER CYCLES INCIDENCE DURING STUDY WITH N=1,195 TOTAL (PER CENT)

^a Adverse experiences reported by >5% of patients.

8.5 Post-Market Adverse Reactions

The most serious undesirable effects associated with the use of COCs are listed in 7 WARNINGS AND PRECAUTIONS. Other side effects that have been reported in users of COCs but for which the association has been neither confirmed nor refuted are:¹

Table 4 - Side effects reported in users of COCs but for which the association has been neither confirmed nor refuted

¹ The most appropriate MedDRA term (version 6.1) to describe a certain adverse reaction is listed. Synonyms or related conditions are not listed, but should be taken into account as well.

9 DRUG INTERACTIONS

9.2 Drug Interactions Overview

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

The concurrent administration of oral contraceptives with other medicinal products may lead to breakthrough bleeding and/or may result in an altered response to either agent (see table 1 and table 2). 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.

Hepatic metabolism: Interactions can occur with medicinal or herbal products that induce microsomal enzymes, specifically cytochrome P450 enzymes (CYP), which can result in increased clearance reducing plasma concentrations of sex hormones and may decrease the effectiveness of combined oral contraceptives, including MIRVALA These products are identified in 9.4 Drug-Drug Interactions and 9.6 Drug-Herb Interactions with an (*). Enzyme induction can occur after a few days of treatment. Maximum enzyme induction is generally observed within a few weeks. After drug therapy is discontinued, enzyme induction can last for about 28 days.

For women on long-term therapy with enzyme-inducing medicinal products, an alternative method of contraception unaffected by enzyme-inducing medicinal products should be considered.

9.4 Drug-Drug Interactions

Table 5: Drugs Which May Decrease the Efficacy of Oral Contraceptives

Oral contraceptives may interfere with the metabolism of other drugs. Accordingly, plasma and tissue may either increase (e.g., cyclosporine) or decrease (e.g. lamotrigine).

If concomitant drug administration runs beyond the end of the tablets in the current COC pack, the next COC pack should be started right away without the usual tablet-free interval.

Table 6 - Modification of Other Drug Action by Oral Contraceptives

When co-administered with hormonal contraceptives, many combinations of HIV protease inhibitors (e.g., nelfinavir) and non-nucleoside reverse transcriptase inhibitors (e.g., nevirapine), and/or combinations with Hepatitis C virus (HCV) medicinal products (e.g., boceprevir, telaprevir) can increase or decrease plasma concentrations of progestins, including etonogestrel, the active metabolite of desogestrel, or estrogens. The net effect of these changes may be clinically relevant in some cases.

During clinical trials with the HCV combination drug regimen ombitasvir /paritaprevir/ritonavir with and without dasabuvir, ALT elevations greater than 5 times the upper limit of normal (ULN) were significantly more frequent in women using ethinylestradiol-containing medications such as CHCs. MIRVALA must be discontinued prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir with or without dasabuvir (see 2 CONTRAINDICATIONS and 7 WARNINGS AND PRECAUTIONS). MIRVALA can be restarted approximately 2 weeks following completion of treatment with the HCV combination drug regimen. Concomitant use with some other HCV antiviral medicinal products, such as those containing glecaprevir/pibrentasvir, may also increase the risk of ALT elevations.

Concomitant administration of strong (e.g., ketoconazole, itraconazole, clarithromycin) or moderate (e.g., fluconazole, diltiazem, erythromycin) CYP 3A4 inhibitors may increase the serum concentrations of estrogens or progestins, including etonogestrel, the active metabolite of desogestrel.

9.5 Drug-Food Interactions

Interactions with food have not been established.

9.6 Drug-Herb Interactions

Herbal products containing St. John’s Wort (*) (hypericum perforatum) may induce hepatic enzymes (cytochrome P450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids. This may also result in breakthrough bleeding. For short course, a barrier contraceptive method should be used in addition to MIRVALA during administration and for 28 days after discontinuation of the herbal product. For long course, use another method of contraception.

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

Aspartate serum transaminase (AST) - variously reported elevations

Alkaline phosphatase and gamma glutamine transaminase (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 two 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

Combination hormonal contraceptives act by the suppression of gonadotropins. The primary mechanism of action is inhibition of ovulation, but other alterations include impaired sperm penetration and “spinnbarkeit” of the cervical mucus, and changes to the endometrium to reduce the likelihood of implantation. Receptor binding studies, as well as studies in animals and humans, have shown etonogestrel, the biologically active metabolite of desogestrel, combines high progestational activity with minimal intrinsic androgenicity. Desogestrel (DSG) in combination with ethinyl estradiol (EE) does not counteract the estrogen-induced increase in SHBG resulting in lower serum levels of free testosterone.

10.2 Pharmacodynamics

The contraceptive effect of COCs is based on the interaction of various factors, the most important of which are seen as the inhibition of ovulation and the changes in the cervical secretion.

Desogestrel, the progestogen component of MIRVALA, displays low androgenic activity in relation to its progestogenic effects and may increase the HDL/LDL ratio and apoprotein A-1/B ratio without affecting HDL₂. Like other oral contraceptives, these changes in lipid profile can be associated with an increase in triglycerides.

Animal and in vitro pharmacology

Animal pharmacology and in vitro receptor binding studies indicate that 3-k-desogestrel, the biologically active metabolite, is a highly selective progestational agent (see table below) with no estrogenic effects, and only residual androgenicity.

Table 7 - COMPARISON OF RELATIVE BINDING AFFINITY OF DESOGESTREL, 3-k-DESOGESTREL AND PROGESTERONE FOR THE PROGESTERONE RECEPTOR IN UTERINE CYTOSOL.*

* Binding affinities were determined at 4NC using the reference standard 16α- ethyl-21-hydroxy-9-nor-pregn-4-ene-3,20-dione.

Desogestrel and its metabolites, other than 3-k-desogestrel and 3-keto-5α-H-desogestrel, display minimal binding affinity for the androgen receptor with respect to dihydrotestosterone, as studied in intact MCF-7 cells. The binding affinity of both 3-k-desogestrel and 3-keto-5α-H-desogestrel is approximately 1/10 of 5α-dihydrotestosterone; suggesting a low androgenic activity. The binding affinity for the androgen receptor in intact MCF-7 cells as displayed by 3-k-desogestrel was also significantly lower than that of other progestogens.

The "selectivity index" (progestogen/androgen receptor binding affinity ratio) for 3-k-desogestrel in intact MCF-7 cells is higher than any other progestogen.

Oral desogestrel displays weak androgenic activity, approximately 0.05 the activity of 17α-methyl-testosterone, in orchidectomized rats, using the Herschberger test.

10.3 Pharmacokinetics

Desogestrel (DSG) is rapidly and almost completely absorbed and converted into 3-ketodesogestrel, (3-K-DSG), its biologically active metabolite. After a single dose of desogestrel and ethinyl estradiol tablets, maximum concentrations of 3-K-DSG of approximately 6 pmol/mL are reached at 1.6 hours. The area under the curve (AUC_0-∞) is approximately 59 pmol/mL.hr after a single dose. At steady state, attained from at least day 19 onwards, maximum concentrations of approximately 18 pmol/mL are reached at 1.4 hours. The minimum plasma levels of 3-K-DSG at steady state are approximately 4 pmol/mL. The AUC_0-24 at steady state is approximately 161 pmol/mL·hr. The relative bioavailability of 3-K-DSG is approximately 84%.

The elimination half-life for 3- K-DSG is approximately 38 hours at steady state.

Major phase I metabolites are 3α-OH-desogestrel, 3β-OH-desogestrel, and 3α-OH-, 5α-OH-desogestrel. These degradation products are in part further converted by conjugation (phase II metabolism) into polar metabolites, mainly sulfates and glucuronides. Approximately 48% of 3-K-DSG is recovered unchanged in urine within 24 hours.

Ethinyl estradiol (EE) is rapidly and almost completely absorbed. After a single dose of desogestrel and ethinyl estradiol tablets, maximum concentrations of EE of approximately 0.3 pmol/mL are reached at 1.6 hours. The AUC_0-∞ is about 4.9 pmol/mL.hr after a single dose. At steady state, attained from at least day 19 onwards, maximum ethinyl estradiol concentrations of approximately 0.5 pmol/mL are reached at about 1.4 hours. The minimum serum levels of ethinyl estradiol at steady state are about 0.08 pmol/mL. The AUC_0-24, at steady state is approximately 4.6 pmol/mL.hr. The relative bioavailability is approximately 83% and the elimination half-life about 26 hr at steady state.

Ethinyl estradiol is subject to a significant degree of presystemic conjugation (phase II metabolism). Ethinyl estradiol escaping gut wall conjugation undergoes phase I metabolism and hepatic conjugation (phase II metabolism). Major phase I metabolites are 2-OH-ethinyl estradiol and 2-methoxy-ethinyl estradiol. Sulfate and glucuronide conjugates of both EE and phase I metabolites, which are excreted in bile, can undergo enterohepatic circulation.

Absorption

Desogestrel (DSG) is rapidly and almost completely absorbed and converted into etonogestrel, (ENG), its biologically active metabolite. Following oral administration, the relative bioavailability of desogestrel, compared to solution, as measured by serum levels of etonogestrel, is approximately 100%. Ethinyl estradiol is rapidly and almost completely absorbed. When the lowest and highest tablet strengths, 0.100 mg desogestrel/0.025 ethinyl estradiol and 0.15 mg desogestrel/0.025 mg ethinyl estradiol, were compared to solution, the relative bioavailability of ethinyl estradiol was 92% and 98% respectively. The effect of food on the bioavailability of desogestrel and ethinyl estradiol tablets following oral administration has not been evaluated.

Distribution

Etonogestrel, the active metabolite of desogestrel, was found to be 98% protein bound, primarily to sex hormone-binding globulin (SHBG). Ethinyl estradiol is primarily bound to plasma albumin. Ethinyl estradiol does not bind to SHBG, but induces SHBG synthesis. Desogestrel, in combination with ethinyl estradiol, does not counteract the estrogen-induced increase in SHBG, resulting in lower serum levels of free testosterone.

Metabolism

Desogestrel: Desogestrel is rapidly and completely metabolized by hydroxylation in the intestinal mucosa and on first pass through the liver to etonogestrel. In vitro data suggest an important role for the cytochrome P450 CYP2C9 in the bioactivation of desogestrel. Further metabolism of etonogestrel into 6β-hydroxy, etonogestrel and 6β-13ethyl-dihydroxylated as major metabolites is catalyzed by CYP3A4. Other metabolites (i.e., 3α-OH-desogestrel, 3β-OH-desogestrel, and 3α-OH-5α-H-desogestrel) also have been identified and these metabolites may undergo glucuronide and sulfate conjugation.

Ethinyl estradiol: Ethinyl estradiol is subject to a significant degree of presystemic conjugation (phase II metabolism). Ethinyl estradiol, escaping gut wall conjugation, undergoes phase I metabolism and hepatic conjugation (phase II metabolism). Major phase I metabolites are 2-OH-ethinyl estradiol and 2-methoxy-ethinyl estradiol. Sulfate and glucuronide conjugates of both ethinyl estradiol and phase I metabolites, which are excreted in bile, can undergo enterohepatic circulation.

Excretion

Etonogestrel and ethinyl estradiol are primarily eliminated in urine, bile and feces. At steady state, on Day 21, the elimination half-lives of etonogestrel and ethinyl estradiol are 37.1±14.8 hours and 28.2±10.5 hours, respectively.

Special Populations and Conditions

Race

There is no information to determine the effect of race on the pharmacokinetics of desogestrel/ethinyl estradiol tablets.

Hepatic Insufficiency

No formal studies were conducted to evaluate the effect of hepatic disease on the disposition of desogestrel and ethinyl estradiol tablets. However, steroid hormones may be poorly metabolized in patients with impaired liver function (see 7 WARNINGS and PRECAUTIONS).

Renal Insufficiency

No formal studies were conducted to evaluate the effect of renal disease on the disposition of desogestrel and ethinyl estradiol tablets.

11 STORAGE, STABILITY AND DISPOSAL

Store at controlled room temperature 15°C to 30°C.

Keep in a safe place out of the reach of children and pets.

12 SPECIAL HANDLING INSTRUCTIONS

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

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

I. Progestogen

Common name: Desogestrel

Chemical name: 17 (α)-13- Ethyl-11-methylene 18, 19-dinor-pregn-4-en-20-yn-17-ol

Molecular formula and molecular mass: C₂₂H₃₀O; 310.48 g/mol

Structural formula:

Physical Form: White, crystalline powder

Solubility: Solubility at 20°C: n-Hexane: 40 mg/mL

Ethanol (96%): > 200 mg/mL

Ethyl acetate: > 150 mg/mL

Water: practically insoluble

Melting Point: 110-112°C

II. Estrogen

Common name: Ethinyl Estradiol

Chemical name: 19-Nor-17α-pregna-1,3,5(10)-trien-20-yne-3,17-diol

Molecular formula and molecular mass: C₂₀H₂₄O_2; 296.4 g/mol

Structural formula:

Physical Form: White, crystalline powder

Solubility: Soluble in ethanol, ether, acetone, chloroform,

Practically insoluble in water.

Melting Point: 182-184°C

14 CLINICAL TRIALS

14.1 Clinical Trial by Indication

Conception control

Table 8 - Summary of patient demographics for pivotal clinical trials (Conception control)

DSG = Desogestrel; EE = Ethinyl Estradiol; qd = daily dosing

*Data does not allow for mean age calculation. Majority of women were less than 30 years of age (78 percent).

Extensive clinical experience, in excess of 125,000 cycles in published reports alone, has documented the efficacy of MIRVALA.

Table 9 - NUMBER OF STUDIES, NUMBER OF SUBJECTS EXPOSED, ESTIMATED MINIMUM EXPOSURE AND NUMBER OF PREGNANCIES BY STUDY SIZE

^a For the purpose of estimation of extent of exposure, it is assumed that dropouts were evenly distributed over the interval of observation (if 60 subjects discontinued over 6 months, it is assumed that 10 discontinued each month).

Several studies provided inadequate information on the number of subjects at subsequent visits. Therefore, the actual number of cycles is likely to be substantially larger.

In addition, several well controlled studies were designed to determine the efficacy and safety of desogestrel and ethinyl estradiol tablets. One of these involved 1,195 patients who completed a total of 11,426 cycles.

1. (a)

   Pearl Index

   The observed Pearl Index among desogestrel and ethinyl estradiol tablet users compares favourably to what has been reported for other low dose oral contraceptives. Nine patients participating in this study became pregnant. User failure accounted for all of these in-treatment pregnancies. Consequently, the Pearl Index for method failure is 0.00.

1. (b) Life Table estimates

Table 10 - The annual cumulative life-table pregnancy rate is estimated as 1.0/100 women years.

1. (c)

   Cycle control

   During the course of the study, 18 subjects (1.5%) discontinued due to menstrual problems. Absence of withdrawal bleeding (AWB) occurred in 1.7% of the cycles, while intermenstrual bleeding (IM) occurred in 8.0% of the total cycles. Both AWB and IM occurred more frequently during the first cycles of usage when compared to subsequent cycles. Spotting was more common than breakthrough bleeding (5.6% versus 2.5% of the cycles).

Table 11 - INCIDENCE BY CYCLE OF INTERMENSTRUAL BLEEDING AND ABSENCE OF WITHDRAWAL BLEEDING

• intermenstrual bleeding (IM) was defined as any bleeding and/or spotting that started during the pill-taking interval that was not early or continued withdrawal bleed;
• absence of withdrawal bleeding (AWB) was defined as no bleeding and/or spotting episode that began during or continued into the pill-free interval;

Table 12 - INCIDENCE BY CYCLE OF BREAKTHROUGH BLEEDING (BTB) AND SPOTTING (BTS)

• breakthrough bleeding (BTB) was defined as any bleeding episode that occurred during the pill-taking interval that was not early or continued withdrawal bleed;
• breakthrough spotting (BTS) was defined as any spotting episode that occurred during the pill- taking interval that was not early or continued withdrawal bleed;

The results indicate that cycle control with desogestrel and ethinyl estradiol tablets is generally excellent, resulting in very few dropouts due to irregular bleeding or to absence of withdrawal bleeding, these results are very similar to those obtained with other oral contraceptives.

1. (d)

   Lipid Metabolism

   A causal relationship between ischemic heart disease and unfavourable plasma lipid/lipoprotein profiles, specifically, a high LDL/HDL ratio, is now widely accepted on the basis of epidemiologic, biochemical and other evidence. It has also been demonstrated that androgens influence the lipid/lipoprotein ratio unfavourably, while estrogens have a beneficial effect, largely by increasing HDL₂ and, to a lesser extent, by reducing LDL levels. Major adverse or counteractive effects on the beneficial action of estrogen are therefore of fundamental importance in any long-term medication.

Desogestrel and ethinyl estradiol tablets increased HDL-C levels, decreased LDL-C, but left HDL₂ and Apo B unchanged. Thus, there was no significant effect on the HDL₂/LDL-C ratio. Like other oral contraceptives, desogestrel and ethinyl estradiol tablets can be associated with an increase in triglyceride plasma levels.

Table 13 - NUMBER OF STUDIES DEMONSTRATING A PARTICULAR EFFECT ON LIPOPROTEIN METABOLISM AFTER 2 TO 4 MONTHS OF USE

14.2 Comparative Bioavailability Studies

A randomized, two-period, two-treatment, single dose (2 x 0.15 mg/0.03 mg), crossover comparative bioavailability study of MIRVALA (Apotex Inc.) and MARVELON21 (Organon Canada Ltd.) was performed in healthy, human, female subjects under fasting conditions. A summary of the comparative bioavailability data based on 3-ketodesogestrel (active metabolite of desogestrel) and ethinyl estradiol from 19 subjects that were included in the statistical analysis are presented in the following tables:

Table 14 - SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

¹ MIRVALA (desogestrel/ethinyl estradiol) tablets, 0.15 mg/0.03 mg (Apotex Inc.)

² MARVELON 21 (desogestrel/ethinyl estradiol) tablets, 0.15 mg/0.03 mg (Organon Canada Ltd.)

³ Expressed as the median (range) only

⁴ Expressed as arithmetic mean (CV %) only

Table 15 - SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

¹ MIRVALA (desogestrel/ethinyl estradiol) tablets, 0.15 mg/0.03 mg (Apotex Inc.)

² MARVELON 21 (desogestrel/ethinyl estradiol) tablets, 0.15 mg/0.03 mg (Organon Canada Ltd.)

³ Expressed as the median (range) only

⁴ Expressed as arithmetic mean (CV %) only

16 NON-CLINICAL TOXICOLOGY

General toxicology:

Acute Toxicity Studies

Acute single dose studies were conducted in both rats and mice, with desogestrel + ethinyl estradiol and desogestrel alone, to determine the upper limits of tolerance and to assess specific signs of toxicity. Both compounds were dosed orally by gavage or intraperitoneal as aqueous suspensions. The oral dosage level of 2000 mg/kg was about 6 x 10⁵ times the projected human clinical dose. The intraperitoneal dosage was 500 mg/kg. Groups of 10 males and 10 females were tested with desogestrel + ethinyl estradiol and groups of 6 males and 6 females with desogestrel alone. The animals were observed for 7 days and then necropsied.

None of the test animals died during the oral or intraperitoneal studies. The oral dosed mice and rats had temporary signs of reduced activity, some motor incoordination, diminished food consumption, and other nonspecific signs related to the large dose of the test material. Likewise, mice and rats dosed intraperitoneal showed similar signs. Some evidence of serositis (localized peritoneal irritation) was associated with the test substances.

These data are consistent with published information on other contraceptive steroids which indicate that steroids in general have a low level of toxicity in single dose acute animal studies.

Multidose Toxicity Studies

The objective of the multidose toxicity studies was to determine whether the chronic oral administration of either desogestrel + ethinyl estradiol or desogestrel alone to mice, rats, dogs, and monkeys would induce either reversible or irreversible systemic adverse effects or cause the development of benign or malignant neoplasms. Desogestrel + ethinyl estradiol, in a ratio of 2.5:1, was employed in most multidose toxicity and multidose tumorigenicity toxicity studies and in a ratio of 5:1 in 52-, 104-week and 3-year studies in dogs and monkeys. The test compounds were administered orally by gavage to mice and rats, orally by tablet or capsule to dogs, and orally by soft drink or by intubation to monkeys.

The protocol for each of these studies was typical of that used for multidose toxicity tests in general. The doses were multiples of the human dose and generally calculated to be 2, 20, and 200 times the expected human usage levels in most multidose and tumorigenicity studies in mouse, rat and dog. In shorter studies, the duration of treatment was 26 or 52 weeks with a 4 to 13 week recovery period incorporated into the study design. In the 52-, 104-week and 3-year dog and monkey studies dose levels were 1, 10, 25 and 2, 10, and 50 times the human dose respectively.

The following table lists the study duration, species tested, and the test compounds:

Table 16 – Multidose Toxicity Studies

DSG = desogestrel EE = ethinyl estradiol

The 52-week study with desogestrel + ethinyl estradiol in rats revealed no direct treatment-associated effect on mortality. Clinical signs of treatment included alopecia and reduction of testicle size, primarily in high dose animals, which were reversible on treatment cessation. Depressed weight gain and/or decreased food consumption was present in both sexes of the intermediate and high dose animals. There was an alteration in APTT, Hb, and PCV were noted along with lowered neutrophil and lymphocyte counts. These changes are known to occur in these types of studies and were found to be reversible upon treatment cessation. No unusual changes were found in blood chemistry or urinalysis. Dose-related lower protein content of the urine in males may be attributed to the atrophic change in secondary sex organs.

Organ weight changes were consistent with those noted with other combination oral contraceptives. The liver weight was increased at 26 and 52 weeks in primarily ID and high dose animals; testes, epididymides, prostate, seminal vesicles, ovaries, uterus, adrenals, and the pituitary gland were also affected by treatment.

Microscopic tissue changes included the following: hepatocytic vacuolation and occasional foci of hepatocellular hyperplasia, especially in high dose animals; a dose-related increase in yellowish pigment in the kidney cortical tubule epithelium, and increased mineralized concretions in high dose males; atrophy of the testes, epididymides, prostate, and seminal vesicles; reduction or absence of corpora lutea in the ovaries; hyalinization or endometrial hyperplasia of the uterus; increased keratinization of the vagina in high dose females; hypertrophy and hyperplasia of the adrenal cortex with sinusoidal telangiectasis; and hypertrophy/hyperplasia of the anterior lobe of the pituitary, especially at 52 weeks in high dose animals.

The 8-week withdrawal period used in this study resulted in a partial reversal of the prior changes. All would have probably reverted to normal with a longer recovery period. There was an increased incidence of benign mammary neoplasms in all drug-treated groups.

The 52-week dog study was conducted with oral dosed desogestrel + ethinyl estradiol tablets in a ratio of 2.5:1. Three high dose mortalities occurred during the study. Two females died and the other was killed in extremis. The cause of death or morbidity was peritonitis, secondary to perforating pyometra. Clinical signs included typical skin thickening and folding with alopecia, interruption of the estrous cycle with swelling of external genitalia in females, vaginal discharge in high dose females, pendulous penile sheath in males with reduction in testicle size, enlarged and/or secretory mammary tissue in females, and 2 transient (1, intermediate dose) and 1 transient and 1 persistent nodule (1, high dose) of the mammary gland. The persistent nodule was an area of hyperplasia.

Changes in certain hematological, coagulation, blood chemistry and urinalysis parameters were neither unusual nor unexpected for this type of compound. Changes either in weight or histomorphological characteristics were noted in the primary and secondary sex organs and liver, primarily in high dose animals. All were associated with the hormonal attributes of the drug.

The multidose toxicity study in the monkey was performed at a 5:1 ratio of desogestrel to ethinyl estradiol with dosing for 21 days followed by a 7-day drug-free period. The 12-month data revealed no unexpected clinical, clinicopathological, or histomorphological findings. Typical hormonally dose-related changes occurred, such as decreased corpora lutea, secretory mammary glands, increased endocervical mucus, decreased thickness of the endometrium with secretory changes, a dose-related decrease in the thickness of the vaginal epithelium and increased pituitary weight.

The multidose studies in rats and dogs with desogestrel alone resulted in fewer alterations in the primary and secondary sex organs and other peripheral hormonally sensitive tissues.

In rats, the absence of ethinyl estradiol in the test compound resulted in expected progestational changes at 26 and 52 weeks, such as secretory changes in the uterine endometrium, mucification of the vaginal epithelium, mild glandular hyperplasia of the mammary glands, and reduced pituitary weights. In the 52-week portion of the study, a small number of benign or malignant neoplasms were observed, but none of these were causally related to the test compound.

The toxicity of multidoses of desogestrel alone in dogs resulted in no unusual or unexpected changes at 26 weeks. The liver weight in high dose animals was increased but this was due primarily to the progestogenic effect of increased glycogen storage. The uterus was increased in both size and weight due to hormonal stimulation of the endometrium and the ovaries had a lack of mature follicles and an absence of corpora lutea. The prostate weight was slightly reduced in high dose males. Lobular development of the mammary glands was increased in intermediate and high dose females.

The 52-week segment of the dog study with desogestrel alone resulted in changes similar to those seen at 26 weeks; however, occasional small mammary nodules (5 mm or less) were present in 1 control (C), 1 low dose (LD), 1 ID, and 4 high dose animals. They disappeared in the 1 C and 2 high dose animals. The remaining nodules were found to be nonneoplastic and proved to be either smaller superficial lymph nodes or dilated ducts. The uterine stimulation was increased at 52 weeks but did not result in the death of any animal.

Four multidose toxicity studies of up to 2 years in duration were conducted in rats, dogs, and monkeys. Desogestrel + ethinyl estradiol was studied in rats, monkeys, and dogs, and desogestrel alone was studied in rats.

In rats, there was no evidence of a neoplastic response when desogestrel was administered alone, however, increased evidence of benign mammary neoplasms were evident in all desogestrel + ethinyl estradiol treated groups. Other clinical, clinicopathological, and histopathological changes were attributable to the hormonal influences of either desogestrel or its combination with ethinyl estradiol.

The 2-year dog study utilized a 5:1 desogestrel + ethinyl estradiol ratio. The test compound was dosed at 1, 10 and 25 times the human dosage levels for 21 days with a 7-day drug-free period. There was evidence of the following: suppression of the estrous cycle in intermediate and high dose animals, an increased incidence of mammary gland development and secretory activity similar to those observed in the normal metestrous phase of the cycle; decreased AP in high dose dogs, and a single focus of ductal epithelial hyperplasia in 1 low dose dog. No tumorigenic effect was present.

The 2-year study of desogestrel + ethinyl estradiol in monkeys caused the expected pattern of hormonally-mediated changes. Menstrual and ovarian activity were reduced in high dose animals. Secretory activity of the mammary glands was increased in a dose-related manner in intermediate and high dose animals. Other hormonally-associated changes included: an increased fibrinogen and APTT; decreased PPT; reduced AP; increased triglycerides and cholesterol levels; and lowered albumen in intermediate and high dose animals; endometrium which was either stimulated (ID and HD) or lacked activity (some high dose animals); and increased acidophils and decreased basophils in the pituitary in intermediate and high dose animals. All of these findings are consistent with contraceptive steroid effects in the monkey.

Multidose tumorigenicity studies were conducted in the mouse (80 to 81 months) and rat (2 years) with either desogestrel + ethinyl estradiol or desogestrel alone, respectively. Desogestrel + ethinyl estradiol in mice resulted in a higher mortality rate; this was primarily due to the increased incidence of pituitary tumors in treated mice, especially high dose animals. Other nonneoplastic alterations occurred, but were within expected limits for a compound of this type. Desogestrel alone in mice did not remarkedly affect the mortality rate and had no influence on tumorigenicity.

Desogestrel + ethinyl estradiol in the rat, resulted in slightly increased mortality at the high dose level and contributed to a dose-dependent increase in the number of pituitary and mammary neoplasms; this increase was largely attributable to the ethinyl estradiol component.

Desogestrel alone in the rat had no influence on mortality and possibly was responsible for a slight lowering effect. Incidences of mammary and pituitary tumors were slightly lessened at the high dose level. This is in contrast to the 104-week rat study with desogestrel + ethinyl estradiol, where the differences noted were considered to have been attributable to the ethinyl estradiol component.

Three year studies were conducted in both Beagle dogs and Rhesus monkeys with desogestrel + ethinyl estradiol with a 1- and 2-year interim sacrifice in monkey and a 2-year interim sacrifice in dogs. No tumorigenic response was noted. Mammary glands of dogs had lobulo-alveolar development with limited secretory change, an expected hormonal effect. Other tissue changes as described under the 2-year interim report, limited to the primary and secondary sex organs, were associated with the hormonal activities of the combination OC.

The monkey study conducted for 3 years, with a 1- and 2- year interim sacrifice, revealed no evidence of a tumorigenic effect. The changes observed, as described at the 2-year interim studies, were typical of the hormonal activities of the combination OC and included effects on the menstrual cycle, cervical mucus and endometrial morphology.

Mutagenicity Studies

The Ames test and the rat Micronucleus test were conducted on desogestrel, either alone or in combination with ethinyl estradiol. Both assays demonstrated that neither desogestrel alone nor in combination with ethinyl estradiol exert any mutagenic effect.

Reproductive and Developmental Toxicology

Nonclinical reproductive toxicity studies included 11 studies conducted in rats and 2 studies conducted in rabbits. Desogestrel, both alone and in combination with ethinyl estradiol, was tested. These studies were conducted to assess what effect, if any, the test substance might have on the reproductive process, including; fertility and reproductive performance, teratogenicity and embryotoxicity, and perinatal and postnatal effects in the offspring.

Four segment I reproductive toxicity studies were conducted in rats; 1 study with desogestrel + ethinyl estradiol and 3 studies with desogestrel alone. The desogestrel + ethinyl estradiol study, conducted using doses of 0.5 mg desogestrel + 0.2 mg ethinyl estradiol/kg/day, demonstrated that the test compound had no adverse effect on mating and pregnancy performance in F₀ females or on the number, anatomical features, development and fertility of the offspring.

Desogestrel alone was studied in both Sprague Dawley and CFY rats. An additional study in Sprague Dawley rats was conducted after microphthalmia was increased in CFY offspring of the desogestrel -treated dams. No increase in microphthalmia was seen in the second Sprague Dawley study. The defect was thus thought to be strain-related. In all 3 studies the contraceptive effect of desogestrel was reversible. Treatment at contraceptive and subcontraceptive dose levels did not cause any serious after effects on the dams or their offspring.

A fertility and embryotoxicity study with desogestrel + ethinyl estradiol at levels causing complete infertility, slight infertility, and no infertility, were conducted in rats. Uninterrupted daily administration of desogestrel + ethinyl estradiol, at subcontraceptive doses before and during pregnancy, reduced the number of offspring but had no effect on the quality of the F₁ generation.

Segment II embryotoxicity studies following the classical design with dosage exclusively during pregnancy and organogenesis were performed in both the rat and rabbit. A total of 5 embryotoxicity studies were conducted; 3 studies with desogestrel alone and 2 studies with desogestrel + ethinyl estradiol.

Desogestrel + ethinyl estradiol tested at high dose levels in rats and rabbits caused maternal toxicity and embryolethality, but at lower doses had no untoward reaction in the dams and no detectable effect on the course of pregnancy, embryonic mortality, or fetal morphology.

Desogestrel alone was tested in both Sprague Dawley and CFY rats and in rabbits. High dosages of desogestrel caused maternal toxicity (2 to 8 mg/kg) in rats, while doses of 2 to 4 mg/kg caused abortion in rabbits. Lower dosages in rats and rabbits caused no discernible effect on the course of pregnancy, embryonic mortality, or on fetal morphology.

The effects of desogestrel alone, when dosed during late pregnancy, was assessed in rats. Dose levels up to 4 mg/kg/day from days 14 to 20 of pregnancy caused neither masculinization of female fetuses nor feminization of male fetuses.

Segment III studies, to evaluate the possible effects on peri- and postnatal development due to transfer of drug through the milk, were conducted with desogestrel, either alone or in combination with ethinyl estradiol. Desogestrel + ethinyl estradiol caused reduced food consumption in intermediate and high dose dams. Retarded pup growth persisted until weaning in the high dose group, but there was no effect on the pre- or post-weaning physical development. Fertility of the F₁ offspring was not affected. Desogestrel alone had no effect on the treated dams, weight gain in the pups, or physical development of the pups. Fertility of the F₁ treated animals was comparable to that of the F₁ control females.

17 SUPPORTING PRODUCT MONOGRAPHS

1. 1. MARVELON^® 21 and MARVELON ^® 28 (0.15 mg desogestrel and 0.03 mg ethinyl estradiol tablets), Submission Control number 286308, Product Monograph, Organon Canada Inc. (NOV 20, 2024).